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Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 42464

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Prof. Dr. Klaus Podar

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Department of Internal Medicine II, University Hospital Krems, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
Interests: multiple myeloma; breast cancer; signal transduction; tumor microenvironment; angiogenesis; bone disease; targeted therapy; apoptosis
Special Issues, Collections and Topics in MDPI journals

Prof. Xavier Leleu

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Service d’Hematologie et Therapie Cellulaire, and Inserm CIC U1402, 86000 Poitiers, France
Interests: myeloma; drug development; treatment sequences; immunology

Special Issue Information

Dear Colleagues,

Despite the challenges and odds imposed by the COVID-19 pandemic, therapeutic progress continues to be made in multiple myeloma (MM). New approvals in 2020 include the CD38 monoclonal antibody (mAb) isatuximab in combination with pomalidomide and dexamethasone; the combination of daratumumab with carfilzomib and dexamethasone; and the antibody drug conjugate (ADC) belantamab-mafodotin, for the treatment of relapsed/refractory (RR)MM; and s.c. daratumumab for all lines of therapy.

The combinatorial use of IMiDs, proteasome inhibitors, and monoclonal antibodies (mAbs), cornerstones of current MM therapy, has revolutionized MM treatment strategies and significantly improved patient survival. Nevertheless, almost all MM patients who have received initial therapy eventually relapse, with responses becoming progressively shorter with each line of therapy. Continuous clinical and basic research to identify novel therapeutic targets, optimal drug combinations and their timing dependent on disease, prior treatment and patient characteristics in a cost-effective and safe manner are therefore needed.

In this issue, eminent experts in the field of MM will summarize the most recent therapeutic developments, and offer evidence-based recommendations for combinatorial treatment approaches in RRMM patients. Among other topics, current strategies to treat MM patients refractory to lenalidomide, PIs, and/or mAbs in early or late relapse; and high-risk patients will be discussed. Moreover, promising biomarkers for drug resistance, therapy response, and tolerability using gene expression and proteomic profiling, as well as FACS analysis will be summarized. In addition, authors will present data on agents whose approval is expected during the next months; and on the impact of the “next-generation” of immunotherapies, chimeric antigen receptor T cells (CAR T cells), bispecific T cell engagers (BiTEs) and ADCs, as well as vaccines, in particular.

Prof. Klaus Podar
Prof. Xavier Leleu
Guest Editors

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Keywords

myeloma relapse setting
drug development
treatment sequences
immunotherapy

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Published Papers (12 papers)

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Research

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16 pages, 2850 KiB

Open AccessArticle

Euchromatic Histone Lysine Methyltransferase 2 Inhibition Enhances Carfilzomib Sensitivity and Overcomes Drug Resistance in Multiple Myeloma Cell Lines

by Elisabetta Mereu, Damiano Abbo, Tina Paradzik, Michela Cumerlato, Cecilia Bandini, Maria Labrador, Monica Maccagno, Domenica Ronchetti, Veronica Manicardi, Antonino Neri and Roberto Piva

Cancers 2023, 15(8), 2199; https://doi.org/10.3390/cancers15082199 - 7 Apr 2023

Cited by 5 | Viewed by 2410

Abstract

Proteasome inhibitors (PIs) are extensively used for the therapy of multiple myeloma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. In addition, adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. Here, to identify compounds that can increase the efficacy of PIs, we performed a functional screening using a library of small-molecule inhibitors covering key signaling pathways. Among the best synthetic lethal interactions, the euchromatic histone-lysine N-methyltransferase 2 (EHMT2) inhibitor UNC0642 displayed a cooperative effect with carfilzomib (CFZ) in numerous multiple myeloma (MM) cell lines, including drug-resistant models. In MM patients, EHMT2 expression correlated to worse overall and progression-free survival. Moreover, EHMT2 levels were significantly increased in bortezomib-resistant patients. We demonstrated that CFZ/UNC0642 combination exhibited a favorable cytotoxicity profile toward peripheral blood mononuclear cells and bone-marrow-derived stromal cells. To exclude off-target effects, we proved that UNC0642 treatment reduces EHMT2-related molecular markers and that an alternative EHMT2 inhibitor recapitulated the synergistic activity with CFZ. Finally, we showed that the combinatorial treatment significantly perturbs autophagy and the DNA damage repair pathways, suggesting a multi-layered mechanism of action. Overall, the present study demonstrates that EHMT2 inhibition could provide a valuable strategy to enhance PI sensitivity and overcome drug resistance in MM patients. Full article

(This article belongs to the Special Issue Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond)

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14 pages, 528 KiB

Open AccessArticle

The Risk of Multiple Myeloma Is Reduced in Metformin Initiators: A Retrospective Cohort Study in Taiwanese Patients with Type 2 Diabetes Mellitus

by Chin-Hsiao Tseng

Cancers 2022, 14(22), 5637; https://doi.org/10.3390/cancers14225637 - 17 Nov 2022

Cited by 4 | Viewed by 1755

Abstract

Background: Whether metformin might reduce the risk of multiple myeloma (MM) has not been extensively researched in humans. Methods: The study subjects were enrolled from the reimbursement database of Taiwan’s National Health Insurance. A total of 739,553 patients who had a new diagnosis of type 2 diabetes mellitus during 1999–2009 were identified. They were categorized as metformin initiators (metformin (+)) and non-metformin initiators (metformin (−)) based on the prescriptions of antidiabetic drugs that included metformin and did not include metformin within the initial 12 months, respectively. MM incidence was calculated after the initial 12 months of treatment group assignment until 31 December 2011. Hazard ratios based on intention-to-treat (ITT) and per-protocol (PP) approaches were estimated by Cox regression weighted by propensity scores. Results: In the ITT analyses, the respective incidence rates for 497,248 metformin (+) and 242,305 metformin (−) were 9.97 and 14.33 per 100,000 person-years. The hazard ratio that compared metformin (+) to metformin (−) in the ITT analysis was 0.710 (95% confidence interval 0.593–0.850). In the PP analysis, the respective incidence rates were 5.14 and 13.98 per 100,000 person-years, and the hazard ratio was 0.355 (95% confidence interval, 0.270–0.466). The lower risk of MM among metformin (+) was supported by subgroup and sensitivity analyses. Conclusions: Type 2 diabetes patients who are initiated with metformin treatment have a significantly lower risk of MM, especially when they adhere to metformin treatment. Full article

(This article belongs to the Special Issue Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond)

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15 pages, 476 KiB

Open AccessArticle

The Dynamics of Nucleotide Variants in the Progression from Low–Intermediate Myeloma Precursor Conditions to Multiple Myeloma: Studying Serial Samples with a Targeted Sequencing Approach

by Bénedith Oben, Charlotte Cosemans, Ellen Geerdens, Loes Linsen, Kimberly Vanhees, Brigitte Maes, Koen Theunissen, Bert Cruys, Marta Lionetti, Ingrid Arijs, Niccolò Bolli, Guy Froyen and Jean-Luc Rummens

Cancers 2022, 14(4), 1035; https://doi.org/10.3390/cancers14041035 - 18 Feb 2022

Viewed by 2146

Abstract

Multiple myeloma (MM), or Kahler’s disease, is an incurable plasma cell (PC) cancer in the bone marrow (BM). This malignancy is preceded by one or more asymptomatic precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). The molecular mechanisms and exact cause of this progression are still not completely understood. In this study, the mutational profile underlying the progression from low–intermediate risk myeloma precursor conditions to MM was studied in serial BM smears. A custom capture-based sequencing platform was developed, including 81 myeloma-related genes. The clonal evolution of single nucleotide variants and short insertions and deletions was studied in serial BM smears from 21 progressed precursor patients with a median time of progression of six years. From the 21 patients, four patients had no variation in one of the 81 studied genes. Interestingly, in 16 of the 17 other patients, at least one variant present in MM was also detected in its precursor BM, even years before progression. Here, the variants were present in the pre-stage at a median of 62 months before progression to MM. Studying these paired BM samples contributes to the knowledge of the evolutionary genetic landscape and provides additional insight into the mutational behavior of mutant clones over time throughout progression. Full article

(This article belongs to the Special Issue Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond)

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14 pages, 2380 KiB

Open AccessArticle

V-Domain Ig Suppressor of T Cell Activation (VISTA) Expression Is an Independent Prognostic Factor in Multiple Myeloma

by Pim Mutsaers, Hayri E. Balcioglu, Rowan Kuiper, Dora Hammerl, Rebecca Wijers, Mark van Duin, Bronno van der Holt, Annemiek Broijl, Walter Gregory, Sonja Zweegman, Pieter Sonneveld and Reno Debets

Cancers 2021, 13(9), 2219; https://doi.org/10.3390/cancers13092219 - 6 May 2021

Cited by 9 | Viewed by 2553

Abstract

Multiple myeloma (MM) is characterized by loss of anti-tumor T cell immunity. Despite moderate success of treatment with anti-PD1 antibodies, effective treatment is still challenged by poor T cell-mediated control of MM. To better enable identification of shortcomings in T-cell immunity that relate to overall survival (OS), we interrogated transcriptomic data of bone marrow samples from eight clinical trials (n = 1654) and one trial-independent patient cohort (n = 718) for multivariate analysis. Gene expression of V-domain Ig suppressor of T cell activation (VISTA) was observed to correlate to OS [hazard ratio (HR): 0.72; 95% CI: 0.61–0.83; p = 0.005]. Upon imaging the immune contexture of MM bone marrow tissues (n = 22) via multiplex in situ stainings, we demonstrated that VISTA was expressed predominantly by CD11b+ myeloid cells. The combination of abundance of VISTA+, CD11b+ cells in the tumor but not stromal tissue together with low presence of CD8+ T cells in the same tissue compartment, termed a high VISTA-associated T cell exclusion score, was significantly associated with short OS [HR: 16.6; 95% CI: 4.54–62.50; p < 0.0001]. Taken together, the prognostic value of a combined score of VISTA+, CD11b+ and CD8+ cells in the tumor compartment could potentially be utilized to guide stratification of MM patients for immune therapies. Full article

(This article belongs to the Special Issue Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond)

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16 pages, 629 KiB

Open AccessArticle

Carfilzomib Improves Bone Metabolism in Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results of the CarMMa Study

by Evangelos Terpos, Ioannis Ntanasis-Stathopoulos, Eirini Katodritou, Marie-Christine Kyrtsonis, Vassiliki Douka, Emmanouil Spanoudakis, Athanasios Papatheodorou, Evangelos Eleutherakis-Papaiakovou, Nikolaos Kanellias, Maria Gavriatopoulou, Polyzois Makras, Efstathios Kastritis and Meletios A Dimopoulos

Cancers 2021, 13(6), 1257; https://doi.org/10.3390/cancers13061257 - 12 Mar 2021

Cited by 9 | Viewed by 2555

Abstract

Carfilzomib with dexamethasone (Kd) is a well-established regimen for the treatment of relapsed/refractory multiple myeloma (RRMM). There is limited information for the effects of Kd on myeloma-related bone disease. This non-interventional study aimed to assess skeletal-related events (SREs) and bone metabolism in patients with RRMM receiving Kd, in the absence of any bone-targeted agent. Twenty-five patients were enrolled with a median of three prior lines of therapy; 72% of them had evidence of osteolytic bone disease at study entry. During Kd treatment, the rate of new SREs was 28%. Kd produced a clinically relevant (≥30%) decrease in C-telopeptide of collagen type-1 (p = 0.048) and of tartrate-resistant acid phosphatase-5b (p = 0.002) at 2 months. This reduction was at least partially due to the reduction in the osteoclast regulator RANKL/osteoprotegerin ratio, at 2 months (p = 0.026). Regarding bone formation, there was a clinically relevant increase in osteocalcin at 6 months (p = 0.03) and in procollagen type I N-propeptide at 8 months post-Kd initiation. Importantly, these bone metabolism changes were independent of myeloma response to treatment. In conclusion, Kd resulted in a low rate of SREs among RRMM patients, along with an early, sustained and clinically relevant decrease in bone resorption, which was accompanied by an increase in bone formation, independently of myeloma response and in the absence of any bone-targeted agent use. Full article

(This article belongs to the Special Issue Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond)

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Review

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22 pages, 747 KiB

Open AccessReview

Extracellular Vesicles in Multiple Myeloma—Cracking the Code to a Better Understanding of the Disease

by Justyna Iskrzak, Przemysław Zygmunciak, Irena Misiewicz-Krzemińska and Bartosz Puła

Cancers 2022, 14(22), 5575; https://doi.org/10.3390/cancers14225575 - 14 Nov 2022

Cited by 3 | Viewed by 1800

Abstract

Multiple myeloma (MM) is a plasma cell-derived malignancy that stands for around 1.5% of newly discovered cancer cases. Despite constantly improving treatment methods, the disease is incurable with over 13,000 deaths in the US and over 30,000 in Europe. Recent studies suggest that extracellular vesicles (EVs) might play a significant role in the pathogenesis and evolution of MM. Further investigation of their role could prove to be beneficial in establishing new therapies and hence, improve the prognosis of MM patients. What is more, EVs might serve as novel markers in diagnosing and monitoring the disease. Great advancements concerning the position of EVs in the pathophysiology of MM have recently been shown in research and in this review, we would like to delve into the still expanding state of knowledge. Full article

(This article belongs to the Special Issue Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond)

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24 pages, 595 KiB

Open AccessReview

Stratification for RRMM and Risk-Adapted Therapy: Sequencing of Therapies in RRMM

by Georg Jeryczynski, Arnold Bolomsky, Hermine Agis and Maria-Theresa Krauth

Cancers 2021, 13(23), 5886; https://doi.org/10.3390/cancers13235886 - 23 Nov 2021

Cited by 7 | Viewed by 3644

Abstract

The treatment landscape for relapsed multiple myeloma (RRMM) has experienced an unprecedented wave of innovation. Implementation of numerous new substances and drug classes with different modes of action is made possible in routine clinical practice. Next generation proteasome inhibitors, monoclonal antibodies, as well as first in class agents such as selinexor and venetoclax have widened the therapeutic spectrum. This has led to an increase in progression-free and overall survival. Consequently, new challenges for treating physicians in choosing the right treatment at the right stage of the disease have been generated. Several trials support the use of novel agents in the frontline treatment of newly diagnosed multiple myeloma. The use of lenalidomide or bortezomib as a backbone in the first-line setting, requires strategies for treatment once these patients relapse and are refractory to these drugs. Despite the variety of options, selecting the optimal treatment strategy is difficult, since multiple factors have to be considered: patient-specific factors such as age and co-morbidities, as well as myeloma/tumor specific factors such as cytogenetics and relapse kinetics. This review intends to summarize the existing data and guidelines regarding the optimal sequencing of treatments of RRMM using already approved agents as well as agents under investigation. Full article

(This article belongs to the Special Issue Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond)

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17 pages, 741 KiB

Open AccessReview

Novel Non-Immunologic Agents for Relapsed and Refractory Multiple Myeloma: A Review Article

by Arthur Bobin, Cécile Gruchet, Stéphanie Guidez, Hélène Gardeney, Laly Nsiala Makunza, Mathilde Vonfeld, Anthony Lévy, Laura Cailly, Florence Sabirou, Thomas Systchenko, Niels Moya and Xavier Leleu

Cancers 2021, 13(20), 5210; https://doi.org/10.3390/cancers13205210 - 18 Oct 2021

Cited by 5 | Viewed by 3909

Abstract

Novel treatments are needed to address the lack of options for patients with relapsed or refractory multiple myeloma. Even though immunotherapy-based treatments have revolutionized the field in recent years, offering new opportunities for patients, there is still no curative therapy. Thus, non-immunologic agents, which have proven effective for decades, are still central to the treatment of multiple myeloma, especially for advanced disease. Building on their efficacy in myeloma, the development of proteasome inhibitors and immunomodulatory drugs has been pursued, and has led to the emergence of a novel generation of agents (e.g., carfilzomib, ixazomib, pomalidomide). The use of alkylating agents is decreasing in most treatment regimens, but melflufen, a peptide-conjugated alkylator with a completely new mechanism of action, offers interesting opportunities. Moreover, with the identification of novel targets, new drug classes have entered the myeloma armamentarium, such as XPO1 inhibitors (selinexor), HDAC inhibitors (panobinostat), and anti-BCL-2 agents (venetoclax). New pathways are still being explored, especially the possibility of a mutation-driven strategy, as biomarkers and targeted treatments are increasing. Though multiple myeloma is still considered incurable, the treatment options are expanding and are progressively becoming more diverse, largely because of the continuous development of non-immunologic agents. Full article

(This article belongs to the Special Issue Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond)

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22 pages, 1171 KiB

Open AccessReview

Relapsed/Refractory Multiple Myeloma in 2020/2021 and Beyond

by Klaus Podar and Xavier Leleu

Cancers 2021, 13(20), 5154; https://doi.org/10.3390/cancers13205154 - 14 Oct 2021

Cited by 38 | Viewed by 7575

Abstract

Despite the challenges imposed by the COVID-19 pandemic, exciting therapeutic progress continues to be made in MM. New drug approvals for relapsed/refractory (RR)MM in 2020/2021 include the second CD38 monoclonal antibody, isatuximab, the first BCMA-targeting therapy and first-in-class antibody–drug conjugate (ADC) belantamab mafodotin, the first BCMA-targeting CAR T cell product Idecabtagen-Vicleucel (bb2121, Ide-Cel), the first in-class XPO-1 inhibitor selinexor, as well as the first-in-class anti-tumor peptide-drug conjugate, melflufen. The present introductory article of the Special Issue on “Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond” summarizes the most recent registration trials and emerging immunotherapies in RRMM, gives an overview on latest insights on MM genomics and on tumor-induced changes within the MM microenvironment, and presents some of the most promising rationally derived future therapeutic strategies. Full article

(This article belongs to the Special Issue Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond)

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17 pages, 307 KiB

Open AccessReview

Advances in the Treatment of Relapsed and Refractory Multiple Myeloma in Patients with Renal Insufficiency: Novel Agents, Immunotherapies and Beyond

by Boris Bozic, Jens Rutner, Chang Zheng, Reinhard Ruckser, Flonza Selimi, Krysztina Racz, Martin Köcher, Georg Tatzreiter and Christian Sebesta

Cancers 2021, 13(20), 5036; https://doi.org/10.3390/cancers13205036 - 9 Oct 2021

Cited by 12 | Viewed by 3994

Abstract

Background: Renal insufficiency is one of the most frequent complications in multiple myeloma. The incidence of renal insufficiency in patients with multiple myeloma ranges from 20% to 50%. Renal impairment in patients with multiple myeloma results primarily from the toxic effects of monoclonal light chains on the kidneys. Dehydration, hypercalcemia, hyperuricemia, the application of nephrotoxic NSARs, antibiotics, contrast agents, etc., all play a major role in the deterioration of renal function in patients with multiple myeloma. The diagnosis and treatment of these patients use an interdisciplinary approach in consultation with hematologist–oncologists, radiologists, nephrologists and intensive care specialists. Using new drugs in the treatment of patients with refractory/relapsed multiple myeloma and renal insufficiency markedly improves progression-free survival and overall survival in these patients. Conclusions: New drugs have helped to widen the treatment options available for patients with renal impairment and refractory/relapsed multiple myeloma, since dose adjustments are unnecessary with carfilzomib as well as with panobinostat, elotuzumab, pomalidomide or daratumumab in patients with renal impairment. Several new substances for the treatment of refractory/relapsed multiple myeloma have been approved in the meantime, including belantamab mafodotin, selinexor, melflufen, venetoclax, CAR T-cell therapy and checkpoint inhibitors. Ongoing studies are investigating their administration in patients with renal impairment. Full article

(This article belongs to the Special Issue Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond)

19 pages, 361 KiB

Open AccessReview

Management of Adverse Events and Supportive Therapy in Relapsed/Refractory Multiple Myeloma

by Samantha Pozzi, Alessia Bari, Martin Pecherstorfer and Sonia Vallet

Cancers 2021, 13(19), 4978; https://doi.org/10.3390/cancers13194978 - 4 Oct 2021

Cited by 9 | Viewed by 3463

Abstract

Relapsed/refractory (RR) multiple myeloma (MM) patients are a fragile population because of prolonged drug exposure and advanced age. Preserving a good quality of life is of high priority for these patients and the treatment of disease- and treatment-related complications plays a key role in their management. By preventing and limiting MM-induced complications, supportive care improves patients’ outcome. Erythropoietin-stimulating agents and bisphosphonates are well-established supportive strategies, yet novel agents are under investigation, such as anabolic bone agents and activin receptor-like kinase (ALK) inhibitors. The recent dramatic changes in the treatment landscape of MM pose an additional challenge for the routine care of RRMM patients. Multidrug combinations in first and later lines increase the risk for long-lasting toxicities, including adverse cardiovascular and neurological events. Moreover, recently approved first-in-class drugs have unique side-effect profiles, such as ocular toxicity of belantamab mafodotin or gastrointestinal toxicity of selinexor. This review discusses current standards in supportive treatment of RRMM patients, including recommendations in light of the recent SARS-CoV-19 pandemic, and critically looks at the incidence and management of side effects of standard as well as next generation anti-MM agents. Full article

(This article belongs to the Special Issue Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond)

17 pages, 2926 KiB

Open AccessReview

Choosing the Right Therapy for Patients with Relapsed/Refractory Multiple Myeloma (RRMM) in Consideration of Patient-, Disease- and Treatment-Related Factors

by Laura Gengenbach, Giulia Graziani, Heike Reinhardt, Amelie Rösner, Magdalena Braun, Mandy-Deborah Möller, Christine Greil, Ralph Wäsch and Monika Engelhardt

Cancers 2021, 13(17), 4320; https://doi.org/10.3390/cancers13174320 - 26 Aug 2021

Cited by 17 | Viewed by 5430

Abstract

Treatment of relapsed/refractory multiple myeloma (RRMM) is more complex today due to the availability of novel therapeutic options, mostly applied as combination regimens. immunotherapy options have especially increased substantially, likewise the understanding that patient-, disease- and treatment-related factors should be considered at all stages of the disease. RRMM is based on definitions of the international myeloma working group (IMWG) and includes biochemical progression, such as paraprotein increase, or symptomatic relapse with CRAB criteria (hypercalcemia, renal impairment, anemia, bone lesions). When choosing RRMM-treatment, the biochemical markers for progression and severity of the disease, dynamic of disease relapse, type and number of prior therapy lines, including toxicity and underlying health status, need to be considered, and shared decision making should be pursued. Objectively characterizing health status via geriatric assessment (GA) at each multiple myeloma (MM) treatment decision point has been shown to be a better estimate than via age and comorbidities alone. The well-established national comprehensive cancer network, IMWG, European myeloma network and other national treatment algorithms consider these issues. Ideally, GA-based clinical trials should be supported in the future to choose wisely and efficaciously from available intervention and treatment options in often-older MM adults in order to further improve morbidity and mortality. Full article

(This article belongs to the Special Issue Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond)

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