**Renal Disease in Multiple Myeloma**

Guray Saydam, Fahri Sahin and Hatice Demet Kiper

*Ege University Hospital, Dept. of Internal Medicine Turkey* 

#### **1. Introduction**

218 Multiple Myeloma – An Overview

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> Renal involvement is a common feature of Multiple Myeloma (MM) that is associated with significant morbidity and shortened survival. At the time of diagnosis, some degree of renal impairment is present in about half of the cases. In some of patients dialysis is required eventually (Hutchison, 2007). A review from the US Renal Data System (USRDS) reports that the number of patients with myeloma associated end-stage renal disease (ESRD) in 2004 in the United States was 5,390, with a prevalence of 1.1%. The presence of renal involvement is commonly associated with a higher tumor burden and worse prognosis, as the severity of renal failure is highly correlated with patient survival. Based on large series in which renal function was evaluated by serum creatinine levels; 43% of 998 patients had a renal insufficiency with the serum creatinine concentrations above 1,5 mg/dl (133 µmol/L) and one-year survival was found 80% in this group, while it was 50% in the patient group who had creatinine levels more than 2,3 mg/dl (200 µmol/L) (Winearls CG,1995). In another report, 22% of 423 patients had a severe renal insufficiency with the values of creatinine concentration greater than 2 mg/dl (177 µmol/L) (Bladé J,et al.,1998). As the serum creatinine level is affected due to the attenuated muscle mass of elderly MM patient population, International Myeloma Working Group has recommended use of glomerular filtration rate calculated by Modification of Diet in Renal Diseaese (MDRD) formula for the assessment of renal functions. For the assessment of the severity of acute renal injury, RIFLE (Risk, Injury, Failure, Loss and End-stage) and AKIN (Acute Kidney Injury Network) criteria may also be used.

> Renal failure is reversible in the majority of the patients and reversibility is an important prognostic factor which is associated with a long-term survival. With appropriate therapy, more than 50% patients with moderate renal insufficiency had improvement in renal functions during the first three months and it was found to be associated with better prognosis. (Knudsen et al.,2000) Successful managment of reversible precipitating factors such as dehydration, hypercalcemia, hyperuricemia, infections and use of nephrotoxic agents like contrast materials, non steroidal anti-inflammatory drugs (NSAID) and angiotensin-converting enzyme inhibitors can successfully contribute to reversal of renal failure. Initiation of early aggressive anti-myeloma therapy results in rapid decline of light chain production which can contribute significantly to renal function recovery.

Renal Disease in Multiple Myeloma 221

FLCs intrinsically occurs in the kidney. In normal individuals, serum FLCs are relatively freely filtered through the glomerulus because of their low molecular weights (22,5 kd for monomeric kappa and 45 kd for dimeric lambda) and cationic net charge. After glomerular filtration; the FLCs in the tubular fluid bind to the tandem scavenger receptor system megalin/cubilin and are endocytosed via the clathrin dependent endosomal/lysosomal pathway (Batuman V et al., 1998). Megalin and cubilin are the two major, multiligand, endocytic receptors which are highly expressed in the apical endocytic apparatus of the renal proximal tubule and they are responsible for the tubular reabsorbtion of most proteins filtered in the glomeruli. Receptor Associated Protein (RAP) is also known as a highaffinated ligand for megalin, thus, it plays a significant role in endocytic function of the proximal tubule (Verroust PJ et al.,2002). Endocytic uptake of FLCs is followed by the hydrolisation and degradation in the lysosomes, and after acidifying in vesicles, the released aminoacids pass through basement membrane and re-circulate back to the system (Leheste

In Multiple Myeloma, over-production of FLCs exceeds the reabsorbation capacity of the proximal tubules and results in the presence of FLCs in the distal nephron and overflow light chain proteinuria (Bence Jones proteinuria). Tamm-Horsfall Mucoprotein (THMP, also known as Uromodulin) is a renal epithelial glycoprotein which is secreted by the cells of the thick ascending limb of the loop of Henle and it forms the gel-like matrix of urinary casts. Over-concentrated FLCs bind to a specific peptide domain on THMP and constitutes the waxy cast formation that aggregates in distal tubules leading to tubular obstruction. Some factors may promote cast formation, such as dehydration (by stasis in tubules), hypercalcemia, acidosis, radiocontrast medications (by interacting with light chains) and furosemide (by increasing luminal sodium chloride). Increasing intra-luminal pressure reduces the glomerular filtration rate, therefore by the loss of metabolism related to GFR, circulating concentration FLCs increases also in the tubules. This circumstance triggers a vicious cycle in the pathogenesis of myeloma kidney. Intra-tubular cast formation usually results in tubular rupture and necrosis that precipitates interstitial inflammatory nephritis (Hill GS et al.,1983) Interstitial fibrosis and tubular atrophy follow : this fact can be accepted as the main pathology underlying the renal impairment related to cast nephropathy. Direct tubular toxicity is one of the another basic mechanisms leads to LCCN and dose-dependent toxicity can be occur in the proximal tubuler epithelial cells (PTEC) by light chains, resulting in tubular necrosis. Type of light chain is also important to determine the degree and the localization of renal injury for the reason that nephrotoxicity may differ based on the characteristics of the light chains. THMP interacts with the hyper-variable regions of the light chains and shows variable affinity to different types (Sanders et al., 1990). This phenomenon can explain why some patients have a severe renal disease with smaller amount of light chains and some have minimal renal dysfunction with larger rates. It is also well known that kappa and lambda light chains are both toxic to the tubule ephitelium but lambda is more associated with amyloidosis whereas kappa is frequently involves in Light

Chain Deposition Disease (LCDD) and acquired adult's Fanconi's syndrome.

Recent studies in last decade put emphasis on the role of proximal tubule cells in the pathogenesis of cast nephropathy. These studies have demonstrated that proximal tubular endocytosis of light chains induces pro-inflammatory and inflammatory cytokine releasing such as IL-6, IL-8, TNF alfa and monocyte chemotactic protein-1 (MCP-1). It has also been

et al., 1999)

Pathogenesis of renal disease in Multiple Myeloma is multifactorial . It is associated with excess production of monoclonal light chains by the neoplastic B-cell clone. Renal lesions occur primarily in tubules; however glomeruli, interstitium and blood vessels may also be involved. Myeloma cast nephropathy (Light Chain Cast Nephropathy –LCCN, Myeloma kidney) is the most prominent type of MM renal involvement and is primarily tubular. Isolated distal or proximal tubular dysfunction and acquired Fanconi Syndrome also may be seen. Glomerular lesions are usually related to AL-amyloidosis and light/heavy deposition disease. Interstitial nephritis and plasma cell infiltration demonstrate the involvement of renal interstitium. Types of pathologic lesions are basically determined by the mutated amino acid sequence of the monoclonal light chain. This was confirmed with LC injected mice that developed the same pattern of renal disease as was seen in the donor MM patient. (Solomon A, Weiss DT, Kattine AA,1991) Autopsy series of patients with myeloma found that the most frequent pathology is LCCN accounts for 40% to 60%, whereas light chain deposition disease and amyloidosis were seen in 5% and7% cases respectively. (Ivanyi B.,1989) In native renal biopsy studies of patients with myeloma and renal disease,40 to 63% had cast nephropathy, 19 to 26% had light-chain deposition disease, 7 to 30% had amyloidosis, and <1% had cryoglobulinemic renal > disease." (Ganewal D.,et al,1992 ve Montseny JJ. et al,1998) Renal biopsy is not indicated many patients for differential diagnosis to concern therapeutic options and estimation of prognosis in patients with the diagnosis of myeloma. (Kidney biopsy is generally not indicated for many of patients)

We have tried to summarize the all pathophysiological mechanisms and clinical presentations of renal involvement in MM patients in this chapter.

#### **2. Light Chain Cast Nephropathy (myeloma kidney)**

LCCN is the most common cause of renal failure associated with myeloma, which accounts for approximately 90% of the cases. (Lin J,et al,2001) Renal failure may present both acutely or chronically but it is often acute in nature and can be severe with serum creatinine levels above 7 mg/dl (Montseny J,et al,1998). Characteristic lesion is a tubulointerstitial nephritis associated with monoclonal free light chains (FLCs) leading to intra-tubular cast formation/obstruction and direct tubular toxicity. Overproduction of FLCs by the neoplastic B-cell clone plays a crucial role in causing typical renal damage characterized by tubular atrophy and tubulointerstitial fibrosis. The degree of renal impairment correlates with tubular injury but not with the extent of cast formation. (Silva FG, et al,1983)The normal amount of light chain excretion is less than 30 mg/day, however it is generally more than 1 gr/day in a myeloma patient with LCCN and can be massive (>20 gr/day) leading to nephrotic syndrome in less than 10% of the cases. The rate of FLC excretion corelates with renal insufficiency. In a demographic study of 1353 patients, 16% of the cases with < 1 gr/d FLC proteinuria had renal failure versus 47% and 63% in those with 1-10 gr/d and > 10 gr/d, respectively (p=0,001) (Knudsen LM,et al,1994) Patients with LCCN are at higher risk of developing advanced myeloma with severe anemia and hypercalcemia (Durie-Salmon stage 3).

#### **2.1 Pathogenesis of LCCN**

The main pathology is cast nephropathy ie : the presence of excess FLCs in the plasma and urine which are produced by a neoplastic clone of plasma cells. Catabolism of circulating

Pathogenesis of renal disease in Multiple Myeloma is multifactorial . It is associated with excess production of monoclonal light chains by the neoplastic B-cell clone. Renal lesions occur primarily in tubules; however glomeruli, interstitium and blood vessels may also be involved. Myeloma cast nephropathy (Light Chain Cast Nephropathy –LCCN, Myeloma kidney) is the most prominent type of MM renal involvement and is primarily tubular. Isolated distal or proximal tubular dysfunction and acquired Fanconi Syndrome also may be seen. Glomerular lesions are usually related to AL-amyloidosis and light/heavy deposition disease. Interstitial nephritis and plasma cell infiltration demonstrate the involvement of renal interstitium. Types of pathologic lesions are basically determined by the mutated amino acid sequence of the monoclonal light chain. This was confirmed with LC injected mice that developed the same pattern of renal disease as was seen in the donor MM patient. (Solomon A, Weiss DT, Kattine AA,1991) Autopsy series of patients with myeloma found that the most frequent pathology is LCCN accounts for 40% to 60%, whereas light chain deposition disease and amyloidosis were seen in 5% and7% cases respectively. (Ivanyi B.,1989) In native renal biopsy studies of patients with myeloma and renal disease,40 to 63% had cast nephropathy, 19 to 26% had light-chain deposition disease, 7 to 30% had amyloidosis, and <1% had cryoglobulinemic renal > disease." (Ganewal D.,et al,1992 ve Montseny JJ. et al,1998) Renal biopsy is not indicated many patients for differential diagnosis to concern therapeutic options and estimation of prognosis in patients with the diagnosis of myeloma. (Kidney biopsy is generally not indicated for many of patients)

We have tried to summarize the all pathophysiological mechanisms and clinical

LCCN is the most common cause of renal failure associated with myeloma, which accounts for approximately 90% of the cases. (Lin J,et al,2001) Renal failure may present both acutely or chronically but it is often acute in nature and can be severe with serum creatinine levels above 7 mg/dl (Montseny J,et al,1998). Characteristic lesion is a tubulointerstitial nephritis associated with monoclonal free light chains (FLCs) leading to intra-tubular cast formation/obstruction and direct tubular toxicity. Overproduction of FLCs by the neoplastic B-cell clone plays a crucial role in causing typical renal damage characterized by tubular atrophy and tubulointerstitial fibrosis. The degree of renal impairment correlates with tubular injury but not with the extent of cast formation. (Silva FG, et al,1983)The normal amount of light chain excretion is less than 30 mg/day, however it is generally more than 1 gr/day in a myeloma patient with LCCN and can be massive (>20 gr/day) leading to nephrotic syndrome in less than 10% of the cases. The rate of FLC excretion corelates with renal insufficiency. In a demographic study of 1353 patients, 16% of the cases with < 1 gr/d FLC proteinuria had renal failure versus 47% and 63% in those with 1-10 gr/d and > 10 gr/d, respectively (p=0,001) (Knudsen LM,et al,1994) Patients with LCCN are at higher risk of developing advanced myeloma with severe anemia and hypercalcemia (Durie-Salmon

The main pathology is cast nephropathy ie : the presence of excess FLCs in the plasma and urine which are produced by a neoplastic clone of plasma cells. Catabolism of circulating

presentations of renal involvement in MM patients in this chapter.

**2. Light Chain Cast Nephropathy (myeloma kidney)** 

stage 3).

**2.1 Pathogenesis of LCCN** 

FLCs intrinsically occurs in the kidney. In normal individuals, serum FLCs are relatively freely filtered through the glomerulus because of their low molecular weights (22,5 kd for monomeric kappa and 45 kd for dimeric lambda) and cationic net charge. After glomerular filtration; the FLCs in the tubular fluid bind to the tandem scavenger receptor system megalin/cubilin and are endocytosed via the clathrin dependent endosomal/lysosomal pathway (Batuman V et al., 1998). Megalin and cubilin are the two major, multiligand, endocytic receptors which are highly expressed in the apical endocytic apparatus of the renal proximal tubule and they are responsible for the tubular reabsorbtion of most proteins filtered in the glomeruli. Receptor Associated Protein (RAP) is also known as a highaffinated ligand for megalin, thus, it plays a significant role in endocytic function of the proximal tubule (Verroust PJ et al.,2002). Endocytic uptake of FLCs is followed by the hydrolisation and degradation in the lysosomes, and after acidifying in vesicles, the released aminoacids pass through basement membrane and re-circulate back to the system (Leheste et al., 1999)

In Multiple Myeloma, over-production of FLCs exceeds the reabsorbation capacity of the proximal tubules and results in the presence of FLCs in the distal nephron and overflow light chain proteinuria (Bence Jones proteinuria). Tamm-Horsfall Mucoprotein (THMP, also known as Uromodulin) is a renal epithelial glycoprotein which is secreted by the cells of the thick ascending limb of the loop of Henle and it forms the gel-like matrix of urinary casts. Over-concentrated FLCs bind to a specific peptide domain on THMP and constitutes the waxy cast formation that aggregates in distal tubules leading to tubular obstruction. Some factors may promote cast formation, such as dehydration (by stasis in tubules), hypercalcemia, acidosis, radiocontrast medications (by interacting with light chains) and furosemide (by increasing luminal sodium chloride). Increasing intra-luminal pressure reduces the glomerular filtration rate, therefore by the loss of metabolism related to GFR, circulating concentration FLCs increases also in the tubules. This circumstance triggers a vicious cycle in the pathogenesis of myeloma kidney. Intra-tubular cast formation usually results in tubular rupture and necrosis that precipitates interstitial inflammatory nephritis (Hill GS et al.,1983) Interstitial fibrosis and tubular atrophy follow : this fact can be accepted as the main pathology underlying the renal impairment related to cast nephropathy. Direct tubular toxicity is one of the another basic mechanisms leads to LCCN and dose-dependent toxicity can be occur in the proximal tubuler epithelial cells (PTEC) by light chains, resulting in tubular necrosis. Type of light chain is also important to determine the degree and the localization of renal injury for the reason that nephrotoxicity may differ based on the characteristics of the light chains. THMP interacts with the hyper-variable regions of the light chains and shows variable affinity to different types (Sanders et al., 1990). This phenomenon can explain why some patients have a severe renal disease with smaller amount of light chains and some have minimal renal dysfunction with larger rates. It is also well known that kappa and lambda light chains are both toxic to the tubule ephitelium but lambda is more associated with amyloidosis whereas kappa is frequently involves in Light Chain Deposition Disease (LCDD) and acquired adult's Fanconi's syndrome.

Recent studies in last decade put emphasis on the role of proximal tubule cells in the pathogenesis of cast nephropathy. These studies have demonstrated that proximal tubular endocytosis of light chains induces pro-inflammatory and inflammatory cytokine releasing such as IL-6, IL-8, TNF alfa and monocyte chemotactic protein-1 (MCP-1). It has also been

Renal Disease in Multiple Myeloma 223

>2.3 mg/dl (200 µmol/L) (Winearls CG, 1995). In cast nephropathy, renal failure is often reversible by appropriate management of the precipitating factors and early aggressive treatment to reduce FLC production. Many studies suggest that renal recovery is closely related with a better prognosis and similar outcomes who have a normal renal function at diagnosis (Bladé J.et al, 1998), however, on the contrary some claims it is not associated with a favorable outcome (Kastritis et al,2007). Renal dysfunction due to LCNN is usually presents in acute nature and some factors may contribute to reduce GFR by inducing cast precipitation or may be the main cause of acute renal failure (ARF). First of all, an appropriate supportive care should be administered to correct the precipitating factors lead

The use of autologous stem cell transplantation (ASCT) for patients with myeloma and renal insufficiency has been studied in last decade. Many of these patients are considered

In a retrospective study of 81 patients with multiple myeloma and renal failure (plasma creatinine >2mg/dl), 60 patients underwent transplantation with melphalan 200 mg/m2, and the remaining 21 had a reduction of the melphalan dose to 140 mg/m2 because of excessive toxicity. The treatment-related mortality rate after the first ASCT was 6% and the 3-year event-free and overall survival rates were 48 and 55%, respectively. The degree of toxicity was acceptable and stem cell collection or engraftment were not negatively affected by renal failure (Badros A,et al,2001). In another large study from Mayo Clinic, it has revealed that creatinine level did not affect complete response rate and time to progression (17 months), but patients with creatinine levels above 2 mg/ml had a higher day-100 mortality rate (13% vs.3%) and a shorter overall survival rate (31 vs 47 months) than those with normal renal function. Platelet engraftment was also significantly delayed for patients with renal insufficiency. In conclusion; ASCT may reverse renal failure in patients with multiple myeloma but it must be used with caution in selected patients with an appropriate

Hypovolemia facilitates cast precipitation by increasing FLC concentration in tubule lumen and lower urine flow contributes to intratubular obstruction. Some of myeloma patients present with acute oliguric renal failure and vigorous fluid therapy should be immediately initiated to replace volume depletion. The goals of fluid therapy are to increase the urine formation and tubule flow rate to prevent intratubular cast precipitation and obstruction. Isotonic or one-half isotonic saline is generally used to administer the hydration regimen with an initial infusion rate of 150 ml/h to achieve a high urine output at least 3 lt/day. Close monitoring should be carried out therefore some patients who have renal or heart failure may develop volume overload. In such cases, hydration regimen should be modified and if it is essential, a loop diuretic may be used to forced diuresis. Adequate hydration usually reverses the pre-renal component of ARF and oliguric status generally responses to

to ARF and it should be followed by a specific anti-myeloma therapy.

ineligible for ASCT because of a high risk of treatment-related toxicity.

**3. Other causes of ARF and prevention and supportive care** 

**Autologous Stem Cell Transplantation in LCCN** 

dose adjustment of melphalan.

therapy preferably in the first 24 hours.

**3.1 Volume depletion** 

suggested that these cytokines and chemokines are mediated by activated transcription factors like NF-kappa β which are signalled through the MAPKs ERK 1/2, JNK and p38. (Sengul S et al., 2002,2003). This inflammatory process results in interstitial fibrosis and tubular damage which is associated most probably with the additon of incremental Transforming Growth Factor β (TGF-β) production (Keeling J, Herrera GA, 2007). There are still ongoing studies to clarify the molecular mechanisms involved in cast nephropathy and further studies are needed to have a clear understanding.

#### **2.2 Diagnosis of LCCN**

According to a renal biopsy study of 259 elderly patients who had unexplained renal failure, LCCN was found in 40% of patients with previously undiagnosed myeloma (Haas M,et al,2000). On this basis, LCCN should be considered in any patient over age 40 who presents with unexplained renal failure. Urine dipstick test is usually inadequate to detect FLCs, because it is primarily sensitive for albumin but insensitive for Bence Jones protein. Therefore, sulfosalicylic acid (SSA) which detects all proteins should be chosen to detect FLCs by the assessment of turbidity. A remarkably positive SSA test when dipstick is relatively negative supports the presence of non-albumin proteins like Bence Jones protein in the urine.Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) should be performed initially in every patient with suspected myeloma. To confirm the diagnosis by measuring the amount and type of the monoclonal protein, immunofixation of serum and 24 h urine collection are also recommended especially in patients with normal protein electrophoretic pattern in cases with strong suspicion for myeloma. FLC assays which reveal the quantification of serum FLC levels, κ/λ ratio and urinary FLC excretion should be obtained on every patient and these assays are particularly important in nonsecretory myeloma patients whom serum and urine immunofixation analysis is negative.

For a definitive diagnosis, renal biopsy is generally needed. Pathologic findings of LCCN basically include the demonstration of prominent tubular casts in distal nephron. With light microscopy, in hematoxylin and eosin-stained sections, the casts are brightly eosinophilic and usually seem large and "brittle" because they are typically lamellated/fractured and also surrounded by macrophages and multinucleated giant cells of foreign-body type diagnostically. The other staining properties of the casts are classified as Periodic acid-Schiff (PAS) negative, fuchsinophilic with Masson's trichrome and less frequently Congo red positive. Immunofluorescence microscopy can differentiate the light chain with THMP from the other serum proteins.

#### **2.3 Prognosis and treatment of LCCN**

Multiple Myeloma is a progressive and incurable disease and median survival is about 6 months or less if it is not treated. In the past decade, by the advances in the myeloma treatment, median survival has increased from an average of 3 years to >5 years. Renal function is an important prognostic factor for MM and renal failure is associated with a worse prognosis as the others like lower serum albumin and higher β-2 microglobulin levels. Severity and reversibility of renal impairment is also important in prognosis. In patients who present with a plasma creatinine concentration of <1,5 mg/dl (130 µmol/L), the one-year survival was 80%, compared with 50% for patients with a creatinine level of

suggested that these cytokines and chemokines are mediated by activated transcription factors like NF-kappa β which are signalled through the MAPKs ERK 1/2, JNK and p38. (Sengul S et al., 2002,2003). This inflammatory process results in interstitial fibrosis and tubular damage which is associated most probably with the additon of incremental Transforming Growth Factor β (TGF-β) production (Keeling J, Herrera GA, 2007). There are still ongoing studies to clarify the molecular mechanisms involved in cast nephropathy and

According to a renal biopsy study of 259 elderly patients who had unexplained renal failure, LCCN was found in 40% of patients with previously undiagnosed myeloma (Haas M,et al,2000). On this basis, LCCN should be considered in any patient over age 40 who presents with unexplained renal failure. Urine dipstick test is usually inadequate to detect FLCs, because it is primarily sensitive for albumin but insensitive for Bence Jones protein. Therefore, sulfosalicylic acid (SSA) which detects all proteins should be chosen to detect FLCs by the assessment of turbidity. A remarkably positive SSA test when dipstick is relatively negative supports the presence of non-albumin proteins like Bence Jones protein in the urine.Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) should be performed initially in every patient with suspected myeloma. To confirm the diagnosis by measuring the amount and type of the monoclonal protein, immunofixation of serum and 24 h urine collection are also recommended especially in patients with normal protein electrophoretic pattern in cases with strong suspicion for myeloma. FLC assays which reveal the quantification of serum FLC levels, κ/λ ratio and urinary FLC excretion should be obtained on every patient and these assays are particularly important in nonsecretory myeloma patients whom serum and urine immunofixation analysis is negative.

For a definitive diagnosis, renal biopsy is generally needed. Pathologic findings of LCCN basically include the demonstration of prominent tubular casts in distal nephron. With light microscopy, in hematoxylin and eosin-stained sections, the casts are brightly eosinophilic and usually seem large and "brittle" because they are typically lamellated/fractured and also surrounded by macrophages and multinucleated giant cells of foreign-body type diagnostically. The other staining properties of the casts are classified as Periodic acid-Schiff (PAS) negative, fuchsinophilic with Masson's trichrome and less frequently Congo red positive. Immunofluorescence microscopy can differentiate the light chain with THMP from

Multiple Myeloma is a progressive and incurable disease and median survival is about 6 months or less if it is not treated. In the past decade, by the advances in the myeloma treatment, median survival has increased from an average of 3 years to >5 years. Renal function is an important prognostic factor for MM and renal failure is associated with a worse prognosis as the others like lower serum albumin and higher β-2 microglobulin levels. Severity and reversibility of renal impairment is also important in prognosis. In patients who present with a plasma creatinine concentration of <1,5 mg/dl (130 µmol/L), the one-year survival was 80%, compared with 50% for patients with a creatinine level of

further studies are needed to have a clear understanding.

**2.2 Diagnosis of LCCN** 

the other serum proteins.

**2.3 Prognosis and treatment of LCCN** 

>2.3 mg/dl (200 µmol/L) (Winearls CG, 1995). In cast nephropathy, renal failure is often reversible by appropriate management of the precipitating factors and early aggressive treatment to reduce FLC production. Many studies suggest that renal recovery is closely related with a better prognosis and similar outcomes who have a normal renal function at diagnosis (Bladé J.et al, 1998), however, on the contrary some claims it is not associated with a favorable outcome (Kastritis et al,2007). Renal dysfunction due to LCNN is usually presents in acute nature and some factors may contribute to reduce GFR by inducing cast precipitation or may be the main cause of acute renal failure (ARF). First of all, an appropriate supportive care should be administered to correct the precipitating factors lead to ARF and it should be followed by a specific anti-myeloma therapy.

#### **Autologous Stem Cell Transplantation in LCCN**

The use of autologous stem cell transplantation (ASCT) for patients with myeloma and renal insufficiency has been studied in last decade. Many of these patients are considered ineligible for ASCT because of a high risk of treatment-related toxicity.

In a retrospective study of 81 patients with multiple myeloma and renal failure (plasma creatinine >2mg/dl), 60 patients underwent transplantation with melphalan 200 mg/m2, and the remaining 21 had a reduction of the melphalan dose to 140 mg/m2 because of excessive toxicity. The treatment-related mortality rate after the first ASCT was 6% and the 3-year event-free and overall survival rates were 48 and 55%, respectively. The degree of toxicity was acceptable and stem cell collection or engraftment were not negatively affected by renal failure (Badros A,et al,2001). In another large study from Mayo Clinic, it has revealed that creatinine level did not affect complete response rate and time to progression (17 months), but patients with creatinine levels above 2 mg/ml had a higher day-100 mortality rate (13% vs.3%) and a shorter overall survival rate (31 vs 47 months) than those with normal renal function. Platelet engraftment was also significantly delayed for patients with renal insufficiency. In conclusion; ASCT may reverse renal failure in patients with multiple myeloma but it must be used with caution in selected patients with an appropriate dose adjustment of melphalan.

#### **3. Other causes of ARF and prevention and supportive care**

#### **3.1 Volume depletion**

Hypovolemia facilitates cast precipitation by increasing FLC concentration in tubule lumen and lower urine flow contributes to intratubular obstruction. Some of myeloma patients present with acute oliguric renal failure and vigorous fluid therapy should be immediately initiated to replace volume depletion. The goals of fluid therapy are to increase the urine formation and tubule flow rate to prevent intratubular cast precipitation and obstruction. Isotonic or one-half isotonic saline is generally used to administer the hydration regimen with an initial infusion rate of 150 ml/h to achieve a high urine output at least 3 lt/day. Close monitoring should be carried out therefore some patients who have renal or heart failure may develop volume overload. In such cases, hydration regimen should be modified and if it is essential, a loop diuretic may be used to forced diuresis. Adequate hydration usually reverses the pre-renal component of ARF and oliguric status generally responses to therapy preferably in the first 24 hours.

Renal Disease in Multiple Myeloma 225

of hypovolemia, contrasts may precipitate acute renal failure in the rate of approximately 1.5 percent (McCarthy CS, Becker JA, 1992). These agents induce light chain precipitation in the tubules and furthermore they may also interact with light chains and contribute to intra-tubular obstruction. However, recent studies suggest that myeloma patients with normal creatinine and low β2-microglobulin levels (< 2.8 mg/L) are at low risk for developing CIN and radiocontrast administration is safe in this group (Pahade JK,et al,2011). Nevertheless, the removal or avoidance of iodinated contrast agents should be preferred primarily but if it is not possible, adequate hydration should be performed during and after the procedure as well as using of low-osmolar or iso-osmolar

NSAIDs basicly block the production of prostaglandins (PGs) via inhibition of cyclooxygenase enzyme activitiy (COX-1 and COX-2). By the suppression of vasodilatatory PGs, renal vasoconstriction occurs and it leads to a reduction in the renal blood flow and glomerular filtration rate which may contribute to ARF. PGs blockage also leads to salt and water retention by the inhibition of chloride reabsorbtion and antidiuretic hormone (ADH). NSAIDs also can develop papillary necrosis and chronic interstitial nephritis. Patients with hypercalcemia or lower renal blood flow due to congestive heart failure, chronic renal failure or any other cause of hypovolemia and sodium depletion, have higher risk for worsening renal functions after using NSAIDs (Murray MD,et al,1995). Thus, NSAID therapy in patients with myeloma should be administered carefully and avoided if possible

ACE inhibitors, angiotensine receptor blockers (ARBs), diuretics and aminoglycosides are the other nephrotoxic agents that affect renal functions adversely in myeloma patients and

Hyperuricemia due to increased nucleic acid turnover, is present in upto 50% myeloma patients at diagnosis. It may also be seen as a result of chemotherapy even though tumor lysis syndrome and acute uric acid nephropathy are rare in multiple myeloma. Adequate hydration, alkalinization of the urine and prophylactic use of allopurinol can overcome this

Hyperviscosity syndrome is a group of symptoms results from increased blood viscosity due to the excessive amounts of circulating proteins and commonly occurs in association with paraprotein disorders, such as Waldenström macroglobulinemia (IgM) and rarely multiple myeloma (IgA,IgG3,kappa). It is classically manifested by spontaneous bleeding from mucous membranes due to impaired platelet function, neurologic and pulmonary symptoms as a result of ischemia in brain and lung tissue and visual defects related to rehinopathy. Although this syndrome rarely affects the kidneys permanently, it may also lead to acute renal failure occasionally. Plasmapheresis may be used to decrease viscosity

radiocontrast media.

to prevent further renal damage.

**3.4 Hyperuricemia** 

complication significantly.

**3.5 Hyperviscosity syndrome** 

should be stopped or avoided if possible.

**3.3.2 Non-steroid anti-inflammatory drugs and others** 

#### **3.2 Hypercalcemia**

Hypercalcemia occurs in more than 25 %of myeloma patients in the course of the disease and 15 %of patients have mild hypercalcemia with serum calcium level 11.0-13.0 mg/dl at diagnosis. Moderate or severe hypercalcemia may also be seen and may contribute to ARF. Hypercalcemia is the second most common cause of renal failure in MM (Blade J, Rosinol L.,2005). As the other malignancy-related hypercalcemias, some osteoclast activating factors and bone resorbing cytokines like lymphotoxin, interleukin-6, interleukin 1-β and a parathyroid related protein are produced by neoplastic cells and results in increased bone resorption (Kitazawa R,et al,2002). Elevated calcium concentration in renal tubules cause intratubular calcium deposition and vasoconstriction in renal vasculature. Decreased glomerular filtration rate induces cast precipitation and probably augments the toxicity of FLCs (Smolens P,et al,1987). Hypercalcemia may also causes nephrogenic diabetes insipidus which is characterized by ADH resistance and with the impairment of renal concentrating ability, polyuria and polydipsia may develop. Increased diuresis results in hypovolemia and aggravates the pre-renal component of renal failure. Renal dysfunction due to hypercalcemia is usually reversible and management strategy should be based on to correct serum calcium concentration. In mild asymptomatic hypercalcemia which can be described as <14 mg/dl (4 mmol/L), initially intravenous hydration should be preferred. Loop diuretics should not be used in myeloma-related hypercalcemia because of their facilitating effect on cast nephrotoxicity by increasing luminal sodium chloride. If there is no response to the fluid therapy within 12 hours, a bisphosphonate should be administered while considering renal functions. Although bisphosphonates are very useful and effective in the management of malignancy-related hypercalcemia, they must be used with caution in myeloma patients because of their nephrotoxicity and the risk of subsequent hypocalcaemia. In addition, beside their hypocalcemic effect, it has been shown that bisphosphonates reduce the incidence of skeletal events and improve life quality (Berenson JR,et al, 1998). Pamidronate (a dose of 60 to 90 mg as a 2 hours infusion) and Zoledronic acid (a dose of 4 mg, as a 15 minutes infusion) are the most common bisphosphonates in clinical use and regimen may be repeated at intervals of 2 or 4 weeks if necessary. Serum calcium and creatinine levels should be monitorized regularly and appropriate dose adjustment should be done in patients with severe renal impairment and vitamin D deficiency. For moderate or severe hypercalcemia, anti-myeloma therapy which includes steroids should be promptly initiated. Calcitonin may also help to reduce serum calcium concentrations without the risk of severe hypocalcemia and nephrotoxicity.

#### **3.3 Nephrotoxic drugs**

Some drugs and radiocontrast materials should not be used in myeloma patients because of their nephrotoxic potential, especially in the state of volume depletion.

#### **3.3.1 Intravenous radiocontrast solutuions**

Contrast induced nephropathy (CIN) is defined as an acute reduction in renal function due to iodinated contrast media administration and it is one of the most common cause of hospital-acquired acute renal failure. Patients with myeloma are at high risk group to develop renal impairment secondary to radiocontrast using and especially in the setting

Hypercalcemia occurs in more than 25 %of myeloma patients in the course of the disease and 15 %of patients have mild hypercalcemia with serum calcium level 11.0-13.0 mg/dl at diagnosis. Moderate or severe hypercalcemia may also be seen and may contribute to ARF. Hypercalcemia is the second most common cause of renal failure in MM (Blade J, Rosinol L.,2005). As the other malignancy-related hypercalcemias, some osteoclast activating factors and bone resorbing cytokines like lymphotoxin, interleukin-6, interleukin 1-β and a parathyroid related protein are produced by neoplastic cells and results in increased bone resorption (Kitazawa R,et al,2002). Elevated calcium concentration in renal tubules cause intratubular calcium deposition and vasoconstriction in renal vasculature. Decreased glomerular filtration rate induces cast precipitation and probably augments the toxicity of FLCs (Smolens P,et al,1987). Hypercalcemia may also causes nephrogenic diabetes insipidus which is characterized by ADH resistance and with the impairment of renal concentrating ability, polyuria and polydipsia may develop. Increased diuresis results in hypovolemia and aggravates the pre-renal component of renal failure. Renal dysfunction due to hypercalcemia is usually reversible and management strategy should be based on to correct serum calcium concentration. In mild asymptomatic hypercalcemia which can be described as <14 mg/dl (4 mmol/L), initially intravenous hydration should be preferred. Loop diuretics should not be used in myeloma-related hypercalcemia because of their facilitating effect on cast nephrotoxicity by increasing luminal sodium chloride. If there is no response to the fluid therapy within 12 hours, a bisphosphonate should be administered while considering renal functions. Although bisphosphonates are very useful and effective in the management of malignancy-related hypercalcemia, they must be used with caution in myeloma patients because of their nephrotoxicity and the risk of subsequent hypocalcaemia. In addition, beside their hypocalcemic effect, it has been shown that bisphosphonates reduce the incidence of skeletal events and improve life quality (Berenson JR,et al, 1998). Pamidronate (a dose of 60 to 90 mg as a 2 hours infusion) and Zoledronic acid (a dose of 4 mg, as a 15 minutes infusion) are the most common bisphosphonates in clinical use and regimen may be repeated at intervals of 2 or 4 weeks if necessary. Serum calcium and creatinine levels should be monitorized regularly and appropriate dose adjustment should be done in patients with severe renal impairment and vitamin D deficiency. For moderate or severe hypercalcemia, anti-myeloma therapy which includes steroids should be promptly initiated. Calcitonin may also help to reduce serum calcium concentrations

without the risk of severe hypocalcemia and nephrotoxicity.

**3.3.1 Intravenous radiocontrast solutuions** 

their nephrotoxic potential, especially in the state of volume depletion.

Some drugs and radiocontrast materials should not be used in myeloma patients because of

Contrast induced nephropathy (CIN) is defined as an acute reduction in renal function due to iodinated contrast media administration and it is one of the most common cause of hospital-acquired acute renal failure. Patients with myeloma are at high risk group to develop renal impairment secondary to radiocontrast using and especially in the setting

**3.3 Nephrotoxic drugs** 

**3.2 Hypercalcemia** 

of hypovolemia, contrasts may precipitate acute renal failure in the rate of approximately 1.5 percent (McCarthy CS, Becker JA, 1992). These agents induce light chain precipitation in the tubules and furthermore they may also interact with light chains and contribute to intra-tubular obstruction. However, recent studies suggest that myeloma patients with normal creatinine and low β2-microglobulin levels (< 2.8 mg/L) are at low risk for developing CIN and radiocontrast administration is safe in this group (Pahade JK,et al,2011). Nevertheless, the removal or avoidance of iodinated contrast agents should be preferred primarily but if it is not possible, adequate hydration should be performed during and after the procedure as well as using of low-osmolar or iso-osmolar radiocontrast media.

#### **3.3.2 Non-steroid anti-inflammatory drugs and others**

NSAIDs basicly block the production of prostaglandins (PGs) via inhibition of cyclooxygenase enzyme activitiy (COX-1 and COX-2). By the suppression of vasodilatatory PGs, renal vasoconstriction occurs and it leads to a reduction in the renal blood flow and glomerular filtration rate which may contribute to ARF. PGs blockage also leads to salt and water retention by the inhibition of chloride reabsorbtion and antidiuretic hormone (ADH). NSAIDs also can develop papillary necrosis and chronic interstitial nephritis. Patients with hypercalcemia or lower renal blood flow due to congestive heart failure, chronic renal failure or any other cause of hypovolemia and sodium depletion, have higher risk for worsening renal functions after using NSAIDs (Murray MD,et al,1995). Thus, NSAID therapy in patients with myeloma should be administered carefully and avoided if possible to prevent further renal damage.

ACE inhibitors, angiotensine receptor blockers (ARBs), diuretics and aminoglycosides are the other nephrotoxic agents that affect renal functions adversely in myeloma patients and should be stopped or avoided if possible.

#### **3.4 Hyperuricemia**

Hyperuricemia due to increased nucleic acid turnover, is present in upto 50% myeloma patients at diagnosis. It may also be seen as a result of chemotherapy even though tumor lysis syndrome and acute uric acid nephropathy are rare in multiple myeloma. Adequate hydration, alkalinization of the urine and prophylactic use of allopurinol can overcome this complication significantly.

#### **3.5 Hyperviscosity syndrome**

Hyperviscosity syndrome is a group of symptoms results from increased blood viscosity due to the excessive amounts of circulating proteins and commonly occurs in association with paraprotein disorders, such as Waldenström macroglobulinemia (IgM) and rarely multiple myeloma (IgA,IgG3,kappa). It is classically manifested by spontaneous bleeding from mucous membranes due to impaired platelet function, neurologic and pulmonary symptoms as a result of ischemia in brain and lung tissue and visual defects related to rehinopathy. Although this syndrome rarely affects the kidneys permanently, it may also lead to acute renal failure occasionally. Plasmapheresis may be used to decrease viscosity

Renal Disease in Multiple Myeloma 227

Renal dysfunction in myeloma patients usually indicates high tumor burden and aggressive disease and it is important to initiate an early, effective therapy to provide a remission and renal reversal immediately. Alkylator-based conventional chemotherapy with Melphalan-Prednisone (MP) was usually reserved for patients who are ineligible for ASCT because of advanced age >70 and/or severe comorbidities (Rajkumar SV,Kyle RA,2005). MP regimen is also insufficient in renal function recovery and dose adjustment problems due to the renal elimination of melphalan limit the efficacy of therapy. In a study of Nordic Myeloma Study Group ,by the treatment with alkylating agents and standard dose steroids, reversal of renal failure was found in 58% of patients, whereas 40% of patients with a creatinine 2.3mg/dl

Combination chemotherapies like Vincristin+ Doxorubicin+ Dexamethasone (VAD),or Cyclophosphamide + Dexamethasone, or Dexamethasone alone are more preferable regimens by clinicians to achieve a rapid control of the disease. Dose modification is not needed in renal failure because of low renal excretion of mentioned agents. From a single instution study in 94 patients who had renal failure with myeloma, renal function recovery was observed in 26% of cases by conventional combination chemotherapy. Median survival for these patients was 28.3 months, compared with 3.8 months for those with irreversible renal failure (P<0.001). Furthermore, survival was not significantly different in patients with renal recovery vs those with normal renal function (P=0.97). Response rate to chemotherapy was found to be considerably lower in patients with renal failure than those with normal renal function (39% versus 56%; P<0.001). However, if patients dying within the first 2 months of treatment were excluded, there was no significant differences in the response rate between patients with renal failure and those with normal renal function. This result can be explained by high rate of early mortality in patients with renal failure accounting for 30% within first two months. Combination chemotherapy was also found to be more effective than MP or CP regimens with the response rates relatively 50% versus 24% (P=0.03) even

High-dose dexamethasone-based regimens are alternatively safe and effective for newly diagnosed myeloma patients with renal impairment. In the first study of pulse dexamethasone therapy in previously untreated patients, the overall response rate was 43% similar to VAD and serious complications were considerably fewer, 4% versus 27% (Alexanian R,et al,1992). In a series of 41 myeloma patients with renal impairment treated with high-dose dexamethasone, rate of renal function recovery was found 73% which was higher than the reversal rate of standart dose steroid included alkylator-based regimens. This study concluded that high-dose dexamethasone was effective even in one-half of patients with negative prognostic factors in terms of reversal such as massive proteinuria, cast nephropathy and severe renal insufficiency. It is also suggested that combination with novel biologic agents, such as thalidomide and/or bortezomib also can provide a more

**4.3 Anti-myeloma treatment** 

**4.3.1 Conventional chemotherapy** 

achieved a normal renal function (Knudsen LM,et al,2000).

though survivals were similar (Blade J,et al,1998).

**4.3.2 High-dose dexamethasone-based regimens** 

rapid improvement in renal function (Kastritis E,et al,2007).

significantly and also exchange transfusions and hydration may be administered in the treatment strategy.

#### **4. Therapy modalities for myeloma kidney**

#### **4.1 Plasmapheresis**

Extracorporeal removal of nephrotoxic light chains from the blood seems to be a reasonable approach in cast nephropathy and plasma exchange has been widely used in clinical practice to decrease serum FLC concentrations. However, there is no convincing evidence about the benefit of plasmapheresis in acute renal failure in multiple myeloma and conflicting outcomes have been reported by many studies ((Zuchelli P,et al,1988, Clark WF,et al,2005, Leung N,et al,2008) .

Currently, plasmapheresis is indicated for patients with acute renal failure due to myeloma cast nephropathy to assist in the rapid removal of circulating excess FLCs and must be done together with dexamethasone-based regimens to limit production of new light chains. Renal biopsy is primarily needed to confirm tissue diagnosis but in emergency conditions presence of very high levels of FLCs in the serum or urine may prompt initiation of plasmapheresis. Standart regimen includes five to seven exchanges within seven or ten days and may be repeated if necessary.

#### **4.2 Dialysis**

Dialysis is an alternative approach to remove FLCs from circulation but it is generally insufficient for large amounts of light chains. Both hemodialysis and peritoneal dialysis may be administered in patients with acute or chronic renal failure, however, plasmapheresis is relatively more effective in the way of light chain reduction acutely.

Recently, newer protein permeable and larger pored hemodialysis membranes that remove the FLCs more efficiently has been developed and studies focused on these high- cut off (HCO) dialysers. It has been demonstrated that daily, extended hemodialysis using the Gambro HCO 1100 dialyzer which has an effective cut-off for <50 kd proteins, could remove continuously large quantities of FLC (Hutchinson CA,et al,2007). A following pilot study handled by same team in 2009 concluded that in dialysis-dependent acute renal failure secondary to cast nephropathy, patients who received uninterrupted chemotherapy and extended HCO-HD had sustained reductions in serum FLC levels and independent renal function recovered in 74 percent of patients. An interruption in chemotherapy was found to be associated with unfavorable outcomes and therefore it was hard to distinguish the benefits of chemotherapy and HCO dialysis separately.

The **EU**ropean trial of free **LI**ght chain removal by ex**TE**nded haemodialysis in cast nephropathy (EuLITE) is a very recent prospective, randomised controlled, multicenter clinical trial of HCO dialysis versus conventional dialysis in patients with with cast nephropathy, dialysis dependent acute renal failure and de novo multiple myeloma who all receive bortezomib, doxorubicin and dexamethasone as chemotherapy (Hutchinson CA,et al,2008). This study is ongoing and if it suggests that if efficacious, this therapy will offer clinicians new options in the management of these patients.

significantly and also exchange transfusions and hydration may be administered in the

Extracorporeal removal of nephrotoxic light chains from the blood seems to be a reasonable approach in cast nephropathy and plasma exchange has been widely used in clinical practice to decrease serum FLC concentrations. However, there is no convincing evidence about the benefit of plasmapheresis in acute renal failure in multiple myeloma and conflicting outcomes have been reported by many studies ((Zuchelli P,et al,1988, Clark

Currently, plasmapheresis is indicated for patients with acute renal failure due to myeloma cast nephropathy to assist in the rapid removal of circulating excess FLCs and must be done together with dexamethasone-based regimens to limit production of new light chains. Renal biopsy is primarily needed to confirm tissue diagnosis but in emergency conditions presence of very high levels of FLCs in the serum or urine may prompt initiation of plasmapheresis. Standart regimen includes five to seven exchanges within seven or ten days

Dialysis is an alternative approach to remove FLCs from circulation but it is generally insufficient for large amounts of light chains. Both hemodialysis and peritoneal dialysis may be administered in patients with acute or chronic renal failure, however, plasmapheresis is

Recently, newer protein permeable and larger pored hemodialysis membranes that remove the FLCs more efficiently has been developed and studies focused on these high- cut off (HCO) dialysers. It has been demonstrated that daily, extended hemodialysis using the Gambro HCO 1100 dialyzer which has an effective cut-off for <50 kd proteins, could remove continuously large quantities of FLC (Hutchinson CA,et al,2007). A following pilot study handled by same team in 2009 concluded that in dialysis-dependent acute renal failure secondary to cast nephropathy, patients who received uninterrupted chemotherapy and extended HCO-HD had sustained reductions in serum FLC levels and independent renal function recovered in 74 percent of patients. An interruption in chemotherapy was found to be associated with unfavorable outcomes and therefore it was hard to distinguish the

The **EU**ropean trial of free **LI**ght chain removal by ex**TE**nded haemodialysis in cast nephropathy (EuLITE) is a very recent prospective, randomised controlled, multicenter clinical trial of HCO dialysis versus conventional dialysis in patients with with cast nephropathy, dialysis dependent acute renal failure and de novo multiple myeloma who all receive bortezomib, doxorubicin and dexamethasone as chemotherapy (Hutchinson CA,et al,2008). This study is ongoing and if it suggests that if efficacious, this therapy will offer

relatively more effective in the way of light chain reduction acutely.

benefits of chemotherapy and HCO dialysis separately.

clinicians new options in the management of these patients.

treatment strategy.

**4.1 Plasmapheresis** 

WF,et al,2005, Leung N,et al,2008) .

and may be repeated if necessary.

**4.2 Dialysis** 

**4. Therapy modalities for myeloma kidney** 

#### **4.3 Anti-myeloma treatment**

#### **4.3.1 Conventional chemotherapy**

Renal dysfunction in myeloma patients usually indicates high tumor burden and aggressive disease and it is important to initiate an early, effective therapy to provide a remission and renal reversal immediately. Alkylator-based conventional chemotherapy with Melphalan-Prednisone (MP) was usually reserved for patients who are ineligible for ASCT because of advanced age >70 and/or severe comorbidities (Rajkumar SV,Kyle RA,2005). MP regimen is also insufficient in renal function recovery and dose adjustment problems due to the renal elimination of melphalan limit the efficacy of therapy. In a study of Nordic Myeloma Study Group ,by the treatment with alkylating agents and standard dose steroids, reversal of renal failure was found in 58% of patients, whereas 40% of patients with a creatinine 2.3mg/dl achieved a normal renal function (Knudsen LM,et al,2000).

Combination chemotherapies like Vincristin+ Doxorubicin+ Dexamethasone (VAD),or Cyclophosphamide + Dexamethasone, or Dexamethasone alone are more preferable regimens by clinicians to achieve a rapid control of the disease. Dose modification is not needed in renal failure because of low renal excretion of mentioned agents. From a single instution study in 94 patients who had renal failure with myeloma, renal function recovery was observed in 26% of cases by conventional combination chemotherapy. Median survival for these patients was 28.3 months, compared with 3.8 months for those with irreversible renal failure (P<0.001). Furthermore, survival was not significantly different in patients with renal recovery vs those with normal renal function (P=0.97). Response rate to chemotherapy was found to be considerably lower in patients with renal failure than those with normal renal function (39% versus 56%; P<0.001). However, if patients dying within the first 2 months of treatment were excluded, there was no significant differences in the response rate between patients with renal failure and those with normal renal function. This result can be explained by high rate of early mortality in patients with renal failure accounting for 30% within first two months. Combination chemotherapy was also found to be more effective than MP or CP regimens with the response rates relatively 50% versus 24% (P=0.03) even though survivals were similar (Blade J,et al,1998).

#### **4.3.2 High-dose dexamethasone-based regimens**

High-dose dexamethasone-based regimens are alternatively safe and effective for newly diagnosed myeloma patients with renal impairment. In the first study of pulse dexamethasone therapy in previously untreated patients, the overall response rate was 43% similar to VAD and serious complications were considerably fewer, 4% versus 27% (Alexanian R,et al,1992). In a series of 41 myeloma patients with renal impairment treated with high-dose dexamethasone, rate of renal function recovery was found 73% which was higher than the reversal rate of standart dose steroid included alkylator-based regimens. This study concluded that high-dose dexamethasone was effective even in one-half of patients with negative prognostic factors in terms of reversal such as massive proteinuria, cast nephropathy and severe renal insufficiency. It is also suggested that combination with novel biologic agents, such as thalidomide and/or bortezomib also can provide a more rapid improvement in renal function (Kastritis E,et al,2007).

Renal Disease in Multiple Myeloma 229

efficacy of lenalidomide in myeloma patients with severe renal failure is limited, because

MM-009 and MM-010 phase 3 studies that compared Lenalidomid plus dexamethasone versus dexamethasone alone in patients with relaps or refractory myeloma demonstrated that there was no difference in disease response rates between patients with any degree of renal impairment and with normal renal function. In moderate or severe renal impairment, 72% of the patients had an improvement in their renal function with Len+Dex, although there was an increased incidence of thrombocytopenia in patients with creatinine clearance <50 ml/min (Dimopoulos MA,et al,2010). In the following study of same researchers, patients treated by Len+Dex at a dose adjusted according to renal function, 3 of 12 patients with renal impairment (25%) achieved complete renal response and 2 (16%) achieved minor renal response, moreover there were no differences in the incidence of adverse events among patients with and without renal dysfunction. A Spanish retrospective analysis reported that with the combination of Len+Dex, response rate was 57% in 15 dialysisdependent myeloma patients ;one patient became independent of dialysis (Roig M,2009). In a phase II study which included treatment-naive patients who received Len+Dex showed that patients with a baseline Cr Cl< 40 ml min were 8.4 times more likely to require lenalidomide dose reduction due to grade 3 or higher myelosupression (Niesvizky R,et al,2007). Eventually available data suggest that lenalidomide may be safely administered to patients with renal impairment at the recommended reduced dose based on renal function with similar anti-myeloma activity and without significant additional toxicity. Recommended administration of lenalidomide is described as no dose reduction for CrCl<50 ml/min, reduce the dose to 10 mg/d in patients with CrCl 30-50 ml/min; to 15 mg every other day in patients with CrCl<30 ml/min not on dialysis and to 5 mg once daily in

Bortezomib is the first proteasome inhibitor with proven activity in both newly diagnosed and relapsed or refractory myeloma. It may be used alone or in combination with steroids and other chemotherapeutic agents safely in patients with renal failure because its pharmacokinetics are independent of renal clearance and no dose adjustment is

In the SUMMIT (Study of Uncontrolled Multiple Myeloma Managed with Proteasome Inhibition Therapy) and CREST (Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma) phase 2 trials; overall response rates were found 45% in patients with CrCl>80 ml/min and 25% in those with CrCl<50 ml/min. Toxicity and discontinuation rates were similar between the patients with renal impairment and normal renal function (Jagannath S, et al, 2005). In APEX (Assessment of Proteasome Inhibition for Extending Remissions), a phase III study, bortezomib versus high-dose dexamethasone was assessed in terms of efficacy and safety in patients with relapsed myeloma with varying degrees of renal impairment. Time to progression (TTP) and overall survival (OS) were similar between the subgroups with CrCl>50 ml/min and <50 ml/min, although there was insignificant trend toward shorter TTP and OS in patients with CrCl 50 ml/min or below. OS was significantly shorter in dexamethasone-treated patients with any degree of renal

most of studies excluded patients with serum creatinine >2 mg/dl.

patients requiring dialysis.

**4.3.3.3 Bortezomib** 

required.

#### **4.3.3 Novel agents**

Overall survival in multiple myeloma has improved remarkably in the last decade with the introduction of three novel agents used in both denovo and relapsed MM; Thalidomide, Bortezomib and Lenalidomide (Kumar SK,et al,2008). Combination of bortezomib and highdose dexamethasone is considered as the primary treatment option for myeloma patients with renal impairment and improves renal function rapidly in most patients. Incorporation of mechanical removal of serum FLCs may also provide an additive benefit to this combination for patients with acute renal failure due to myeloma cast nephropathy. Thalidomide is also therapeutic choice for the patients with severe renal impairment; however there is limited experience and data about it. Lenalidomide can reverse renal dysfunction in a subgroup of myeloma patients with mild or moderate renal impairment, thus it is effective and safe if administered at reduced doses according to renal function.

#### **4.3.3.1 Thalidomide**

Since the relationship between bone marrow angiogenesis and disease progression in myeloma has been well established, anti-angiogenic drug thalidomide has been demonstrated to be useful in the treatment of myeloma. Thalidomide is the first immunomodulatory drug (Imid) with proven anti-myeloma activity. No dose adjustment is required for the patients with renal impairment owing to the fact that it is not excreted in kidneys.

In a study of 20 patients with stage III relapsed or refractory myeloma and chronic renal failure, treatment with thalidomide alone or in combination with dexamethasone resulted in 12 of 15 responsive patients who recovered to normal renal function. Furthermore two patients who were dialysis-dependant showed a reduction in serum creatinine. Toxicity profile of thalidomide with or without dexamethasone was not significantly different among the patients with renal failure and normal renal function. Thus, it has concluded that thalidomide can be safely administered in patients with advanced myeloma and renal failure (Tosi P,et al,2004). In another study reversal of renal failure observed in 80% of previously untreated patients who received thalidomide in combination with high-dose dexamethasone with or without bortezomib (Kastritis E,et al,2007). Although many studies indicate similar toxicity in any level of renal dysfunction, some reports have suggested that toxic effects of thalidomide as severe neuropathy, constipation, lethargy and bradycardia are more frequent in patients with a serum creatinine level over 3mg/dl (Pineda-Roman M, Tricot G,2007). Treatment with thalidomide has been also reported in association with severe hyperkalemia in small part of patients with renal impairment (Harris E,et al,2003). More recently in a study of highcut off haemodialysis with thalidomide therapy, 14 of 19 patients recovered renal function and became independent of dialysis (Hutchison CA,et al,2009).

#### **4.3.3.2 Lenalidomide**

Lenalidomide is a small molecule analogue of thalidomide and a second generation immunomodulatory drug which is highly effective in patients with relapsed or refractory myeloma, especially in combination with dexamethasone or alkylator agents. It is mainly excreted in kidneys by both glomerular filtration and active tubular reabsorption and dose adjustment is required for the patients with renal impairment. Therefore, data on the

Overall survival in multiple myeloma has improved remarkably in the last decade with the introduction of three novel agents used in both denovo and relapsed MM; Thalidomide, Bortezomib and Lenalidomide (Kumar SK,et al,2008). Combination of bortezomib and highdose dexamethasone is considered as the primary treatment option for myeloma patients with renal impairment and improves renal function rapidly in most patients. Incorporation of mechanical removal of serum FLCs may also provide an additive benefit to this combination for patients with acute renal failure due to myeloma cast nephropathy. Thalidomide is also therapeutic choice for the patients with severe renal impairment; however there is limited experience and data about it. Lenalidomide can reverse renal dysfunction in a subgroup of myeloma patients with mild or moderate renal impairment, thus it is effective and safe if administered at reduced doses according to renal function.

Since the relationship between bone marrow angiogenesis and disease progression in myeloma has been well established, anti-angiogenic drug thalidomide has been demonstrated to be useful in the treatment of myeloma. Thalidomide is the first immunomodulatory drug (Imid) with proven anti-myeloma activity. No dose adjustment is required for the patients with renal impairment owing to the fact that it is not excreted in

In a study of 20 patients with stage III relapsed or refractory myeloma and chronic renal failure, treatment with thalidomide alone or in combination with dexamethasone resulted in 12 of 15 responsive patients who recovered to normal renal function. Furthermore two patients who were dialysis-dependant showed a reduction in serum creatinine. Toxicity profile of thalidomide with or without dexamethasone was not significantly different among the patients with renal failure and normal renal function. Thus, it has concluded that thalidomide can be safely administered in patients with advanced myeloma and renal failure (Tosi P,et al,2004). In another study reversal of renal failure observed in 80% of previously untreated patients who received thalidomide in combination with high-dose dexamethasone with or without bortezomib (Kastritis E,et al,2007). Although many studies indicate similar toxicity in any level of renal dysfunction, some reports have suggested that toxic effects of thalidomide as severe neuropathy, constipation, lethargy and bradycardia are more frequent in patients with a serum creatinine level over 3mg/dl (Pineda-Roman M, Tricot G,2007). Treatment with thalidomide has been also reported in association with severe hyperkalemia in small part of patients with renal impairment (Harris E,et al,2003). More recently in a study of highcut off haemodialysis with thalidomide therapy, 14 of 19 patients recovered renal function and became independent of dialysis (Hutchison CA,et

Lenalidomide is a small molecule analogue of thalidomide and a second generation immunomodulatory drug which is highly effective in patients with relapsed or refractory myeloma, especially in combination with dexamethasone or alkylator agents. It is mainly excreted in kidneys by both glomerular filtration and active tubular reabsorption and dose adjustment is required for the patients with renal impairment. Therefore, data on the

**4.3.3 Novel agents** 

**4.3.3.1 Thalidomide** 

kidneys.

al,2009).

**4.3.3.2 Lenalidomide** 

efficacy of lenalidomide in myeloma patients with severe renal failure is limited, because most of studies excluded patients with serum creatinine >2 mg/dl.

MM-009 and MM-010 phase 3 studies that compared Lenalidomid plus dexamethasone versus dexamethasone alone in patients with relaps or refractory myeloma demonstrated that there was no difference in disease response rates between patients with any degree of renal impairment and with normal renal function. In moderate or severe renal impairment, 72% of the patients had an improvement in their renal function with Len+Dex, although there was an increased incidence of thrombocytopenia in patients with creatinine clearance <50 ml/min (Dimopoulos MA,et al,2010). In the following study of same researchers, patients treated by Len+Dex at a dose adjusted according to renal function, 3 of 12 patients with renal impairment (25%) achieved complete renal response and 2 (16%) achieved minor renal response, moreover there were no differences in the incidence of adverse events among patients with and without renal dysfunction. A Spanish retrospective analysis reported that with the combination of Len+Dex, response rate was 57% in 15 dialysisdependent myeloma patients ;one patient became independent of dialysis (Roig M,2009). In a phase II study which included treatment-naive patients who received Len+Dex showed that patients with a baseline Cr Cl< 40 ml min were 8.4 times more likely to require lenalidomide dose reduction due to grade 3 or higher myelosupression (Niesvizky R,et al,2007). Eventually available data suggest that lenalidomide may be safely administered to patients with renal impairment at the recommended reduced dose based on renal function with similar anti-myeloma activity and without significant additional toxicity. Recommended administration of lenalidomide is described as no dose reduction for CrCl<50 ml/min, reduce the dose to 10 mg/d in patients with CrCl 30-50 ml/min; to 15 mg every other day in patients with CrCl<30 ml/min not on dialysis and to 5 mg once daily in patients requiring dialysis.

#### **4.3.3.3 Bortezomib**

Bortezomib is the first proteasome inhibitor with proven activity in both newly diagnosed and relapsed or refractory myeloma. It may be used alone or in combination with steroids and other chemotherapeutic agents safely in patients with renal failure because its pharmacokinetics are independent of renal clearance and no dose adjustment is required.

In the SUMMIT (Study of Uncontrolled Multiple Myeloma Managed with Proteasome Inhibition Therapy) and CREST (Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma) phase 2 trials; overall response rates were found 45% in patients with CrCl>80 ml/min and 25% in those with CrCl<50 ml/min. Toxicity and discontinuation rates were similar between the patients with renal impairment and normal renal function (Jagannath S, et al, 2005). In APEX (Assessment of Proteasome Inhibition for Extending Remissions), a phase III study, bortezomib versus high-dose dexamethasone was assessed in terms of efficacy and safety in patients with relapsed myeloma with varying degrees of renal impairment. Time to progression (TTP) and overall survival (OS) were similar between the subgroups with CrCl>50 ml/min and <50 ml/min, although there was insignificant trend toward shorter TTP and OS in patients with CrCl 50 ml/min or below. OS was significantly shorter in dexamethasone-treated patients with any degree of renal

Renal Disease in Multiple Myeloma 231

of the kidney may be involved though predominant localisation is glomerulus. Renal failure at presentation is seen in 20% of patients generally observed with massive proteinuria and progresses to end-stage renal disease (ESRD) in ∼40% of patients over a median time of 35 months (Bergesio F,et al,2008). In approximately 10% of patients, amyloid deposition occurs in the renal vasculature or tubulointerstitium rather than glomeruli, resulting in renal

AL amyloid fibrils are derived from the N-terminal region of monoclonal immunoglobulin light chain which contains a variable (VL) domain. It is postulated that certain amino acid sequences for λ light chains change the thermodynamic stability and hydrophoby of the protein, leading to increased potential of fibril forming. It has been shown that λ VI light chains are more specifically associated with AL-amyloidosis (Solomon A,et al,1982). Furhermore posttranslational modifications of the light chains, such as glycosylation, may promote the amyloidogenic potential by protecting the fibril from degradation. β-pleated sheets are mainly responsible for the aggregation of light chains to form oligomers which do not dissolve in normal proteolysis and these aggregates are stabilized with other proteins, including glycosaminoglycans, proteoglycans, serum amyloid P (SAP), fibronectin and

Mesangium is the initial site of the glomerular injury and amyloid fibrils replace the normal mesangial matrix by endocytosis of mesangial cells and transporting into lysosomes. Extracellular amyloid fibrils also stimulate the activation of matrix metalloproteinases (MMPs) and inhibit TGF- β as a regulator of matrix production, result in decreased synthesis of mesangial matrix. Tissue architecture is destroyed by amyloid deposits with its secondary effects on matrix and also direct toxicity, thus glomerular damage occurs which leads to

AL amyloidosis is a rare disorder and it is difficult to diagnose because of nonspecific early clinic manifestations before specific organ failure occurs. Its diagnosis should be suspected in any patient with non-diabetic nephrotic syndrome, peripheral neuropathy, hypertrophic cardiomyopathy, hepatomegaly and macroglossia, especially when they are associated in a

All amyloidosis-suspected patients need the diagnosis which is confirmed histologically. Abdominal subcutaneous fat aspiration is recommended as the initial minimal invasive diagnostic procedure and when it is combined with bone marrow biopsy, amyloid deposits may be identified in 90% of patients. If both examinations are negative, then a renal biopsy may be indicated and diagnostic in >95% of patients with manifest renal disease. Histopathological assessment characteristically contains congo red-positive staining leads to the apple-green birefringence under the polarized light microscopy. Amyloid deposits are always seen as diffuse amorphous hyaline material in glomeruli especially in mesangium and also in the wall of blood vessels. Electrophoresis with serum (71% sensitivity) and urine (84% sensitivity) immunofixation needs to be performed in all patients . after confirming the histopathologic diagnosis, to differentiate the type of amyloidosis Quantitative Ig

dysfunction without significant proteinuria.

**5.1 Pathogenesis of AL amyloidosis** 

apolipoprotein E.

renal failure.

**5.2 Diagnosis of AL amyloidosis** 

patient with typical age of >60 and male sex.

dysfunction (P=0.003), indicating that bortezomib is more effective than dexamethasone in overcoming the poor prognostic effect of renal failure. Toxicity of bortezomib was similar between subgroups (San Miguel JF,et al,2008).

In a retrospective analysis of 24 relapsed or refractory myeloma patients who were all dialysis-dependent, overall response rate was reported 75% with complete or near complete renal response (CR or nCR) rate of 30%. Three patients became dialysis-independent after bortezomib therapy and safety profile of bortezomib was found similar in any stage of renal impairment (Chanan-Khan AA,et al,2007). In a phase II study that assessed the efficacy of BDD (bortezomib + doxorubicin + dexamethasone) therapy in patients with multiple myeloma with light chain-induced acute renal failure, myeloma response and renal response were obtained in 72% and 62% of patients respectively. Survivals were not different between patients with and without renal response but was lower in previously treated patients (P <0 .001) (Ludwig H,et al,2009).

VISTA (Velcade as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone) is the largest analysis of a phase III trial comparing VMP (bortezomib+melphalan+prednisone) and MP (melphalan+prednisone) combinations in myeloma patients with renal impairment. Response rates were higher and TTP and OS longer with VMP versus MP across renal cohorts. Response rates in VMP arm and TTP in both arms did not appear significantly different between patients with CrCl ≤ 50 or >50 ml/min; OS appeared slightly longer in patients with normal renal function in both arms. Renal impairment reversal was seen in 49 of 111 (44%) patients receiving VMP versus 40 of 116 (34%) patients receiving MP. In both arms, rates of grade 3 and 4 adverse events appeared higher in patients with renal impairment; with VMP, rates of discontinuations or bortezomib dose reductions due to adverse effects did not appear affected (Dimopoulos MA,et al,2009).

According to the consensus statement on behalf of the International Myeloma Working Group, high dose dexamethasone and bortezomib are the recommended treatment for MM in patients with any degree of renal impairment especially for those with light chain cast nephropathy.

#### **5. Light chain amyloidosis (Primary, AL amyloidosis)**

Light-chain amyloidosis (AL) is the most common form of systemic amyloidosis in western countries, with an estimated incidence of 0.8 per 100,000 person years. This entity is characterized by tissue deposits of insoluble immunoglobulin light chain fragments which polymerize into extracellular amyloid fibrils with a typical β-pleated sheet secondary structure. Amyloid deposits derived from light chains accumulate in normal tissues like most commonly in the kidney, heart, liver and peripheral nervous system, resulting in structural organ dysfunction. It may be associated with an underlying plasma cell disorder like multiple myeloma, Waldenström Macroglobulinemia or MGUS (monoclonal gammopathy of undetermined significance). It is more commonly derived from the variable region of lambda light chain than kappa (75% vs. 25%) and rarely seen in association with heavy chains (AH-amyloidosis). Renal involvement is the most common manifestation in about 60–74% of cases and usually presents as nephrotic syndrome with progressive worsening of renal function (Kyle RA, Gertz MA,1995, Obici L,et al,2005). All compartments

dysfunction (P=0.003), indicating that bortezomib is more effective than dexamethasone in overcoming the poor prognostic effect of renal failure. Toxicity of bortezomib was similar

In a retrospective analysis of 24 relapsed or refractory myeloma patients who were all dialysis-dependent, overall response rate was reported 75% with complete or near complete renal response (CR or nCR) rate of 30%. Three patients became dialysis-independent after bortezomib therapy and safety profile of bortezomib was found similar in any stage of renal impairment (Chanan-Khan AA,et al,2007). In a phase II study that assessed the efficacy of BDD (bortezomib + doxorubicin + dexamethasone) therapy in patients with multiple myeloma with light chain-induced acute renal failure, myeloma response and renal response were obtained in 72% and 62% of patients respectively. Survivals were not different between patients with and without renal response but was lower in previously

VISTA (Velcade as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone) is the largest analysis of a phase III trial comparing VMP (bortezomib+melphalan+prednisone) and MP (melphalan+prednisone) combinations in myeloma patients with renal impairment. Response rates were higher and TTP and OS longer with VMP versus MP across renal cohorts. Response rates in VMP arm and TTP in both arms did not appear significantly different between patients with CrCl ≤ 50 or >50 ml/min; OS appeared slightly longer in patients with normal renal function in both arms. Renal impairment reversal was seen in 49 of 111 (44%) patients receiving VMP versus 40 of 116 (34%) patients receiving MP. In both arms, rates of grade 3 and 4 adverse events appeared higher in patients with renal impairment; with VMP, rates of discontinuations or bortezomib dose reductions due to adverse effects did not appear affected (Dimopoulos

According to the consensus statement on behalf of the International Myeloma Working Group, high dose dexamethasone and bortezomib are the recommended treatment for MM in patients with any degree of renal impairment especially for those with light chain cast

Light-chain amyloidosis (AL) is the most common form of systemic amyloidosis in western countries, with an estimated incidence of 0.8 per 100,000 person years. This entity is characterized by tissue deposits of insoluble immunoglobulin light chain fragments which polymerize into extracellular amyloid fibrils with a typical β-pleated sheet secondary structure. Amyloid deposits derived from light chains accumulate in normal tissues like most commonly in the kidney, heart, liver and peripheral nervous system, resulting in structural organ dysfunction. It may be associated with an underlying plasma cell disorder like multiple myeloma, Waldenström Macroglobulinemia or MGUS (monoclonal gammopathy of undetermined significance). It is more commonly derived from the variable region of lambda light chain than kappa (75% vs. 25%) and rarely seen in association with heavy chains (AH-amyloidosis). Renal involvement is the most common manifestation in about 60–74% of cases and usually presents as nephrotic syndrome with progressive worsening of renal function (Kyle RA, Gertz MA,1995, Obici L,et al,2005). All compartments

**5. Light chain amyloidosis (Primary, AL amyloidosis)** 

between subgroups (San Miguel JF,et al,2008).

treated patients (P <0 .001) (Ludwig H,et al,2009).

MA,et al,2009).

nephropathy.

of the kidney may be involved though predominant localisation is glomerulus. Renal failure at presentation is seen in 20% of patients generally observed with massive proteinuria and progresses to end-stage renal disease (ESRD) in ∼40% of patients over a median time of 35 months (Bergesio F,et al,2008). In approximately 10% of patients, amyloid deposition occurs in the renal vasculature or tubulointerstitium rather than glomeruli, resulting in renal dysfunction without significant proteinuria.

#### **5.1 Pathogenesis of AL amyloidosis**

AL amyloid fibrils are derived from the N-terminal region of monoclonal immunoglobulin light chain which contains a variable (VL) domain. It is postulated that certain amino acid sequences for λ light chains change the thermodynamic stability and hydrophoby of the protein, leading to increased potential of fibril forming. It has been shown that λ VI light chains are more specifically associated with AL-amyloidosis (Solomon A,et al,1982). Furhermore posttranslational modifications of the light chains, such as glycosylation, may promote the amyloidogenic potential by protecting the fibril from degradation. β-pleated sheets are mainly responsible for the aggregation of light chains to form oligomers which do not dissolve in normal proteolysis and these aggregates are stabilized with other proteins, including glycosaminoglycans, proteoglycans, serum amyloid P (SAP), fibronectin and apolipoprotein E.

Mesangium is the initial site of the glomerular injury and amyloid fibrils replace the normal mesangial matrix by endocytosis of mesangial cells and transporting into lysosomes. Extracellular amyloid fibrils also stimulate the activation of matrix metalloproteinases (MMPs) and inhibit TGF- β as a regulator of matrix production, result in decreased synthesis of mesangial matrix. Tissue architecture is destroyed by amyloid deposits with its secondary effects on matrix and also direct toxicity, thus glomerular damage occurs which leads to renal failure.

#### **5.2 Diagnosis of AL amyloidosis**

AL amyloidosis is a rare disorder and it is difficult to diagnose because of nonspecific early clinic manifestations before specific organ failure occurs. Its diagnosis should be suspected in any patient with non-diabetic nephrotic syndrome, peripheral neuropathy, hypertrophic cardiomyopathy, hepatomegaly and macroglossia, especially when they are associated in a patient with typical age of >60 and male sex.

All amyloidosis-suspected patients need the diagnosis which is confirmed histologically. Abdominal subcutaneous fat aspiration is recommended as the initial minimal invasive diagnostic procedure and when it is combined with bone marrow biopsy, amyloid deposits may be identified in 90% of patients. If both examinations are negative, then a renal biopsy may be indicated and diagnostic in >95% of patients with manifest renal disease. Histopathological assessment characteristically contains congo red-positive staining leads to the apple-green birefringence under the polarized light microscopy. Amyloid deposits are always seen as diffuse amorphous hyaline material in glomeruli especially in mesangium and also in the wall of blood vessels. Electrophoresis with serum (71% sensitivity) and urine (84% sensitivity) immunofixation needs to be performed in all patients . after confirming the histopathologic diagnosis, to differentiate the type of amyloidosis Quantitative Ig

Renal Disease in Multiple Myeloma 233

patient who have stage V renal disease with hemodialysis support and age above 65 years, relatvelygood response with acceptable tolerance has been shown with bortezomib+high-

In a selected patient group who are eligible for ASCT, by using a risk-adapted approach such as dose escalation of melphalan in patients with renal dysfunction, use of myeloablative chemotherapy followed by ASCT may be the most successful approach. In a study of 123 AL patients treated with high-dose melphalan followed by ASCT, renal response was noted in 43.4% of the patients with a better survival. It was also found that the severity of proteinuria was an independent predictor of renal response after ASCT and the recovery of renal function and prevention of ESRD after ASCT depended on the the degree

Nonamyloidotic monoclonal Ig deposition disease (MIDD) is characterized by deposition of monoclonal Ig subunits in kidney with an excess accumulation of extracellular matrix, leading to nodular sclerosing glomerulopathy, interstitial fibrosis, proteinuria, and renal insufficiency. According to the Ig deposition type, three subtypes of MIDD have been described, including light chain DD (LCDD), light-and heavy-chain (LHCDD) and heavy chain DD (HCDD). LCDD is the most prevalent subtype and found in 5% of patients with myeloma at autopsy series (Ivanyi B,1990). The most common cause is myeloma with the ratio of 65%, however 32% of cases are not associated with a manifested haematologic disorder. Although they are similar entities, in comparison to AL amyloidosis, the deposited light chains are kappa chains in 85% of LCDD cases, do not have a fibrillar organization and do not bind congo red. The majority of patients have a severe renal insufficiency with a median serum creatinine level of 3.8 mg/dl and usually tend to present with a higher serum creatinine concentration and lower rate of protein excretion than patients with AL amyloidosis (Harris AA,et al,1997). Cardiac, hepatic or small intestinal involvement also

Initial process in MIDD usually includes the interaction between abnormal kappa chain (κ-I or κ-IV) and the mesangial cells of the glomerulus. Light chains were shown to stimulate the mesangial proliferation and secretion of transforming growth factor-beta (TGF-β) (Zhu L,et al,1995). TGF-β increases the production of collagen IV, laminin, and fibronectin which are deposited in the extracellular matrix (ECM) of the kidneys and also decrease the levels of collagenase, metalloproteinases, serin protease and other enzymes that degrades matrix proteins. Progressive light chain deposition and accumulation of ECM components inevitably lead to organ fibrosis and dysfunction. In MIDD, deposits predominantly localized in the tubular basement membranes and Bowman's capsule rather than in the glomeruli, though nodular glomerulosclerosis is present 60% of cases associated with a nephrotic range proteinuria. Tubular lesions are characterized by the deposition of a granular, punctuate, eosinophilic, periodic acid-Schiff (PAS)-positive, ribbon-like material along the interstitial side of the tubular basement membrane in electron microscopy. Glomerular lesions are usually associated with diffuse mesangial expansion by PAS positive

dose dexamethasone regimen (Mello RA,et al,2011).

of preexisting damage to the kidney (Leung N,et al,2007).

may be seen in MIDD.

**6.1 Pathogenesis of MIDD** 

**6. Monoclonal Immunoglobulin Deposition Disease (MIDD)** 

measurement, Ig-free light chain λ and κ testing, 24-hour urine total protein measurement (more than 0.5 g per day; mainly albumin), complete blood count, creatinine level, alkaline phosphatase level, measurement of troponin, brain natriuretic peptide, or N-terminal pro– brain natriuretic peptide levels, and echocardiography should be the following examinations for a complete diagnosis of AL amyloidosis.

#### **5.3 Prognosis and treatment of AL amyloidosis**

The survival of patients with amyloidosis is considerably variable, depending on some prognostic factors like the presence of coexisting myeloma, the number of organs involved especially the presence and severity of cardiac involvement, and response to therapy. Although the median survival is ranging from 12 to 18 months in different series, by the developments in treatment approaches, quality of life and survival have been considerably improved. In a retrospective analysis of 147 patients with AL amyloidosis, 20 patients had concurrent multiple myeloma and patients with both AL and myeloma had a significantly worse prognosis than those with AL alone with OS as 14 versus 32 months (Pardanani A,et al,2003). In a prospective study of 220 patients with primary systemic amyloidosis, the most important prognostic factor was reported as cardiac involvement and it was associated with the poorest prognosis with median survival less than 6 months. Nephrotic syndrome and renal failure were also poor prognostic factors with median survival rates of 15 and 16 months respectively, compared with 26 months in patients with normal renal function (P=0.007) (Kyle RA,et al,1997)

Standart cytotoxic chemotherapies have been widely used in last decades to inhibit the production of amyloidogenic light chains which usually include melphalan and prednisone or high dose dexamethasone. In a few small studies; combination of melphalan+prednisone achieved a reduction or complete resolution of proteinuria and improvement in renal function (Cohen J,et al,1975, Benson MD,1986). In a phase 2 study of 45 patients who were ineligible for ASCT, the combination of high-dose dexamethasone with melphalan was found more effective with a hematological response of 67% and functional organ improvement as 48% (Palladini G,et al,2004).

Although thalidomide is poorly tolerated by amyloidosis patients and treatment-related toxicity is frequent, with dose escalation, thalidomide+dexamethasone can be considered an option, alone or in combination with cyclophosphamide for the treatment of patients who relapse after melphalan-dexamethasone or ASCT. In a trial of 75 patients which compared the safety and efficacy of CTD in standart and attenuated doses, organ responses were found in 31% of the 48 hematologic responders, but no patient with ESRD became dialysis independent and no objective cardiac responses were observed. (Wechalekar AD,et al,2007) Lenalidomide also has been combined with dexamethasone in the treatment of AL amyloidosis and a phase 2 trial demonstrated that haematologic response rate was 67% and 41% of the patients with renal involvement experienced more than 50% reduction in urinary protein excretion without worsening of renal function (Sanchorawala V,et al,2007). Recent studies have suggested that bortezomib with or without dexamethasone is significantly active in AL amyloidosis and induces rapid responses and high rates of hematologic and organ responses. In a retrospective report which includes the AL patients who were treated or untreated previously, overall response rates were found 81% and 76% respectively, with bortezomib+dexamethasone combination (Kastritis E,et al,2010). In a case report of an AL

measurement, Ig-free light chain λ and κ testing, 24-hour urine total protein measurement (more than 0.5 g per day; mainly albumin), complete blood count, creatinine level, alkaline phosphatase level, measurement of troponin, brain natriuretic peptide, or N-terminal pro– brain natriuretic peptide levels, and echocardiography should be the following

The survival of patients with amyloidosis is considerably variable, depending on some prognostic factors like the presence of coexisting myeloma, the number of organs involved especially the presence and severity of cardiac involvement, and response to therapy. Although the median survival is ranging from 12 to 18 months in different series, by the developments in treatment approaches, quality of life and survival have been considerably improved. In a retrospective analysis of 147 patients with AL amyloidosis, 20 patients had concurrent multiple myeloma and patients with both AL and myeloma had a significantly worse prognosis than those with AL alone with OS as 14 versus 32 months (Pardanani A,et al,2003). In a prospective study of 220 patients with primary systemic amyloidosis, the most important prognostic factor was reported as cardiac involvement and it was associated with the poorest prognosis with median survival less than 6 months. Nephrotic syndrome and renal failure were also poor prognostic factors with median survival rates of 15 and 16 months respectively, compared with 26 months in patients with normal renal function

Standart cytotoxic chemotherapies have been widely used in last decades to inhibit the production of amyloidogenic light chains which usually include melphalan and prednisone or high dose dexamethasone. In a few small studies; combination of melphalan+prednisone achieved a reduction or complete resolution of proteinuria and improvement in renal function (Cohen J,et al,1975, Benson MD,1986). In a phase 2 study of 45 patients who were ineligible for ASCT, the combination of high-dose dexamethasone with melphalan was found more effective with a hematological response of 67% and functional organ

Although thalidomide is poorly tolerated by amyloidosis patients and treatment-related toxicity is frequent, with dose escalation, thalidomide+dexamethasone can be considered an option, alone or in combination with cyclophosphamide for the treatment of patients who relapse after melphalan-dexamethasone or ASCT. In a trial of 75 patients which compared the safety and efficacy of CTD in standart and attenuated doses, organ responses were found in 31% of the 48 hematologic responders, but no patient with ESRD became dialysis independent and no objective cardiac responses were observed. (Wechalekar AD,et al,2007) Lenalidomide also has been combined with dexamethasone in the treatment of AL amyloidosis and a phase 2 trial demonstrated that haematologic response rate was 67% and 41% of the patients with renal involvement experienced more than 50% reduction in urinary protein excretion without worsening of renal function (Sanchorawala V,et al,2007). Recent studies have suggested that bortezomib with or without dexamethasone is significantly active in AL amyloidosis and induces rapid responses and high rates of hematologic and organ responses. In a retrospective report which includes the AL patients who were treated or untreated previously, overall response rates were found 81% and 76% respectively, with bortezomib+dexamethasone combination (Kastritis E,et al,2010). In a case report of an AL

examinations for a complete diagnosis of AL amyloidosis.

**5.3 Prognosis and treatment of AL amyloidosis** 

(P=0.007) (Kyle RA,et al,1997)

improvement as 48% (Palladini G,et al,2004).

patient who have stage V renal disease with hemodialysis support and age above 65 years, relatvelygood response with acceptable tolerance has been shown with bortezomib+highdose dexamethasone regimen (Mello RA,et al,2011).

In a selected patient group who are eligible for ASCT, by using a risk-adapted approach such as dose escalation of melphalan in patients with renal dysfunction, use of myeloablative chemotherapy followed by ASCT may be the most successful approach. In a study of 123 AL patients treated with high-dose melphalan followed by ASCT, renal response was noted in 43.4% of the patients with a better survival. It was also found that the severity of proteinuria was an independent predictor of renal response after ASCT and the recovery of renal function and prevention of ESRD after ASCT depended on the the degree of preexisting damage to the kidney (Leung N,et al,2007).

#### **6. Monoclonal Immunoglobulin Deposition Disease (MIDD)**

Nonamyloidotic monoclonal Ig deposition disease (MIDD) is characterized by deposition of monoclonal Ig subunits in kidney with an excess accumulation of extracellular matrix, leading to nodular sclerosing glomerulopathy, interstitial fibrosis, proteinuria, and renal insufficiency. According to the Ig deposition type, three subtypes of MIDD have been described, including light chain DD (LCDD), light-and heavy-chain (LHCDD) and heavy chain DD (HCDD). LCDD is the most prevalent subtype and found in 5% of patients with myeloma at autopsy series (Ivanyi B,1990). The most common cause is myeloma with the ratio of 65%, however 32% of cases are not associated with a manifested haematologic disorder. Although they are similar entities, in comparison to AL amyloidosis, the deposited light chains are kappa chains in 85% of LCDD cases, do not have a fibrillar organization and do not bind congo red. The majority of patients have a severe renal insufficiency with a median serum creatinine level of 3.8 mg/dl and usually tend to present with a higher serum creatinine concentration and lower rate of protein excretion than patients with AL amyloidosis (Harris AA,et al,1997). Cardiac, hepatic or small intestinal involvement also may be seen in MIDD.

#### **6.1 Pathogenesis of MIDD**

Initial process in MIDD usually includes the interaction between abnormal kappa chain (κ-I or κ-IV) and the mesangial cells of the glomerulus. Light chains were shown to stimulate the mesangial proliferation and secretion of transforming growth factor-beta (TGF-β) (Zhu L,et al,1995). TGF-β increases the production of collagen IV, laminin, and fibronectin which are deposited in the extracellular matrix (ECM) of the kidneys and also decrease the levels of collagenase, metalloproteinases, serin protease and other enzymes that degrades matrix proteins. Progressive light chain deposition and accumulation of ECM components inevitably lead to organ fibrosis and dysfunction. In MIDD, deposits predominantly localized in the tubular basement membranes and Bowman's capsule rather than in the glomeruli, though nodular glomerulosclerosis is present 60% of cases associated with a nephrotic range proteinuria. Tubular lesions are characterized by the deposition of a granular, punctuate, eosinophilic, periodic acid-Schiff (PAS)-positive, ribbon-like material along the interstitial side of the tubular basement membrane in electron microscopy. Glomerular lesions are usually associated with diffuse mesangial expansion by PAS positive

Renal Disease in Multiple Myeloma 235

Multiple myeloma is the most common cause of proximal renal tubular acidosis in the adult. The toxic effect of light chains may be limited to tubular dysfunction and presented without renal insufficiency. This entity commonly occurs with kappa light chains. Some biochemical characteristics in the variable domain of the light chain has the capacity for resistance to protease degradation and a tendency to accumulate in tubule epithelial cells and form intracellular crystal formation. By the released intracellular lysosomal enzymes and the direct toxic effects of light chains, tubular damage occurs and clinic presentation includes the symptoms of Fanconi syndrome. Proximal renal tubular acidosis with loosing the potassium, phosphate, uric acid and bicarbonate resuting in aminoaciduria, renal glycosuria, hypophosphatemia, hyperchloremic metabolic acidosis, hypokalemia, proteinuria of tubular origin, and hypouricemia. Osteomalacia, chronic renal failure and chronic acidosis are the most common manifestations of Fanconi syndrome related to light chains. Episodes of dehydration may be seen due to polyuria and polydipsia. Furthermore, myeloma kidney may be aggravated with proximal dysfunction because of reduced light chain reabsorption and elevated precipitation in the distal nephron. With appropriate therapeutic management of underlying myeloma and vitamin D, calcium, and phosphorus supplementation for osteomalasic patients, considerable improvement can be obtained.

As we have tried to summarize above, kidney should be accepted one of the main targets in the course of myeloma especially in the diagnosis and treatment. Early diagnosis and prevention could result in preventing many renal complications and potential hazards

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**7. Renal tubular dysfunction** 

**8. Conclusion** 

**9. References** 

and Congo red negative nonfibrillar matrix that focally forms nodules. Deposits may also be seen in renal vasculature with same staining properties.

#### **6.2 Diagnosis of MIDD**

LCDD should be considered in the differential diagnosis of any patients with nephrotic syndrome and renal insufficiency of unknown origin. Standart testing procedure should be administered initially as in other plasma cell dyscrasias, and in most of the patients, elevated ratio of κ/λ free light chains in the serum and urine and a predominance of κ light chain–positive plasma cells on bone marrow biopsy help to confirm LCDD diagnosis. However, approximately 25% of patients have no demonstrable light chain in serum or urine by immunoelectrophoresis or immunofixation. A definitive diagnosis of LCDD is based on renal biopsy with elaborate histological examination and electron microscopy. Characteristic light microscopic, immunofluorescence, and electron microscopic findings which are mentioned before are the important keys for the diagnosis.

#### **6.3 Prognosis and treatment of MIDD**

The median survival of a patient with MIDD is 4 years, with survival at 1 yr and 8 yr of 66% and 31%, respectively. In largest studies, the variables that were independently associated with a worse patient survival were shown as age, initial creatinine, underlying multiple myeloma, and extrarenal LC deposition. Median time to progression to ESRD was reported to be 2.7 years and the 5-year uremia free survival was 37%. The only variables that were independently associated with renal survival were age and degree of renal insufficiency at presentation (Pozzi C,et al,2003). Renal and patient survivals were significantly worse in patients with LCDD who had coexisting cast nephropathy (Lin J,et al,2001).

Therapy of MIDD is similar to that for multiple myeloma and the main goal is to reduce Ig production in order to preserve renal function and improve survival. Combination of melphalan and prednisone has been used, but the response rates have been low with an 5 yr patient and renal survival of 70% and 37%, respectively. In patients with a serum creatinine < 4 mg/dl at presentation, stabilization or improvement in renal function after chemotherapy was found 60%, whereas 82% of patients with a serum creatinine >4 mg/dl progressed to ESRD despite therapy (Heilman RL,et al,1992). A combination of high-dose melphalan and autologous stem cell transplantation was reported to improve renal function without excessive morbidity or mortality. The largest study of ASCT in MIDD revealed that, serum creatinine improved by 50% or more in 4 of 11 patients and the nephrotic syndrome resolved in all, after ASCT (Royer B,et al,2004). In another study, patients who survived ASCT, high-dose chemotherapy and ASCT led to a median reduction in proteinuria of 92% and median improvement in GFR as 95% (Lorenz EC,et al,2008). Renal transplantation is associated with recurrence of LCDD in the transplanted kidney and effective chemotherapy or ASCT should be administered concurrently to control the underlying plasma cell dyscrasia. It is well established that bortezomib decreases TGF-β expression through inhibiting the NFκB pathway, thus recent researches focus on bortezomib-based chemotherapy in the treatment of MIDD and it appears to be safe and effective for the patients with renal dysfunction (Gharwan H, Truica CI,2011).

and Congo red negative nonfibrillar matrix that focally forms nodules. Deposits may also be

LCDD should be considered in the differential diagnosis of any patients with nephrotic syndrome and renal insufficiency of unknown origin. Standart testing procedure should be administered initially as in other plasma cell dyscrasias, and in most of the patients, elevated ratio of κ/λ free light chains in the serum and urine and a predominance of κ light chain–positive plasma cells on bone marrow biopsy help to confirm LCDD diagnosis. However, approximately 25% of patients have no demonstrable light chain in serum or urine by immunoelectrophoresis or immunofixation. A definitive diagnosis of LCDD is based on renal biopsy with elaborate histological examination and electron microscopy. Characteristic light microscopic, immunofluorescence, and electron microscopic findings

The median survival of a patient with MIDD is 4 years, with survival at 1 yr and 8 yr of 66% and 31%, respectively. In largest studies, the variables that were independently associated with a worse patient survival were shown as age, initial creatinine, underlying multiple myeloma, and extrarenal LC deposition. Median time to progression to ESRD was reported to be 2.7 years and the 5-year uremia free survival was 37%. The only variables that were independently associated with renal survival were age and degree of renal insufficiency at presentation (Pozzi C,et al,2003). Renal and patient survivals were significantly worse in

Therapy of MIDD is similar to that for multiple myeloma and the main goal is to reduce Ig production in order to preserve renal function and improve survival. Combination of melphalan and prednisone has been used, but the response rates have been low with an 5 yr patient and renal survival of 70% and 37%, respectively. In patients with a serum creatinine < 4 mg/dl at presentation, stabilization or improvement in renal function after chemotherapy was found 60%, whereas 82% of patients with a serum creatinine >4 mg/dl progressed to ESRD despite therapy (Heilman RL,et al,1992). A combination of high-dose melphalan and autologous stem cell transplantation was reported to improve renal function without excessive morbidity or mortality. The largest study of ASCT in MIDD revealed that, serum creatinine improved by 50% or more in 4 of 11 patients and the nephrotic syndrome resolved in all, after ASCT (Royer B,et al,2004). In another study, patients who survived ASCT, high-dose chemotherapy and ASCT led to a median reduction in proteinuria of 92% and median improvement in GFR as 95% (Lorenz EC,et al,2008). Renal transplantation is associated with recurrence of LCDD in the transplanted kidney and effective chemotherapy or ASCT should be administered concurrently to control the underlying plasma cell dyscrasia. It is well established that bortezomib decreases TGF-β expression through inhibiting the NFκB pathway, thus recent researches focus on bortezomib-based chemotherapy in the treatment of MIDD and it appears to be safe and effective for the

seen in renal vasculature with same staining properties.

which are mentioned before are the important keys for the diagnosis.

patients with LCDD who had coexisting cast nephropathy (Lin J,et al,2001).

patients with renal dysfunction (Gharwan H, Truica CI,2011).

**6.2 Diagnosis of MIDD** 

**6.3 Prognosis and treatment of MIDD** 

#### **7. Renal tubular dysfunction**

Multiple myeloma is the most common cause of proximal renal tubular acidosis in the adult. The toxic effect of light chains may be limited to tubular dysfunction and presented without renal insufficiency. This entity commonly occurs with kappa light chains. Some biochemical characteristics in the variable domain of the light chain has the capacity for resistance to protease degradation and a tendency to accumulate in tubule epithelial cells and form intracellular crystal formation. By the released intracellular lysosomal enzymes and the direct toxic effects of light chains, tubular damage occurs and clinic presentation includes the symptoms of Fanconi syndrome. Proximal renal tubular acidosis with loosing the potassium, phosphate, uric acid and bicarbonate resuting in aminoaciduria, renal glycosuria, hypophosphatemia, hyperchloremic metabolic acidosis, hypokalemia, proteinuria of tubular origin, and hypouricemia. Osteomalacia, chronic renal failure and chronic acidosis are the most common manifestations of Fanconi syndrome related to light chains. Episodes of dehydration may be seen due to polyuria and polydipsia. Furthermore, myeloma kidney may be aggravated with proximal dysfunction because of reduced light chain reabsorption and elevated precipitation in the distal nephron. With appropriate therapeutic management of underlying myeloma and vitamin D, calcium, and phosphorus supplementation for osteomalasic patients, considerable improvement can be obtained.

#### **8. Conclusion**

As we have tried to summarize above, kidney should be accepted one of the main targets in the course of myeloma especially in the diagnosis and treatment. Early diagnosis and prevention could result in preventing many renal complications and potential hazards during treatment period and if planned, stem cell transplantation.

#### **9. References**


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**13** 

*Turkey* 

**Stem Cell Moblzaton in Multple Myeloma** 

High dose melphalan supported by autologous hematopoietic cell transplantation (AHCT) has been shown to prolong survival and decrease relapse rates compared to conventional chemotherapies in elligible patients with plasma cell myeloma (PCM) (Attal et al., 1996; Child et al., 2003; Fermand et al., 2005; Koreth et al., 2007; Palumbo et al., 2004). Patients who are considered candidates for high dose therapy receive 2-4 cycles of non-melphalan containing induction therapies followed by peripheral blood progenitor cell(PBPC) mobilization and collection. Pateints proceed to high dose melphalan (200 mg/m2) supported with AHCT. High dose melphalan and AHCT has been the gold standard treatment approach in patients with PCM younger than 65 but can be extended to mid-70's in patients otherwise in good performance status. Second AHCT has been shown to increase survival, especially those who could not achieve very good partial response (VGPR) after the first AHCT (Attal et al., 2003, Barlogie et al., 2006). Additionally, patients who had a long progression free survival after the first transplantation may benefit from salvage transplantation at relapse (Ljungman et al., 2010). These advances have mandated the mobilization and collection of PBPCs adequate for double transplants. Although not prospectively studied, the traditional minimum and optimum CD34+ cell dose limits have been 2 x 106/kg and ≥ 4 x 106/kg for single ; 4 x 106/kg and ≥ 8-10 x106/kg for double AHCT, respectively (Bensinger et al., 1995, Giralt et al., 2009). Therefore, successfull stem cell mobilization and collection are crucial for treatment of PCM. Risk factors such as age >60 years, the extend of prior chemotherapy or radiotherapy and prolonged disease duration are recognized predictors for poor mobilization. The induction treatment given before the process of PBPC mobilization and collection should not be toxic to the bone marrow. It has been clearly revealed over the past decades that the traditional induction regimens; vincristine, adriamycin, dexamathasone (VAD) or single agent dexamathasone have no impact on PBPC mobilization. However, today, they have been completely replaced with novel agents which are associated with better response rates. During the recent years, the impact of these novel induction agents (thalidomide, lenalidomide and bortezomib) on PBPC mobilization have been of major concern. Although the classical PBPC mobilization methods (G-CSF alone or G-CSF after chemotherapy) have been generally successful in PCM, there is still a considerable amount of mobilization failures. Studies have been focused on the investigational agents alone or in conjunction with G-CSF to imrove PBPC mobilization efficiency, prevent mobilization failures and the need for second or subsequent

**1. Introduction** 

*Department of Hematology & Stem Cell Transplantation Unit, Ankara,* 

Şule Mine Bakanay and Taner Demirer

*Ankara University Medical School,* 


## **Stem Cell Moblzaton in Multple Myeloma**

Şule Mine Bakanay and Taner Demirer

*Ankara University Medical School, Department of Hematology & Stem Cell Transplantation Unit, Ankara, Turkey* 

#### **1. Introduction**

240 Multiple Myeloma – An Overview

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High dose melphalan supported by autologous hematopoietic cell transplantation (AHCT) has been shown to prolong survival and decrease relapse rates compared to conventional chemotherapies in elligible patients with plasma cell myeloma (PCM) (Attal et al., 1996; Child et al., 2003; Fermand et al., 2005; Koreth et al., 2007; Palumbo et al., 2004). Patients who are considered candidates for high dose therapy receive 2-4 cycles of non-melphalan containing induction therapies followed by peripheral blood progenitor cell(PBPC) mobilization and collection. Pateints proceed to high dose melphalan (200 mg/m2) supported with AHCT. High dose melphalan and AHCT has been the gold standard treatment approach in patients with PCM younger than 65 but can be extended to mid-70's in patients otherwise in good performance status. Second AHCT has been shown to increase survival, especially those who could not achieve very good partial response (VGPR) after the first AHCT (Attal et al., 2003, Barlogie et al., 2006). Additionally, patients who had a long progression free survival after the first transplantation may benefit from salvage transplantation at relapse (Ljungman et al., 2010). These advances have mandated the mobilization and collection of PBPCs adequate for double transplants. Although not prospectively studied, the traditional minimum and optimum CD34+ cell dose limits have been 2 x 106/kg and ≥ 4 x 106/kg for single ; 4 x 106/kg and ≥ 8-10 x106/kg for double AHCT, respectively (Bensinger et al., 1995, Giralt et al., 2009). Therefore, successfull stem cell mobilization and collection are crucial for treatment of PCM. Risk factors such as age >60 years, the extend of prior chemotherapy or radiotherapy and prolonged disease duration are recognized predictors for poor mobilization. The induction treatment given before the process of PBPC mobilization and collection should not be toxic to the bone marrow. It has been clearly revealed over the past decades that the traditional induction regimens; vincristine, adriamycin, dexamathasone (VAD) or single agent dexamathasone have no impact on PBPC mobilization. However, today, they have been completely replaced with novel agents which are associated with better response rates. During the recent years, the impact of these novel induction agents (thalidomide, lenalidomide and bortezomib) on PBPC mobilization have been of major concern. Although the classical PBPC mobilization methods (G-CSF alone or G-CSF after chemotherapy) have been generally successful in PCM, there is still a considerable amount of mobilization failures. Studies have been focused on the investigational agents alone or in conjunction with G-CSF to imrove PBPC mobilization efficiency, prevent mobilization failures and the need for second or subsequent

Stem Cell Moblzaton in Multple Myeloma 243

being explored. Due to its long plasma half-life compared to unconjugated G-CSF (33 vs 4-6 hours), it has the advantage of maintaining clinically effective serum levels over about two weeks after a single 6mg s.c. administration and achieving patient compliance. Its effect is self-limited and is terminated with cellular uptake by the recovering neutrophils (Hunter et al., 2003; Molineux et al., 1999). Clinical studies have demonstrated that pegfilgrastim is at least as efficient as filgrastim in mobilizing PBPCs after chemotherapy and this effect was not dose dependent. Pegfilgrastim was associated with a more rapid leukocyte recovery and an earlier performance of the first apheresis procedure in comparison to unconjugated G-CSF in PCM patients (Bruns et al., 2006; Fruehauf et al., 2007; Stiedl et al., 2005). Additionally, in a tandem transplant study, PBPC mobilization with chemotherapy plus pegfilgrastim in 237 PCM patients, a second booster injection of 6mg pegfilgrastim on day 13 after an initial administration on day 6, improved the serum G-CSF concentrations and the mobilization results (Tricot et al., 2008). In contrast to mobilization after chemotherapy, growth factor-only mobilization requires higher doses of pegfilgrastim to provide effective serum G-CSF levels (Hosing et al., 2006; Willis et al., 2009). However, this approach is not cost-effective when compared with unconjugated G-CSF. Pegfilgrastim is well tolerated with an advese event profile similar to that of unconjugated G-CSF. Bone pain is the most common complaint and a case of splenic rupture that may not have been related to

The standard chemomobilization in myeloma consists of cyclophosphamide(CY) plus growth factor (Goldschmidt et al., 1996). High dose CY has been prefered in patients who fail initial mobilization attempt with growth factor only or for patients who could not achieve at least partial remission after induction regimens with the hope to control the high tumor burden before transplantation. However, it has been demonstrated that high dose CY does not increase overall complete remission rates or improve the time to progression for patients with myeloma undergoing AHCT (Dingli et al., 2006). At our center, CY 4 gr/m2 with the same dose MESNA to prevent hemorrhagic cystitis is administered on day 1 and recombinant human G-CSF (10 μg/kg/day, in two divided doses) is started either on day 4 or day 7. The optimal timing for G-CSF initiation has not been determined conclusively. We have demonstrated that late (day 7) administration of G-CSF was as efficient and more cost-effective than early administration (Ozcelik et al., 2009). Flow cytometric quantification of peripheral blood(PB) CD34+ cells is performed when the WBC count reaches >1000/μl from the chemotherapy induced nadir. The apheresis is started when PB CD34+ cell count exceeds 10 cells/μl and continued until adequate number of CD34+ cells are collected usually for 1-3 apheresis procedures. Transfusion support should be given to keep the pre-apheresis Hb and platelet counts at ≥

The dose of CY reported for mobilization has ranged from 1.5 to 7 gr/m2. Retrospective studies comparing CY doses of 4 gr/m2 versus 7 gr/m2 and 1.2-2 gr/m2 versus 4 gr/m2 have favored lower doses because of similar stem cell mobilization efficiency but with considerably lower toxicity (Fitoussi et al., 2001; Jantunen et al., 2003). In a randomized study in myeloma patients comparing single dose 7 g/m2 with 2.4 g/m2 , higher number CD34+ cells were collected on the first apheresis day and there was a lower consumption of

pegfilgrastim was reported in one trial (Fenk et al., 2006).

10gr/dl and ≥ 20 000-30 000/μl, respectively.

**2.3 Chemomobilization** 

mobilization attempts which often delay the timely performance of the transplantation and increase the morbidity and the cost. In this chapter, we will focus on the current stem cell mobilization strategies as well as the novel mobilizing agents in PCM and the impact of novel anti-myeloma drugs on PBPC mobilization.

#### **2. Mobilization approaches in PCM**

#### **2.1 G-CSF alone**

The optimal PBPC mobilization strategy in PCM is unclear. Both growth factor alone or chemotherapy followed by growth factor (chemomobilization) have been the most frequently used approaches. In growth factor-only mobilization, recombinant human granulocyte-colony stimulating factor (G-CSF) is commonly administered at 10 μg/kg/day s.c. for 4 days , PBPCs are collected from day 5 onwards and G-CSF continued until the last day of apheresis. PBPCs are collected by continuous flow apheresis procedure often processing 2-2.5 times the patient's blood volume. CD34+ cell enumeration is performed by flow cytometry according to the ISHAGE guidelines(Sutherland et al., 1996). The stem cell product is then cryopreseved until use for AHCT. Recombinant human G-CSF is reliable, with predictable mobilization efficiency. The most common toxicities observed during G-CSF administration such as bone pain, low grade fever, headache, are generally managable. However, G-CSF may be associated with rare serious adverse events such as spontaneous splenic rupture, thrombosis, flare of autoimmune disease and precipitation of sickle crisis (Cashen et al., 2007).

#### **2.2 G-CSF analogs**

#### **2.2.1 Filgrastim and lenograstim**

Filgrastim (Neupogen, F Hoffmann-La Roche, Basel, Switzerland) and lenograstim (Granocyte, Chugai-Aventis Pharmaceuticals, France) are nonglycosylated and glycosylated analogs of recombinant human G-CSF approved for PBPC mobilization. Studies investigating the patients with hematological malignancies who underwent PBSC mobilization for AHCT could not demonstrate any difference between glycosylated and non-glycosylated G-CSF in terms of both efficacy and toxicity (Kopf et al., 2006; Lefrere et al., 1999). The glycosylation of G-CSF contributes to a greater chemical-physical stability of lenograstim: the glycosylated G-CSF is more stable and resistant to degradation. The recommended dosage of lenograstim when used alone for PBPC mobilization is 5 μ/kg/day (s.c./i.v.). On the other hand, equal doses of 10 μ/kg/day of filgrastim and lenograstim have been recommended for mobilization of CD34+ cells without associated chemotherapy. However, a recent study has suggested that lower dose (7.5 μ/kg/day) of glycosylated G-CSF may be as effective as the standard dose of non-glycosylated G-CSF for PBPC mobilization in patients undergoing AHCT (Ataergin et al., 2008).

#### **2.2.2 Pegfilgrastim**

Pegylated G-CSF (pegfilgrastim, Neulasta, Amgen Inc.,CA, USA) is currently approved by the US FDA for prevention of prolonged neutropenia after chemotherapy for nonmyeloid malignancies (Neulasta; package insert). Its potential in PBPC mobilization is currently

mobilization attempts which often delay the timely performance of the transplantation and increase the morbidity and the cost. In this chapter, we will focus on the current stem cell mobilization strategies as well as the novel mobilizing agents in PCM and the impact of

The optimal PBPC mobilization strategy in PCM is unclear. Both growth factor alone or chemotherapy followed by growth factor (chemomobilization) have been the most frequently used approaches. In growth factor-only mobilization, recombinant human granulocyte-colony stimulating factor (G-CSF) is commonly administered at 10 μg/kg/day s.c. for 4 days , PBPCs are collected from day 5 onwards and G-CSF continued until the last day of apheresis. PBPCs are collected by continuous flow apheresis procedure often processing 2-2.5 times the patient's blood volume. CD34+ cell enumeration is performed by flow cytometry according to the ISHAGE guidelines(Sutherland et al., 1996). The stem cell product is then cryopreseved until use for AHCT. Recombinant human G-CSF is reliable, with predictable mobilization efficiency. The most common toxicities observed during G-CSF administration such as bone pain, low grade fever, headache, are generally managable. However, G-CSF may be associated with rare serious adverse events such as spontaneous splenic rupture, thrombosis, flare of autoimmune disease and precipitation of sickle crisis

Filgrastim (Neupogen, F Hoffmann-La Roche, Basel, Switzerland) and lenograstim (Granocyte, Chugai-Aventis Pharmaceuticals, France) are nonglycosylated and glycosylated analogs of recombinant human G-CSF approved for PBPC mobilization. Studies investigating the patients with hematological malignancies who underwent PBSC mobilization for AHCT could not demonstrate any difference between glycosylated and non-glycosylated G-CSF in terms of both efficacy and toxicity (Kopf et al., 2006; Lefrere et al., 1999). The glycosylation of G-CSF contributes to a greater chemical-physical stability of lenograstim: the glycosylated G-CSF is more stable and resistant to degradation. The recommended dosage of lenograstim when used alone for PBPC mobilization is 5 μ/kg/day (s.c./i.v.). On the other hand, equal doses of 10 μ/kg/day of filgrastim and lenograstim have been recommended for mobilization of CD34+ cells without associated chemotherapy. However, a recent study has suggested that lower dose (7.5 μ/kg/day) of glycosylated G-CSF may be as effective as the standard dose of non-glycosylated G-CSF for PBPC

Pegylated G-CSF (pegfilgrastim, Neulasta, Amgen Inc.,CA, USA) is currently approved by the US FDA for prevention of prolonged neutropenia after chemotherapy for nonmyeloid malignancies (Neulasta; package insert). Its potential in PBPC mobilization is currently

mobilization in patients undergoing AHCT (Ataergin et al., 2008).

novel anti-myeloma drugs on PBPC mobilization.

**2. Mobilization approaches in PCM** 

**2.1 G-CSF alone** 

(Cashen et al., 2007).

**2.2 G-CSF analogs** 

**2.2.2 Pegfilgrastim** 

**2.2.1 Filgrastim and lenograstim** 

being explored. Due to its long plasma half-life compared to unconjugated G-CSF (33 vs 4-6 hours), it has the advantage of maintaining clinically effective serum levels over about two weeks after a single 6mg s.c. administration and achieving patient compliance. Its effect is self-limited and is terminated with cellular uptake by the recovering neutrophils (Hunter et al., 2003; Molineux et al., 1999). Clinical studies have demonstrated that pegfilgrastim is at least as efficient as filgrastim in mobilizing PBPCs after chemotherapy and this effect was not dose dependent. Pegfilgrastim was associated with a more rapid leukocyte recovery and an earlier performance of the first apheresis procedure in comparison to unconjugated G-CSF in PCM patients (Bruns et al., 2006; Fruehauf et al., 2007; Stiedl et al., 2005). Additionally, in a tandem transplant study, PBPC mobilization with chemotherapy plus pegfilgrastim in 237 PCM patients, a second booster injection of 6mg pegfilgrastim on day 13 after an initial administration on day 6, improved the serum G-CSF concentrations and the mobilization results (Tricot et al., 2008). In contrast to mobilization after chemotherapy, growth factor-only mobilization requires higher doses of pegfilgrastim to provide effective serum G-CSF levels (Hosing et al., 2006; Willis et al., 2009). However, this approach is not cost-effective when compared with unconjugated G-CSF. Pegfilgrastim is well tolerated with an advese event profile similar to that of unconjugated G-CSF. Bone pain is the most common complaint and a case of splenic rupture that may not have been related to pegfilgrastim was reported in one trial (Fenk et al., 2006).

#### **2.3 Chemomobilization**

The standard chemomobilization in myeloma consists of cyclophosphamide(CY) plus growth factor (Goldschmidt et al., 1996). High dose CY has been prefered in patients who fail initial mobilization attempt with growth factor only or for patients who could not achieve at least partial remission after induction regimens with the hope to control the high tumor burden before transplantation. However, it has been demonstrated that high dose CY does not increase overall complete remission rates or improve the time to progression for patients with myeloma undergoing AHCT (Dingli et al., 2006). At our center, CY 4 gr/m2 with the same dose MESNA to prevent hemorrhagic cystitis is administered on day 1 and recombinant human G-CSF (10 μg/kg/day, in two divided doses) is started either on day 4 or day 7. The optimal timing for G-CSF initiation has not been determined conclusively. We have demonstrated that late (day 7) administration of G-CSF was as efficient and more cost-effective than early administration (Ozcelik et al., 2009). Flow cytometric quantification of peripheral blood(PB) CD34+ cells is performed when the WBC count reaches >1000/μl from the chemotherapy induced nadir. The apheresis is started when PB CD34+ cell count exceeds 10 cells/μl and continued until adequate number of CD34+ cells are collected usually for 1-3 apheresis procedures. Transfusion support should be given to keep the pre-apheresis Hb and platelet counts at ≥ 10gr/dl and ≥ 20 000-30 000/μl, respectively.

The dose of CY reported for mobilization has ranged from 1.5 to 7 gr/m2. Retrospective studies comparing CY doses of 4 gr/m2 versus 7 gr/m2 and 1.2-2 gr/m2 versus 4 gr/m2 have favored lower doses because of similar stem cell mobilization efficiency but with considerably lower toxicity (Fitoussi et al., 2001; Jantunen et al., 2003). In a randomized study in myeloma patients comparing single dose 7 g/m2 with 2.4 g/m2 , higher number CD34+ cells were collected on the first apheresis day and there was a lower consumption of

Stem Cell Moblzaton in Multple Myeloma 245

more effective than CY for PBPC mobilization. Moreover, high-dose CY has limited antimyeloma activity compared to DCEP. One study demonstrated the comparable efficiency and lower toxicity of shorter-infusional schedule of DCEP with respect to full-infusional schedule (Corso et al., 2002, 2005). Another study combined DCEP-short with a single dose 6mg s.c. pegfilgrastim and reported promising results (Zappasodi et al., 2008). In a pilot study, vinorelbin combined with CY 1.5 g/m2 had similar efficiency compared to CY 4 g/m2 in PBPC mobilization and less toxicity and no requirement for hospitalization (Annunziata et al., 2006). Melphalan i.v. 60mg/m2 plus G-CSF 10 μg/kg/day was successful in mobilizing PBPC from myeloma patients. However, toxicity was notable and duration of mobilization was longer compared with CY 3 g/m2 (16.5 days vs 10 days)(Gupta et al., 2005). Melphalan is a highly effective anti-myeloma drug but due to its stem cell toxicity, it is neither used for PBSC mobilization, nor recommended as an initial therapy for patients elligible for AHCT. In a retrospective analysis, single agent etoposide (1.5 g/m2) plus G-CSF was most potent at mobilizing PBPCs compared to CY (2-4 g/m2) plus G-CSF or G-CSF alone. Although the success rate for collecting the minimum CD34+ dose was similar in all groups, higher proportion of patients mobilized with etoposide could achieve the optimum dose required for tandem transplant. There was no difference in the progression free survival among the groups (Nakasone et al., 2009). Recently, in a retrospective single center review, intermediate dose etoposide (375 mg/m2, day 1 and 2) followed by G-CSF was found to be highly effective in myeloma patients including the high risk patients for mobilization failure (Wood et al., 2011). However, myelosuppressive mobilization regimens neither seem to have any anti-myeloma effects nor appear to improve outcome (Attal et al., 2003). And most centers no longer routinely use CY for

Although there may be variations in each center's definition of mobilization failure, generally it can be defined as lack of achievement of ≥ 2 x106/kg CD34+ yield after 3 consecutive apheresis procedure or inability to start apheresis because of not reaching to >10 CD34+ cells/μl of PB . Extensive BM involvement with malignancy, prior radiotherapy especially to marrow-rich sites, prior treatment with alkylating agents, prior multiple chemotherapy regimens and older age have been associated with increased risk of mobilization failure (Bensinger et al., 2009; Demirer et al., 1996; Leung et al., 2010). Although the number of CD34+ cells collected decreases with increasing age, the experience has revealed that sufficient stem cell yield for ≥ 1 AHCT can be safely obtained in elderly patients up to 69-72 years (Roncon et al., 2011; Tempescul et al., 2010). On the other hand, in one retrospective study including myeloma and lymphoma patients, the total number of cycles of previous chemotherapy and previous treatment with melphalan were more significant predictors of poor mobilization than sex, age or body weight (Wuchter et al., 2010). Recently, prior prolonged exposure to novel agent lenalidomide has also been considered as a risk factor, which will be discussed later. With the current mobilization strategies about 5-10% of patients with PCM still end up with mobilization failure (Bensinger et al., 2009; Pusic et al., 2008). The classical strategy when patients fail G-CSF only mobilizations has been CY followed by G-CSF. However, this results in unnecessary exposure of the patients to chemotherapy toxicity for sole mobilization purposes, which

patients in first plateau.

**3. High risk patients for mobilization failure** 

means that novel PBPC mobilization approaches are required.

G-CSF with the lower-dose CY regimen, which also permitted collection to occur as an outpatient procedure and was more cost-effective (Petrucci et al., 2003). Hiwase et al in their retrospective analysis have demonstrated that compared with low dose (1-2 gr/m2) CY, patients receiving intermediate dose (3-4 gr/m2) CY were more likely to collect the CD34+ cell number (≥4 x106/kg) adequate for tandem transplant. Febrile neutropenia was more frequent in intermediate dose CY group (38% vs 13%) but the increased toxicity was managable and acceptable (Hiwase et al., 2007). In the light of these studies, most centers prefer 3-4 gr/m2 CY in their chemomobilization protocol (Gertz et al., 2010a).

High dose CY plus G-CSF is very efficient for PBPC mobilization in PCM patients but when compared with growth factor-only mobilization, chemotherapy plus growth factor mobilizes higher number of PBPCs in lower number of apheresis procedures but with the cost of increased toxicity; nausea- emesis, neutropenic fever, non-staphylococal bacteremia, sepsis, hemorrhagic cystitis, cardiac toxicity, hospitalization, requirement for transfusion support and with mortality rate of 1-2%. Moreover, there is increased possibility of delayed engraftment after AHCT if transplanted early after (e.g. <30 days) stem cell procurement (Gertz et al., 2009; To et al., 1990).

With the purpose of decreasing toxicity and at least preserving the efficiency, various alternative chemomobilization protocols with or without CY have also been investigated. Addition of etoposide (2 gr/m2) to CY (4.5 gr/m2) mobilization in a non-randomized study, resulted in increased toxicity without significant improvement in CD34+ cell yield (Gojo et al., 2004). In CAD protocol, CY (1gr/m2, day 1) was combined with doxorubicin (15 mg/m2, day 1-4) and dexamethasone (40 mg, day 1-4) followed by a single dose 12 mg pegfilgrastim on day 5. Eighty-eight percent of patients achieved their CD34+ cell harvest target of 7.5 x 106 CD34/kg following a median of two apheresis. Mobilization efficiency and engraftment following transplantation using pegfilgrastim was comparable to filgrastim and patients mobilized with CAD plus pegfilgrastim had decreased time to first apheresis (13 vs 15 days)(Fruehauf et al., 2007). The former common induction protocol VAD followed by daily G-CSF 10 μg/kg from day 10 to day 15 was found to be as effective and less toxic than high-dose CY followed by daily G-CSF 5 μg/kg from day 8 in newly diagnosed myeloma patients (Lefrère et al., 2006). Blood stem cell collection results after mobilization with combination chemotherapy containing ifosfamide, epirubicin, and etoposide (IEV) followed by G-CSF in myeloma were favorable and allowed to support a tandem transplantation procedure in younger and elder patients in 97 and 95%, respectively. Grade ¾ hematological toxicity was observed in majority of patients and extramedullary toxicity including nephrotoxicity and neurotoxicity in 5–10% (Straka et al., 2003). IEV mobilized peripheral blood stem cells more efficiently than cyclophosphamide and etoposide, achieving a threshold of 6 x 106 CD34/kg in 97 vs. 71% with comparable major toxicities and similar tumor response rates, although there was one treatmentrelated death due to septic shock in the IEV chemotherapy group (Hart et al., 2007). DCEP protocol includes dexamethasone (40 mg/d, day 1-4 ) , CY 400 mg/m2, etoposide 40 mg/m2 and cisplatin 10 mg/m2, daily continuous infusion for 4 days and has proved to be an effective salvage therapy for relapsed/refractory myeloma patients. G-CSF 5 μg/kg/day starting 48 h after the end of DCEP has been an effective mobilization protocol with 87 and 75% of patients achieving ≥ 2 x 106 and >4 x 106 /kg CD34+ cells, respectively (Lazzarino et al., 2001). The same group of investigators compared DCEP with CY (4 g/m2) followed by G-CSF and concluded that DCEP is better tolerated and

G-CSF with the lower-dose CY regimen, which also permitted collection to occur as an outpatient procedure and was more cost-effective (Petrucci et al., 2003). Hiwase et al in their retrospective analysis have demonstrated that compared with low dose (1-2 gr/m2) CY, patients receiving intermediate dose (3-4 gr/m2) CY were more likely to collect the CD34+ cell number (≥4 x106/kg) adequate for tandem transplant. Febrile neutropenia was more frequent in intermediate dose CY group (38% vs 13%) but the increased toxicity was managable and acceptable (Hiwase et al., 2007). In the light of these studies, most centers

High dose CY plus G-CSF is very efficient for PBPC mobilization in PCM patients but when compared with growth factor-only mobilization, chemotherapy plus growth factor mobilizes higher number of PBPCs in lower number of apheresis procedures but with the cost of increased toxicity; nausea- emesis, neutropenic fever, non-staphylococal bacteremia, sepsis, hemorrhagic cystitis, cardiac toxicity, hospitalization, requirement for transfusion support and with mortality rate of 1-2%. Moreover, there is increased possibility of delayed engraftment after AHCT if transplanted early after (e.g. <30 days) stem cell procurement

With the purpose of decreasing toxicity and at least preserving the efficiency, various alternative chemomobilization protocols with or without CY have also been investigated. Addition of etoposide (2 gr/m2) to CY (4.5 gr/m2) mobilization in a non-randomized study, resulted in increased toxicity without significant improvement in CD34+ cell yield (Gojo et al., 2004). In CAD protocol, CY (1gr/m2, day 1) was combined with doxorubicin (15 mg/m2, day 1-4) and dexamethasone (40 mg, day 1-4) followed by a single dose 12 mg pegfilgrastim on day 5. Eighty-eight percent of patients achieved their CD34+ cell harvest target of 7.5 x 106 CD34/kg following a median of two apheresis. Mobilization efficiency and engraftment following transplantation using pegfilgrastim was comparable to filgrastim and patients mobilized with CAD plus pegfilgrastim had decreased time to first apheresis (13 vs 15 days)(Fruehauf et al., 2007). The former common induction protocol VAD followed by daily G-CSF 10 μg/kg from day 10 to day 15 was found to be as effective and less toxic than high-dose CY followed by daily G-CSF 5 μg/kg from day 8 in newly diagnosed myeloma patients (Lefrère et al., 2006). Blood stem cell collection results after mobilization with combination chemotherapy containing ifosfamide, epirubicin, and etoposide (IEV) followed by G-CSF in myeloma were favorable and allowed to support a tandem transplantation procedure in younger and elder patients in 97 and 95%, respectively. Grade ¾ hematological toxicity was observed in majority of patients and extramedullary toxicity including nephrotoxicity and neurotoxicity in 5–10% (Straka et al., 2003). IEV mobilized peripheral blood stem cells more efficiently than cyclophosphamide and etoposide, achieving a threshold of 6 x 106 CD34/kg in 97 vs. 71% with comparable major toxicities and similar tumor response rates, although there was one treatmentrelated death due to septic shock in the IEV chemotherapy group (Hart et al., 2007). DCEP protocol includes dexamethasone (40 mg/d, day 1-4 ) , CY 400 mg/m2, etoposide 40 mg/m2 and cisplatin 10 mg/m2, daily continuous infusion for 4 days and has proved to be an effective salvage therapy for relapsed/refractory myeloma patients. G-CSF 5 μg/kg/day starting 48 h after the end of DCEP has been an effective mobilization protocol with 87 and 75% of patients achieving ≥ 2 x 106 and >4 x 106 /kg CD34+ cells, respectively (Lazzarino et al., 2001). The same group of investigators compared DCEP with CY (4 g/m2) followed by G-CSF and concluded that DCEP is better tolerated and

prefer 3-4 gr/m2 CY in their chemomobilization protocol (Gertz et al., 2010a).

(Gertz et al., 2009; To et al., 1990).

more effective than CY for PBPC mobilization. Moreover, high-dose CY has limited antimyeloma activity compared to DCEP. One study demonstrated the comparable efficiency and lower toxicity of shorter-infusional schedule of DCEP with respect to full-infusional schedule (Corso et al., 2002, 2005). Another study combined DCEP-short with a single dose 6mg s.c. pegfilgrastim and reported promising results (Zappasodi et al., 2008). In a pilot study, vinorelbin combined with CY 1.5 g/m2 had similar efficiency compared to CY 4 g/m2 in PBPC mobilization and less toxicity and no requirement for hospitalization (Annunziata et al., 2006). Melphalan i.v. 60mg/m2 plus G-CSF 10 μg/kg/day was successful in mobilizing PBPC from myeloma patients. However, toxicity was notable and duration of mobilization was longer compared with CY 3 g/m2 (16.5 days vs 10 days)(Gupta et al., 2005). Melphalan is a highly effective anti-myeloma drug but due to its stem cell toxicity, it is neither used for PBSC mobilization, nor recommended as an initial therapy for patients elligible for AHCT. In a retrospective analysis, single agent etoposide (1.5 g/m2) plus G-CSF was most potent at mobilizing PBPCs compared to CY (2-4 g/m2) plus G-CSF or G-CSF alone. Although the success rate for collecting the minimum CD34+ dose was similar in all groups, higher proportion of patients mobilized with etoposide could achieve the optimum dose required for tandem transplant. There was no difference in the progression free survival among the groups (Nakasone et al., 2009). Recently, in a retrospective single center review, intermediate dose etoposide (375 mg/m2, day 1 and 2) followed by G-CSF was found to be highly effective in myeloma patients including the high risk patients for mobilization failure (Wood et al., 2011). However, myelosuppressive mobilization regimens neither seem to have any anti-myeloma effects nor appear to improve outcome (Attal et al., 2003). And most centers no longer routinely use CY for patients in first plateau.

#### **3. High risk patients for mobilization failure**

Although there may be variations in each center's definition of mobilization failure, generally it can be defined as lack of achievement of ≥ 2 x106/kg CD34+ yield after 3 consecutive apheresis procedure or inability to start apheresis because of not reaching to >10 CD34+ cells/μl of PB . Extensive BM involvement with malignancy, prior radiotherapy especially to marrow-rich sites, prior treatment with alkylating agents, prior multiple chemotherapy regimens and older age have been associated with increased risk of mobilization failure (Bensinger et al., 2009; Demirer et al., 1996; Leung et al., 2010). Although the number of CD34+ cells collected decreases with increasing age, the experience has revealed that sufficient stem cell yield for ≥ 1 AHCT can be safely obtained in elderly patients up to 69-72 years (Roncon et al., 2011; Tempescul et al., 2010). On the other hand, in one retrospective study including myeloma and lymphoma patients, the total number of cycles of previous chemotherapy and previous treatment with melphalan were more significant predictors of poor mobilization than sex, age or body weight (Wuchter et al., 2010). Recently, prior prolonged exposure to novel agent lenalidomide has also been considered as a risk factor, which will be discussed later. With the current mobilization strategies about 5-10% of patients with PCM still end up with mobilization failure (Bensinger et al., 2009; Pusic et al., 2008). The classical strategy when patients fail G-CSF only mobilizations has been CY followed by G-CSF. However, this results in unnecessary exposure of the patients to chemotherapy toxicity for sole mobilization purposes, which means that novel PBPC mobilization approaches are required.

Stem Cell Moblzaton in Multple Myeloma 247

myeloma patients mobilized more CD34+ cells per day of apheresis than G-CSF alone (4.4 vs 3-3.5 fold) with 95 to 100% of the patients achieving the minimum number ( ≥ 2 x106/kg) of target CD34+ cells in a median of 1-2 apheresis days. Even the heavily pretreated patients had the median 2.5 fold increase in the PB CD34+ cells and could proceed with high dose therapy and AHCT (Stewart et al., 2009; Stiff et al., 2009). In a randomized, placebocontrolled phase III study the proportion of patients from whom ≥ 6 x106 CD34+ cells/kg were collected in ≤2 days of apheresis served as the primary end point. The protocol for plerixafor plus G-CSF mobilization has been summarized(Table 2). The results demonstrated that the addition of plerixafor to G-CSF resulted in a significantly higher probability of achieving the optimal CD34+ cell target for tandem transplantation in fewer days of apheresis in PCM patients without any additional toxicity(Table 3). Peripheral blood stem cells mobilized by plerixafor and G-CSF resulted in prompt and durable engraftment

after AHCT(DiPersio et al., 2009a).

Median number of apheresis

Median(range) collected CD34

cells x106/kg

GCSF 10 μg/kg/day s.c. on days 1-4

Plerixafor 240 μg/kg/day s.c. started on the evening of day 4

maximum number of apheresis (4-5) was reached Table 2. Mobilization protocol of Plerixafor plus GCSF

Apheresis initiated 10 h after the first dose of plerixafor on the morning of day 5 Daily GCSF before apheresis in the morning and plerixafor in the evening

N=148

10.96

(0.66-104.57)

Table 3. Phase III Clinical trial of PBPC mobilization with Plerixafor plus G-CSF in PCM

There is lack of sufficient information on direct comparison of mobilization with G-CSF and plerixafor to mobilization with chemotherapy and G-CSF. In a retrospective comparison, both G-CSF plus plerixafor and CY plus G-CSF resulted in similar numbers of cells collected as well as costs of mobilization and clinical outcomes (Shaughnessy et al., 2011). For the patients from whom sufficient number of CD34+ cells could not be collected after the first mobilization attempt with G-CSF alone, a second(rescue) mobilization has been traditionally attempted with chemotherapy plus G-CSF. However, instead of chemomobilization, a rescue stem cell mobilization with G-CSF and plerixafor can be offered in patients who only require PBPC mobilization and collection without any need for further tumor reduction. In compassionate use programs, plerixafor has been used successfully in myeloma patients who were either proven or predicted to be poor mobilizers. About 75% of the patients could

Achieved primary end point (%) 71.6 34.4 Achieved min. collection (%) 95.9 92.9 Fold increase PB CD34/μl 4.8 1.7

days to collect the target 1 4

Failed mobilization (%) 0 4.6

Continued until the target CD34+ cells ≥ 6 x 106/kg was collected or a predetermined

Plerixafor + G-CSF

Placebo + G-CSF

N=154

6.18

(0.11-42.66)

#### **4. Novel agents for PBPC mobilization**

Historically, attempts to increase the mobilization efficiency concentrated on using high doses of G-CSF or combining G-CSF with other cytokines and growth factors some of which are currently used in other indications. However, either due to inefficiency or AEs, most of these agents could not become a part of the standart mobilization. In recent years, several cytokines and chemokines have been investigated that may prove useful for amplifying yields of CD34+ cells without introducing additional toxicity. There are also investigational agents which are yet in preclinical and phase I clinical trials (Table 1) (Bakanay & Demirer, 2011).

#### **Growth Factors**

Granulocyte-Macrophage Colony Stimulating Factor Recombinant human erythropoietin Recombinant human stem cell factor Recombinant human thrombopoietin Parathyroid hormone Recombinant human growth hormone

#### **Chemokine axis mobilizers**

AMD3100 GRO-β analogs (SB-251353)

#### **Other small molecules and peptides**

Very Late Antigen-1 antibodies Retinoic acid receptor alpha agonists Thrombopoietin receptor agonists

Table 1. Agents investigated as adjunct to G-CSF for PBPC mobilization

#### **4.1 Plerixafor**

Plerixafor (AMD3100, Mozobil, Genzyme Corporation, Cambridge, MA, USA) is a bicyclam molecule which selectively and reversibly antagonizes CXCR4 and disrupts its interaction with stromal cell derived factor-1 (SDF-1), thereby releasing hematopoietic stem cells into the circulation (Gerlach et al., 2001; Hendrix et al., 2000). Plerixafor has received approval by the US FDA and the European Medicines Evaluation Agency for use in combination with G-CSF to mobilize PBPCs for collection and subsequent AHCT in patients with NHL and PCM who previously failed mobilization with G-CSF alone (DiPersio et al. 2009a,2009b; Mozobil package insert). Plerixafor results in rapid mobilization of PBPC, which peaks at approximately 10 hours. Plerixafor has been shown to synergize with G-CSF for mobilizing stem cells in patients with PCM in various clinical conditions (Calandra et al., 2008; DiPersio et al., 2009a; Flomenberg et al., 2005; Stiff et al., 2009; Tricot et al., 2010). The results from phase II studies indicated that plerixafor added to G-CSF for PBPC mobilization from

Historically, attempts to increase the mobilization efficiency concentrated on using high doses of G-CSF or combining G-CSF with other cytokines and growth factors some of which are currently used in other indications. However, either due to inefficiency or AEs, most of these agents could not become a part of the standart mobilization. In recent years, several cytokines and chemokines have been investigated that may prove useful for amplifying yields of CD34+ cells without introducing additional toxicity. There are also investigational agents which are yet in preclinical and phase I clinical trials (Table 1) (Bakanay & Demirer,

**4. Novel agents for PBPC mobilization** 

Granulocyte-Macrophage Colony Stimulating Factor

Table 1. Agents investigated as adjunct to G-CSF for PBPC mobilization

Plerixafor (AMD3100, Mozobil, Genzyme Corporation, Cambridge, MA, USA) is a bicyclam molecule which selectively and reversibly antagonizes CXCR4 and disrupts its interaction with stromal cell derived factor-1 (SDF-1), thereby releasing hematopoietic stem cells into the circulation (Gerlach et al., 2001; Hendrix et al., 2000). Plerixafor has received approval by the US FDA and the European Medicines Evaluation Agency for use in combination with G-CSF to mobilize PBPCs for collection and subsequent AHCT in patients with NHL and PCM who previously failed mobilization with G-CSF alone (DiPersio et al. 2009a,2009b; Mozobil package insert). Plerixafor results in rapid mobilization of PBPC, which peaks at approximately 10 hours. Plerixafor has been shown to synergize with G-CSF for mobilizing stem cells in patients with PCM in various clinical conditions (Calandra et al., 2008; DiPersio et al., 2009a; Flomenberg et al., 2005; Stiff et al., 2009; Tricot et al., 2010). The results from phase II studies indicated that plerixafor added to G-CSF for PBPC mobilization from

Recombinant human erythropoietin Recombinant human stem cell factor Recombinant human thrombopoietin

Recombinant human growth hormone

**Other small molecules and peptides**  Very Late Antigen-1 antibodies Retinoic acid receptor alpha agonists Thrombopoietin receptor agonists

2011).

**Growth Factors** 

AMD3100

**4.1 Plerixafor** 

Parathyroid hormone

**Chemokine axis mobilizers** 

GRO-β analogs (SB-251353)

myeloma patients mobilized more CD34+ cells per day of apheresis than G-CSF alone (4.4 vs 3-3.5 fold) with 95 to 100% of the patients achieving the minimum number ( ≥ 2 x106/kg) of target CD34+ cells in a median of 1-2 apheresis days. Even the heavily pretreated patients had the median 2.5 fold increase in the PB CD34+ cells and could proceed with high dose therapy and AHCT (Stewart et al., 2009; Stiff et al., 2009). In a randomized, placebocontrolled phase III study the proportion of patients from whom ≥ 6 x106 CD34+ cells/kg were collected in ≤2 days of apheresis served as the primary end point. The protocol for plerixafor plus G-CSF mobilization has been summarized(Table 2). The results demonstrated that the addition of plerixafor to G-CSF resulted in a significantly higher probability of achieving the optimal CD34+ cell target for tandem transplantation in fewer days of apheresis in PCM patients without any additional toxicity(Table 3). Peripheral blood stem cells mobilized by plerixafor and G-CSF resulted in prompt and durable engraftment after AHCT(DiPersio et al., 2009a).


Table 2. Mobilization protocol of Plerixafor plus GCSF

Table 3. Phase III Clinical trial of PBPC mobilization with Plerixafor plus G-CSF in PCM

There is lack of sufficient information on direct comparison of mobilization with G-CSF and plerixafor to mobilization with chemotherapy and G-CSF. In a retrospective comparison, both G-CSF plus plerixafor and CY plus G-CSF resulted in similar numbers of cells collected as well as costs of mobilization and clinical outcomes (Shaughnessy et al., 2011). For the patients from whom sufficient number of CD34+ cells could not be collected after the first mobilization attempt with G-CSF alone, a second(rescue) mobilization has been traditionally attempted with chemotherapy plus G-CSF. However, instead of chemomobilization, a rescue stem cell mobilization with G-CSF and plerixafor can be offered in patients who only require PBPC mobilization and collection without any need for further tumor reduction. In compassionate use programs, plerixafor has been used successfully in myeloma patients who were either proven or predicted to be poor mobilizers. About 75% of the patients could

Stem Cell Moblzaton in Multple Myeloma 249

plerixafor dose reduction to 160 µg/kg in patients with a creatinine clearance value ≤ 50 mL/min is recommended (Douglas et al., 2011; MacFarland et al., 2010; Pinto et al., 2010). Plerixafor addition to G-CSF has undoubtedly increased the number of patients who could proceed with high dose therapy and AHCT. Plerixafor incorporation in the first line mobilization protocols in patients who are predicted poor mobilizers will eliminate the need for further mobilization attempts and the cost-effectiveness of such approaches should be clarified. Recently, the International Myeloma Working Group(IMWG) have proposed some strategies to overcome the risk factors for poor PBPC mobilization in PCM (Giralt et al.,

History of melphalan exposure Consider upfront chemomobilization or

Table 5. Strategies proposed by IMWG to overcome the risk factors for poor PBPC

**5. The effect of novel induction protocols on PBPC mobilization in PCM** 

et al., 2007; Harousseau et al., 2010; Kumar et al., 2009; Rajkumar et al., 2006).

Until the last decade, the standard first line therapy for PCM has been either VAD or single agent dexamethasone. These therapies clearly do not have any adverse effects on PBPC mobilization from the bone marrow. However, they have been replaced by more efficient novel agents such as IMIDs ( thalidomide and lenalidomide) and proteosome inhibitor bortezomib. Novel induction agents in myeloma are effective as first line therapy enhancing the quality of responses prior to AHCT and by controlling the tumor load at diagnosis they decrease the early mortality and prolong the overall survival. With the novel induction agents, the time from diagnosis to planned AHCT is shorter and most patients can achieve ≥ VGPR after the transplantation which eliminates the need for tandem AHCT for most patients. In fact it also neccesitates re-exploration of the role of first line AHCT in selected patients, moving AHCT to a second line position. The novel agents are also used as adjuncts to transplant conditioning regimen or as maintenance therapy after transplant (Dimopoulos

The IMIDs have antiangiogenesis, immunomodulatory activity and direct cyctotoxic affects on myeloma cells. Pretransplant treatment with IMIDs appear to have no impact on

plerixafor

plerixafor

chemomobilization

changes before collection

changes before collection

Harvest early between cycles 2-4 Consider upfront plerixafor or

Assess marrow for secondary dysplastic

Consider collection before radiotherapy Consider upfront chemomobilization or

Assess marrow for secondary dysplastic

**Risk Factor Proposed strategy**  Age>60 Consider plerixafor

Extensive prior therapy and prolonged

Extensive radiotherapy to marrow bearing

2009) (Table 5).

disease duration

mobilization in PCM

**5.1 Thalidomide**

tissue

be rescued after failure from chemotherapy (Basak et al., 2011a; Calandra et al., 2008; Duarte et al., 2011). Plerixafor plus G-CSF can also be an option for myeloma patients who had received a previous AHCT and who require a repeated mobilization for a second transplantation. In a recent study, successful mobilization of PBPCs was performed in a similar proportion of the previously transplanted patients and other patients who had not undergone ASCT (70% vs 82.6%) (Basak et al., 2011b).

Plerixafor combined with chemotherapy and G-CSF in a recent open-label, multicenter trial on 40 patients with PCM and NHL, also proved to be a feasible method of stem cell mobilization. However, further studies are warranted to evaluate the exact timing of incorporating plerixafor into chemomobilization (Dugan et al., 2010). Table 4 gives a single center approach to mobilization in the era of novel mobilizing agent, plerixafor (Gertz, 2010b). In one single center experience, preemptive use of plerixafor was successful in patients who had either PB CD34+ counts <10/μl at the time of marrow recovery or poor yield of first apheresis CD34+ <1x 106 /kg (Jantunen et al., 2011). Similarly, a promising approach with growth factor and patient-adapted use of plerixafor has been recently suggested to be superior to chemotherapy and growth factor for autologous PBPC mobilization. The preemptive use of plerixafor using the PB CD34+ cell count on day 4 of G-CSF administration and the collection target to decide between continuing G-CSF only or adding plerixafor to the mobilization regimen may potentially reduce the percentage of failure in first-line mobilizations (Costa et al., 2011a, 2011b). A recent study demonstrated that the quantity of CD34+ cells collected on day 1, rather than the PB CD34+ cell count, might identify patients unlikely to achieve adequate stem cell collection for AHCT and suggested that patients who collect <0.70 x106 CD34+ cells/kg on day 1 could be considered for treatment modifications such as adding plerixafor (Duong et al., 2011).

G-CSF 10 μg/kg single dose x 4 days If collecting for 1 transplant: if CD34+ < 10 x 106/L, add plerixafor If collecting for >1 transplant: if CD34+ < 20 x106/L, add plerixafor

If relapsed or primary refractory myeloma or circulating plasma cells: CY 1.5 g/m2 x 2 days, begin G-CSF 5 μg/kg on day 3 Check CD34+ when WBC >1000 x 106/L. If CD34+ < 10 x 106/L continue to check for three consecutive days. If CD34 remains < 10 x106/L, begin plerixafor

Table 4. The Mayo Clinic Rochester approach to PBPC mobilization in myeloma

Plerixafor is well tolerated and adverse events are usually mild and transient. The most common adverse events are diarrhea, nausea, vomiting, flatulance and injection-site reactions, fatigue, arthralgia, headache, dizziness and insomnia. Severe adverse events such as hypotension and dizziness after drug administration and thrombocytopenia after apheresis are very rare (DiPersio et al., 2009, Mozobil package insert). No case of splenic rupture due to plerixafor has been reported to date. No evidence of tumor cell mobilization could be demonstrated after plerixafor in PCM and NHL patients(Fruehauf et al., 2010). A

be rescued after failure from chemotherapy (Basak et al., 2011a; Calandra et al., 2008; Duarte et al., 2011). Plerixafor plus G-CSF can also be an option for myeloma patients who had received a previous AHCT and who require a repeated mobilization for a second transplantation. In a recent study, successful mobilization of PBPCs was performed in a similar proportion of the previously transplanted patients and other patients who had not

Plerixafor combined with chemotherapy and G-CSF in a recent open-label, multicenter trial on 40 patients with PCM and NHL, also proved to be a feasible method of stem cell mobilization. However, further studies are warranted to evaluate the exact timing of incorporating plerixafor into chemomobilization (Dugan et al., 2010). Table 4 gives a single center approach to mobilization in the era of novel mobilizing agent, plerixafor (Gertz, 2010b). In one single center experience, preemptive use of plerixafor was successful in patients who had either PB CD34+ counts <10/μl at the time of marrow recovery or poor yield of first apheresis CD34+ <1x 106 /kg (Jantunen et al., 2011). Similarly, a promising approach with growth factor and patient-adapted use of plerixafor has been recently suggested to be superior to chemotherapy and growth factor for autologous PBPC mobilization. The preemptive use of plerixafor using the PB CD34+ cell count on day 4 of G-CSF administration and the collection target to decide between continuing G-CSF only or adding plerixafor to the mobilization regimen may potentially reduce the percentage of failure in first-line mobilizations (Costa et al., 2011a, 2011b). A recent study demonstrated that the quantity of CD34+ cells collected on day 1, rather than the PB CD34+ cell count, might identify patients unlikely to achieve adequate stem cell collection for AHCT and suggested that patients who collect <0.70 x106 CD34+ cells/kg on day 1 could be considered

for treatment modifications such as adding plerixafor (Duong et al., 2011).

If collecting for 1 transplant: if CD34+ < 10 x 106/L, add plerixafor If collecting for >1 transplant: if CD34+ < 20 x106/L, add plerixafor

If relapsed or primary refractory myeloma or circulating plasma cells:

If CD34+ < 10 x 106/L continue to check for three consecutive days.

Table 4. The Mayo Clinic Rochester approach to PBPC mobilization in myeloma

Plerixafor is well tolerated and adverse events are usually mild and transient. The most common adverse events are diarrhea, nausea, vomiting, flatulance and injection-site reactions, fatigue, arthralgia, headache, dizziness and insomnia. Severe adverse events such as hypotension and dizziness after drug administration and thrombocytopenia after apheresis are very rare (DiPersio et al., 2009, Mozobil package insert). No case of splenic rupture due to plerixafor has been reported to date. No evidence of tumor cell mobilization could be demonstrated after plerixafor in PCM and NHL patients(Fruehauf et al., 2010). A

CY 1.5 g/m2 x 2 days, begin G-CSF 5 μg/kg on day 3

G-CSF 10 μg/kg single dose x 4 days

Check CD34+ when WBC >1000 x 106/L.

If CD34 remains < 10 x106/L, begin plerixafor

undergone ASCT (70% vs 82.6%) (Basak et al., 2011b).

plerixafor dose reduction to 160 µg/kg in patients with a creatinine clearance value ≤ 50 mL/min is recommended (Douglas et al., 2011; MacFarland et al., 2010; Pinto et al., 2010). Plerixafor addition to G-CSF has undoubtedly increased the number of patients who could proceed with high dose therapy and AHCT. Plerixafor incorporation in the first line mobilization protocols in patients who are predicted poor mobilizers will eliminate the need for further mobilization attempts and the cost-effectiveness of such approaches should be clarified. Recently, the International Myeloma Working Group(IMWG) have proposed some strategies to overcome the risk factors for poor PBPC mobilization in PCM (Giralt et al., 2009) (Table 5).


Table 5. Strategies proposed by IMWG to overcome the risk factors for poor PBPC mobilization in PCM

#### **5. The effect of novel induction protocols on PBPC mobilization in PCM**

Until the last decade, the standard first line therapy for PCM has been either VAD or single agent dexamethasone. These therapies clearly do not have any adverse effects on PBPC mobilization from the bone marrow. However, they have been replaced by more efficient novel agents such as IMIDs ( thalidomide and lenalidomide) and proteosome inhibitor bortezomib. Novel induction agents in myeloma are effective as first line therapy enhancing the quality of responses prior to AHCT and by controlling the tumor load at diagnosis they decrease the early mortality and prolong the overall survival. With the novel induction agents, the time from diagnosis to planned AHCT is shorter and most patients can achieve ≥ VGPR after the transplantation which eliminates the need for tandem AHCT for most patients. In fact it also neccesitates re-exploration of the role of first line AHCT in selected patients, moving AHCT to a second line position. The novel agents are also used as adjuncts to transplant conditioning regimen or as maintenance therapy after transplant (Dimopoulos et al., 2007; Harousseau et al., 2010; Kumar et al., 2009; Rajkumar et al., 2006).

#### **5.1 Thalidomide**

The IMIDs have antiangiogenesis, immunomodulatory activity and direct cyctotoxic affects on myeloma cells. Pretransplant treatment with IMIDs appear to have no impact on

Stem Cell Moblzaton in Multple Myeloma 251

mobilized with CY plus G-CSF versus only 33% of patients mobilized with G-CSF alone. Some studies demonstarted lower stem cell yield with increasing duration of lenalidomide therapy but other studies could not demonstrate such correlation (Mark et al., 2008; Mazumder et al., 2008; Nazha et al., 2011). Since addition of CY + G-CSF does not increase the responses to myeloma therapy, exposing patients to the risks of chemomobilization for sole mobilization purposes should be avoided. Plerixafor is a promising alternative to chemomobilization in patients with PCM who received prior therapy with lenalidomide. Retrospective data analysis for 60 patients who received plerixafor plus G-CSF for front-line mobilization in a phase 3 clinical trial or for remobilization in a compassionate use program demonstrated that CD34+ cells can be successfully and predictably mobilized and collected in majority of patients with PCM who have been previously treated with lenalidomide (Micallef et al., 2010) (Table 6). The IMWG have published the consensus report focusing on the approach to stem cell mobilization in era of novel agents in PCM (Kumar et al.,

> Frontline P + G-CSF

seen on ability to collect stem cells (Goldschmidt et al., 2008).

cells/kg 100% 80% 86.7%

cells/kg 95% 47.5% 63.3%

Table 6. Mobilization response to Plerixafor plus GCSF in lenalidomide-treated patients

Bortezomib is effective in patients with relapsed or refractory disease as well as in untreated patients No definitive impact of initial therapy with bortezomib on stem cell harvest could be demonstrated (Benson et al., 2010; Corso et al., 2010; Horousseau et al., 2010; Jagannath et al., 2005). In the IFM2005/01 trial comparing bortezomib/dexamethasone to VAD, there was a trend towards lower CD34+ numbers among those receiving bortezomib. However, a single mobilization with G-CSF was adequate and allowed the harvest of sufficient number of CD34+ cells for a single transplant in 97% and for a tandem transplant 77% of the patients treated upfront with bortezomib/dexamethasone. Compared with VAD, a higher number of patients in bortezomib/dexamethasone arm required a second mobilization attempt to reach the target 5 x 106 CD34+ cells/kg for tandem transplantation (Horousseau et al., 2010; Moreau et al., 2010). HOVON65/GMMG-HD4 randomized phase 3 trial comparing bortezomib, adriamycin, dexamethasone (PAD) versus VAD, no impact of bortezomib was

Studies combining bortezomib with lenalidomide or thalidomide also did not reveal any adverse effect of bortezomib on stem cell mobilization (Richardson et al., 2010; Bensinger et al., 2010; Kaufman et al., 2010). Simultaneous use of bortezomib in combination with thalidomide and chemotherapy (DT-PACE; cisplatin, doxorubicin, CY, etoposide and dexamethasone) was also effective, safe and allowed for adequate stem cell collection (Badros et al., 2006). Addition of alkylating agents to initial therapy especially in combination, may increase the risk of mobilization failures but no comparative data is available. Phase 2 studies combining CY with lenalidomide and CY with thalidomide

Remobilization

P + G-CSF Total

2009)(Table 7).

**5.3 Bortezomib** 

Minimal ≥ 2 x 106 CD34+

Optimal ≥ 5 x 106 CD34+

engraftment kinetics suggesting that both thalidomide and lenolidomide do not have qualitative effects on stem cells. Thalidomide was the first IMID to be used in PCM and initial therapy with thalidomide-dexamethasone (thal/dex) was superior to dexamethasone alone (Rajkumar et al., 2006). Although there has been controversial reports, most studies have shown no impact of thalidomide on stem cell mobilization and >80% of patients who received thal/dex were able to collect adequate stem cells for tandem transplant (Cavo et al., 2005). In a phase III randomized study, patients treated with induction regimen TAD (Thalidomide, doxorubicine, dexamethasone) had fewer CD34+ cell collection following CAD plus G-CSF mobilization than patients who received VAD as induction. However, the number of CD34+ cells were sufficient to support double AHCT in 82% of TAD treated patients (Breitkreutz et al., 2007). However, in a recent study thalidomide in combination with CY and dexamethasone (CTD) as induction regimen had significantly (49%) lower PBPC yield and higher percentage of mobilization failures for one (25.4 vs 5.8%) or two (39.4 vs 15.9%) transplants compared with VAD and a VAD-like induction regimen. The authors have pointed that thalidomide and CY with no previously reported negative impact on stem cell mobilization can have substantial impact when used in combination (Auner et al., 2011).

#### **5.2 Lenalidomide**

Lenalidomide in combination with dexamethasone (Len/dex) have been associated with better outcomes and improved survival rates in patients with PCM (Rajkumar et al., 2005, Dimopuolos et al., 2007, Wang et al., 2008). However, lenalidomide can cause myelosuppression and concerns have been raised that its use may negatively impact the ability to mobilize stem cells in patients who received lenalidomide as part of their induction therapies (Kumar et al., 2007; Mazumder et al., 2008; Paripati et al., 2008; Popat et al., 2009). Kumar have indicated that among patients mobilized with G-CSF alone there was a significant decrease in total CD34+ cells collected, average daily collection, day 1 collection and increased number of apheresis in patients treated with lenalidomide compared to patients treated with other regimens(Kumar et al., 2007). One retrospective analysis demonstrated higher mobilization failure rates with filgrastim among lenalidomide- treated patients compared with patients who had not received lenalidomide (25% vs 4%, p<0.001). Failure rate was very high in patients who received >3 cycles of lenalidomide. Majority of the lenalidomide-treated patients(77%) could be rescued with chemotherapy plus filgrastim(Popat et al., 2009). A multicenter prospective study of 346 patients with newly diagnosed PCM, has demonstrated that 21% of the patientswho received 4 cycles of len/dex as induction regimen, could not achieve the target 4 x 106 CD34+ cells/kg after CY plus G-CSF mobilization whereas only 9% of patients failed after a second mobilization attempt with the same mobilization protocol. Lenalidomide as a part of the induction regimen did not adversely affect the PBPC mobilization and a second mobilization procedure with CY plus G-CSF may be an appropriate strategy to rescue poor mobilizers(Cavallo et al., 2011). In different studies where patients were mobilized after len/dex induction therapy, mobilization with CY plus G-CSF yielded clearly higher (range 6.3 to 14.2 x 106/kg) number of stem cells with respect to mobilization with G-CSF alone (range 3.1 to 7.9 x 106/kg) (Kumar et al., 2007; Mark et al., 2008; Mazumder et al., 2008; Paripati et al., 2008; Popat et al., 2009). Incorporation of lenalidomide into induction therapy for PCM did not have clinically significant impact on PBPC mobilization when CY plus G-CSF was used as mobilization protocol. Sufficient stem cells for tandem auto-HCT were collected from all patients

engraftment kinetics suggesting that both thalidomide and lenolidomide do not have qualitative effects on stem cells. Thalidomide was the first IMID to be used in PCM and initial therapy with thalidomide-dexamethasone (thal/dex) was superior to dexamethasone alone (Rajkumar et al., 2006). Although there has been controversial reports, most studies have shown no impact of thalidomide on stem cell mobilization and >80% of patients who received thal/dex were able to collect adequate stem cells for tandem transplant (Cavo et al., 2005). In a phase III randomized study, patients treated with induction regimen TAD (Thalidomide, doxorubicine, dexamethasone) had fewer CD34+ cell collection following CAD plus G-CSF mobilization than patients who received VAD as induction. However, the number of CD34+ cells were sufficient to support double AHCT in 82% of TAD treated patients (Breitkreutz et al., 2007). However, in a recent study thalidomide in combination with CY and dexamethasone (CTD) as induction regimen had significantly (49%) lower PBPC yield and higher percentage of mobilization failures for one (25.4 vs 5.8%) or two (39.4 vs 15.9%) transplants compared with VAD and a VAD-like induction regimen. The authors have pointed that thalidomide and CY with no previously reported negative impact on stem cell mobilization can have substantial impact when used in combination (Auner et al., 2011).

Lenalidomide in combination with dexamethasone (Len/dex) have been associated with better outcomes and improved survival rates in patients with PCM (Rajkumar et al., 2005, Dimopuolos et al., 2007, Wang et al., 2008). However, lenalidomide can cause myelosuppression and concerns have been raised that its use may negatively impact the ability to mobilize stem cells in patients who received lenalidomide as part of their induction therapies (Kumar et al., 2007; Mazumder et al., 2008; Paripati et al., 2008; Popat et al., 2009). Kumar have indicated that among patients mobilized with G-CSF alone there was a significant decrease in total CD34+ cells collected, average daily collection, day 1 collection and increased number of apheresis in patients treated with lenalidomide compared to patients treated with other regimens(Kumar et al., 2007). One retrospective analysis demonstrated higher mobilization failure rates with filgrastim among lenalidomide- treated patients compared with patients who had not received lenalidomide (25% vs 4%, p<0.001). Failure rate was very high in patients who received >3 cycles of lenalidomide. Majority of the lenalidomide-treated patients(77%) could be rescued with chemotherapy plus filgrastim(Popat et al., 2009). A multicenter prospective study of 346 patients with newly diagnosed PCM, has demonstrated that 21% of the patientswho received 4 cycles of len/dex as induction regimen, could not achieve the target 4 x 106 CD34+ cells/kg after CY plus G-CSF mobilization whereas only 9% of patients failed after a second mobilization attempt with the same mobilization protocol. Lenalidomide as a part of the induction regimen did not adversely affect the PBPC mobilization and a second mobilization procedure with CY plus G-CSF may be an appropriate strategy to rescue poor mobilizers(Cavallo et al., 2011). In different studies where patients were mobilized after len/dex induction therapy, mobilization with CY plus G-CSF yielded clearly higher (range 6.3 to 14.2 x 106/kg) number of stem cells with respect to mobilization with G-CSF alone (range 3.1 to 7.9 x 106/kg) (Kumar et al., 2007; Mark et al., 2008; Mazumder et al., 2008; Paripati et al., 2008; Popat et al., 2009). Incorporation of lenalidomide into induction therapy for PCM did not have clinically significant impact on PBPC mobilization when CY plus G-CSF was used as mobilization protocol. Sufficient stem cells for tandem auto-HCT were collected from all patients

**5.2 Lenalidomide** 

mobilized with CY plus G-CSF versus only 33% of patients mobilized with G-CSF alone. Some studies demonstarted lower stem cell yield with increasing duration of lenalidomide therapy but other studies could not demonstrate such correlation (Mark et al., 2008; Mazumder et al., 2008; Nazha et al., 2011). Since addition of CY + G-CSF does not increase the responses to myeloma therapy, exposing patients to the risks of chemomobilization for sole mobilization purposes should be avoided. Plerixafor is a promising alternative to chemomobilization in patients with PCM who received prior therapy with lenalidomide. Retrospective data analysis for 60 patients who received plerixafor plus G-CSF for front-line mobilization in a phase 3 clinical trial or for remobilization in a compassionate use program demonstrated that CD34+ cells can be successfully and predictably mobilized and collected in majority of patients with PCM who have been previously treated with lenalidomide (Micallef et al., 2010) (Table 6). The IMWG have published the consensus report focusing on the approach to stem cell mobilization in era of novel agents in PCM (Kumar et al., 2009)(Table 7).


Table 6. Mobilization response to Plerixafor plus GCSF in lenalidomide-treated patients

#### **5.3 Bortezomib**

Bortezomib is effective in patients with relapsed or refractory disease as well as in untreated patients No definitive impact of initial therapy with bortezomib on stem cell harvest could be demonstrated (Benson et al., 2010; Corso et al., 2010; Horousseau et al., 2010; Jagannath et al., 2005). In the IFM2005/01 trial comparing bortezomib/dexamethasone to VAD, there was a trend towards lower CD34+ numbers among those receiving bortezomib. However, a single mobilization with G-CSF was adequate and allowed the harvest of sufficient number of CD34+ cells for a single transplant in 97% and for a tandem transplant 77% of the patients treated upfront with bortezomib/dexamethasone. Compared with VAD, a higher number of patients in bortezomib/dexamethasone arm required a second mobilization attempt to reach the target 5 x 106 CD34+ cells/kg for tandem transplantation (Horousseau et al., 2010; Moreau et al., 2010). HOVON65/GMMG-HD4 randomized phase 3 trial comparing bortezomib, adriamycin, dexamethasone (PAD) versus VAD, no impact of bortezomib was seen on ability to collect stem cells (Goldschmidt et al., 2008).

Studies combining bortezomib with lenalidomide or thalidomide also did not reveal any adverse effect of bortezomib on stem cell mobilization (Richardson et al., 2010; Bensinger et al., 2010; Kaufman et al., 2010). Simultaneous use of bortezomib in combination with thalidomide and chemotherapy (DT-PACE; cisplatin, doxorubicin, CY, etoposide and dexamethasone) was also effective, safe and allowed for adequate stem cell collection (Badros et al., 2006). Addition of alkylating agents to initial therapy especially in combination, may increase the risk of mobilization failures but no comparative data is available. Phase 2 studies combining CY with lenalidomide and CY with thalidomide

Stem Cell Moblzaton in Multple Myeloma 253

chemotherapies are better reserved for relapsed or refractory cases. Current studies focus on the novel investigational agents as adjuncts to G-CSF to improve the PBPC yields. Plerixafor, which selectively and reversibly antagonizes CXCR4 and disrupts its interaction with SDF-1, has the ability of rapid mobilization of PBPCs from BM and gained approval as an adjunct to G-CSF for poor mobilizers. At the present, it is challenging to search for the best approach using the available drugs with appropriate timing to provide sufficient CD34+ yield after initial mobilization attempt and in a cost-effective manner avoiding

Annunziata M, Celentano M, Pocali B, D'Amico MR, Palmieri S, Viola A, Copia C,Falco C,

Ataergin S, Arpaci F, Turan M, Solchaga L, Cetin T, Ozturk M, Ozet A, Komurcu S & Ozturk

Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P,Maisonneuve

Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, Monconduit M,Hulin C,

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**7. References** 

85(6):394-9.


reported mobilization failures while combination of CY with bortezomib did not reveal any failure (Reeder et al., 2009).

Table 7. Approach to stem cell mobilization in era of novel agents in PCM : IMWG consensus perspectives

#### **6. Conclusions**

As the novel anti-myeloma drugs (thalidomide, lenalidomide, bortezomib) in combination with dexamethasone or other agents have replaced the traditional VAD or single agent dexamethasone as first line therapy for myeloma, there has been concern about their impact on PBPC mobilization from the bone marrow. Studies could not demonstrate any deleretious effect of bortezomib on stem cell mobilization. There has been contraversy regarding thalidomide's impact especially when combined with other cytotoxic agents such as CY. However, the thal/dex combination has proved to allow for adequate PBPC yield for tandem transplantation. On the other hand, prolonged exposure to lenalidomide definitely affects the stem cell yield. Early PBPC mobilization with (<4 cycles) is recommended after lenalidomide-containing regimens. If this condition can not be satisfied, mobilization with CY+ G-CSF or addition of plerixafor to G-CSF should be considered. Although the integration of the novel anti-myeloma agents in the upfront treatment of PCM has started questioning the place of the high dose therapy supported with AHCT as first line approach, it is still the gold standard approach in elligible patients with PCM. This requires the mobilization and collection of adequate number of PBPCs following an initial induction threatment. Traditionally, G-CSF alone or after chemotherapy (mostly CY) have been the most commonly used protocols. Generally, CY plus G-CSF is used in the second mobilization attempt after failing G-CSF. However, this approach does not improve the overall outcome of the myeloma patients. So, it is unnecessary to expose the patients to toxic effects of chemotherapy for sole mobilization purposes. And the combined cytotoxic chemotherapies are better reserved for relapsed or refractory cases. Current studies focus on the novel investigational agents as adjuncts to G-CSF to improve the PBPC yields. Plerixafor, which selectively and reversibly antagonizes CXCR4 and disrupts its interaction with SDF-1, has the ability of rapid mobilization of PBPCs from BM and gained approval as an adjunct to G-CSF for poor mobilizers. At the present, it is challenging to search for the best approach using the available drugs with appropriate timing to provide sufficient CD34+ yield after initial mobilization attempt and in a cost-effective manner avoiding further mobilization attempts and exposure to chemotherapy.

#### **7. References**

252 Multiple Myeloma – An Overview

reported mobilization failures while combination of CY with bortezomib did not reveal any

G-CSF alone

CY + G-CSF

CY + G-CSF G-CSF + Plerixafor G-CSF + GM-CSF

Table 7. Approach to stem cell mobilization in era of novel agents in PCM : IMWG

As the novel anti-myeloma drugs (thalidomide, lenalidomide, bortezomib) in combination with dexamethasone or other agents have replaced the traditional VAD or single agent dexamethasone as first line therapy for myeloma, there has been concern about their impact on PBPC mobilization from the bone marrow. Studies could not demonstrate any deleretious effect of bortezomib on stem cell mobilization. There has been contraversy regarding thalidomide's impact especially when combined with other cytotoxic agents such as CY. However, the thal/dex combination has proved to allow for adequate PBPC yield for tandem transplantation. On the other hand, prolonged exposure to lenalidomide definitely affects the stem cell yield. Early PBPC mobilization with (<4 cycles) is recommended after lenalidomide-containing regimens. If this condition can not be satisfied, mobilization with CY+ G-CSF or addition of plerixafor to G-CSF should be considered. Although the integration of the novel anti-myeloma agents in the upfront treatment of PCM has started questioning the place of the high dose therapy supported with AHCT as first line approach, it is still the gold standard approach in elligible patients with PCM. This requires the mobilization and collection of adequate number of PBPCs following an initial induction threatment. Traditionally, G-CSF alone or after chemotherapy (mostly CY) have been the most commonly used protocols. Generally, CY plus G-CSF is used in the second mobilization attempt after failing G-CSF. However, this approach does not improve the overall outcome of the myeloma patients. So, it is unnecessary to expose the patients to toxic effects of chemotherapy for sole mobilization purposes. And the combined cytotoxic

Reduced dose CY + G-CSF

yields <2 x 106 CD34+ cells/kg

G-CSF alone with the addition of plerixafor before second apheresis if first apheresis

**Condition Recommended approach** 

lenalidomide plus dexamethasone CY + G-CSF

failure (Reeder et al., 2009).

younger than 65 years

older than 65 years

with lenalidomide

consensus perspectives

**6. Conclusions** 

Initial therapy with thalidomide or bortezomib plus dexamethasone Patients who received <4 cycles of lenalidomide plus dexamethasone and

Patients who received ≥4 cycles of

Patients who received ≥4 cycles of lenalidomide plus dexamethasone and

myelosuppressive drugs in combination

Failed mobilization with G-CSF alone in

Patients who received other

lenalidomide-treated patients


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**14** 

Ajay Gupta

*India* 

**The Current Role of Stem Cell** 

*Medical Oncology, Max Cancer Centre, Saket, New Delhi,* 

**Transplantation in Multiple Myeloma** 

Multiple myeloma accounts for 10% of hematological cancers and 1% of all cancers. It is currently the most common indication for ASCT in North America and Europe. ASCT remains the standard of care in eligible patients aged below 65-70 years (though age is not a criterion in the United States) performed either upfront or at relapse. It is mostly performed upfront after induction therapy. The attainment of complete response (CR) is held to be a surrogate for improved survival and is the aim of the ASCT. CR is characterized by undetectable serum and urine monoclonal proteins (by immnofixation), absence of plasmacytosis (<5% plasma cells in marrow), disappearance of plasmacytomas and stable or improving bone disease. Stringent CR (sCR) is a new criterion which refers to normalization of the free light chain ratios (FLC) as well as the absence of monoclonal plasma cells in the marrow. Very good partial response (VGPR) refers to the absence of monoclonal proteins by electrophoresis but not by immunofixation or more than 90% reduction in level of serum M

component proteins as well as urinary M proteins less than 100 mg/24 hours.[1]

has resulted in Higher rates of CR and very good partial response (VGPR).

47.8 to 67 months and 3 to 7%, respectively. [3],[4],[5],[6],[7],[8]

With conventional chemotherapy comprising melphalan and prednisolone, CR was attained in less than 5% patients. However the median OS in patients achieving CR was 5.1 years as compared to 3.3 years for other responders.[2] ASCT has helped improve CR and VGPR rates over and above CC and is usually performed after induction therapy as consolidation. Introduction of agents like bortezomib, lenalidomide, thalidomide, liposomal doxorubicin

Ongoing debates regarding redefining the inclusion criteria/timing and expected benefits

Prospective randomized trials have been conducted to evaluate the efficacy of ASCT in terms of attainment of CR, response rate (RR), improvements in progression free survival (PFS) and overall survival (OS) as well as transplant-related mortality (TRM).

CR rates, median PFS, median OS and TRM have ranged from 17 to 44.5%, 25 to 42 months,

of ASCT as compared to maintenance with these drugs however await further trials.

**1. Introduction** 

**2. ASCT in myeloma** 

[3],[4],[5],[6],[7],[8]

