**3. New insights into the pathogenesis of MM**

Despite the recent progress in understanding MM, the pathogenesis of the disease is incompletely understood and is apparently multifactorial in nature [27]. The 10 hallmarks of cancer are: (1) self-sufficiency in growth signaling, (2) evasion of apoptosis, (3) insensitivity to antigrowth mechanisms, (4) tissue invasion and metastases, (5) limitless replicative potential, (6) sustained angiogenesis, (7) avoidance of immune destruction, (8) reprogramming of energy metabolism, (9) tumor-promoting inflammation and (10) genome instability and mutation. All the 10 hallmarks of cancer are present and active in MM and they contribute to tumor initiation, drug resistance, disease progression and relapse [28–30].

and it accounts for approximately 10% of all HMs [8]. The median age of MM at diagnosis is

The diagnostic criteria for MM are: (1) clonal BM plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma and (2) at least one of the following: (a) evidence of end-organ damage such as anemia, lytic bone lesions, hypercalcemia and renal insufficiency, (b) clonal BM plasma cells ≥60%, (c) involved:uninvolved serum free light chain ratio ≥100 and (d) at

MM is usually classified into three stages: (1) stage I; all the following: serum albumin ≥3.5 g/ dL, serum beta 2 microglobulin (B2M) < 3.5 mg/L, normal serum lactic dehydrogenase (LDH) and no high-risk (HR) cytogenetics; (2) stage II: not fitting stages I and III with serum B2M: 3.5–5.5 mg/L, and (3) stage III; all the following: serum B2M > 3.5 mg/L and HR cytogenetics

The following cytogenetic abnormalities have been reported in patients with MM: trisomies; monosomies; 17 p deletion; amp (1q20); t(14,16); t(14,20); t(4,14); t(6,14) and t(11,14) [8, 13, 16]. Also, the following molecular mutations have been reported in MM patients: NRAS, KRAS, TP53, BRAF, CCND1, FAM46C, MYC, XBP1, EZH2 and CHST15 [17–21]. Recently, the following laboratory techniques have been utilized in the diagnosis and follow-up of patients with MM: (1) next-generation sequencing (NGS), (2) genomic and epigenetic studies, (3) micro-RNA and (4) minimal residual disease (MRD) evaluation by flow cytometry, polymerase chain reaction, and NGS [17–22]. Mass accumulation rate will be used in the near future for

The HR features in MM include: (1) cytogenetic and molecular abnormalities that include: hypodiploid, 17 p deletion, t(4,14), t(14,16), t(14,20) and EZH2; (2) international scoring system stage II or III; (3) presence of comorbid medical conditions that limit therapy; (4) extramedullary disease (EMD) and (5) renal failure, high serum LDH level and plasma cell leukemia [13, 16, 21, 24, 25]. MM patients are stratified into three risk groups based on their cytogenetic profiles as follows: (1) HR that includes 17 p deletion, t(14,16) or t(14,20); (2) intermediate risk that includes: t(4,14) and amp (1q20)/gain (1q) and (3) standard risk that includes: trisomies, t(11,14) and t(6,14) [8, 13, 16]. Additional poor prognostic features include: age ≥60 years and

Despite the recent progress in understanding MM, the pathogenesis of the disease is incompletely understood and is apparently multifactorial in nature [27]. The 10 hallmarks of cancer are: (1) self-sufficiency in growth signaling, (2) evasion of apoptosis, (3) insensitivity to antigrowth mechanisms, (4) tissue invasion and metastases, (5) limitless replicative potential, (6) sustained angiogenesis, (7) avoidance of immune destruction, (8) reprogramming of energy metabolism, (9) tumor-promoting inflammation and (10) genome instability and mutation.

70 years in the United States of America (USA) and 72 years in Europe [9].

**2. Diagnosis, staging, genetics and risk stratification**

least two focal lesions on magnetic resonance imaging [8, 10–15].

susceptibility of human MM cell lines to standard-of-care therapies [23].

or elevated serum LDH level [8, 13].

128 Update on Multiple Myeloma

refractory and/or relapsed MM (R/R-MM) [26].

**3. New insights into the pathogenesis of MM**

BM adipose tissue is a newly recognized contributor to MM oncogenesis and disease progression, particularly affecting MM cell metabolism, immune action and inflammation in addition to influencing angiogenesis [28]. BM adipose tissue may support MM through: (1) bioactive lipids such as fuel source, signaling molecule and substrate for lipid peroxidation and (2) MM supportive adipokines such as interleukin (IL)-6, tumor necrosis factor-α, MCP-1, PAI-1, resistin and leptin. The interaction between hypoxia, BM adipose tissue and angiogenesis is complicated [28].

The BM niche in patients with MM appears to play an important role in differentiation, migration, survival and drug resistance of malignant plasma cells [31, 32]. The BM niche is composed of (1) cellular compartment that contains the following constituents: hematopoietic and nonhematopoietic cells, stromal cells, osteoblasts, osteoclasts, endothelial cells and immune cells and (2) noncellular compartment, which has the following constituents: extracellular matrix (ECM) and liquid milieu that has cytokines, chemokines and growth factors [31–34]. MM cells home to the BM, adhere to the ECM and BM stromal cells. Trafficking or homing ingress allows progression or metastasis of disease to new BM sites [31].

Bone destruction is the hallmark of MM and is mediated by osteoblasts [35]. Osteoblasts are the most important components of the MM microenvironment. They largely affect disease progression either directly or indirectly. Also, they may slow MM growth [36]. Normally, there is a balance between osteoblastic and osteoclastic activity and imbalance leads to development of disease lesions. Hence, increased osteoclastic activity is associated with MM [37]. Osteoclasts are the primary mediators of bone resorption in both healthy and pathological bone turnover. Bone anabolic agents hold potential for antimyeloma and antiosteolysis therapies [36].

MM pathophysiology is the result of the interaction between clonal plasma cells and the surrounding BM microenvironment [31, 32, 38–40]. BM angiogenesis represents a constant hallmark of MM progression partly driven by the release of proangiogenic cytokines from the tumor plasma cells, BM stromal cells and osteoclasts such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and metalloproteinases [31]. Also, BM stromal cells from MM patients express several proangiogenic molecules such as VEGF, bFGF, angiopoietin-1, transforming growth factor-β, hepatocyte growth factor, platelet-derived growth factor and IL-1 [31]. The signaling pathways that are active in MM microenvironment include Ras GAP, FAK, phosphoinositide 3-kinase (PI-3K)-akt, MEK-ERK and STAT [38]. Other signaling pathways that may also become new therapeutic targets in MM include RANKL, DKK1, sclerostin and activing-A [31, 39].

MicroRNAs play a crucial role in cancer progression [40]. They are the novel crossroads between MM cells and MM microenvironment [41]. Several microRNAs are dysregulated in MM [40]. Dysregulation of microRNAs in MM cells and MM microenvironment has important impacts on initiation of MM, disease progression and drug resistance [42, 43]. Approximately 95 microRNAs are expressed at high levels in MM, particularly miR-125b, miR-133a, miR-1 and miR-124a [40]. Deregulated microRNAs target genes regulating cell cycle, apoptosis, survival and cell growth [40]. Interactions between various constituents of BM microenvironment, particularly MM mesenchymal stem cells and MM cancer stem cells, 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 MM [27, 53–58].

Myeloma Working Group response criteria and new studies have demonstrated that achievement of MRD negativity is a stronger predictor of survival than is traditional com-

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

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

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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

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].

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

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

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

cell hemolysis and reduction in platelet aggregation and activity [78].

plete response (CR) [72].

**6.1. Autologous HSCT**

of early autologous HSCT [75].

**6. HSCT in patients with MM**
