2. Etiopathogenesis of multiple myeloma and its significance in its management

The etiology of multiple myeloma is unknown. However, previous studies have identified factors implicated as "potentially etiologic multiple myeloma risk factors" [5, 6]. These factors include increasing age (>65 years), male gender, black race, and positive family history (firstdegree family relatives) of multiple myeloma. Other causes include environmental agents such as cumulative exposure to ionizing radiation and certain chemicals such as dioxin, herbicides, and pesticides. There is a hypothesis that these specific pesticides are causatively linked to myelomatogenesis through the hypothesized precursors of multiple myeloma such as essential monoclonal gammopathy (MGUS) and solitary multiple myeloma (SMM) [7, 8].

Physiologically, a plasma cell is an immunologically activated B-cell that produces antibody. A B-cell goes through series of rearrangement with the immunoglobulin gene to generate functional antibody. It can enter into the circulation to interact directly with antigen to differentiate into a short-lived plasma cell that lives for about 3 days. On the other hand, a myeloma cell is a postgerminal center plasma cell that has undergone immunoglobulin gene recombination, class switching, and somatic hypermutation, and homes to the bone marrow to become long-lived plasma cell (i.e., can live for ≥30 days) [9]. Cytogenetically, MM is divided into two groups based on karyotype gain or loss into hyperdiploid and non-hyperdiploid MM. The hyperdiploid MM, which constitutes about 55–60% of MM primary tumor, is characterized by hyperdiploid karyotype with chromosome range of 48–78 and trisomies of odd number chromosomes, including 15, 9, 5, 19, 3, 11, 7, and 21 (ordered by decreasing frequency). The hyperdiploid variants are typically the IgG kappa-types with bone involvements. The non-hyperdiploid karyotype accounts for the remaining 40–45% of MM primary tumor, and it includes the hypodiploid or neartetraploid chromosome numbers (i.e., fewer than 48 or more than 74 chromosomes). Chromosomal translocations affect more commonly the non-hyperdiploid karyotypes. In terms of prognosis, hyperdiploid MM is better than non-hyperdiploid karyotype provided the former is not associated with deletion of chromosome 13 (RB1 gene and miRNA-15a/16-1 cluster dysregulation) and 17 (involving the TP53 locus) or amplification of chromosome 1q21 [9, 10]. The critical role of pathogenesis of MM is to give insight into the biology of the disease. Also, the pathways of the pathogenesis of the disease serve as potential sites for therapeutic interventions, especially the target therapies, which can utilize them for their actions.

## 3. Requirements for standard diagnosis and staging of multiple myeloma

The diagnosis of multiple myeloma is based on a constellation of hematologic, immunologic, histologic, and radiographic features. There are two methods of diagnosis of MM: the old and new methods. In the old method, a minimum of two major criteria, or one major criterion plus one minor criterion, or three minor criteria is used in making diagnosis of MM [11]. The major criteria are plasmacytoma on tissue biopsy, bone marrow infiltration with greater than 30% BMPCs, monoclonal globulin spike on serum electrophoresis, while the minor criteria include bone marrow infiltration with 10–30% BMPCs, paraprotein less than the defined quantity for major criteria, and lytic bone lesion. Table 1 shows the criteria for diagnosis of MM using the old method. The newer method of diagnosis takes into cognizance of the popularly known criteria which uses the end-organ damage as defined using both the classic as "CRAB" criteria for hypercalcemia, renal failure, anemia, and bone lesions and additional criteria including recurrent bacterial infections (> 2 in 12 months), amyloidosis, or symptomatic hyperviscocity. In the newer method, initiation of therapy is an evidence of organ or tissue damage (end-organ damage) [9]. Diagnosis is made by clonal BMPCs of not less than 10% of biopsy-proven bony or extramedullary plasmacytoma or any evidence of myeloma-defining events. The myelomadefining events in this context include any evidence of end-organ damage or presence of any one or more biomarkers of malignancy such as clonal BMPCs greater than 60%, serum-free

of public health importance in low-income countries of Sub-Saharan Africa. It accounts for 10– 15% of all lymphohematopoietic cancers, 1% of all cancer diagnosis, and 0.9–2% of all cancerrelated deaths globally [1]. According to 2009 cancer statistics, the cumulative incidence of MM in the United States is 20,580 cases with an estimated number of deaths of 10,580 and a case fatality rate greater than 51% [2]. The prevalence of MM is in the increase in African continent especially in the oil-rich Niger-Delta Nigeria where it accounts for about 8.2% of all hematological malignancies [3, 4]. The management of MM starts with a good history, which brings into limelight the epidemiology, pathogenesis, and the clinical features of the disease. This is followed by a series of investigations to make the diagnosis and to clinically stage the disease before therapeutic interventions. The major challenges in the management of MM in developing countries are in the diagnosis and treatment. The duo are majorly responsible for the complications, poor prognosis, and survival outcome of people living with MM in the region. This chapter highlights the management of multiple myeloma and some of the challenges encountered in the diagnosis and treatment of this disease in developing countries using

2. Etiopathogenesis of multiple myeloma and its significance in its

monoclonal gammopathy (MGUS) and solitary multiple myeloma (SMM) [7, 8].

The etiology of multiple myeloma is unknown. However, previous studies have identified factors implicated as "potentially etiologic multiple myeloma risk factors" [5, 6]. These factors include increasing age (>65 years), male gender, black race, and positive family history (firstdegree family relatives) of multiple myeloma. Other causes include environmental agents such as cumulative exposure to ionizing radiation and certain chemicals such as dioxin, herbicides, and pesticides. There is a hypothesis that these specific pesticides are causatively linked to myelomatogenesis through the hypothesized precursors of multiple myeloma such as essential

Physiologically, a plasma cell is an immunologically activated B-cell that produces antibody. A B-cell goes through series of rearrangement with the immunoglobulin gene to generate functional antibody. It can enter into the circulation to interact directly with antigen to differentiate into a short-lived plasma cell that lives for about 3 days. On the other hand, a myeloma cell is a postgerminal center plasma cell that has undergone immunoglobulin gene recombination, class switching, and somatic hypermutation, and homes to the bone marrow to become long-lived plasma cell (i.e., can live for ≥30 days) [9]. Cytogenetically, MM is divided into two groups based on karyotype gain or loss into hyperdiploid and non-hyperdiploid MM. The hyperdiploid MM, which constitutes about 55–60% of MM primary tumor, is characterized by hyperdiploid karyotype with chromosome range of 48–78 and trisomies of odd number chromosomes, including 15, 9, 5, 19, 3, 11, 7, and 21 (ordered by decreasing frequency). The hyperdiploid variants are typically the IgG kappa-types with bone involvements. The non-hyperdiploid karyotype accounts for the remaining 40–45% of MM primary tumor, and it includes the hypodiploid or neartetraploid chromosome numbers (i.e., fewer than 48 or more than 74 chromosomes). Chromosomal translocations affect more commonly the non-hyperdiploid karyotypes. In terms of prognosis,

Nigerian experience as a prototype.

management

208 Update on Multiple Myeloma

Minor criteria:

A = Bone marrow infiltration with 10–30% plasma cells

C = Lytic bone lesions

Abbreviations: MM, multiple myeloma; BMPC, bone marrow plasma cell; IgG, immunoglobulin G; IgA, immunoglobulin A; IgM, immunoglobulin M.

Table 1. Criteria for the diagnosis of MM (old method).

Major criteria:

I Plasmacytoma on tissue biopsy

II Bone marrow infiltration with >30% BMPCs

III Monoclonal globulin spike (paraprotein) on serum electrophoresis (IgG >35 g/L and IgA >20 g/L) or on concentrated urine electrophoresis (>1 g/24 h or kappa or lambda light chain)

B = Paraprotein less than the level defined earlier

D = Normal IgM <0.5 g/L, IgA <1 g/L or IgG <6 g/L

1. Clonal BMPCs ≥10% of biopsy-proven bony or extramedullary plasmacytoma Any one of the following myeloma-defining events:

• Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:

light chain ratio greater than 100, and or greater than one focal lesions on magnetic resonance

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The staging of MM is another important step after diagnosis. The essence of staging is for decisionmaking on therapeutic interventions and for prognostication of the disease. There are two clinical staging systems for MM. They include the Durie-Salmon staging system and the international staging system (ISS). The Durie-Salmon (D-S) clinical staging system has been in use for more than 30 years, but it has been remodified to a newer staging system useful for the assessment of myeloma tumor mass [9, 12] The old D-S staging system has three stages (I, II, and III) and two subclassifications (A and B). Here, the staging of MM is based on five parameters viz.: the hemoglobin concentration, the serum calcium level, osteolytic bone lesions, serum, and urinary immunoglobulin quantification. The subclassification A in the staging connotes "normal renal status" (evidenced by normal serum creatinine level), while B connotes "abnormal renal state" (evidenced by deranged serum creatinine level). This is shown in Table 3. The modified Salmon-Durie assesses myeloma tumor mass using the old system to stage MM into high tumor mass (stage III), low tumor mass (I), and intermediate tumor mass myelomas (II), which is shown in Table 4. The ISS is based on two widely available parameters, serum beta-2 microglobulin and albumin. This staging system recognizes three stages and can be useful for prognostication of

The standard assessment of MM requires a panel of investigations, which are carried out periodically postdiagnosis for prognostication and monitoring of the disease response to treatment. These investigations include complete blood count, blood chemistry, serum and

> ) \*

) \*

All patients who do not qualify for high or low tumor mass categories are considered to have intermediate tumor

) \*

imagery studies. Table 2 shows the current criteria of diagnosis of MM.

survival intervals of MM patients (Table 5) [13].

(I) High tumor mass (stage III) (>1.2 <sup>10</sup><sup>12</sup> myeloma cells/m<sup>2</sup>

3. Urine light chains >12 g/24 h

(II) Low tumor mass (stage I) (<0.6 <sup>10</sup><sup>12</sup> myeloma cells/m<sup>2</sup>

A. Hemoglobin >10.5 g/dl, or hematocrit >32%

C. Low serum myeloma protein production rates:

(III) Intermediate tumor mass (stage II) (0.6 to 1.2 <sup>10</sup><sup>12</sup> myeloma cells/m<sup>2</sup>

Data adapted from Durie and Salmon [12]. A remodified D-S staging system.

B. Serum calcium >12 mg/dL

1. IgG peak >7 g/dL 2. IgA peak >5 g/dL

All of the following must be present:

1. IgG peak <5 g/dl 2. IgA peak <3 g/dl 3. Urine light chains <4 g/24 h D. No bone lesions or osteoporosis

A. No renal failure (creatinine ≤2 mg/dl) B. Renal failure (creatinine >2 mg/dl)

Table 4. Assessment of myeloma tumor mass (Salmon-Durie).

B. Serum calcium normal

Estimated number of neoplastic plasma cells.

mass

\*

One of the following abnormalities must be present A. Hemoglobin <8.5 g/dL, hematocrit <25%

C. Very high serum or urine myeloma protein production rates:

D. More than three lytic bone lesions on bone survey (bone scan not acceptable)

	- a. Clonal bone marrow plasma cell percentage\* ≥ 60%
	- b. Involved: uninvolved serum free light chain ratio ≥ 100
	- c. >1 focal lesions on MRI studies

\*Clonal should be established by showing kappa/lambda-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. BMPC percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used. Source: In Table 107-2 [9].

Table 2. Criteria for diagnosis of MM (newer method).


Table 3. D-S staging system.

light chain ratio greater than 100, and or greater than one focal lesions on magnetic resonance imagery studies. Table 2 shows the current criteria of diagnosis of MM.

The staging of MM is another important step after diagnosis. The essence of staging is for decisionmaking on therapeutic interventions and for prognostication of the disease. There are two clinical staging systems for MM. They include the Durie-Salmon staging system and the international staging system (ISS). The Durie-Salmon (D-S) clinical staging system has been in use for more than 30 years, but it has been remodified to a newer staging system useful for the assessment of myeloma tumor mass [9, 12] The old D-S staging system has three stages (I, II, and III) and two subclassifications (A and B). Here, the staging of MM is based on five parameters viz.: the hemoglobin concentration, the serum calcium level, osteolytic bone lesions, serum, and urinary immunoglobulin quantification. The subclassification A in the staging connotes "normal renal status" (evidenced by normal serum creatinine level), while B connotes "abnormal renal state" (evidenced by deranged serum creatinine level). This is shown in Table 3. The modified Salmon-Durie assesses myeloma tumor mass using the old system to stage MM into high tumor mass (stage III), low tumor mass (I), and intermediate tumor mass myelomas (II), which is shown in Table 4. The ISS is based on two widely available parameters, serum beta-2 microglobulin and albumin. This staging system recognizes three stages and can be useful for prognostication of survival intervals of MM patients (Table 5) [13].

The standard assessment of MM requires a panel of investigations, which are carried out periodically postdiagnosis for prognostication and monitoring of the disease response to treatment. These investigations include complete blood count, blood chemistry, serum and

	- A. Hemoglobin >10.5 g/dl, or hematocrit >32%
	- B. Serum calcium normal

1. Clonal BMPCs ≥10% of biopsy-proven bony or extramedullary plasmacytoma

disparity between the aspirate and core biopsy, the highest value should be used.

X-ray showing normal bone structure or solitary bone plasmacytoma only

Advanced lytic bone lesions (more than three lytic lesions)

D-S, Durie-Salmon; IgG, immunoglobulin G; IgA, immunoglobulin A.

• Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifi-

b. Renal insufficiency: creatinine clearance <40 mL per min or serum creatinine >177 μmol/L (>2 mg/mg/dL) c. Anemia: hemoglobin value of 20 g/L below the lower limit of normal, or a hemoglobin value <100 g/L

\*Clonal should be established by showing kappa/lambda-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. BMPC percentage should preferably be estimated from a core biopsy specimen; in case of a

a. Hypercalcemia: serum calcium >0.025 mmol/L (>1 mg/dL) higher than the upper limit of normal

d. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT

Any one of the following myeloma-defining events:

or >2.75 mmol/L (>11 mg/dL)

c. >1 focal lesions on MRI studies

Table 2. Criteria for diagnosis of MM (newer method).

• Any one or more of the following biomarkers of malignancy: a. Clonal bone marrow plasma cell percentage\* ≥ 60% b. Involved: uninvolved serum free light chain ratio ≥ 100

cally:

210 Update on Multiple Myeloma

Source: In Table 107-2 [9].

1. All of the following Hemoglobin >10.5 g/dL Serum calcium normal

Low paraprotein levels

Urinary light chain <4 g/24 h 2. Fitting neither stage I or stage III 3. One or more of the following: Hemoglobin <8.5 g/dL Serum calcium >3 mmol/L

High paraprotein levels

Urinary light chain >12 g/24 h

Table 3. D-S staging system.

A. Serum creatinine <170 μmol/L B. Serum creatinine ≥170 μmol/L

IgG >70 g/L IgA >50 g/L

Subclassification

IgG < 50 g/L IgA < 30 g/L

	- 1. IgG peak <5 g/dl
	- 2. IgA peak <3 g/dl
	- 3. Urine light chains <4 g/24 h
	- A. No renal failure (creatinine ≤2 mg/dl)
	- B. Renal failure (creatinine >2 mg/dl)

\* Estimated number of neoplastic plasma cells.

Data adapted from Durie and Salmon [12]. A remodified D-S staging system.

Table 4. Assessment of myeloma tumor mass (Salmon-Durie).


myeloma is 59.9 years (45–78 years) [14–17]. This age is less than the 65 years median age of diagnosis recorded by SEER cancer statistics review of 1975–2007 in the USA [18]. The implication of this early age of diagnosis is that more people may likely be diagnosed with MM by the time they attend the age of 65, hence increasing the burden of the disease. The male to female ratio of about 2:1 recorded by most of the studies shows a gender disparity of the disease. However, the later may not have much role to play on the increased prevalence of MM

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There is a dearth of data on the diagnosis or prevalence of premalignant plasma cell disease in low- and some middle-income countries. The two known hypothesized precursors of MM are MGUS and smoldering MM. Based on retrospective data from Mayo clinic, MGUS is associated with 1% annual risk of progression to MM, while SMM has 10% annual risk of progression to MM. However, due to lack of resources for making diagnosis at this early stage, these premalignant diagnoses are missed. This ultimately leaves the attending physicians with MM

The diagnosis of MM is made late, usually between Durie-Salmon stages II-A (intermediate myeloma mass) and III-B (high myeloma mass) in developing countries [14–17]. The mean duration from onset of symptoms to diagnosis in a study was 13.12 months (95% CI, 6.65–19.58) [6, 17]. In some geographic regions, the onset of symptoms to diagnosis can last as long as 10 years [17]. The lack of modern equipments for diagnosis and staging of the disease are the key players in the late diagnosis of MM in most developing countries including Nigeria [14]. Most health institutions in developing countries (especially the low-income) do not have the infrastructural and medical capacities to handle comprehensive assessment investigations for MM patients. In a recent study in Nigeria, it was found that only 72% of patients with a preliminary diagnosis of MM could afford basic assessment tests required for confirmation and staging of the disease. Out of this number, 43 and 55.7% could do immunoglobulin quantification and Bence Jones Protein

The commonest assessment tests done by the patients are hematocrit, erythrocyte sedimentation rate, skeletal x-ray, bone marrow aspiration, and trephine biopsy in centers where there are hematologists [14–17]. About 56–60% of MM patients could afford serum electrolyte urea and creatinine assessment tests required for staging the disease [Table 2], while less than 50% of the patients could do serum protein, globulin, and albumin level estimation. The serum albumin is one of the analytes essential for international prognostic staging of MM. The β2M, serum immunofixation test, marrow aspirate and trephine biopsy with metaphase cytogenetic, FISH, immunophenotyping, gene expression profiling (GEP), and plasma cell labeling index (PCLI) are myeloma assessment tests, which are not readily available in developing countries due to the cost and prevailing poverty in the countries. The implication of this is that most MM diagnosed in these regions are cytogenetically unknown and are not internationally staged. Hence, MM patients do not benefit from accurate risk stratification and prognostic assessments

These challenges in diagnoses and disease staging contribute to the poor survival outcome of people living with MM in these regions. In a 10-year retrospective study of 26 MM patients in Niger-delta region of Nigeria, only one (3.8%) of the patients could do a marrow metaphase

in developing countries.

tests, respectively.

patients who present at advanced stages of the disease.

as offered to their counterparts in developed countries [19].

ALB, serum albumin in g/dL; β2M,serum β2-microglobulin in mg/L. Data from Greipp et al. [13].

Table 5. International staging system (ISS).

Complete Blood Count and differential count; examination of blood film Chemistry screen, including calcium, creatinine, lactate dehydrogenase, BNP, proBNP β2-microglobulin; C-reactive protein Serum protein electrophoresis, immunofixation, quantification of immunoglobulin, serum-free light chains 24-hour urine collection for protein electrophoresis, immunofixation, quantification of immunoglobulins, including light chains Marrow aspirate and trephine biopsy with metaphase cytogenetics, FISH, immunophenotyping; gene array, and plasma labeling index (if available) Bone survey and MRI; PET-CT Echocardiogram with assessment of diastolic function and measurement of interventricular septal thickness; EKG (if amyloidosis suspected)

BNP, brain natriuretic peptide, CT, computed tomography; EKG, electrocardiogram; FISH, fluorescence in situ hybridization, MRI, Magnetic resonance imaging; PET, positron emission tomography; proBNP, prohormone B-type natriuretic peptide. Source: In Table 107-4 [9].

Table 6. Assessment of myeloma.

urine monoclonal protein assay, C-reactive protein, beta-2 microglobulin test, marrow study, skeletal survey, echocardiogram, immunophenotyping, cytogenetic tests, etc. (Table 6).

## 4. Challenges in diagnosis of multiple myeloma

The prevalence of MM is on the increase in developing countries such as those found in Sub-Saharan Africa [3, 14]. The oil-rich regions are worse hit probably due to a wide range of environmental pollution, flaring of gases, water pollution, oil spillage, and lack of effective environmental policies [6]. This is understandable based on the hypothesis that occupation studies of chemical, petroleum, and radiation industry workers have provided inconsistent evidence of causal association with MM [5]. Another potential etiologic factor that could be a key player in the increasing prevalence is the median age of diagnosis. Studies in Nigeria, Africa's most populous black nation, have shown that the median age of diagnosis of multiple myeloma is 59.9 years (45–78 years) [14–17]. This age is less than the 65 years median age of diagnosis recorded by SEER cancer statistics review of 1975–2007 in the USA [18]. The implication of this early age of diagnosis is that more people may likely be diagnosed with MM by the time they attend the age of 65, hence increasing the burden of the disease. The male to female ratio of about 2:1 recorded by most of the studies shows a gender disparity of the disease. However, the later may not have much role to play on the increased prevalence of MM in developing countries.

There is a dearth of data on the diagnosis or prevalence of premalignant plasma cell disease in low- and some middle-income countries. The two known hypothesized precursors of MM are MGUS and smoldering MM. Based on retrospective data from Mayo clinic, MGUS is associated with 1% annual risk of progression to MM, while SMM has 10% annual risk of progression to MM. However, due to lack of resources for making diagnosis at this early stage, these premalignant diagnoses are missed. This ultimately leaves the attending physicians with MM patients who present at advanced stages of the disease.

The diagnosis of MM is made late, usually between Durie-Salmon stages II-A (intermediate myeloma mass) and III-B (high myeloma mass) in developing countries [14–17]. The mean duration from onset of symptoms to diagnosis in a study was 13.12 months (95% CI, 6.65–19.58) [6, 17]. In some geographic regions, the onset of symptoms to diagnosis can last as long as 10 years [17]. The lack of modern equipments for diagnosis and staging of the disease are the key players in the late diagnosis of MM in most developing countries including Nigeria [14]. Most health institutions in developing countries (especially the low-income) do not have the infrastructural and medical capacities to handle comprehensive assessment investigations for MM patients. In a recent study in Nigeria, it was found that only 72% of patients with a preliminary diagnosis of MM could afford basic assessment tests required for confirmation and staging of the disease. Out of this number, 43 and 55.7% could do immunoglobulin quantification and Bence Jones Protein tests, respectively.

The commonest assessment tests done by the patients are hematocrit, erythrocyte sedimentation rate, skeletal x-ray, bone marrow aspiration, and trephine biopsy in centers where there are hematologists [14–17]. About 56–60% of MM patients could afford serum electrolyte urea and creatinine assessment tests required for staging the disease [Table 2], while less than 50% of the patients could do serum protein, globulin, and albumin level estimation. The serum albumin is one of the analytes essential for international prognostic staging of MM. The β2M, serum immunofixation test, marrow aspirate and trephine biopsy with metaphase cytogenetic, FISH, immunophenotyping, gene expression profiling (GEP), and plasma cell labeling index (PCLI) are myeloma assessment tests, which are not readily available in developing countries due to the cost and prevailing poverty in the countries. The implication of this is that most MM diagnosed in these regions are cytogenetically unknown and are not internationally staged. Hence, MM patients do not benefit from accurate risk stratification and prognostic assessments as offered to their counterparts in developed countries [19].

urine monoclonal protein assay, C-reactive protein, beta-2 microglobulin test, marrow study, skeletal survey, echocardiogram, immunophenotyping, cytogenetic tests, etc. (Table 6).

The prevalence of MM is on the increase in developing countries such as those found in Sub-Saharan Africa [3, 14]. The oil-rich regions are worse hit probably due to a wide range of environmental pollution, flaring of gases, water pollution, oil spillage, and lack of effective environmental policies [6]. This is understandable based on the hypothesis that occupation studies of chemical, petroleum, and radiation industry workers have provided inconsistent evidence of causal association with MM [5]. Another potential etiologic factor that could be a key player in the increasing prevalence is the median age of diagnosis. Studies in Nigeria, Africa's most populous black nation, have shown that the median age of diagnosis of multiple

4. Challenges in diagnosis of multiple myeloma

Complete Blood Count and differential count; examination of blood film

Stage I β2M < 3.5

Stage II β2M < 3.5

Stage III β2M > 5.5 ALB, serum albumin in g/dL; β2M,serum β2-microglobulin in mg/L.

β2-microglobulin; C-reactive protein

Table 5. International staging system (ISS).

labeling index (if available) Bone survey and MRI; PET-CT

Data from Greipp et al. [13].

212 Update on Multiple Myeloma

amyloidosis suspected)

Source: In Table 107-4 [9].

Table 6. Assessment of myeloma.

chains

peptide.

Chemistry screen, including calcium, creatinine, lactate dehydrogenase, BNP, proBNP

Serum protein electrophoresis, immunofixation, quantification of immunoglobulin, serum-free light chains

24-hour urine collection for protein electrophoresis, immunofixation, quantification of immunoglobulins, including light

ALB ≥ 3.5

ALB < 3.5 or β2M 3.5–5.5

Marrow aspirate and trephine biopsy with metaphase cytogenetics, FISH, immunophenotyping; gene array, and plasma

BNP, brain natriuretic peptide, CT, computed tomography; EKG, electrocardiogram; FISH, fluorescence in situ hybridization, MRI, Magnetic resonance imaging; PET, positron emission tomography; proBNP, prohormone B-type natriuretic

Echocardiogram with assessment of diastolic function and measurement of interventricular septal thickness; EKG (if

These challenges in diagnoses and disease staging contribute to the poor survival outcome of people living with MM in these regions. In a 10-year retrospective study of 26 MM patients in Niger-delta region of Nigeria, only one (3.8%) of the patients could do a marrow metaphase cytogenetic (FISH) test and this happened to be a high risk category (t(4,14) immunoglobulin A)multiple myeloma [3, 20]. In the study, only four subjects could afford immunofixation test, which showed IgA:IgG-type myeloma ratio of 1:3 and this was in keeping with previous study by Salawu and Durosimi [16].

Surveillance, Epidemiology, and End Results (SEER) cancer statistics review of 1975–2002 and 1975–2007, respectively, in the USA. The implication is that many LMICs are more than 40 years backward in terms of management of MM compared to high-income countries such as the USA. The two major challenges in the treatment of MM in developing countries are

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The standard supportive care for MM patients at advanced stage of the disease, which include the use of analgesics, bisphosphonates (BPs), component blood therapy, antibiotics therapy, renal dialysis viz-a-viz renal transplant, radiotherapy, orthopedic care, is grossly inadequate. Chronic bone pain appears to be one of the commonest clinical features of MM, and analgesic drug is the first supportive therapy offered to patients with the disease. However, in the assessment and treatment of pain in MM patients in some low-income countries such as Nigeria, the WHO analgesic ladder for cancer pain control is not usually adhered to, as only few centers can access oral morphine and other opiate analgesics [27]. This leads to analgesic abuse (self-medication), most of which are nephrotoxic, hence, worsening the prognosis of the disease. A study showed that less than 40% of MM patients could afford BPs. BPs are useful in preventing, reducing, and delaying MM SREs such as bone pain, osteoporosis, and other lytic bone lesions. They can also help to control the growth of extramedullary tumors, hence the

There is a gross inadequate access to radiation therapy in LICs including Nigeria. Studies have shown that only about 3.8–20% (average 12%) of MM patients who need radiotherapy at one point or the other of the disease could access it [3, 17]. The major reason is that the megavoltage radiotherapy machine per population size is grossly inadequate (1-MV machine per 24 million population as against the International Atomic Energy Agency (IAEA) requirement of 1-MV machine per 250,000 population or per 350–400 new cancer patients in centers with excellent

About 60% of MM patients seen in LICs such as Nigeria present with severe grade of anemia (hemoglobin <7 g/dL). The implication is that they will rely on blood transfusion therapy in order to improve the quality of their life. Unfortunately, many of the LICs do not practice safe blood transfusion. They depend majorly on commercial (paid) blood donation as against voluntary non-remunerated blood donation (VNRBD), thereby predisposing the patients to transfusion transmissible infectious diseases (TTIs) including HIV [30]. The facilities for component blood therapy (i.e., apheresis machines) are not available in most health centers. For instance, there was no documented beneficiary from component blood therapy in previous studies in Nigeria. All severely anemic patients that require blood transfusion benefited from either allogeneic whole blood transfusion (50%) or the use of erythroid growth factor such as

Infection is one of the major killers in MM in LICs, especially when immune paresis has set in. About 11.1% of MM patients present with neutropenic sepsis in this region. Infection control is by the use of antibiotic therapy/prophylaxis and colony forming unit-granulocyte-monocyte

anchored on the supportive and definitive treatment of MM.

6.1. Challenges in supportive treatment of MM

need to scale-up their usage in MM [22, 28].

human recombinant erythropoietin (38%) [3, 14].

cancer registry) [29].
