Management of Relapsed and Refractory Multiple Myeloma: Recent advances

Abstract Multiple myeloma (MM) accounts for ∼10% of total hematologic malignancies worldwide. In India, the incidence of MM has increased two-fold with marked heterogeneity. Significant improvements in terms of clinical outcomes have been observed in the management of MM in recent years. However, most patients develop a disease relapse with the first or subsequent treatments. A combination of immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (PIs; bortezomib) has been the mainstay for the therapeutic management of relapsed/refractory multiple myeloma (RRMM). This review highlights the management of RRMM with newer agents such as belantamab, carfilzomib, daratumumab, elotuzumab, ixazomib, mafadotin, selinexor, panobinostat, and venetoclax, with more focus on PIs. As a single agent and in combination with other drugs including dexamethasone and carfilzomib has been studied extensively and approved by the United States, European Union, and India. Clinical trials of these newer agents, either alone or in combination, for the treatment of RRMM in Western countries indicate survival, improved outcomes, and overall well-being. However, evidence in Indian patients is evolving from ongoing studies on carfilzomib and daratumumab, which will ascertain their efficacy and safety. Currently, several guidelines recommend carfilzomib-based, daratumumab-based, and panobinostat-based regimens in RRMM patients. Currently, with more accessible generic versions of these drugs, more Indian patients may attain survival benefits and improved quality of life.

Introduction patients who have been refractory to the currently used drugs. 11,12 Over the last few years, there has been a visible shift in the treatment of relapsed and/or refractory MM (RRMM). Several newer agents or combinations of agents targeting various relapse phases are currently available with improved patient survival and quality of life. This review focuses on clinical trial results of second-generation proteasome inhibitors (PIs), ixazomib and carfilzomib, and also provides an overview on other novel therapies, including daratumumab, isatuximab, elotuzumab, belantamab mafodotin, and panobinostat, for the management of RRMM.

Definition of RRMM
RRMM is characterized as cancer that becomes progressive within 60 days of receiving the most recent therapy in those who attained a minimal response or improved on previous treatment or cancer that is nonresponsive while on salvage treatment. 13 While in the nonsecretory subtype, relapse of myeloma is characterized as an absolute rise in the bone marrow plasma cells by ! 10%. 14

Biology of Resistant MM
Relapsed MM is a biologically and genetically advanced heterogeneous cancer. 15 There are several reasons for relapse in MM cells, including the clonal evolution of MM cells and decreased capacity to adapt to the bone marrow microenvironment changes, 16 old age, 17 comorbidities, 18 and high-risk cytogenetics. 19 The International Myeloma Workshop Group (IMWG) defines the type of relapse based on clinical aggressiveness. In biochemical relapse, the disease progression correlates with an increase in M protein levels in an asymptomatic patient, whereas clinical relapses are accompanied by symptoms with or without organ dysfunction and an increase in M protein levels. A quick onset of symptoms characterizes aggressive relapse, widespread malignancy on laboratory, radiographic, or pathologic findings, and rapid organ dysfunction. The other high-risk features include unfavorable cytogenetic defects, high β2M (>5.5 mg/L) or low albumin (<3.5 g/dL), hypodiploidy, extramedullary disease, International Staging System stage II/III at relapse, and isotype makeover (hyposecretory disease, light chain escape). The presence or re-emergence of one or more CRAB characteristics (calcium, renal impairment, anemia, and destructive bone lesions) or a swift and consistent biochemical relapse is indicated for relapse treatment. 14 The evolution of RRMM is dependent on the modifications in the intrinsic biology of tumor cells, tumor microenvironment, and host-specific factors. The tumor-specific molecular events contributing to RRMM development include accumulating cytogenetic aberrations (chromosomal translocations, gains, and deletions), alterations in signaling pathways (NF-κB, RAS-MAPK, JAK-STAT3), mutations in genes related to tumor suppression and drug resistance (TP53, RB1, CRBN, CUL4B), and epigenetic aberrations (DNA methylation, histone modification). 20 Primary cytogenetic abnormalities, such as trisomies and IgH translocations, occur early when the normal plasma cell transitions to a clonal, premalignant stage. Secondary cytogenetic abnormalities, including Del 17p, Del 1p, t (14:16), and t (14:20), occur during the progression of the malignancy to RRMM. 21

RRMM Treatment
Treatment selection for RRMM is based usually on previous therapy, duration of disease, transplant status, performance status, cancer-associated factors, such as nature of relapse, disease risk, genomic abnormalities, and overall disease burden, and patient-related factors, such as patient preferences for drug intake, age, and comorbidities, including renal insufficiency. 22 With the introduction of immunomodulatory drugs (IMiDs), such as thalidomide, pomalidomide and lenalidomide, second-generation PIs, and more recently monoclonal antibodies targeting CD38, treatment options have been expanded for RRMM management. 23 Currently, new treatment strategies, such as oral HDAC6 inhibitors, bispecific T cell engager antibodies, chimeric antigen receptor T cell (CAR-T) therapy, and cyclin-dependent kinase inhibitors, are being studied in clinical trials. Novel agents, such as second-generation PIs, are generally well-tolerated with a better quality of life (QoL) among adults. 24 In a metaanalysis comparing all available agents for RRMM, PIs were the most efficient treatment options with the lowest toxic effects. 25 The National Comprehensive Cancer Network guidelines list 8 preferred regimens and more than 20 optional regimens constituting carfilzomib and daratumumab for previously treated MM. 22 However, as the prevalence of MM in elderly patients is expected to increase in the future, optimal care should focus on improving outcomes while preserving the QoL.
In the following section, we will briefly discuss relevant studies and the clinical utility of carfilzomib, ixazomib, daratumumab, isatuximab, elotuzumab, belantamab mafodotin, panobinostat, and selinexor in the management of RRMM exposed to IMiDs and bortezomib.

Carfilzomib
The US Food and Drug Administration (FDA) approved carfilzomib in 2012 as a treatment for individuals with advanced MM, who have used at least one or more prior therapies. 26 Unlike bortezomib, carfilzomib selectively and irreversibly inhibits the 20S proteasome's chymotrypsin-like activity and is less susceptible to drug resistance. 26 Later, it was approved as a combination with lenalidomide plus dexamethasone or with dexamethasone for the treatment of RRMM, with less than or equal to three lines of prior treatment. In RRMM patients, the FDA recently expanded the prescribing information for carfilzomib to include weekly administration in combination with dexamethasone (Kd70 once weekly). 27 Combination of carfilzomib and lenalidomide plus dexamethasone was approved in 2015 by the European Medicines Agency (EMA) for adults with MM who have had at least one previous treatment. 28 In 2017, the Drugs Controller General of India approved carfilzomib and dexamethasone combination or carfilzomib and lenalidomide plus dexamethasone combination for RRMM patients who have received at least one previous treatment.

Carfilzomib and its Combinations
The efficacy and safety of carfilzomib in combination with dexamethasone were determined in clinical studies (►Table 1). [29][30][31][32] Based on these findings, the USA and European countries have approved the combination of low-dose dexamethasone and carfilzomib. Safety and tolerability of carfilzomib in combination with lenalidomide and low-dose dexamethasone were determined in phase 1b dose-escalation, 33 phase 2 dose-expansion 34 (PX-171-006), and phase 3 35 studies (►Table 1). A randomized phase 3 study investigated the efficacy of carfilzomib versus low-dose corticosteroids with optional cyclophosphamide in RRMM (FOCUS trial) (►Table 1). 36 A meta-analysis by Shah et al analyzed carfilzomibbased medicines for the treatment of RRMM (2906 patients); seven trials used carfilzomib plus other agents: dexamethasone (4 studies), lenalidomide plus dexamethasone (2 studies), and panobinostat (1 study). 37 The pooled overall response rate (ORR) and clinical benefit rate (CBR) were 45% (95% CI: 29-62) and 56% (95% CI: 41-71), respectively. In a separate analysis of three RCTs (ENDEAVOR, FOCUS, and ASPIRE), ORR and CBR improved significantly in the carfilzomib group compared with the control group. There was no difference between carfilzomib and low-dose corticosteroids alone for overall survival (OR) or progression-free survival (PFS) in patients who had received five previous regimens of low-dose corticosteroids for RRMM; this suggests that carfilzomib needs to be combined with certain drugs and used as first-line chemotherapy (FOCUS trial). 37 Compared with a single therapy, combination therapy showed improved ORR and CBR. Further, the treatment response in terms of ORR improved significantly with a more dose of carfilzomib (>20/27 mg/m 2 ) compared with the normal dose (65% versus 35%, p ¼ 0.03). While cardiotoxicity and hypertension were significantly high, peripheral neuropathy events were similar between the two groups. 37 In another meta-analysis of eight clinical studies (1,446 patients), Chen et al presented four trials of carfilzomib (monotherapy) for RRMM, two trials of lenalidomide and dexamethasone in combination, and two trials with or without dexamethasone. The pooled ORR and CBR with carfilzomib were 0.44 (95% CI, 0.18-0.69; p ¼ 0.000) and 0.54 (95% CI, 0.33-0.76, p ¼ 0.000), respectively. 38 In another meta-analysis of 24 studies (10,853 patients), Luo et al identified the time to progression, OS, and PFS of 21 different regimens and recommended triplet therapy of carfilzomib, daratumumab, and elotuzumab or ixazomib, plus dexamethasone and lenalidomide as the preferred choice in patients with RRMM. 39 In another meta-analysis of 20 prospective studies (2,220 patients) by Liu et al, the ORR and very good partial response were found to be 61% and 29%, respectively, with the carfilzomib combination regimens in 1,211 RRMM patients. 40 Several other studies have also determined the safety and efficacy of carfilzomib with dexamethasone and pomalidomide, 41 ibrutinib and dexamethasone, 42 and daratumumab and dexamethasone. 43 In the subgroup analysis of Asian patients, carfilzomib treatment caused increased cardiovascular toxicities (grade 3 or higher) (ARROW and ENDEAVOR trials). 44

Polyneuropathy
In a pooled analysis of four phase 2 studies, 71.9% of 84.8% of patients at baseline experienced polyneuropathy (PNP) of grade 1 or 2. PNP grade 3 occurs in $1.3% of patients. 45 However, the ENDEAVOR trial has reported a lower incidence of PNP with carfilzomib versus bortezomib, 31 whereas the ASPIRE trial observed a similar incidence of PNP between the lenalidomide and dexamethasone (Rd) and carfilzomib, lenalidomide, and dexamethasone (KRd) groups. 35 Cardiotoxicity Carfilzomib can cause chest pain, myocardial infarction, cardiac failure, hypertension, and peripheral edema. In a meta-analysis of 24 prospective studies (N ¼ 2594), adverse cardiovascular events of any grade were seen in 18.1% of patients and of high degree (!3) in 8.2% of patients. The incidence of these events was two times higher than the control group. 46 In another meta-analysis of 29 studies (4,164 patients), incidences of high-grade and any-grade cardiotoxicity were found to be 4.92% and 8.68%, respectively. The carfilzomib group had significantly higher odds of developing cardiotoxicity than the control group (OR, 2.03; 95% CI, 1.19-3.46; p ¼ 0.010 for any grade and OR, 2.04; 95% CI, 1.31-3.17, p ¼ 0.002 for high grade). The incidence of cardiotoxicity was similar in recently diagnosed compared with RRMM and in a high dose compared with a standard dose of carfilzomib. 47 However, the risk seems to be high with the addition of IMiDs compared with without addition (6.54% vs. 4.35%, p ¼ 0.033). Clinicians need to be aware of these adverse events, and more research is required to develop risk mitigation strategies. 46

Renal Toxicity
Acute kidney injury is another crucial adverse event of carfilzomib, especially in individuals with RRMM. In a recent metaanalysis of four RCTs (2,954 patients), renal toxicities were reported to be 21.3% for any grade and 8.3% for high grade in the carfilzomib group. The risk of renal toxicity was significantly high in the carfilzomib group compared with the control group (p < 0.001) (pooled relative risk [RR], 1.79; 95% CI, 1.43-2.23 for any grade and RR, 2.29; 95% CI, 1.59-3.30 for high grade). The incidence of renal toxicities did not differ based on carfilzomib dose, infusion duration, and treatment setting. 48

Ixazomib
The safety and tolerability of oral ixazomib and its maximum tolerated dose were determined in a phase 1 trial. 49 The efficacy and safety of ixazomib in combination with lenalidomide and dexamethasone, 50 as well as pomalidomide and dexamethasone, 51,52 were investigated in different clinical studies. (►Table 1).

Daratumumab
The FDA in 2015 approved daratumumab, a first-in-class human IgG1j monoclonal antibody against CD38, in patients treated before for MM. In 2016, it was authorized in the combination of dexamethasone and bortezomib or dexamethasone and lenalidomide. In 2017, the combination with dexamethasone and pomalidomide was approved for RRMM. 53 The EMA has approved a combination of dexamethasone and daratumumab plus either lenalidomide or bortezomib with a minimum of one previous treatment in MM patients or as monotherapy with previous treatment of a PI and an immunomodulatory agent, and who had disease progression on previous therapy in adult RRMM patients. 54

Daratumumab Monotherapy and Other Combinations
The efficacy and safety of daratumumab monotherapy 55,56 or its combination with bortezomib and dexamethasone, 57 as well as lenalidomide plus dexamethasone, 58 were investigated in different clinical trials (►Table 1).
In one of the meta-analyses, out of 18 therapy choices, daratumumab/lenalidomide/dexamethasone combination was found better in PFS (HR, 0.13; 95% CI, 0.09-0.19) and likely to be the very best option (99% of the simulations). 59 In comparison to dexamethasone/bortezomib/dexamethasone, and lenalidomide/dexamethasone, this combination reduced progression or death by 87%, 81%, and 63%, respectively. 59 In another meta-analysis of 27 RCTs, both daratumumab/lenalidomide/dexamethasone and daratumumab/bortezomib/ dexamethasone were found likely of being the best treatment options and were associated with the minimum chance of progression or mortality versus other FDA-authorized therapy of MM. 60

Safety of Daratumumab
Daratumumab is generally well tolerated. In a pooled analysis (GEN501 part 2 and SIRIUS), anemia, cough, fatigue, nausea, back pain, neutropenia, upper respiratory tract infection, and thrombocytopenia were commonly reported adverse events. 56 The most frequent adverse events (grade 3/4) listed in the CASTOR and POLLUX trials were thrombocytopenia, neutropenia, and anemia. In both trials, neutropenia events (grade 3/4) were higher in the daratumumab than in the control group (13% vs. 4% in CASTOR and 52% vs. 37% in the POLLUX trial). CASTOR trial participants with daratumumab experienced more thrombocytopenia events (grade ¾) than those with control medication (45 vs. 33%). 57,58

Elotuzumab-Based Combinations in RRMM
It is a humanized immunostimulatory monoclonal antibody against signaling lymphocytic activating molecule family member 7. The FDA has approved it in combination with either lenalidomide or bortezomib and dexamethasone after a minimum of one line of failed therapy in the appropriate setting. 61,62 Its combination with dexamethasone and lena-lidomide 63 or pomalidomide and dexamethasone 64 showed a significant relative reduction in the risk of disease progression or death in patients with RRMM (►Table 1).

Belantamab Mafadotin
It is an anti-B-cell antigen bound to monomethyl auristatin, a microtubule inhibitor that, in the phase 2 DREAMM-2 study, produced an overall response in 31% and 34% of patients, respectively, in the 2.5 mg/kg and 3.4 mg/kg cohorts of highly pre-treated patients with RRMM. Thrombocytopenia, anemia, and rarely keratopathy were common adverse events (►Table 1). 65 The FDA has approved it for RRMM after four lines of failure (including an IMiD, PI, and anti-CD38 monoclonal antibody).

Panobinostat
The PANOROMA I trial evaluated the outcomes of a combination of panobinostat (a pan-histone deacetylase [HDAC] inhibitor) and bortezomib/dexamethasone and suggested that panobinostat could be beneficial for patients with RRMM who had a minimum of one previous treatment. 66 In a recent meta-analysis of 19 trials (2,193 patients), the pooled ORR for panobinostat-treated patients was 0.64, whereas, for HDAC inhibitor-treated bortezomib-or lenalidomide-refractory patients, ORRs were 0.36 and 0.46, respectively. 67 The US FDA and EMA authorized the combination of panobinostat and bortezomib/dexamethasone in patients who had a minimum of two previous treatments, containing IMiD and bortezomib. 68 The same combination was approved in India in 2016. The FDA has approved panobinostat for RRMM patients with failed response to lenalidomide and bortezomib.

Safety of Panobinostat
The commonly found hematologic adverse events (grade 3/4) were neutropenia, thrombocytopenia, and anemia. 66 The most frequent nonhematologic adverse events with panobinostat were gastric-related. 68

Selinexor
The safety and efficacy of selinexor, a nuclear export inhibitor inducing apoptosis, were evaluated in a phase 2b trial (STORM), 69 which led to its approval by the FDA for use with dexamethasone in RRMM following four lines of therapy failing IMiDs, PIs, and two monoclonal antibodies. A phase 3 trial (BOSTON) revealed significant improvement in PFS with the addition of selinexor to bortezomib and dexamethasone in patients who had previously received treatment for MM (►Table 1). 70 Venetoclax A phase 1 study revealed an acceptable safety profile and effectiveness of venetoclax (a BCL-2 inhibitor) monotherapy in patients with RRMM harboring t (11;14). 71 Real-world data on the safety and efficacy of venetoclax-based regimens in RRMM patients harboring t (11;14) showed an overall response rate of 78%. 72 The efficacy and safety of venetoclax plus daratumumab and dexamethasone, with or without bortezomib, were evaluated in patients with RRMM with and without t(11;14) 73 and those of venetoclax plus bortezomib and dexamethasone were evaluated in patients with RRMM (BELLINI trial) 74 as shown in ►Table 1.

Teclistamab
Teclistamab is an under-investigation fully humanized IgG4 bispecific antibody that targets both the T cell receptor CD3 and the B cell maturation antigen (BCMA). It works by rerouting CD3þ T lymphocytes to promote T cell activation and lysis of myeloma cells that express BCMA. 75 The safety and efficacy of teclistamab in patients with RRMM who have received at least three other lines of therapy are being studied in ongoing clinical studies (►Table 1). Additionally, two trials are investigating its effectiveness and safety in combination with other agents for the treatment of patients with RRMM. 76 Common adverse events include cytokine release syndrome, neutropenia, and thrombocytopenia. 77,78

Treatment of Patients with RRMM in India
In India, most of the patients receive bortezomib, lenalidomide, or thalidomide-based medications as treatment for RRMM. 79 The market for generic medications is growing in India. The cost of these medications is relatively lower because of the stiff competition among many generic drug manufacturers in the country. Thus, the development of generic versions of medications, such as pomalidomide and carfilzomib, makes them more accessible and affordable for cancer patients. 80 Since 2017, generic pomalidomide has been available in India. The results are comparable to those reported in the literature for the original molecule. Hence, it is considered an effective treatment choice for those with RRMM, as well as a less expensive alternative to original pomalidomide in India and other developing countries where affordability is an issue. 81,82 ►Table 2 shows data from clinical studies that investigated the efficacy and safety of drugs or their combinations for the treatment of RRMM patients in the Indian setting. [82][83][84][85][86][87] The CAR-T therapy is a novel and emerging therapy for MM. Global clinical trials have demonstrated that CAR-T treatment is beneficial in RRMM patients. Although this technology has a great deal of therapeutic potential for cancer patients, it is still not available in India because of the exorbitant cost. In this regard, researchers at the Department of Bioscience and Bioengineering, IIT, Mumbai, designed and manufactured the country's first CAR T cells using lentiviral technology. 88 In June 2021, India's first CAR-T therapy was done at the bone marrow transplant unit at Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Hospital, Mumbai. 88 Furthermore, the first CAR-T product HCAR19 showed favorable efficacy and less toxicity with no relapse in 10 lymphoma  patients in a phase 1 clinical trial conducted at ACTREC, Mumbai. A phase 2 trial involving 40 patients is currently underway. 88 The researchers were able to significantly reduce the cost through this innovation, making it affordable and accessible to patients.

Guideline and Cancer Group Recommendations for RRMM
Patients with relapsed myeloma who have failed to respond to bortezomib and lenalidomide should be treated with pomalidomide or carfilzomib (IMWG). Carfilzomib must be taken along with low-dose dexamethasone and lenalidomide. The working group also recommends a combination of panobinostat, bortezomib, and dexamethasone for those with a few treatment options and who have a positive performance status. 89 According to the ESMO guidelines on the clinical management of MM, treatment options at second or subsequent relapse include daratumumab monotherapy or a combination of pomalidomide with dexamethasone plus daratumumab. 90 According to the Mayo Stratification for Myeloma and Risk-Adapted Therapy guidelines, daratumumab, bortezomib, and dexamethasone (DVd) for IMiD refractory; daratumumab, lenalidomide, and dexamethasone (DRd) for PI refractory; carfilzomib, lenalidomide, and dexamethasone (KRd) or carfilzomib, pomalidomide, and dexamethasone (KPd) for dual refractory to bortezomib/ixazomib and lenalidomide; daratumumab, pomalidomide, and dexamethasone (DPd) or daratumumab, pomalidomide, cyclophosphamide, and dexamethasone (DPCd) for triple refractory to carfilzomib, lenalidomide, and bortezomib/ixazomib; daratumumab based or PI and panobinostat for triple refractory to lenalidomide, bortezomib/ixazomib, and pomalidomide have been recommended. 91 The FDA had authorized selinexor in association with dexamethasone for adult RRMM patients who had a minimum of four previous treatments and whose disease is refractory to a minimum of two PIs, two IMiDs, and an anti-CD38 monoclonal antibody. 92

Conclusion
The approval of PIs, IMiDs, and mAbs in patients with RRMM has considerably modified the treatment options of RRMM in the last few years. Several randomized clinical trials have demonstrated favorable outcomes of these novel drugs in combination therapies. Further studies evaluating the longterm safety and efficacy of combination therapies are warranted. The availability of less expensive generic versions of carfilzomib, daratumumab, and panobinostat in India should pave way for a change in the outlook of patients with improved outcomes, survival, and QoL.

Authors' Contributions
The manuscript has been read and approved by all authors. All authors contributed equally to the development of the article, and its review and approval.

Funding
None.

Conflict of Interest
None declared.