**6. HSCT in patients with MM**

#### **6.1. Autologous HSCT**

may be involved in disease initiation such as bone involvement, disease progression, relapse and drug resistance, so microRNAs may become very useful in designing targeted therapies in the field of precision medicine [27, 44–52]. Additionally, circulating microRNAs may serve as diagnostic and prognostic markers due to their impact on gene expression, biological function and survival, and microRNA-based assays may help in improving risk stratification in

Over the past two decades, management of MM has dramatically changed and this has translated into significant improvements in disease outcomes and prognosis. This unprecedented progress can be attributed to (1) the application of high-dose (HD) chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT), (2) improvement in supportive care strategies and (3) the introduction of several novel agents particularly immunomodulatory agents and proteasome inhibitors in the treatment of patients with MM [10, 13, 16, 59–61]. Cytotoxic agents that have been used in the treatment of MM include (1) corticosteroids such as dexamethasone and prednisolone, (2) conventional chemotherapies including melphalan, cyclophosphamide, liposomal doxorubicin, bendamustine, carmustine (BCNU), D-PACE (dexamethasone, cisplatin, doxorubicin, cyclophosphamide, etoposide) and DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin) [62]. However, remarkable improvements in survival of patients with MM have been achieved following the introduction of thalidomide, bortezomib and lenalidomide, as well as the recent introduction and approval of the following novel therapeutic agents: (1) newer proteasome inhibitors such as carfilzomib and ixazomib; (2) histone deacetylase inhibitors such as panobinostat and vorinostat; (3) new immunomodulatory drugs such as pomalidomide; (4) monoclonal antibodies such as daratumumab and elotuzumab; (5) Bruton tyrosine kinase inhibitors such as ibrutinib; (6) IL-6 inhibitors such as siltuximab; (7) PI-3 K inhibitors and (8) various immunotherapeutic

strategies including chimeric antigen receptor (CAR) T cells [10, 13, 15, 62–64].

Several studies have shown that VRD (bortezomib, lenalidomide, dexamethasone) regimen is well tolerated and highly effective in the treatment of newly diagnosed MM patients [65–70]. Once used as first-line therapy for MM, VRD has been shown to be superior to the doublet regimen of lenalidomide plus dexamethasone, as well as the triplet regimens VCD (bortezomib, cyclophosphamide, dexamethasone) and VTD (bortezomib, thalidomide, dexamethasone) [68]. Carfilzomib, lenalidomide, dexamethasone (KRD) is an alternative promising regimen but has only been evaluated in small phase II studies in the frontline setting [68].

Response criteria in patients with MM subjected to various therapeutic regimens include MRD evaluation by multicolor flow cytometry or sequencing on bone marrow samples and imaging for EMD [59, 71]. MRD has recently been incorporated into the International

**5. Frontline and induction therapies in MM**

MM [27, 53–58].

130 Update on Multiple Myeloma

**4. Management of MM**

Autologous HSCT, performed at the time of initial diagnosis or at relapse, is considered the standard of care for patients with newly diagnosed MM who are younger than 70 years [8, 73, 74]. Even in the era of novel therapies, timing of performance of autologous HSCT, whether upfront or at relapse, is still controversial although there is global consensus strongly in favor of early autologous HSCT [75].

Autologous HSCT is not curative for MM [8, 73]. Allogeneic HSCT is the only curative therapy for MM but at the expense of increased treatment-related mortality (TRM), so candidates for allografts should be carefully selected from the pool of young patients with R/R-MM [76]. Several randomized clinical trials have shown that, compared with conventional chemotherapy alone, HD chemotherapy followed by stem cell rescue is associated with prolonged eventfree survival (EFS) and overall survival (OS) [8, 73, 74]. The recent widespread implementation of autologous HSCT in conjunction with novel therapies has revolutionized the management of MM and has markedly altered the natural history of the disease by improving disease responses and response duration ultimately leading to significant improvement in OS [73].

Eligibility for autologous HSCT is determined by age, performance status, presence and severity of comorbid medical conditions, and frailty score as frailty has been shown to be a predictor of short survival and is considered an exclusion criterion for autologous HSCT [8].

#### **6.2. Cryopreservation versus noncryopreservation of stem cells**

For most types of transplants, cryopreservation of HSCs is necessary and is an essential component of the clinical protocol [77]. Dimethyl sulfoxide (DMSO) is widely used as a cryopreservant for various types of stem cells and other body tissues. It has the following adverse effects: skin irritation, garlic breath or body odor; abdominal pain, nausea, vomiting and diarrhea; bronchospasm, chest tightness and dyspnea; altered heart rate and blood pressure, arrhythmias, heart block and myocardial ischemia; various degrees of organ dysfunction and death [77, 78]. Additionally, DMSO has in vitro toxicity in the form of induction of red blood cell hemolysis and reduction in platelet aggregation and activity [78].

Several studies and one meta-analysis have shown that noncryopreserved autologous HSCT for MM is simple, safe and cost-effective and gives results that are at least equivalent to autologous HSCT with cryopreservation [79–84]. TRM at day 100 post-HSCT has ranged between 0.0 and 3.4% [80, 82–84]. Noncryopreserved stem cells can be infused till day 5 postapheresis without viability loss provided they are stored at +4°C in conventional blood bank refrigerator [79, 81, 82, 84]. In a systematic review that included 16 studies having 560 patients with various HMs including MM, hematopoietic engraftment was universal and only one graft failure was reported [79, 81]. The median times for engraftment following noncryopreserved autografts were 9–14 days for neutrophils and 14–25 days for platelets [79, 81]. Other recent studies on noncryopreserved autologous HSCT in patients with MM have shown the following results: neutrophil engraftment between 10 and 14 days and platelet engraftment between 13 and 25 days postautologous HSCT [85–92].

performance status and favorable comorbidity profile [91]. Lack of caregiver is a limiting factor

Hematopoietic Stem Cell Transplantation in Multiple Myeloma in the Era of Novel Therapies

http://dx.doi.org/10.5772/intechopen.79999

133

Even before the era of novel therapies, tandem autologous HSCT had been performed in patients with MM and the results of tandem transplants showed superior outcomes compared to single autologous HSCTs [102, 103]. Later on, two single-center retrospective analyses showed higher rates of progression-free survival (PFS) and OS in patients subjected to tandem autologous HSCT compared to recipients of single autologous HSCT [104, 105]. A meta-analysis that included six studies comparing tandem to single autologous HSCT in patients with MM showed: (1) no difference between the two forms of autologous HSCT with respect to OS and EFS and (2) tandem autologous HSCT was associated with improved response rates but at the expense of increased TRM [106]. However, this meta-analysis was

Several studies have shown that a second autologous HSCT used as part of salvage therapy in patients with MM relapsing after the first autologous HSCT has been found to be safe and feasible particularly in carefully selected patients [108–112]. Factors associated with the success of second autologous HSCT include younger age, B2M < 2.5 mg/L at diagnosis, remission duration >9 months from first autologous HSCT, > partial response achieved in response to the first autologous HSCT and performance of second autologous HSCT before relapse and

Although allogeneic HSCT represents the only potentially curative therapeutic modality in patients with MM, it is associated with relatively high TRM [76, 115, 116]. The advent of reduced intensity conditioning (RIC) and the application of autologous-allogeneic tandem HSCT approaches have broadened the use of allogeneic HSCT in patients with MM. Autologousallogeneic tandem HSCT may overcome the negative impact of 17 p deletion and/or t(4,14) and the achievement of molecular remission in patients having HR cytogenetics has resulted

In patients with HR disease or those relapsing after autologous HSCT, particularly younger patients who are fit for allografts, salvage therapy with novel agents followed by RIC allogeneic HSCT has been shown to provide significant PFS benefit [76, 118–121]. In patients lacking human leukocyte antigen (HLA)-matching sibling donors, alternate donors such as matched unrelated donors, cord blood transplantation and haploidentical forms of allogeneic HSCT have been employed and they have shown feasibility and effectiveness [115, 122–124].

Almost all patients with MM relapse after autologous HSCT. Hence, treatment given in the postautologous HSCT period is aimed at suppression of residual disease in order to prolong

criticized as it included a study with significant statistical errors [107].

within 6–12 months from the first autologous HSCT [113, 114].

**7. Consolidation and maintenance therapies in MM**

duration of response, OS and PFS while minimizing toxicity [125, 126].

for outpatient autologous HSCT [92].

**6.4. Tandem and second AHSCT**

**6.5. Allogeneic HSCT in MM**

in long-term freedom from disease [117].

Melphalan is the standard chemotherapeutic agent that is used in the conditioning therapy prior to autologous HSCT in MM. The dose ranges between 140 and 200 mg/m2 , given intravenously (IV) [79, 81, 82, 93]. It is cleared from plasma and urine in 1 and 6 hours, respectively. Stem cells can be safely infused as early as 8–24 hours following melphalan administration [79, 81].

Recently, other drugs have been used in the conditioning therapy prior to autologous HSCT in MM either alone or in combination with HD melphalan [94–97]. Compared to HD melphalan, the use of ixazomib, BCNU, bortezomib and IV busulfan either alone or in various combinations with HD melphalan in the conditioning therapies has increased the overall response rates and the median OS without additional toxicity [93–97].

HSCT without cryopreservation has several advantages including (1) simplicity of implementation, (2) allowing autologous HSCT to be performed entirely as outpatient, (3) reduction of transplantation costs, (4) reducing the time between the last induction therapy and HD chemotherapy, (5) prevention of DMSO toxicity, (6) no significant loss of viability of the collected HSCs provided stem cell infusion is made within 5 days of apheresis, (7) expansion of the number of medical institutions performing stem cell therapies and (8) potent engraftment syndrome and autologous graft versus host disease (GVHD) [79–84, 98, 99]. HSCT without cryopreservation has the following disadvantages: (1) plenty of coordination is needed between various teams regarding timing of stem cell mobilization, apheresis, administration of conditioning therapy and infusion of stem cells; (2) limitation of the use of standard HD chemotherapy schedules such as BEAM (BCNU, etoposide, cytarabine and melphalan) employed in the autologous HSCT for lymphoma and (3) inability to store part of the collection and reserving it for a second autologous HSCT in case a rich product is obtained [79–84].

#### **6.3. Outpatient HSCT**

MM is the leading indication for autologous HSCT worldwide. Patients with MM are ideal candidates for outpatient autologous HSCT because of the following reasons: the ease of administering HD melphalan, the relatively low extra-hematological toxicity and the short period of neutropenia [85].

Outpatient autologous HSCT for MM is not yet established as a routine procedure, due to reluctance of certain centers and due to the absence of guidelines. However, reduction of costs and period of hospitalization are the driving forces behind the adoption of outpatient HSCT. The mixed inpatient/outpatient model has been shown to be highly feasible with very low rates of rehospitalization and TRM [100, 101].

Several studies have shown safety, feasibility and cost-effectiveness of outpatient autologous HSCT for MM [86–90]. Selection criteria for outpatient autologous HSCT include expected compliance, proximity to the HSCT center for daily visits, 24-hour caregiver support, favorable performance status and favorable comorbidity profile [91]. Lack of caregiver is a limiting factor for outpatient autologous HSCT [92].

#### **6.4. Tandem and second AHSCT**

various HMs including MM, hematopoietic engraftment was universal and only one graft failure was reported [79, 81]. The median times for engraftment following noncryopreserved autografts were 9–14 days for neutrophils and 14–25 days for platelets [79, 81]. Other recent studies on noncryopreserved autologous HSCT in patients with MM have shown the following results: neutrophil engraftment between 10 and 14 days and platelet engraftment between

Melphalan is the standard chemotherapeutic agent that is used in the conditioning therapy

nously (IV) [79, 81, 82, 93]. It is cleared from plasma and urine in 1 and 6 hours, respectively. Stem cells can be safely infused as early as 8–24 hours following melphalan administration

Recently, other drugs have been used in the conditioning therapy prior to autologous HSCT in MM either alone or in combination with HD melphalan [94–97]. Compared to HD melphalan, the use of ixazomib, BCNU, bortezomib and IV busulfan either alone or in various combinations with HD melphalan in the conditioning therapies has increased the overall response

HSCT without cryopreservation has several advantages including (1) simplicity of implementation, (2) allowing autologous HSCT to be performed entirely as outpatient, (3) reduction of transplantation costs, (4) reducing the time between the last induction therapy and HD chemotherapy, (5) prevention of DMSO toxicity, (6) no significant loss of viability of the collected HSCs provided stem cell infusion is made within 5 days of apheresis, (7) expansion of the number of medical institutions performing stem cell therapies and (8) potent engraftment syndrome and autologous graft versus host disease (GVHD) [79–84, 98, 99]. HSCT without cryopreservation has the following disadvantages: (1) plenty of coordination is needed between various teams regarding timing of stem cell mobilization, apheresis, administration of conditioning therapy and infusion of stem cells; (2) limitation of the use of standard HD chemotherapy schedules such as BEAM (BCNU, etoposide, cytarabine and melphalan) employed in the autologous HSCT for lymphoma and (3) inability to store part of the collection and reserving it for a second autologous HSCT in case a rich product is obtained [79–84].

MM is the leading indication for autologous HSCT worldwide. Patients with MM are ideal candidates for outpatient autologous HSCT because of the following reasons: the ease of administering HD melphalan, the relatively low extra-hematological toxicity and the short

Outpatient autologous HSCT for MM is not yet established as a routine procedure, due to reluctance of certain centers and due to the absence of guidelines. However, reduction of costs and period of hospitalization are the driving forces behind the adoption of outpatient HSCT. The mixed inpatient/outpatient model has been shown to be highly feasible with very

Several studies have shown safety, feasibility and cost-effectiveness of outpatient autologous HSCT for MM [86–90]. Selection criteria for outpatient autologous HSCT include expected compliance, proximity to the HSCT center for daily visits, 24-hour caregiver support, favorable

, given intrave-

prior to autologous HSCT in MM. The dose ranges between 140 and 200 mg/m2

rates and the median OS without additional toxicity [93–97].

13 and 25 days postautologous HSCT [85–92].

[79, 81].

132 Update on Multiple Myeloma

**6.3. Outpatient HSCT**

period of neutropenia [85].

low rates of rehospitalization and TRM [100, 101].

Even before the era of novel therapies, tandem autologous HSCT had been performed in patients with MM and the results of tandem transplants showed superior outcomes compared to single autologous HSCTs [102, 103]. Later on, two single-center retrospective analyses showed higher rates of progression-free survival (PFS) and OS in patients subjected to tandem autologous HSCT compared to recipients of single autologous HSCT [104, 105]. A meta-analysis that included six studies comparing tandem to single autologous HSCT in patients with MM showed: (1) no difference between the two forms of autologous HSCT with respect to OS and EFS and (2) tandem autologous HSCT was associated with improved response rates but at the expense of increased TRM [106]. However, this meta-analysis was criticized as it included a study with significant statistical errors [107].

Several studies have shown that a second autologous HSCT used as part of salvage therapy in patients with MM relapsing after the first autologous HSCT has been found to be safe and feasible particularly in carefully selected patients [108–112]. Factors associated with the success of second autologous HSCT include younger age, B2M < 2.5 mg/L at diagnosis, remission duration >9 months from first autologous HSCT, > partial response achieved in response to the first autologous HSCT and performance of second autologous HSCT before relapse and within 6–12 months from the first autologous HSCT [113, 114].

#### **6.5. Allogeneic HSCT in MM**

Although allogeneic HSCT represents the only potentially curative therapeutic modality in patients with MM, it is associated with relatively high TRM [76, 115, 116]. The advent of reduced intensity conditioning (RIC) and the application of autologous-allogeneic tandem HSCT approaches have broadened the use of allogeneic HSCT in patients with MM. Autologousallogeneic tandem HSCT may overcome the negative impact of 17 p deletion and/or t(4,14) and the achievement of molecular remission in patients having HR cytogenetics has resulted in long-term freedom from disease [117].

In patients with HR disease or those relapsing after autologous HSCT, particularly younger patients who are fit for allografts, salvage therapy with novel agents followed by RIC allogeneic HSCT has been shown to provide significant PFS benefit [76, 118–121]. In patients lacking human leukocyte antigen (HLA)-matching sibling donors, alternate donors such as matched unrelated donors, cord blood transplantation and haploidentical forms of allogeneic HSCT have been employed and they have shown feasibility and effectiveness [115, 122–124].
