Open access peer-reviewed chapter

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

Written By

Khalid Ahmed Al-Anazi

Submitted: May 24th, 2018 Reviewed: July 6th, 2018 Published: November 5th, 2018

DOI: 10.5772/intechopen.79999

Chapter metrics overview

1,443 Chapter Downloads

View Full Metrics

Abstract

Multiple myeloma is the second commonest hematologic malignancy. It is characterized by neoplastic proliferation of a single clone of plasma cells in the bone marrow producing a monoclonal immunoglobulin and ultimately causing various complications and organ dysfunction. Over the last 10 years, management of multiple myeloma has dramatically changed due to the introduction of several novel therapies that have improved the disease outcome and prognosis, as well as the quality of life of patients with myeloma due to their safety, tolerability and efficacy. Additionally, the widespread utilization of autologous hematopoietic stem cell transplantation, which is still the standard of care for transplant-eligible patients, and the implementation of new therapeutic strategies such as drug combinations in addition to consolidation and maintenance therapies have resulted in further improvements in response rates and survival in patients with multiple myeloma. This book chapter will be an update on the novel therapies and the recent treatment strategies in myeloma. The role of stem cell treatments in the era of novel therapies will be discussed thoroughly.

Keywords

  • multiple myeloma
  • hematopoietic stem cell transplantation
  • novel therapies
  • monoclonal antibodies

1. Introduction

Multiple myeloma (MM) is an incurable, debilitating and heterogeneous malignancy that has highly variable clinical course [1, 2, 3, 4, 5, 6]. It is a plasma cell neoplasm characterized by neoplastic proliferation of a single clone of plasma cells in the bone marrow (BM) producing a monoclonal immunoglobulin and causing anemia, renal failure, bone destruction and infectious complications [7, 8, 9]. It is the second most commonly diagnosed hematologic malignancy (HM) and it accounts for approximately 10% of all HMs [8]. The median age of MM at diagnosis is 70 years in the United States of America (USA) and 72 years in Europe [9].

Advertisement

2. Diagnosis, staging, genetics and risk stratification

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 least two focal lesions on magnetic resonance imaging [8, 10, 11, 12, 13, 14, 15].

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 or elevated serum LDH level [8, 13].

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, 18, 19, 20, 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, 18, 19, 20, 21, 22]. Mass accumulation rate will be used in the near future for susceptibility of human MM cell lines to standard-of-care therapies [23].

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

Advertisement

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, 29, 30].

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, 32, 33, 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, 39, 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, 45, 46, 47, 48, 49, 50, 51, 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, 54, 55, 56, 57, 58].

Advertisement

4. Management of MM

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, 60, 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, 63, 64].

Advertisement

5. Frontline and induction therapies in MM

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, 66, 67, 68, 69, 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 Myeloma Working Group response criteria and new studies have demonstrated that achievement of MRD negativity is a stronger predictor of survival than is traditional complete response (CR) [72].

Advertisement

6. HSCT in patients with MM

6.1. Autologous HSCT

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 event-free 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, 80, 81, 82, 83, 84]. TRM at day 100 post-HSCT has ranged between 0.0 and 3.4% [80, 82, 83, 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, 86, 87, 88, 89, 90, 91, 92].

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, 95, 96, 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, 94, 95, 96, 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, 80, 81, 82, 83, 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, 80, 81, 82, 83, 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, 87, 88, 89, 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

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, 109, 110, 111, 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. Autologous-allogeneic 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, 119, 120, 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, 123, 124].

Advertisement

7. Consolidation and maintenance therapies in MM

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

The use of novel therapies in the consolidation phase following single or tandem autologous HSCT has been shown to enhance the rate as well as the quality of response thus contributing to improvements in clinical outcomes including prolongation of PFS [126]. Bortezomib-based regimens used as consolidation therapy after autologous HSCT in patients with MM have been shown to be effective in the improving PFS and decreasing relapse rate [127].

Maintenance therapy represents an important therapeutic strategy to delay disease progression and relapse [125, 126]. The following drugs have been used in postautologous HSCT maintenance: interferon, thalidomide, bortezomib and carfilzomib [125, 126, 128, 129, 130]. Bortezomib is safe, well tolerated and efficacious and it can be used with no risk of second malignancy till disease progression, but its disadvantages include cost and effects on quality of life (QoL) [126, 130].

In February 2017, the Food and Drug Administration in the USA approved the use of lenalidomide as maintenance therapy after autologous HSCT for patients with MM, after showing efficacy and safety in several studies [131]. Lenalidomide has tumoricidal and immunomodulatory activities against MM [132]. Several studies have shown the efficacy of lenalidomide maintenance after autologous HSCT as this therapy has been shown to be associated with significant improvements in OS, PFS and longer time to disease progression [133, 134, 135, 136]. A multicenter, randomized double-blind study that included 306 patients with newly diagnosed MM ≥65 years of age and ineligible for autologous HSCT treated initially with melphalan, prednisolone and lenalidomide induction followed by lenalidomide versus placebo maintenance showed the following results: (1) significant prolongation of PFS, (2) maximum benefit was achieved in patients 65–75 years of age and (3) 3-year second primary tumor of 7% in the lenalidomide arm versus 3% in the placebo arm [132]. Other studies on lenalidomide maintenance have shown more toxicity and low rate of development of second tumors [133, 134]. Lenalidomide maintenance can be initiated as early as day 100 postautologous HSCT [133]. Duration of lenalidomide maintenance longer than 3 years has been associated with further improvement in survival [134]. Several studies performed in patients with newly diagnosed MM subjected to autologous HSCT have shown continuous therapy to be more effective in prolongation of OS and PFS that limited the duration of treatment [137, 138, 139, 140, 141].

Advertisement

8. Novel therapies in MM

The novel therapies that have recently been introduced into the treatment of MM include (1) proteasome inhibitors such as bortezomib, carfilzomib and ixazomib; (2) immunomodulatory agents such as thalidomide, lenalidomide and pomalidomide; (3) monoclonal antibodies such as daratumumab and elotuzumab and (4) histone deacetylase inhibitors such as panobinostat, in addition to other classes of medications that can also be used in the treatment of MM such as glucocorticoids, DNA alkylating agents, as well as doxorubicin, cisplatinum and etoposide [10, 13, 15, 62, 63, 64]. Novel agents and targeted therapies that are either currently used or under development for the treatment of MM are shown in Table 1 [61, 62, 142, 143, 144, 145, 146, 147, 148, 149, 150].

  1. Monoclonal antibodies: Anti-CD 38 (daratumumab, elotuzumab, isatuximab, MOR202), anti-CD138 (indatuximab ravtansine), anti-interleukin-6 (siltuximab), anti-RANKL (denosumab), anti-KIR2DL1/2/4 (IPH2101)

  2. Immunomodulatory agents: thalidomide, lenalidomide, pomalidomide

  3. Proteasome inhibitors: bortezomib, carfilzomib, ixazomib

  4. Histone deacetylase inhibitors: panobinostat, vorinostat, romidepsin, ricolinostat

  5. mTOR inhibitors: everolimus, temsirolimus

  6. Checkpoint (programmed cell death protein 1) inhibitors: nivolumab, pembrolizumab

  7. Bruton’s tyrosine kinase inhibitors: ibrutinib

  8. BCL2 antagonists (BH3 mimetics): venetoclax, obatoclax, navitoclax

  9. Cyclin-dependent kinase inhibitors: dinaciclib

  10. MEK inhibitors: selumetinib

  11. Kinesin spindle protein 1 inhibitors: filanesib, array 520

  12. Selective inhibitors of nuclear transport: selinexor

  13. Phosphoinositide 3-kinase-Akt inhibitors: perifosine, afuresertib

  14. PIM kinase inhibitors: LGH 447

  15. Vaccines: PVH-410

  16. Chimeric antigen receptor T cells (CAR T cells): directed against:

    1. CD-19

    2. CD-38

    3. B-cell maturation antigen

    4. Cell surface glycoprotein

Table 1.

Novel agents and targeted therapies that are either currently used or under development for the treatment of multiple myeloma.

Several cell cycle regulatory proteins have been proposed as therapeutic targets in patients with MM. Other targets that have already been identified in MM include microtubules, kinesin motor proteins, aurora kinases, polo-like kinases and the anaphase-promoting complex/cyclosome [151]. The novel therapies that are used in the treatment of MM differ in their modes of action. Nevertheless, each drug has its own side effects that should be considered particularly once treating patients with comorbid medical conditions and once these novel agents are used in combination with other drugs [152].

8.1. Daratumumab

Daratumumab is a human IgGk monoclonal antibody that targets CD38, which is a cell surface protein that is overexpressed in MM cells. It is given IV at a dose of 16 mg/kg weekly [153, 154, 155, 156]. It induces death of MM cells by several mechanisms including (1) complement-dependent cytotoxicity, (2) antibody-dependent cell-mediated cytotoxicity, (3) antibody-dependent cellular phagocytosis and (4) apoptosis [153, 154, 155, 156].

Daratumumab has shown substantial efficacy as monotherapy in heavily pretreated patients with MM as well as in combination with bortezomib in patients with newly diagnosed MM [154]. Two phase III randomized clinical trials in R/R MM using daratumumab in combination with either bortezomib and dexamethasone or lenalidomide and dexamethasone showed significantly longer PFS with manageable toxicity [154, 156]. In a phase III randomized clinical trial performed in patients with newly diagnosed MM, not eligible for autologous HSCT, the addition of daratumumab to bortezomib, melphalan and prednisolone decreased the risk of death and disease progression but was also associated with higher rates of infections [155]. The adverse effects of daratumumab include infusion-related reactions, hematologic toxicity in the form of neutropenia and thrombocytopenia and various infectious complications [153, 154, 155, 156].

8.2. Elotuzumab

Elotuzumab is an immunostimulatory monoclonal antibody targeting signaling lymphocyte activation molecule F7 (SLAMF7) [157]. While no responses to elotuzumab as a single agent were obtained, the addition of elotuzumab to lenalidomide and dexamethasone in RR-MM patients resulted in overall response rate (ORR) of 79% compared to 66% ORR obtained with lenalidomide and dexamethasone alone [142, 158]. Also, in a phase III randomized clinical trial in patients with R/R-MM, the combination of elotuzumab, lenalidomide and dexamethasone decreased the risks of death and disease progression by 30% [157].

8.3. Pomalidomide

Pomalidomide is a third-generation immunomodulatory agent that has been approved for patients with progressive MM or those who have received at least two lines of therapy [159]. It has been shown to be effective in combination with dexamethasone ± carfilzomib or other agents in patients with R/R-MM or in those with HR cytogenetics [159, 160, 161, 162]. The use of pomalidomide combined with low-dose dexamethasone in heavily pretreated patients with R/R-MM has been shown to be cost-effective as the combination has produced clinical outcomes comparable to those obtained by daratumumab alone or carfilzomib alone [5].

8.4. Carfilzomib

Carfilzomib is a second-generation proteasome inhibitor [163]. It is well tolerated and causes minimal neurotoxicity. It has demonstrated promising activity in patients with MM who are refractory to bortezomib or immunomodulatory agents [163, 164, 165]. It can be combined with dexamethasone or other novel agents [164, 165, 166].

It is able to sensitize 24% of bortezomib-refractory MM patients. When combined with dexamethasone in R/R-MM, it resulted in superior outcome in terms of ORR and PFS compared to bortezomib and dexamethasone combination [158]. Also, it is under evaluation for patients with newly diagnosed MM [166].

8.5. Panobinostat

Histone deacetylase inhibitors such as panobinostat and vorinostat have demonstrated some activity against MM and they have multiple proposed mechanisms of actions once used in the treatment of MM [167]. Panobinostat is a potent oral pan-deacetylase inhibitor. It affects growth and survival of MM cells through alteration of (1) gene expression through epigenetic modification and (2) protein metabolism by inhibiting protein degradation [168, 169, 170, 171]. The approval of panobinostat for the treatment of MM was based on the results of phase III randomized double-blind clinical trial (PANORAMA 1), which demonstrated improvement in median PFS of 7.8 months for panobinostat, bortezomib and dexamethasone in comparison with placebo, bortezomib and dexamethasone [168, 169, 170, 171]. Panobinostat, in combination with bortezomib and dexamethasone, was recently approved in the USA, Europe and Japan for the treatment of patients with MM who had failed at least two prior regimens including bortezomib and an immunomodulatory agent [168, 169, 170, 171]. A meta-analysis that included 11 clinical trials and 700 patients with R/R-MM treated with panobinostat demonstrated not only efficacy but also safety of panobinostat in combination with other agents [172]. The main toxic effects of panobinostat are thrombocytopenia and diarrhea. However, several studies showed other adverse effects including lymphopenia, neutropenia and anemia, nausea, vomiting, constipation and abdominal pain, asthenia, fatigue, peripheral edema and peripheral neuropathy [167, 168, 169, 170, 171, 172]. Ongoing clinical trials are evaluating the role of panobinostat in combination with drugs other than bortezomib in R/R-MM, in combination with various drugs in newly diagnosed disease and in maintenance therapy of myeloma [169].

8.6. CAR T cells

CAR is a hybrid antigen receptor that is composed of an extracellular antigen-binding domain and an intracellular signaling domain. T cells genetically targeted with a CAR to B-cell malignancies have demonstrated tremendous clinical outcome [173]. Immunotherapy using CAR-mediated T cells has demonstrated high response rates in patients with B-cell malignancies. CAR T-cell therapy is a cellular therapy that redirects a patient’s T cells to specifically target and destroy tumor cells [174]. CARs are genetically engineered fusion proteins composed of antigen recognition domain derived from a monoclonal antibody as well as an intracellular T-cell signaling domain and a costimulatory domain [174].

There are multiple steps in the production of CAR T cells and these include (1) leukapheresis to separate leukocytes; (2) enrichment of leukapheresis product with T cells; (3) separation of T-cell subsets at the level of CD4/CD8 composition using specific antibody-based conjugates or markers; (4) T-cell selection or activation, gene transfer or genetic modification and viral transduction; (5) volume expansion of T cells, isolation, washing and culture followed by cryopreservation and (6) infusion of CAR T cells [174, 175].

Adverse effects of CAR T-cell therapy include cytokine release syndrome (CRS), neurotoxicity, on target/off tumor recognition and anaphylaxis. Additionally, theoretical toxicities of CAR T cells include clonal expansion secondary to insertional oncogenesis, GVHD and off-target antigen recognition [176]. Management of CAR T-cell toxicity includes supportive measures, immunosuppression with tocilizumab (IL-6) receptor blockade for CRS and suicide or elimination genes to allow for selective depletion of CAR T cells [176].

CAR expressing T cells have demonstrated success in the treatment of B-cell lymphoid malignancies particularly CD19+ acute lymphoblastic leukemia and chronic lymphocytic leukemia [177]. Cell surface glycoprotein (CS1) is highly expressed on MM cells and is an ideal target for the treatment of MM, that is, CS1 can be targeted by CAR natural killer cells to treat MM [177]. A patient with advanced and refractory MM received myeloablative treatment with melphalan 140 mg/m2, followed by autologous HSCT, and then infusion of CTL019 CAR resulted in CR with no disease progression for 12 months after CAR T-cell infusion [178]. CAR T cells can target the following antigens in patients with MM: B-cell maturation antigen (BCMA), CD138, CD19 and kappa-light chain [179]. A bispecific T-cell engager (BiTE) targeting BCMA and CD3E (BI 836909) has been developed and it has been shown to be highly potent and efficacious to selectively deplete BCMA-positive MM cells; thus, it represents a novel immunotherapeutic approach in the treatment of MM [180]. CARs are proteins that incorporate antigen domain, costimulatory domains and T-cell activation domains [181]. Only a limited number of patients with MM received CAR T-cell therapy, but preliminary results are encouraging [179].

BCMA is only expressed on some B cells, normal plasma cells and malignant plasma cells. The first clinical trial using CAR T cells targeting BCMA that is expressed in most cases of MM included 12 patients [181]. After dose escalation in the infusion of CAR-BCMA cells was used, the trial showed remarkable success and impressive activity against MM cells as BM plasma cells became undetectable by flow cytometry and patients entered stringent CR lasting for 17 weeks before relapse [181]. Another clinical trial using CAR-BCMA that included 21 patients showed increase in response rate from 89 to 100% after dose escalation [182].

Advertisement

9. Refractory and/or relapsed MM (R/R-MM)

The course of MM progression is highly variable as almost all patients with MM who respond to initial therapy will eventually relapse and require further treatment [6]. The introduction of novel agents over the last 15 years, the implementation of new therapeutic strategies and the adoption of drug combinations that include highly effective and tolerable drugs have improved (1) the clinical outcome dramatically as response rates have increased from approximately 30% with single agents to about 90% with combination therapies and (2) the QoL even in heavily pretreated patients. However, determining the optimal sequence and combination as well as timing of each agent is necessary [6]. In a retrospective analysis of 628 patients with newly diagnosed MM who developed relapse after initial therapy, it was found that prolonged duration of treatment was associated with improved survival [141]. Unfortunately, secondary plasma cell leukemia and EMD still present difficult therapeutic challenges [16].

There is no standard of care for MM relapse after autologous HSCT [183, 184]. Regimens that are composed of combination therapy with (1) drugs having synergistic effect and no cross-resistance and (2) one or two novel therapies are generally preferred as they lead to deeper and longer responses that are translated into improved survival [16, 183, 184, 185]. However, treatment should be individualized based on toxicity as well as patient and disease characteristics [184]. A meta-analysis of phase III randomized controlled trials showed that, compared to doublet regimens, triplets resulted in improved OS, PFS, very good partial response and CR although the risk of having grade III/IV drug adverse effects was higher with triplet regimens [185].

Mechanisms of drug resistance in MM include (1) multidrug-resistant gene polymorphism, (2) P-glycoprotein overexpression in MM cells, (3) microenvironmental changes, (4) clonal evolution including, (5) cancer stem cells, (6) upregulation and downregulation of various micro-RNAs and (7) selected CD34+, CD 138+, B7-, H1+, CD19- plasma cell accumulation after treatment [40].

Therapeutic options for patients with R/R-MM include (1) salvage therapy; combination of old and new therapies such as (a) bortezomib, thalidomide, cisplatin, cyclophosphamide, etoposide and doxorubicin (VTD-PACE); (b) KRD/carfilzomib, pomalidomide and dexamethasone (KPD) ± PACE or (c) daratumumab-based therapy; (2) second autologous HSCT; (3) allogeneic HSCT in carefully selected patients and (4) enrollment in clinical trials [8, 11, 13, 16]. Specific agents that are used in the treatment of R/R-MM include (1) immunomodulatory agents such as thalidomide, lenalidomide and pomalidomide; (2) proteasome inhibitors such as bortezomib, carfilzomib and ixazomib; (3) monoclonal antibodies such as daratumumab and elotuzumab; (4) histone deacetylase inhibitors such as panobinostat and (5) pembrolizumab [6, 142, 157, 158, 164, 186]. The use of pembrolizumab (antiprogrammed cell death 1) in combination with lenalidomide and dexamethasone in patients with R/R-MM resulted in 76% ORR [142, 158].

Advertisement

10. Management of MM patients having renal failure

Renal impairment (RI) is one of the most common complications of MM as 20–50% of patients with newly diagnosed MM present with RI, while 40–50% of patients develop RI during the course of the disease and about 5% of myeloma patients have dialysis-dependent renal failure (RF) at presentation [187, 188, 189, 190, 191]. In patients with MM, the causes of RI include myeloma cast nephropathy, excess of monoclonal free light chains causing proximal renal tubular damage, dehydration, infectious complications, hypercalcemia, hyperuricemia, use of nephrotoxic drugs and contrast media, hyperviscosity, myeloma cell infiltration and amyloid deposition [187, 188, 189, 192].

Bortezomib, thalidomide, lenalidomide and dexamethasone in various combinations can be used in the treatment of MM patients having RF and their use has been associated with high response rates and recovery of even partial or complete recovery of renal function [187, 188, 189, 191, 192]. In early chemotherapy trials, RF was considered a predictor of poor prognosis, patients with hemodialysis were reported to have a poorer prognosis and RF was considered an exclusion criterion from autologous HSCT because of the concerns about higher rates of treatment-related toxicity and nonrelapse mortality (NRM) due to mucositis, infectious complications and encephalopathy [187, 190]. However, recent studies have shown that autologous HSCT in patients with MM and RF has been associated with partial or complete recovery of renal function even in dialysis-dependent patients [190]. Therefore, autologous HSCT can be offered to patients with MM and RF with acceptable toxicity and NRM and a significant improvement in renal function that may be encountered in approximately one third of patients [187, 190]. In patients with MM and RF, a melphalan dose of 200 mg/m2 can be administered in the conditioning therapy of auto-HSCT without an increase in toxicity and NRM [190].

Kidney transplantation is the treatment of choice for most patients with end-stage renal failure (ESRD) as it is associated with improved survival and QoL compared to hemodialysis [193]. Even in patients with MM having RF, kidney transplantation is a valid therapeutic option in well-selected patients who achieve control of their disease and maintain a durable remission preferably for 3–5 years and have stable light chain levels but this option should be considered early in the course of the disease [194, 195, 196, 197]. Combined HSCT, predominantly autologous HSCT, and renal transplantation have been performed for patients having various hematological disorders such as plasma cell dyscrasias [198, 199, 200, 201, 202]. Patients with MM having ESRD, either on regular hemodialysis or not, can be offered not only HSCT but also combined HSCT and renal transplantation either simultaneously or sequentially [198, 199, 203, 204, 205, 206].

11. Conclusions and future directions

The introduction of several novel agents and targeted therapies over the last 10 years has revolutionized the management of MM and has produced unprecedented outcomes in terms of disease control and OS. Currently, novel agents and targeted therapies are used in the following settings: (1) prior to HSCT to reduce tumor burden and to optimally control MM, (2) following HSCT as consolidation and maintenance therapy to allow long-term disease control and (3) as salvage therapy in case of relapse of MM after HSCT.

However, novel agents and targeted therapies should not be considered as a form of replacement to HSCT, but instead these two valuable therapeutic interventions should be considered complementary to each other. The smart combination of novel agents and targeted therapies with various forms of HSCT in the new treatment paradigm of MM will ultimately lead to higher cure rates and longer disease controls.

References

  1. 1. Dimopoulos MA, Kaufman JL, White D, Cook G, Rizzo M, Xu Y, et al. A comparison of the efficacy of immunomodulatory-containing regimens in relapsed/refractory multiple myeloma: a network meta-analysis. Clinical Lymphoma, Myeloma & Leukemia. 2018;18(3):163-173.e6. DOI: 10.1016/j.clml.2017.12.011. [Epub Jan 5, 2018]
  2. 2. Maiese EM, Ainsworth C, Le Moine JG, Ahdesmäki O, Bell J, Hawe E. Comparative efficacy of treatments for previously treated multiple myeloma: A systematic literature review and network meta-analysis. Clinical Therapeutics. 2018;40(3):480-494.e23. DOI: 10.1016/j.clinthera.2018.01.014. [Epub Feb 28, 2018]
  3. 3. Walters DK, Arendt BK, Tschumper RC, Wu X, Jelinek DF. Characterization and use of the novel human multiple myeloma cell line MC-B11/14 to study biological consequences of CRISPR-mediated loss of immunoglobulin A heavy chain. Experimental Hematology. 2018;57:42-49.e1. DOI: 10.1016/j.exphem.2017.09.010 [Epub Oct 13, 2017]
  4. 4. Jakab S, Lázár E, Benedek I, Köpeczi J, Pakucs A, Benedek I. New treatment methods in multiple myeloma. Journal of Interdisciplinary Medicine. 2017;2(2):144-149. DOI: 10.1515/jim-2017-0055
  5. 5. Pelligra CG, Parikh K, Guo S, Chandler C, Mouro J, Abouzaid S, et al. Cost-effectiveness of pomalidomide, carfilzomib, and daratumumab for the treatment of patients with heavily pretreated relapsed-refractory multiple myeloma in the United States. Clinical Therapeutics. 2017;39(10):1986-2005.e5. DOI: 10.1016/j.clinthera.2017.08.010 [Epub Sep 28, 2017]
  6. 6. Sonneveld P, De Wit E, Moreau P. How have evolutions in strategies for the treatment of relapsed/refractory multiple myeloma translated into improved outcomes for patients? Critical Reviews in Oncology/Hematology. 2017;112:153-170. DOI: 10.1016/j.critrevonc.2017.02.007 [Epub Feb 14, 2017]
  7. 7. Fonseca R, Abouzaid S, Bonafede M, Cai Q, Parikh K, Cosler L, et al. Trends in overall survival and costs of multiple myeloma, 2000-2014. Leukemia. 2017;31(9):1915-1921. DOI: 10.1038/leu.2016.380 [Epub Dec 23, 2016]
  8. 8. Rajkumar SV. Clinical features, laboratory manifestations, and diagnosis of multiple myeloma. Up to date 2018. Edited by Kyle RA, Connor RF
  9. 9. Ludwig H, Bolejack V, Crowley J, Bladé J, Miguel JS, Kyle RA, et al. Survival and years of life lost in different age cohorts of patients with multiple myeloma. Journal of Clinical Oncology. 2010;28(9):1599-1605. DOI: 10.1200/JCO.2009.25.2114 [Epub Feb 22, 2010]
  10. 10. Rajkumar SV, Kumar S. Multiple myeloma: Diagnosis and treatment. Mayo Clinic Proceedings. 2016;91(1):101-119. DOI: 10.1016/j.mayocp.2015.11.007
  11. 11. Sonneveld P, Avet-Loiseau H, Lonial S, Usmani S, Siegel D, et al. Treatment of multiple myeloma with high-risk cytogenetics:A consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955-2962. DOI: 10.1182/blood-2016-01-631200 [Epub Mar 21, 2016]
  12. 12. Johnson SK, Heuck CJ, Albino AP, Qu P, Zhang Q, Barlogie B, et al. The use of molecular-based risk stratification and pharmacogenomics for outcome prediction and personalized therapeutic management of multiple myeloma. International Journal of Hematology. 2011;94(4):321-333. DOI: 10.1007/s12185-011-0948-y [Epub Oct 15, 2011]
  13. 13. Rajkumar SV. Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management. American Journal of Hematology. 2016;91(7):719-734. DOI: 10.1002/ajh.24402
  14. 14. Fonseca R, Monge J, Dimopoulos MA. Staging and prognostication of multiple myeloma. Expert Review of Hematology. 2014;7(1):21-31. DOI: 10.1586/17474086.2014. 882224
  15. 15. Raza S, Safyan RA, Rosenbaum E, Bowman AS, Lentzsch S. Optimizing current and emerging therapies in multiple myeloma: A guide for the hematologist. Therapeutic Advances in Hematology. 2017;8(2):55-70. DOI: 10.1177/2040620716680548 [Epub Dec 9, 2016]
  16. 16. Dingli D, Ailawadhi S, Bergsagel PL, Buadi FK, Dispenzieri A, Fonseca R, et al. Therapy for relapsed multiple myeloma: Guidelines from the Mayo stratification for myeloma and risk-adapted therapy. Mayo Clinic Proceedings. 2017;92(4):578-598. DOI: 10.1016/j.mayocp.2017.01.003 [Epub Mar 11, 2017]
  17. 17. Rossi A, Voigtlaender M, Janjetovic S, Thiele B, Alawi M, März M, et al. Mutational landscape reflects the biological continuum of plasma cell dyscrasias. Blood Cancer Journal. 2017;7(2):e537. DOI: 10.1038/bcj.2017.19
  18. 18. Bolli N, Avet-Loiseau H, Wedge DC, Van Loo P, Alexandrov LB, Martincorena I, et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nature Communications. 2014;5:2997. DOI: 10.1038/ncomms3997
  19. 19. Talley PJ, Chantry AD, Buckle CH. Genetics in myeloma: Genetic technologies and their application to screening approaches in myeloma. British Medical Bulletin. 2015;113(1):15-30. DOI: 10.1093/bmb/ldu041
  20. 20. Rustad EH, Coward E, Skytøen ER, Misund K, Holien T, Standal T, et al. Monitoring multiple myeloma by quantification of recurrent mutations in serum. Haematologica. 2017;102(7):1266-1272. DOI: 10.3324/haematol.2016.160564 [Epub Apr 6, 2017]
  21. 21. Pawlyn C, Bright MD, Buros AF, Stein CK, Walters Z, Aronson LI, et al. Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control. Blood Cancer Journal. 2017;7(3):e549. DOI: 10.1038/bcj.2017.27
  22. 22. Lionetti M, Neri A. Utilizing next-generation sequencing in the management of multiple myeloma. Expert Review of Molecular Diagnostics. 2017;17(7):653-663. DOI: 10.1080/14737159.2017.1332996 [Epub May 26, 2017]
  23. 23. Cetin AE, Stevens MM, Calistri NL, Fulciniti M, Olcum S, Kimmerling RJ, et al. Determining therapeutic susceptibility in multiple myeloma by single-cell mass accumulation. Nature Communications. 2017;8(1):1613. DOI: 10.1038/s41467-017-01593-2
  24. 24. Celotto K, Lee K, Holstein SA. End-stage myeloma with extramedullary plasmacytomas in the era of novel therapies. American Journal of Hematology Oncology. 2017;13(2):21-23
  25. 25. Lancman G, Tremblay D, Barley K, Barlogie B, Cho HJ, Jagannath S, et al. The effect of novel therapies in high-molecular-risk multiple myeloma. Clinical Advances in Hematology & Oncology. 2017;15(11):870-879
  26. 26. Thoennissen GB, Görlich D, Bacher U, Aufenberg T, Hüsken AC, Hansmeier AA, et al. Autologous stem cell transplantation in multiple myeloma in the era of novel drug induction: A retrospective single-center analysis. Acta Haematologica. 2017;137(3):163-172. DOI: 10.1159/000463534 [Epub Apr 12, 2017]
  27. 27. Yamamoto T, Kosaka N, Hattori Y, Ochiya T. A challenge to aging society by microRNA in extracellular vesicles: MicroRNA in extracellular vesicles as promising biomarkers and novel therapeutic targets in multiple myeloma. Journal of Clinical Medicine. 2018;7(3). DOI: 10.3390/jcm7030055
  28. 28. Falank C, Fairfield H, Reagan MR. Signaling interplay between bone marrow adipose tissue and multiple Myeloma cells. Frontiers in Endocrinology (Lausanne). 2016;7:67. DOI: 10.3389/fendo.216.00067 [eCollection 2016]
  29. 29. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70
  30. 30. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144(5):646-674. DOI: 10.1016/j.cell. 2011.02.013
  31. 31. Manier S, Sacco A, Leleu X, Ghobrial IM, Roccaro AM. Bone marrow microenvironment in multiple myeloma progression. Journal of Biomedicine & Biotechnology. 2012;2012:157496. DOI: 10.1155/2012/157496 [Epub Oct 3, 2012]
  32. 32. Jurczyszyn A, Czepiel J, Gdula-Argasińska J, Perucki W, Skotnicki AB, Majka M. The analysis of the relationship between multiple myeloma cells and their microenvironment. Journal of Cancer. 2015;6(2):160-168. DOI: 10.7150/jca.10873 [eCollection 2015]
  33. 33. Kawano Y, Moschetta M, Manier S, Glavey S, Görgün GT, Roccaro AM, et al. Targeting the bone marrow microenvironment in multiple myeloma. Immunological Reviews. 2015;263(1):160-172. DOI: 10.1111/imr.12233
  34. 34. Podar K, Chauhan D, Anderson KC. Bone marrow microenvironment and the identification of new targets for myeloma therapy. Leukemia. 2009;23(1):10-24. DOI: 10.1038/leu.2008.259 [Epub Oct 9, 2008]
  35. 35. Shay G, Hazlehurst L, Lynch CC. Dissecting the multiple myeloma-bone microenvironment reveals new therapeutic opportunities. Journal of Molecular Medicine (Berl). 2016;94(1):21-35. DOI: 10.1007/s00109-015-1345-4 [Epub Oct 1, 2015]
  36. 36. Reagan MR, Liaw L, Rosen CJ, Ghobrial IM. Dynamic interplay between bone and multiple myeloma: Emerging roles of the osteoblast. Bone. 2015;75:161-169. DOI: 10.1016/j.bone. 2015.02.021 [Epub Feb 26, 2015]
  37. 37. Qiao M, Wu D, Carey M, Zhou X, Zhang L. Multi-scale agent-based multiple myeloma cancer modeling and the related study of the balance between osteoclasts and osteoblasts. PLoS One. 2015;10(12):e0143206. DOI: 10.1371/journal.pone. 0143206 [eCollection 2015]
  38. 38. Fairfield H, Falank C, Avery L, Reagan MR. Multiple myeloma in the marrow: Pathogenesis and treatments. Annals of the New York Academy of Sciences. 2016;1364:32-51. DOI: 10.1111/nyas.13038
  39. 39. Flodr P, Latalova P, Pusciznova P, Pika T, Bacovsky J, Scudla V, et al. Multiple myeloma and bone marrow microenvironment immunohistochemical study of the expression of 15 proteins related to myeloma bone disease. Blood. 2015;126:5318
  40. 40. Yang WC, Lin SF. Mechanisms of drug resistance in relapse and refractory multiple myeloma. BioMed Research International. 2015;2015:341430. DOI: 10.1155/2015/341430 [Epub Nov 16, 2015]
  41. 41. Raimondi L, De Luca A, Morelli E, Giavaresi G, Tagliaferri P, Tassone P, et al. MicroRNAs: Novel crossroads between myeloma cells and the bone marrow microenvironment. BioMed Research International. 2016;2016:6504593. DOI: 10.1155/2016/6504593 [Epub Jan 4, 2016]
  42. 42. Zhang J, Xiao X, Liu J. The role of circulating miRNAs in multiple myeloma. Science China. Life Sciences. 2015;58(12):1262-1269. DOI: 10.1007/s11427-015-4969-2 [Epub Nov 25, 2015]
  43. 43. Abdi J, Jian H, Chang H. Role of micro-RNAs in drug resistance of multiple myeloma. Oncotarget. 2016;7(37):60723-60735. DOI: 10.18632/oncotarget.11032 [Epub Aug 2, 2016]
  44. 44. Brennan SK, Matsui W. Cancer stem cells: Controversies in multiple myeloma. Journal of Molecular Medicine (Berl). 2009;87(11):1079-1085. DOI: 10.1007/s00109-009-0531-7 [Epub Sep 17, 2009]
  45. 45. Gao M, Kong Y, Yang G, Gao L, Shi J. Multiple myeloma cancer stem cells. Oncotarget. 2016;7(23):35466-35477. DOI: 10.18632/oncotarget.8154
  46. 46. Huff CA, Matsui W. Multiple myeloma cancer stem cells. Journal of Clinical Oncology. 2008;26(17):2895-2900. DOI: 10.1200/JCO.2007. 15.8428
  47. 47. Kellner J, Liu B, Kang Y, Li Z. Fact or fiction—Identifying the elusive multiple myeloma stem cell. Journal of Hematology & Oncology. 2013;6:91. DOI: 10.1186/1756-8722-6-91
  48. 48. Johnsen HE, Bøgsted M, Schmitz A, Bødker JS, El-Galaly TC, Johansen P, et al. The myeloma stem cell concept, revisited: From phenomenology to operational terms. Haematologica. 2016;101(12):1451-1459. DOI: 10.3324/haematol.2015.138826 [Epub Nov 10, 2016]
  49. 49. Franqui-Machin R, Wendlandt EB, Janz S, Zhan F, Tricot G. Cancer stem cells are the cause of drug resistance in multiple myeloma: fact or fiction? Oncotarget. 2015;6(38):40496-40506. DOI: 10.18632/oncotarget.5800
  50. 50. Basak GW, Carrier E. The search for multiple myeloma stem cells: The long and winding road. Biology of Blood and Marrow Transplantation. 2010;16(5):587-594. DOI: 10.1016/j.bbmt.2009. 10.024 [Epub Nov 4, 2009]
  51. 51. Matsui W, Wang Q, Barber JP, Brennan S, Smith BD, Borrello I, et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Research. 2008;68(1):190-197. DOI: 10.1158/0008-5472.CAN-07-3096
  52. 52. Bleker de Oliveira M, Eugenio AI, Fook Alves VL, Zanatta D, Yamamoto M, Strauss BE, et al. Heat shock protein 70 inhibitor, alone or in combination with bortezomib, prevented plasmacytoma development in immunodeficient mice transplanted with myeloma cell lines. Blood. 2016;128:5658
  53. 53. Xu YN, Xiao CR, Huang YD, Lu QY. Circulating serum microRNA as diagnostic biomarkers for multiple myeloma. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2017;25(2):471-475. DOI: 10.7534/j.issn.1009-2137.2017.02.029
  54. 54. Seckinger A, Meißner T, Moreaux J, Benes V, Hillengass J, Castoldi M, et al. MiRNAs in multiple myeloma—A survival relevant complex regulator of gene expression. Oncotarget. 2015;6(36):39165-39183. DOI: 10.18632/oncotarget.5381
  55. 55. Kubiczkova L, Kryukov F, Slaby O, Dementyeva E, Jarkovsky J, Nekvindova J, et al. Circulating serum microRNAs as novel diagnostic and prognostic biomarkers for multiple myeloma and monoclonal gammopathy of undetermined significance. Haematologica. 2014;99(3):511-518. DOI: 10.3324/haematol.2013.093500 [Epub Nov 15, 2013]
  56. 56. Jones CI, Zabolotskaya MV, King AJ, Stewart HJS, Horne GA, Chevassut TJ, et al. Identification of circulating microRNAs as diagnostic biomarkers for use in multiple myeloma. British Journal of Cancer. 2012;107(12):1987-1996. DOI: 10.1038/bjc.2012.525 [Epub Nov 20, 2012]
  57. 57. Manier S, Liu CJ, Avet-Loiseau H, Park J, Shi J, Campigotto F, et al. Prognostic role of circulating exosomal miRNAs in multiple myeloma. Blood. 2017;129(17):2429-2436. DOI: 10.1182/blood-2016-09-742296 [Epub Feb 17, 2017]
  58. 58. Wu P, Agnelli L, Walker BA, Todoerti K, Lionetti M, Johnson DC, et al. Improved risk stratification in myeloma using a microRNA-based classifier. British Journal of Haematology. 2013;162(3):348-359. DOI: 10.1111/bjh.12394 [Epub May 30, 2013]
  59. 59. Anderson KC. Progress and paradigms in multiple myeloma. Clinical Cancer Research. 2016;22(22):5419-5427. DOI: 10.1158/1078-0432.CCR-16-0625
  60. 60. Cavo MS, Rajkumar V, Palumbo A, Moreau P, Orlowski R, Bladé J, et al., on behalf of the International Myeloma Working Group. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood. 2011;117(23):6063-6073. DOI: 10.1182/blood-2011-02-297325 [Epub Mar 29, 2011]
  61. 61. Nijhof IS, van de Donk NWCJ, Zweegman S, Lokhorst HM. Current and new therapeutic strategies for relapsed and refractory multiple myeloma: An update. Drugs. 2018;78(1):19-37. DOI: 10.1007/s40265-017-0841-y
  62. 62. Tremblay D, Chari A. Novel targets in multiple myeloma. American Journal of Hematology Oncology. 2016;12(10):18-25
  63. 63. Naymagon L, Abdul-Hay M. Novel agents in the treatment of multiple myeloma: A review about the future. Journal of Hematology & Oncology. 2016;9(1):52. DOI: 10.1186/s13045-016-0282-1
  64. 64. Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017;130(24):2594-2602. DOI: 10.1182/blood-2017-06-793869 [Epub Sep 19, 2017]
  65. 65. Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, et al. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: A phase II study by the Intergroupe Francophone du Myélome. Journal of Clinical Oncology. 2014;32(25):2712-2717. DOI: 10.1200/JCO. 2013.54.8164
  66. 66. Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116(5):679-686. DOI: 10.1182/blood-2010-02-268862 [Epub Apr 12, 2010]
  67. 67. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al., IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. New England Journal of Medicine 2017;376(14):1311-1320. DOI: 10.1056/NEJMoa1611750
  68. 68. Rajan AM, Rajkumar V. Treatment of newly diagnosed myeloma: Bortezomib-based triplet. Seminars in Oncology. 2016;43(6):700-702. DOI: 10.1053/j.seminoncol.2016.11.003
  69. 69. Chakraborty R, Muchtar E, Kumar S, Buadi FK, Dingli D, Dispenzieri A, et al. The impact of induction regimen on transplant outcome in newly diagnosed multiple myeloma in the era of novel agents. Bone Marrow Transplantation. 2017;52(1):34-40. DOI: 10.1038/bmt.2016.214 [Epub Aug 22, 2016]
  70. 70. Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. DOI: 10.1016/S0140-6736(16)31594-X [Epub Dec 23, 2016]
  71. 71. Jelinek T, Bezdekova R, Zatopkova M, Burgos L, Simicek M, Sevcikova T, et al. Current applications of multiparameter flow cytometry in plasma cell disorders. Blood Cancer Journal. 2017;7(10):e617. DOI: 10.1038/bcj.2017.90
  72. 72. Holstein SA, Avet-Loiseau H, Hahn T, Ho CM, Lohr JG, Munshi NC, et al. BMT CTN myeloma intergroup workshop on minimal residual disease and immune profiling: Summary and recommendations from the organizing committee. Biology of Blood and Marrow Transplantation. 2018;24(4):641-648. DOI: 10.1016/j.bbmt.2017.12.774 [Epub Dec 11, 2017]
  73. 73. Bhatnagar B, Badros AZ. Controversies in autologous stem cell transplantation for the treatment of multiple myeloma. In: Demirer T, editor. Innovations in Stem Cell Transplantation. Intech Open; 2013. DOI: 10.5772/54115
  74. 74. Mohty M, Harousseau JL. Treatment of autologous stem cell transplant-eligible multiple myeloma patients: Ten questions and answers. Haematologica. 2014;99(3):408-416. DOI: 10.3324/haematol.2013.096149
  75. 75. Brioli A. First line vs delayed transplantation in myeloma: Certainties and controversies. World Journal of Transplantation. 2016;6(2):321-330. DOI: 10.5500/wjt.v6.i2.321
  76. 76. Patriarca F, Einsele H, Spina F, Bruno B, Isola M, Nozzoli C, et al. Allogeneic stem cell transplantation in multiple myeloma relapsed after autograft: A multicenter retrospective study based on donor availability. Biology of Blood and Marrow Transplantation. 2012;18(4):617-626. DOI: 10.1016/j.bbmt.2011. 07.026 [Epub Aug 3, 2011]
  77. 77. Shu Z, Heimfeld S, Gao D. Hematopoietic stem cell transplantation with cryopreserved grafts: adverse reactions after transplantation and cryoprotectant removal prior to infusion. Bone Marrow Transplantation. 2014;49(4):469-476. DOI: 10.1038/bmt.2013.152. [Epub Sep 30, 2013]
  78. 78. Yi X, Liu M, Luo Q, Zhuo H, Cao H, Wang J, et al. Toxic effects of dimethyl sulfoxide on red blood cells, platelets, and vascular endothelial cells in vitro. FEBS Open Bio. 2017;7:485-494
  79. 79. Wannesson L, Panzarella T, Mikhael J, Keating A. Feasibility and safety of autotransplants with noncryopreserved marrow or peripheral blood stem cells: A systematic review. Annals of Oncology. 2007;18(4):623-632
  80. 80. Jasuja SK, Kukar (jasuja) N, Jain R, Bhateja A, Jasuja A, Rohit Jain, et al. A simplified method at lowest cost for autologous, non-cryopreserved, unmanipulated, peripheral hematopoietic stem cell transplant in multiple myeloma and non-Hodgkin's lymphoma: Asian scenario. Journal of Clinical Oncology. 2010;28(15):ė18545
  81. 81. Al-Anazi KA. Autologous hematopoietic stem cell transplantation for multiple myeloma without cryopreservation. Bone Marrow Research. 2012;2012:917361
  82. 82. Ramzi M, Zakerinia M, Nourani H, Dehghani M, Vojdani R, Haghighinejad H. Non-cryopreserved hematopoietic stem cell transplantation in multiple myeloma, a single center experience. Clinical Transplantation. 2012;26(1):117-122
  83. 83. Kayal S, Sharma A, Iqbal S, Tejomurtula T, Cyriac SL, Raina V, et al. High-dose chemotherapy and autologous stem cell transplantation in multiple myeloma: A single institution experience at All India Institute of Medical Sciences, New Delhi, using non-cryopreserved peripheral blood stem cells. Clinical Lymphoma, Myeloma & Leukemia. 2014;14(2):140-147. DOI: 10.1016/j.clml.2013.09.001 Epub 2013 Sep 28
  84. 84. Bekadja MA, Brahimi M, Osmani S, Arabi A, Bouhass R, Yafour N, et al. A simplified method for autologous stem cell transplantation in multiple myeloma. Hematology Oncology and Stem Cell Therapy. 2012;5(1):49-53. DOI: 10.5144/1658-3876.2012.49
  85. 85. Martino M, Lemoli RM, Girmenia C, Castagna L, Bruno B, Cavallo F, et al. Italian consensus conference for the outpatient autologous stem cell transplantation management in multiple myeloma. Bone Marrow Transplantation. 2016;51(8):1032-1040. DOI: 10.1038/bmt.2016.79 [Epub Apr 4, 2016]
  86. 86. Jagannath S, Vesole DH, Zhang M, Desikan KR, Copeland N, Jagannath M, et al. Feasibility and cost-effectiveness of outpatient autotransplants in multiple myeloma. Bone Marrow Transplantation. 1997;20(6):445-450. DOI: 10.1038/sj.bmt.1700900
  87. 87. Ferrara F, Palmieri S, Viola A, Copia C, Schiavone EM, De Simone M, et al. Outpatient-based peripheral blood stem cell transplantation for patients with multiple myeloma. The Hematology Journal. 2004;5(3):222-226. DOI: 10.1038/sj.thj.6200349
  88. 88. Holbro A, Ahmad I, Cohen S, Roy J, Lachance S, Chagnon M, et al. Safety and cost-effectiveness of outpatient autologous stem cell transplantation in patients with multiple myeloma. Biology of Blood and Marrow Transplantation. 2013;19(4):547-551. DOI: 10.1016/j.bbmt.2012.12.006 [Epub Dec 16, 2012]
  89. 89. Graff TM, Singavi AK, Schmidt W, Eastwood D, Drobyski WR, Horowitz M, et al. Safety of outpatient autologous hematopoietic cell transplantation for multiple myeloma and lymphoma. Bone Marrow Transplantation. 2015;50(7):947-953. DOI: 10.1038/bmt. 2015.46 [Epub Apr 13, 2015]
  90. 90. Lisenko K, Sauer S, Bruckner T, Egerer G, Goldschmidt H, Hillengass J, et al. High-dose chemotherapy and autologous stem cell transplantation of patients with multiple myeloma in an outpatient setting. BMC Cancer. 2017;17(1):151. DOI: 10.1186/s12885-017-3137-4
  91. 91. Kroll TM, Singavi A, Schmidt W, Eastwood D, Drobski W, Horowitz MM, et al. Safety of outpatient autologous hematopoietic cell transplantation (AuHCT) for multiple myeloma and lymphoma. Biology of Blood and Marrow Transplantation. 2014;20(Suppl 2):S114. DOI: 10.1016/j.bbmt.2013.12.166
  92. 92. Frey P, Stinson T, Siston A, Knight SJ, Ferdman E, Traynor A, et al. Lack of caregivers limits use of outpatient hematopoietic stem cell transplant program. Bone Marrow Transplantation. 2002;30(11):741-748. DOI: 10.1038/sj.bmt. 1703676
  93. 93. Sivaraj D, Bacon W, Long GD, Rizzieri DA, Horwitz ME, Sullivan KM, et al. High-dose BCNU/melphalan conditioning regimen before autologous stem cell transplantation in newly diagnosed multiple myeloma. Bone Marrow Transplantation. 2018;53(1):34-38. DOI: 10.1038/bmt.2017.208 [Epub Oct 30, 2017]
  94. 94. Striha A, Ashcroft AJ, Hockaday A, Cairns DA, Boardman K, Jacques G, Williams C, et al. The role of ixazomib as an augmented conditioning therapy in salvage autologous stem cell transplant (ASCT) and as a post-ASCT consolidation and maintenance strategy in patients with relapsed multiple myeloma (ACCoRd [UK-MRA myeloma XII] trial): Study protocol for a phase III randomised controlled trial. Trials. 2018;19(1):169. DOI: 10.1186/s13063-018-2524-8
  95. 95. Jimenez-Zepeda VH, Duggan P, Neri P, Chaudhry A, Murray K, Culham M, et al. Bortezomib and melphalan conditioning increases the rate of complete response and MRD negativity for patients with multiple myeloma undergoing single autologous stem cell transplant. Leukemia & Lymphoma. 2016;57(4):973-976. DOI: 10.3109/10428194. 2015.1085534 [Epub Oct 8, 2015]
  96. 96. Blanes M, Lahuerta JJ, González JD, Ribas P, Solano C, Alegre A, et al. Intravenous busulfan and melphalan as a conditioning regimen for autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: A matched comparison to a melphalan-only approach. Biology of Blood and Marrow Transplantation. 2013;19(1):69-74. DOI: 10.1016/j.bbmt.2012.08. 009 [Epub Aug 13, 2012]
  97. 97. Barta SK, Jain R, Mazumder A, Carter J, Almanzar L, Browne R, et al. Pharmacokinetics-directed intravenous busulfan combined with high-dose melphalan and bortezomib as a conditioning regimen for atients with multiple myeloma. Clinical Lymphoma, Myeloma & Leukemia. 2017;17(10):650-657. DOI: 10.1016/j.clml.2017.06.005 [Epub Jun 17, 2017]
  98. 98. Mutahar E, Al-Anazi KA. Engraftment syndrome: An updated review. Journal of Stem Cell and Transplantation. 2017;1(3):16. DOI: 10.21767/2575-7725.100016
  99. 99. Kanfar S, Al-Anazi KA. Autologous graft versus host disease: An updated review. Annals of Stem Cells and Regenerative Medicine. 2018;1(1):1002
  100. 100. Morabito F, Martino M, Stelitano C, Oliva E, Kropp M, Irrera G, et al. Feasibility of a mixed inpatient-outpatient model of peripheral blood stem cell transplantation for multiple myeloma. Haematologica. 2002;87(11):1192-1199
  101. 101. Clemens AB, Anderegg S. Mixed outpatient-inpatient autologous stem cell transplant for multiple myeloma: A cost-saving initiative in a resource constrained environment. Journal of Oncology Pharmacy Practice. 2017;23(5):384-388. DOI: 10.1177/1078155216639753 [Epub Mar 21, 2016]
  102. 102. Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S, et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1997;89(3):789-793
  103. 103. Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, et al., InterGroupe Francophone du Myélome. Single versus double autologous stem-cell transplantation for multiple myeloma. New England Journal of Medicine. 2003;349(26):2495-2502. DOI: 10.1056/NEJMoa032290
  104. 104. Bergantim R, Trigo F, Guimarães JE. Impact of tandem autologous stem cell transplantation and response to transplant in the outcome of multiple myeloma. Experimental Hematology & Oncology. 2012;1(1):35. DOI: 10.1186/2162-3619-1-35
  105. 105. Elice F, Raimondi R, Tosetto A, D'Emilio A, Di Bona E, Piccin A, et al. Prolonged overall survival with second on-demand autologous transplant in multiple myeloma. American Journal of Hematology. 2006;81(6):426-431. DOI: 10.1002/ajh.20641
  106. 106. Kumar A, Kharfan-Dabaja MA, Glasmacher A, Djulbegovic B. Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: A systematic review and meta-analysis. Journal of the National Cancer Institute. 2009;101(2):100-106. DOI: 10.1093/jnci/djn439 [Epub Jan 13, 2009]
  107. 107. Mehta J. Re: Tandem vs single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: A systematic review and meta-analysis. Journal of the National Cancer Institute. 2009;101(20):1430-1431
  108. 108. Singh Abbi KK, Zheng J, Devlin SM, Giralt S, Landau H. Second autologous stem cell transplant: An effective therapy for relapsed multiple myeloma. Biology of Blood and Marrow Transplantation. 2015;21(3):468-472. DOI: 10.1016/j.bbmt. 2014. 11.677 [Epub Dec 18, 2014]
  109. 109. Olin RL, Vogl DT, Porter DL, Luger SM, Schuster SJ, Tsai DE, et al. Second auto-SCT is safe and effective salvage therapy for relapsed multiple myeloma. Bone Marrow Transplantation. 2009;43(5):417-422. DOI: 10.1038/bmt.2008.334 [Epub Oct 13, 2008]
  110. 110. Jimenez-Zepeda VH, Mikhael J, Winter A, Franke N, Masih-Khan E, Trudel S, et al. Second autologous stem cell transplantation as salvage therapy for multiple myeloma: Impact on progression-free and overall survival. Biology of Blood and Marrow Transplantation. 2012;18(5):773-779. DOI: 10.1016/j.bbmt. 2011.10. 044 [Epub Nov 4, 2011]
  111. 111. Gonsalves WI, Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK, et al. Second auto-SCT for treatment of relapsed multiple myeloma. Bone Marrow Transplantation. 2013;48(4):568-573. DOI: 10.1038/bmt.2012.183. [Epub Sep 24, 2012]
  112. 112. Atanackovic D, Schilling G. Second autologous transplant as salvage therapy in multiple myeloma. British Journal of Haematology. 2013;163(5):565-572. DOI: 10.1111/bjh.12579 [Epub Sep 24, 2013]
  113. 113. Cook G, Liakopoulou E, Pearce R, Cavet J, Morgan GJ, Kirkland K, et al., British Society of Blood & Marrow Transplantation Clinical Trials Committee. Factors influencing the outcome of a second autologous stem cell transplant (ASCT) in relapsed multiple myeloma: A study from the British Society of Blood and Marrow Transplantation Registry. Biology of Blood and Marrow Transplantation 2011;17(11):1638-1645. DOI: 10.1016/j.bbmt. 2011.04.005. [Epub Apr 23, 2011]
  114. 114. Morris C, Iacobelli S, Brand R, Bjorkstrand B, Drake M, Niederwieser D, et al., Chronic Leukaemia Working Party Myeloma Subcommittee, European Group for Blood and Marrow Transplantation. Benefit and timing of second transplantations in multiple myeloma: Clinical findings and methodological limitations in a European Group for Blood and Marrow Transplantation registry study. Journal of Clinical Oncology. 2004;22(9):1674-1681. DOI: 10.1200/JCO.2004.06.144 [Epub Mar 22, 2004]
  115. 115. Castagna L, Mussetti A, Devillier R, Dominietto A, Marcatti M, Milone G, et al. Haploidentical allogeneic hematopoietic cell transplantation for multiple myeloma using post-transplantation cyclophosphamide graft-versus-host disease prophylaxis. Biology of Blood and Marrow Transplantation. 2017;23(9):1549-1554. DOI: 10.1016/j.bbmt.2017.05.006 [Epub May 10, 2017]
  116. 116. Mir MA, Kapoor P, Kumar S, Pandey S, Dispenzieri A, Lacy MQ, et al. Trends and outcomes in allogeneic hematopoietic stem cell transplant for multiple myeloma at Mayo Clinic. Clinical Lymphoma, Myeloma & Leukemia. 2015;15(6):349-357.e2. DOI: 10.1016/j.clml.2015.03.016 [Epub Apr 2, 2015]
  117. 117. Kröger N, Badbaran A, Zabelina T, Ayuk F, Wolschke C, Alchalby H, et al. Impact of high-risk cytogenetics and achievement of molecular remission on long-term freedom from disease after autologous-allogeneic tandem transplantation in patients with multiple myeloma. Biology of Blood and Marrow Transplantation. 2013;19(3):398-404. DOI: 10.1016/j.bbmt.2012.10.008 [Epub Oct 16, 2012]
  118. 118. Giaccone L, Evangelista A, Patriarca F, Sorasio R, Pini M, Carnevale-Schianca F, et al. Impact of new drugs on the long-term follow-up of upfront tandem autograft-allograft in multiple myeloma. Biology of Blood and Marrow Transplantation. 2018;24(1):189-193. DOI: 10.1016/j.bbmt.2017.09.017 [Epub Oct 4, 2017]
  119. 119. Gay F, Engelhardt M, Terpos E, Wäsch R, Giaccone L, Auner HW, et al. From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives. Haematologica. 2018;103(2):197-211. DOI: 10.3324/haematol.2017.174573 [Epub Dec 7, 2017]
  120. 120. Pawarode A, Mineishi S, Reddy P, Braun TM, Khaled YA, Choi SW, et al. Reducing treatment-related mortality did not improve outcomes of allogeneic myeloablative hematopoietic cell transplantation for high-risk multiple myeloma: A university of Michigan prospective series. Biology of Blood and Marrow Transplantation. 2016;22(1):54-60. DOI: 10.1016/j.bbmt.2015.07.021 [Epub Jul 26, 2015]
  121. 121. Rasche L, Röllig C, Stuhler G, Danhof S, Mielke S, Grigoleit GU, et al. Allogeneic hematopoietic cell transplantation in multiple myeloma: Focus on longitudinal assessment of donor chimerism, extramedullary disease, and high-risk cytogenetic features. Biology of Blood and Marrow Transplantation. 2016;22(11):1988-1996. DOI: 10.1016/j.bbmt.2016.08.024 [Epub Aug 31, 2016]
  122. 122. Kawamura K, Takamatsu H, Ikeda T, Komatsu T, Aotsuka N, Amano I, et al. Cord blood transplantation for multiple myeloma: A study from the multiple myeloma working group of the Japan society for hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation. 2015;21(7):1291-1298. DOI: 10.1016/j.bbmt.2015.02.015 [Epub Feb 21, 2015]
  123. 123. Ghosh N, Ye X, Tsai HL, Bolaños-Meade J, Fuchs EJ, Luznik L, et al. Allogeneic blood or marrow transplantation with post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis in multiple myeloma. Biology of Blood and Marrow Transplantation. 2017;23(11):1903-1909. DOI: 10.1016/j.bbmt.2017.07.003 [Epub Jul 12, 2017]
  124. 124. Passera R, Pollichieni S, Brunello L, Patriarca F, Bonifazi F, Montefusco V, et al. Allogeneic hematopoietic cell transplantation from unrelated donors in multiple myeloma: Study from the Italian bone marrow donor registry. Biology of Blood and Marrow Transplantation. 2013;19(6):940-948. DOI: 10.1016/j.bbmt.2013.03.012 [Epub Mar 26, 2013]
  125. 125. Cornell RF, D'Souza A, Kassim AA, Costa LJ, Innis-Shelton RD, Zhang MJ, et al. Maintenance versus induction therapy choice on outcomes after autologous transplantation for multiple myeloma. Biology of Blood and Marrow Transplantation. 2017;23(2):269-277. DOI: 10.1016/j.bbmt.2016.11.011 [Epub Nov 15, 2016]
  126. 126. Lee HS, Min CK. Optimal maintenance and consolidation therapy for multiple myeloma in actual clinical practice. The Korean Journal of Internal Medicine. 2016;31(5):809-819. DOI: 10.3904/kjim.2016.110 [Epub Sep 1, 2016]
  127. 127. Talhi S, Osmani S, Brahimi M, Amani K, Ouldjeriouat H, Bouchama S, et al. Bortezomib-based regimens as consolidation therapy after autologous hematopoietic stem cell transplantation in multiple myeloma: A single center experience from Oran (Algeria). Blood. 2016;128:5121
  128. 128. Alexanian R, Weber D, Giralt S, Delasalle K. Consolidation therapy of multiple myeloma with thalidomide-dexamethasone after intensive chemotherapy. Annals of Oncology. 2002;13(7):1116-1119
  129. 129. Mohty M, Richardson PG, McCarthy PL, Attal M. Consolidation and maintenance therapy for multiple myeloma after autologous transplantation: Where do we stand? Bone Marrow Transplantation. 2015;50(8):1024-1029. DOI: 10.1038/bmt.2015.83 [Epub Apr 20, 2015]
  130. 130. Sivaraj D, Green MM, Li Z, Sung AD, Sarantopoulos S, Kang Y, et al. Outcomes of maintenance therapy with bortezomib after autologous stem cell transplantation for patients with multiple myeloma. Biology of Blood and Marrow Transplantation. 2017;23(2):262-268. DOI: 10.1016/j.bbmt.2016.11.010 [Epub Nov 14, 2016]
  131. 131. Pulte ED, Dmytrijuk A, Nie L, Goldberg KB, McKee AE, Farrell AT, et al. FDA approval summary: Lenalidomide as maintenance therapy after autologous stem cell transplant in newly diagnosed multiple myeloma. Oncologist. 2018;23(6):734-739. DOI: 10.1634/theoncologist.2017-0440
  132. 132. Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, et al., MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. The New England Journal of Medicine. 2012;366(19):1759-1769. DOI: 10.1056/NEJMoa1112704
  133. 133. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. The New England Journal of Medicine. 2012;366(19):1770-1781. DOI: 10.1056/NEJMoa1114083
  134. 134. Mian M, Tinelli M, De March E, Turri G, Meneghini V, Pescosta N, et al. Bortezomib, thalidomide and lenalidomide: Have they really changed the outcome of multiple myeloma? Anticancer Research. 2016;36(3):1059-1065
  135. 135. McCarthy PL, Holstein SA, Petrucci MT, Richardson PG, Hulin C, Tosi P, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: A meta-analysis. Journal of Clinical Oncology. 2017;35(29):3279-3289. DOI: 10.1200/JCO.2017.72.6679 [Epub Jul 25, 2017]
  136. 136. Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al., IFM Investigators. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. The New England Journal of Medicine. 2012;366(19):1782-1791. DOI: 10.1056/NEJMoa1114138
  137. 137. Ludwig H, Zojer N. Fixed duration vs continuous therapy in multiple myeloma. Hematology. American Society of Hematology. Education Program. 2017;2017(1):212-222. DOI: 10.1182/asheducation-2017.1.212
  138. 138. Palumbo A, Gay F, Cavallo F, Di Raimondo F, Larocca A, Hardan I, et al. Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma. Journal of Clinical Oncology. 2015;33(30):3459-3466. DOI: 10.1200/JCO.2014.60.2466 [Epub Aug 17, 2015]
  139. 139. Guglielmelli T, Palumbo A. Multiple myeloma: Is a shift toward continuous therapy needed to move forward? Expert Review of Hematology. 2015;8(3):253-256. DOI: 10.1586/17474086.2015.1001360 [Epub Jan 12, 2015]
  140. 140. Bahlis NJ, Corso A, Mugge LO, Shen ZX, Desjardins P, Stoppa AM, et al. Benefit of continuous treatment for responders with newly diagnosed multiple myeloma in the randomized FIRST trial. Leukemia. 2017;31(11):2435-2442. DOI: 10.1038/leu.2017.111 [Epub Apr 4, 2017]
  141. 141. Hari P, Romanus D, Palumbo A, Luptakova K, Rifkin RM, Tran LM, et al. Prolonged duration of therapy is associated with improved survival in patients treated for relapsed/refractory multiple myeloma in routine clinical care in the United States. Clinical Lymphoma, Myeloma & Leukemia. 2018;18(2):152-160. DOI: 10.1016/j.clml.2017.12.012 [Epub Jan 5, 2018]
  142. 142. Zhang T, Wang S, Lin T, Xie J, Zhao L, Liang Z, et al. Systematic review and meta-analysis of the efficacy and safety of novel monoclonal antibodies for treatment of relapsed/refractory multiple myeloma. Oncotarget. 2017;8(20):34001-34017. DOI: 10.18632/oncotarget.16987
  143. 143. Kumar SK, LaPlant B, Chng WJ, Zonder J, Callander N, Fonseca R, et al., Mayo Phase 2 Consortium. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood. 2015;125(3):443-448. DOI: 10.1182/blood-2014-05-573741. [Epub Nov 13, 2014]
  144. 144. Richardson PG, Bensinger WI, Huff CA, Costello CL, Lendvai N, Berdeja JG, et al. Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: Phase 2 trial results. British Journal of Haematology. 2018;180(6):821-830. DOI: 10.1111/bjh.15058 [Epub Feb 13, 2018]
  145. 145. Ashjian E, Redic K. Multiple myeloma: Updates for pharmacists in the treatment of relapsed and refractory disease. Journal of Oncology Pharmacy Practice. 2016;22(2):289-302. DOI: 10.1177/1078155215572036 [Epub Feb 17, 2015]
  146. 146. El-Amm J, Tabbara IA. Emerging therapies in multiple myeloma. American Journal of Clinical Oncology. 2015;38(3):315-321. DOI: 10.1097/COC.0b013e3182a4676b
  147. 147. Rosean TR, Tompkins VS, Tricot G, Holman CJ, Olivier AK, Zhan F, et al. Preclinical validation of interleukin 6 as a therapeutic target in multiple myeloma. Immunologic Research. 2014;59(1-3):188-202. DOI: 10.1007/s12026-014-8528-x
  148. 148. Redic KA, Hough SM, Price EM. Clinical developments in the treatment of relapsed or relapsed and refractory multiple myeloma: Impact of panobinostat, the first-in-class histone deacetylase inhibitor. OncoTargets and Therapy. 2016;9:2783-2793. DOI: 10.2147/OTT.S87962 [eCollection 2016]
  149. 149. de la Puente P, Muz B, Azab F, Luderer M, Azab AK. Molecularly targeted therapies in multiple myeloma. Leukemia Research and Treatment. 2014;2014:976567. DOI: 10.1155/2014/976567. [Epub Apr 16, 2014]
  150. 150. Gonsalves WI, Milani P, Derudas D, Buadi FK. The next generation of novel therapies for the management of relapsed multiple myeloma. Future Oncology. 2017;13(1):63-75. DOI: 10.2217/fon-2016-0200 [Epub Aug 11, 2016]
  151. 151. Maes A, Menu E, Veirman K, Maes K, Vand Erkerken K, De Bruyne E. The therapeutic potential of cell cycle targeting in multiple myeloma. Oncotarget. 2017;8(52):90501-90520. DOI: 10.18632/oncotarget.18765 [eCollection Oct 27, 2107]
  152. 152. Ludwig H, Delforge M, Facon T, Einsele H, Gay F, Moreau P, et al. Prevention and management of adverse events of Novel agents in multiple myeloma: A consensus of the european myeloma network. Leukemia. 2018. DOI: 10.1038/s41375-018-0040-1 [Epub ahead of print]
  153. 153. Sanchez L, Wang Y, Siegel DS, Wang ML. Daratumumab: A first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma. Journal of Hematology & Oncology. 2016;9(1):51. DOI: 10.1186/s13045-016-0283-0
  154. 154. Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al., CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. The New England Journal of Medicine. 2016;375(8):754-766. DOI: 10.1056/NEJMoa1606038
  155. 155. Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, et al., ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. The New England Journal of Medicine. 2018;378(6):518-528. DOI: 10.1056/NEJMoa1714678. [Epub Dec 12, 2017]
  156. 156. Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al., POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. The New England Journal of Medicine. 2016;375(14):1319-1331. DOI: 10.1056/NEJMoa1607751
  157. 157. Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, et al., ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. The New England Journal of Medicine. 2015;373(7):621-631. DOI: 10.1056/NEJMoa1505654 [Epub Jun 2, 2015]
  158. 158. Wallington-Beddoe CT, Pitson SM. Novel therapies for multiple myeloma. Aging (Albany NY). 2017;9(8):1857-1858. DOI: 10.18632/aging.101284 [Epub Aug 28, 2017]
  159. 159. Ríos-Tamayo R, Martín-García A, Alarcón-Payer C, Sánchez-Rodríguez D, de la Guardia AMDVD, García Collado CG, et al. Pomalidomide in the treatment of multiple myeloma: Design, development and place in therapy. Drug Design, Development and Therapy. 2017;11:2399-2408. DOI: 10.2147/DDDT.S115456 [eCollection 2017]
  160. 160. Richardson PG, Baz R, Wang M, Jakubowiak AJ, Laubach JP, Harvey RD, et al. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014;124(7):1038-1406. DOI: 10.1182/blood-2014-01-548826 [Epub Jun 11, 2014]
  161. 161. Uccello G, Petrungaro A, Mazzone C, Recchia AG, Greco R, Mendicino F, et al. Pomalidomide in multiple myeloma. Expert Opinion on Pharmacotherapy. 2017;18(2):133-137. DOI: 10.1080/14656566.2016.1274973 [Epub Dec 26, 2016]
  162. 162. Sriskandarajah P, Jolly H, Pawlyn C, Mohammed K, Dearden C, Potter M, et al. Retrospective cohort analysis examining the efficacy and safety of (V) DTPACE in newly diagnosed and relapsed/refractory myeloma patients-the UK experience. Clinical Lymphoma, Myeloma & Leukemia. 2016;16(Suppl 2):S80. DOI: 10.1016/j.clml.2016.07.112
  163. 163. Jain S, Diefenbach CM, Zain JM, O’Connor OA. Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma. Core Evidence. 2011;6:43-57. DOI: 10.2147/CE.S13838 [Epub Apr 4, 2011]
  164. 164. Dimopoulos MA, Kimball AS. Carfilzomib for relapsed or refractory multiple myeloma -Authors' reply. The Lancet Oncology. 2018;19(1):e2. DOI: 10.1016/S1470-2045(17)30920-8
  165. 165. Tanimoto T, Tsuda K, Oshima K, Mori J, Shimmura H. Carfilzomib for relapsed or refractory multiple myeloma. The Lancet Oncology. 2018;19(1):e1. DOI: 10.1016/S1470-2045(17)30859-8
  166. 166. Muchtar E, Gertz MA, Magen H. A practical review on carfilzomib in multiple myeloma. European Journal of Haematology. 2016;96(6):564-577. DOI: 10.1111/ejh.12749 [Epub Mar 9, 2016]
  167. 167. Afifi S, Michael A, Azimi M, Rodriguez M, Lendvai N, Landgren O. Role of histone deacetylase inhibitors in relapsed refractory multiple myeloma: A focus on vorinostat and panobinostat. Pharmacotherapy. 2015;35(12):1173-1188. DOI: 10.1002/phar.1671
  168. 168. Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, et al. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: Outcomes by prior treatment. Blood. 2016;127(6):713-721. DOI: 10.1182/blood-2015-09-665018 [Epub Dec 2, 2015]
  169. 169. Laubach JP, Moreau P, San-Miguel JF, Richardson PG. Panobinostat for the treatment of multiple myeloma. Clinical Cancer Research. 2015;21(21):4767-4773. DOI: 10.1158/1078-0432.CCR-15-0530 [Epub Sep 11, 2015]
  170. 170. Mu S, Kuroda Y, Shibayama H, Hino M, Tajima T, Corrado C, et al. Panobinostat PK/PD profile in combination with bortezomib and dexamethasone in patients with relapsed and relapsed/refractory multiple myeloma. European Journal of Clinical Pharmacology. 2016;72(2):153-161. DOI: 10.1007/s00228-015-1967-z [Epub Oct 22, 2015]
  171. 171. San-Miguel JF, Einsele H, Moreau P. The role of panobinostat plus bortezomib and dexamethasone in treating relapsed or relapsed and refractory multiple myeloma: A European perspective. Advances in Therapy. 2016;33(11):1896-1920. DOI: 10.1007/s12325-016-0413-7 [Epub Sep 27, 2016]
  172. 172. Liu JD, Sun CY, Tang L, Wu YY, Wang QY, Hu B, et al. Efficacy and safety of panobinostat in relapsed or/and refractory multiple myeloma: Meta analyses of clinical trials and systematic review. Scientific Reports. 2016;6:27361. DOI: 10.1038/srep27361
  173. 173. Abate-Daga D, Davila ML. CAR models: Next-generation CAR modifications for enhanced T-cell function. Molecular Therapy—Oncolytics. 2016;3:16014. DOI: 10.1038/mto.2016.14 [eCollection 2016]
  174. 174. Levine BL, Miskin J, Wonnacott K, Keir C. Global manufacturing of CAR T cell therapy. Molecular Therapy—Methods and Clinical Development. 2016;4:92-101. DOI: 10.1016/j.omtm.2016.12.006 [eCollection Mar 17, 2017]
  175. 175. Wang X, Xiao Q, Wang Z, Feng WL. CAR-T therapy for leukemia: Progress and challenges. Translational Research. 2017;182:135-144. DOI: 10.1016/j.trsl.2016.10.008 [Epub Oct 27, 2016]
  176. 176. Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Molecular Therapy—Oncolytics. 2016;3:16011. DOI: 10.1038/mto.2016.11 [eCollection 2016]
  177. 177. Chu J, Deng Y, Benson DM, He S, Hughes T, Zhang J, et al. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Leukemia. 2014;28(4):917-927. DOI: 10.1038/leu.2013.279 [Epub Sep 26, 2013]
  178. 178. Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, Melenhorst JJ, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. The New England Journal of Medicine. 2015;373(11):1040-1047. DOI: 10.1056/NEJMoa1504542
  179. 179. Ormhøj M, Bedoya F, Frigault MJ, Maus MV. CARs in the lead against multiple myeloma. Current Hematologic Malignancy Reports. 2017;12(2):119-125. DOI: 10.1007/s11899-017-0373-2
  180. 180. Hipp S, Tai YT, Blanset D, Deegen P, Wahl J, Thomas O, et al. A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo. Leukemia. 2017;31(8):1743-1751. DOI: 10.1038/leu.2016.388 [Epub Dec 27, 2016]
  181. 181. Ali SA, Shi V, Maric I, Wang M, Stroncek DF, Rose JJ, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood. 2016;128(13):1688-1700. DOI: 10.1182/blood-2016-04-711903 [Epub Jul 13, 2016]
  182. 182. Yee AJ, Raje N. Best of 2017 in multiple myeloma. American Society of Hematology. The Hematologist, ASH News and Reports. January-February 2018:15(1)
  183. 183. Chim CS, Kumar SK, Orlowski RZ, Cook G, Richardson PG, Gertz MA, et al. Management of relapsed and refractory multiple myeloma: Novel agents, antibodies, immunotherapies and beyond. Leukemia. 2018;32(2):252-262. DOI: 10.1038/leu. 2017.329 [Epub Nov 16, 2017]
  184. 184. Malard F, Harousseau JL, Mohty M. Multiple myeloma treatment at relapse after autologous stem cell transplantation: A practical analysis. Cancer Treatment Reviews. 2017;52:41-47. DOI: 10.1016/j.ctrv.2016.11.005 [Epub Nov 15, 2016]
  185. 185. Sun Z, Zheng F, Wu S, Liu Y, Guo H, Liu Y. Triplet versus doublet combination regimens for the treatment of relapsed or refractory multiple myeloma: A meta-analysis of phase III randomized controlled trials. Critical Reviews in Oncology/Hematology. 2017;113:249-255. DOI: 10.1016/j.critrevonc.2017.03.018 [Epub Mar 18, 2017]
  186. 186. Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, et al., ENDEAVOR Investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): A randomised, phase 3, open-label, multicentre study. The Lancet Oncology. 2016;17(1):27-38. DOI: 10.1016/S1470-2045(15)00464-7. [Epub Dec 5, 2015]
  187. 187. Yadav P, Cook M, Cockwell P. Current trends of renal impairment in multiple myeloma. Kidney Diseases (Basel). 2016;1(4):241-527. DOI: 10.1159/000442511 [Epub Feb 3, 2016]
  188. 188. Gaballa MR, Laubach JP, Schlossman RL, Redman K, Noonan K, Mitsiades CS, et al. Management of myeloma-associated renal dysfunction in the era of novel therapies. Expert Review of Hematology. 2012;5:51-66 (quiz 67-8). DOI: 10.1586/ehm.11.72
  189. 189. Gavriatopoulou M, Terpos E, Kastritis E, Dimopoulos MA. Current treatments for renal failure due to multiple myeloma. Expert Opinion on Pharmacotherapy. 2016;17(16):2165-2177. DOI: 10.1080/14656566.2016.1236915 [Epub Sep 27, 2016]
  190. 190. Parikh GC, Amjad AI, Saliba RM, Kazmi SM, Khan ZU, Lahoti A, et al. Autologous hematopoietic stem cell transplantation may reverse renal failure in patients with multiple myeloma. Biology of Blood and Marrow Transplantation. 2009;15:812-816. DOI: 10.1016/j.bbmt.2009.03.021
  191. 191. Dimopoulos MA, Roussou M, Gkotzamanidou M, Nikitas N, Psimenou E, Mparmparoussi D, et al. The role of novel agents on the reversibility of renal impairment in newly diagnosed symptomatic patients with multiple myeloma. Leukemia. 2013;27:423-429. DOI: 10.1038/leu.2012.182 [Epub Jul 5, 2012]
  192. 192. Terpos E, Kleber M, Engelhardt M, Zweegman S, Gay F, Kastritis E, et al., European Myeloma Network. European Myeloma Network guidelines for the management of multiple myeloma-related complications. Haematologica. 2015;100(10):1254-1266. DOI: 10.3324/haematol.2014.117176
  193. 193. Raghavan R, Jeroudi A, Achkar K, Gaber AO, Patel SJ, Abdellatif A. Bortezomib in kidney transplantation. Journal of Transplantation. 2010. DOI: 10.1155/2010/698594 [Epub Sep 27, 2010]
  194. 194. Heher EC, Rennke HG, Laubach JP, Richardson PG. Kidney disease and multiple myeloma. Clinical Journal of the American Society of Nephrology. 2013;8(11):2007-2017. DOI: 10.2215/CJN.12231212 [Epub Jul 18, 2013]
  195. 195. Penfield JG. Multiple myeloma in end-stage renal disease. Seminars in Dialysis. 2006;19:329-334. DOI: 10.1111/j.1525-139X.2006.00181.x
  196. 196. Heher EC, Goes NB, Spitzer TR, Raje NS, Humphreys BD, Anderson KC, et al. Kidney disease associated with plasma cell dyscrasias. Blood. 2010;116:1397-1404. DOI: 10.1182/blood-2010-03-258608 [Epub May 12, 2010]
  197. 197. Bansal T, Garg A, Snowden JA, McKane W. Defining the role of renal transplantation in the modern management of multiple myeloma and other plasma cell dyscrasias. Nephron. Clinical Practice. 2012;120:228-235. DOI: 10.1159/000341760 [Epub Oct 5, 2012]
  198. 198. Al-Anazi KA, Bacal J, Mokhtar N, Kawari M, AlHashmi H, Kalogiannidis P, et al. A young patient with refractory multiple myeloma and dialysis-dependent renal failure has been cured by non-cryopreserved autologous stem cell transplantation followed by live-related kidney transplantation. Journal of Stem Cell Biology and Transplantation. 2017;1(2):13. DOI: 10.21767/2575-7725.100013
  199. 199. Baraldi O, Grandinetti V, Donati G, Comai G, Battaglino G, Cuna V, et al. Hematopoietic cell and renal transplantation in plasma cell dyscrasia patients. Cell Transplantation. 2016;25:995-1005. DOI: 10.3727/096368915X688560 [Epub Jul 8, 2015]
  200. 200. Doney KC, Mielcarek M, Stewart FM, Appelbaum FR. Hematopoietic cell transplantation after solid organ transplantation. Biology of Blood and Marrow Transplantation. 2015;21:2123-2128. DOI: 10.1016/j.bbmt. 2015.08.004 [Epub Aug 10, 2015]
  201. 201. Kawai T, Sachs DH, Sprangers B, Spitzer TR, Saidman SL, Zorn E, et al. Long-term results in recipients of combined HLA-mismatched kidney and bone marrow transplantation without maintenance immunosuppression. American Journal of Transplantation. 2014;14:1599-1611. DOI: 10.1111/ajt.12731 [Epub Jun 5, 2014]
  202. 202. Chen YB, Kawai T, Spitzer TR. Combined bone marrow and kidney transplantation for the induction of specific tolerance. Advances in Hematology. 2016;2016:6471901. DOI: 10.1155/2016/6471901 [Epub Apr 30, 2016]
  203. 203. Spitzer TR, Sykes M, Tolkoff-Rubin N, Kawai T, McAfee SL, Dey BR, et al. Long-term follow-up of recipients of combined human leukocyte antigen-matched bone marrow and kidney transplantation for multiple myeloma with end-stage renal disease. Transplantation. 2011;91:672-676. DOI: 10.1097/TP.0b013e31820a3068
  204. 204. Kawai T, Chen Y-B, Sykes M, Benedict C, Tolkoff-Rubin N, Day B et al. HLA identical or haploidentical combined kidney and bone marrow transplantation for multiple myeloma with end-stage renal failure. American Transplant Congress. June 13, 2016; (abstract number: 187)
  205. 205. Ruiz-Delgado GJ, León-Peña AA, Medina-Ceballos E, Vargas-Espinosa J, León-González M, Ruiz-Argüelles GJ, et al. Double transplant in a patient with multiple myeloma: Bone marrow and kidney. Revista de Hematología (Mex.). 2015;16:333-337
  206. 206. Khoriaty R, Otrock ZK, Medawar WA, Khauli RB, Bazarbachi A. A case of successful double sequential bone marrow and kidney transplantations in a patient with multiple myeloma. Nephrology, Dialysis, Transplantation. 2006;21:3585-3358. DOI: 10.1093/ndt/gfl403 [Epub Sep 12, 2006]

Written By

Khalid Ahmed Al-Anazi

Submitted: May 24th, 2018 Reviewed: July 6th, 2018 Published: November 5th, 2018