Comparative effectiveness of lenalidomide/dexamethasone-based triplet regimens for treatment of relapsed and/or refractory multiple myeloma in the United States: An analysis of real-world electronic health records data.

BACKGROUND: This retrospective longitudinal study compared the effectiveness of dexamethasone+lenalidomide (Rd)-based triplet regimens containing proteasome inhibitors (PIs) ixazomib (IRd), carfilzomib (KRd), and bortezomib (VRd) or monoclonal antibodies (MABs) elotuzumab (ERd) and daratumumab (DRd) in patients with relapsed/refractory multiple myeloma (RRMM)-including those with high cytogenetic risk-primarily treated at community oncology clinics in the United States. METHODS: Electronic health records of adult RRMM patients in a deidentified real-world database (01/01/2014-09/30/2020) who initiated IRd, KRd, VRd, ERd, or DRd in the second or later line of therapy (LOT) were analyzed. The index date was the date of initiation of each LOT and baseline was the 6-month pre-index period. Duration of therapy (DOT), time to next therapy (TTNT), progression-free survival (PFS), and overall survival (OS) were compared across regimens with multivariable Cox proportional hazards models. RESULTS: Of the 1,185 patients contributing 1,332 LOTs, 985 had standard cytogenetic risk (median age, 71 years) and 180 had high risk (median age, 69 years). Compared with other regimens, DRd was associated with longer DOT overall (adjusted hazard ratio [95 % confidence interval]: 1.84 [1.42, 2.38] vs. KRd, 1.65 [1.20, 2.28] vs. ERd, 1.58 [1.23, 2.04] vs. IRd, and 1.54 [1.18, 2.00] vs. VRd), and longer TTNT and PFS. KRd was associated with shorter OS compared with DRd (1.45 [1.01, 2.08]) and VRd (1.32 [1.01, 1.73]). High-risk patients had similar outcomes with all triplet regimens. CONCLUSION: Although DRd improved clinical outcomes overall, Rd-based triplet regimens containing a PI or MAB are similarly effective in high-risk RRMM.

Prevalence and impact of diabetes on survival of patients with multiple myeloma in different racial groups.

ABSTRACT: Multiple myeloma (MM) is twice as common in Black individuals compared with in White individuals, and diabetes mellitus (DM) disproportionately affects Black patients. Although numerous studies have shown a correlation between DM and MM, this has not been studied in the context of race and in vivo mechanisms. We conducted a retrospective clinical study of 5383 patients with MM of which 15% had DM (White, 12% and Black, 25%). Multivariable Cox models showed reduced overall survival (OS) for patients with DM (hazard ratio, 1.27; 95% confidence interval, 1.11-1.47; P < .001). This appeared to be driven by a marked difference in OS between White patients with and without DM but not in Black patients. In contrast, obesity was associated with better OS in Black patients but not in White patients. To complement this analysis, we assessed MM growth in a genetically engineered immunocompromised nonobese diabetic (Rag1-/-/muscle creatinine kinase promoter expression of a human IGF1R [M] with a lysine [K] to arginine [R] point mutation) mouse model to evaluate the mechanisms linking DM and MM. MM.1S xenografts grew in more Rag1-/-/MKR mice and grew more rapidly in the Rag1-/-/MKR mice compared with in controls. Western blot analysis found that MM1.S xenografts from Rag1-/-/MKR mice had higher phosphorylated S6 ribosomal protein (Ser235/236) levels, indicating greater activation of the mammalian target of rapamycin pathway. Our study is, to our knowledge, the first to evaluate racial differences in DM prevalence and survival in MM, as well as the effect of DM on tumor growth in mouse models. Our results suggest that DM may contribute to the higher incidence of MM in Black patients; and to improve survival in MM, DM management cannot be ignored.

Comparison of health care costs and resource utilization for commonly used proteasome inhibitor-immunomodulatory drug-based triplet regimens for the management of patients with relapsed/refractory multiple myeloma in the United States.

BACKGROUND: Economic differences among currently available proteasome inhibitors (PI)-based lenalidomide-dexamethasone (Rd)-backbone triplet regimens-ixazomib (I), bortezomib (V), and carfilzomib (K) plus Rd-remain poorly understood. OBJECTIVE: To assess health care resource utilization (HCRU) and health care costs of patients with relapsed/refractory multiple myeloma (RRMM) in the United States treated with IRd, VRd, and KRd. METHODS: This retrospective longitudinal cohort study using IQVIA PharMetrics Plus adjudicated claims US data (January 1, 2015, to September 30, 2020) included adult patients with all available data who initiated IRd, VRd, or KRd in second line of therapy or later (LOT2+) on or after September 1, 2015. The index date was the treatment initiation date for each LOT (multiple LOTs per patient were included) and the baseline was 6 months pre-index. MM-related and all-cause HCRU/costs were assessed during follow-up and reported per patient per month (PPPM; 2020 US Dollars). For MM-related costs only, treatment administration costs were excluded from outpatient (OP) costs and instead summed with pharmacy costs. HCRU/costs were compared between treatment groups using generalized linear models (GLMs). Cost variables were compared using 2-part models and GLM with log transformation and γ distribution. Inverse probability of treatment weighting (IPTW) adjusted for imbalance of baseline confounders across treatment groups. RESULTS: The study included 511 patients contributing 542 LOTs (IRd: n = 153; VRd: n = 262; KRd: n = 127). Before IPTW, mean observed time spent on therapy was 8.5, 9.3, and 7.3 months for the IRd, VRd, and KRd cohorts, respectively. During follow-up and after IPTW, IRd and VRd were associated with significantly fewer OP visits vs KRd. Post-IPTW comparisons of MM-related costs for IRd vs KRd yielded lower OP costs for IRd (mean diff. PPPM: -$3,428; P < 0.001), contributing to lower total medical costs (-$3,813; P < 0.001) and total health care cost savings with IRd vs KRd (-$5,813; P = 0.001). MM-related OP costs were lower for VRd (mean diff. PPPM: -$3,543; P < 0.001) than KRd, reducing its total MM-related medical costs (-$3,997; P = 0.002), leading to total MM-related health care cost savings with VRd vs KRd (-$12,357; P < 0.001). All-cause cost comparisons yielded similar results (total health care cost savings for IRd and VRd vs KRd: -$6,371 and -$13,629, respectively; all P < 0.001). CONCLUSIONS: From the US insurance-payer perspective, patients treated with IRd and VRd had significant medical cost savings vs KRd due to lower OP costs when excluding treatment administration costs. The differential economic impacts of PI-Rd regimens in this study may help to inform treatment decisions for patients with MM. DISCLOSURES: This study and article were supported by Takeda Development Center Americas, Inc. Dr Sanchez has no conflicts to declare. Dr Chari has the following relationships: Research Support/Principal Investigator: Amgen, Array Biopharma, Celgene, Glaxo Smith Klein, Janssen, Millenium/Takeda, Novartis Pharmaceuticals, Oncoceutics, Pharmacyclics, Seattle Genetics; Consultant: Amgen, Bristol-Myers Squibb, Celgene, Millenium/Takeda, Janssen, Karyopharm; Scientific Advisory Board: Amgen, Celgene, Millenium/Takeda, Janssen, Karyopharm, Sanofi, Seattle Genetics. Drs Cherepanov, Huang, Dabora, and Noga are current employees of Takeda, while Drs Stull and Young are ex-employees of Takeda; Drs Cherepanov and Huang also own stocks in Takeda. Dr DerSarkissian, Ms Cheng, Ms Zhang, Mr Banatwala, and Dr Duh are employees of Analysis Group, Inc. (AG), a consulting firm that received funding from Takeda to conduct this study. Ms Pi was an employee of AG at the time of the study. Dr Ailawadhi has the following relationships to declare: Research Support and Consulting for BMS, GSK, and Janssen; Research Support from AbbVie, Arch Oncology, Cellectar, Medimmune, Pharmacyclics, and Xencor; Consulting for Beigene, Oncopeptides, Regeneron, Sanofi, and Takeda.

IVIg Use Associated with Ten-Fold Reduction of Serious Infections in Multiple Myeloma Patients Treated with Anti-BCMA Bispecific Antibodies.

BCMA-targeted bispecific antibodies (BiAb) are efficacious in relapsed/refractory multiple myeloma; however, serious infections have emerged as important toxicities. In this retrospective study, we characterized all infections and their risk factors, and evaluated the impact of infection prophylaxis in patients treated with BCMA-targeted BiAbs. Among 37 patients, 15 (41%) experienced a grade 3-5 infection, with two infection-related deaths during deep remissions. Most (84%) infections occurred during disease remissions. The cumulative probability of grade 3-5 infection increased over time with no plateau. Among responders (n = 26), profound hypogammaglobulinemia occurred in 100% and continued throughout the entire duration of treatment. During periods when patients were receiving intravenous immunoglobulin (IVIg), the rate of grade 3-5 infections was 90% lower than during observation (incidence rate ratio, 0.10; 95% confidence interval, 0.01-0.80; P = 0.0307). No other risk factors for infection were identified. This study demonstrates that profound hypogammaglobulinemia is universal with BCMA-targeted BiAbs, with intravenous immunoglobulin potentially abrogating most of the infection risk. SIGNIFICANCE: To the best of our knowledge, this is the first study to comprehensively analyze risk factors and mitigation strategies to prevent infections in myeloma patients receiving anti-BCMA bispecific antibodies. Profound and prolonged hypogammaglobulinemia was universal among responders, while immunoglobulin replacement was associated with 90% lower rates of grade 3-5 infections. See related commentary by Garfall and Stadtmauer, p. 427 . This article is featured in Selected Articles from This Issue, p. 419.

Trial designs and endpoints for immune therapies in multiple myeloma.

Immune therapies, including CAR-T cells, bispecific antibodies, and antibody-drug conjugates, are revolutionizing the treatment of multiple myeloma. In this review, we discuss clinical trial design considerations relevant to immune therapies. We first examine issues pertinent to specific populations, including elderly, patients with renal impairment, high-risk/extramedullary disease, and prior immune therapies. We then highlight trial designs to optimize the selection of dose and schedule, explore rational combination therapies based on preclinical data, and evaluate the nuances of commonly used endpoints. By exploiting their pharmacokinetic/pharmacodynamic profiles and utilizing novel translational insights, we can optimize the use of immune therapies in multiple myeloma.

Bridging advanced myeloma patients to subsequent treatments and clinical trials with classical chemotherapy and stem cell support.

Rapidly progressing relapsed/refractory multiple myeloma (RRMM) patients with compromised marrow have limited treatment options. Thus, non-myeloablative chemotherapy with a stem cell boost (SCB) may provide disease control and hematopoietic improvement as bridge to subsequent therapies. We identified 96 patients who received a SCB between January 2011 and December 2019 at the Mount Sinai Hospital. Patients had a median age of 64 years, received a median of 7 prior lines of therapy and 68 and 42% were triple-class and penta-drug refractory, respectively. Chemotherapy included melphalan (MEL) (n = 16), melphalan + carmustine (BCNU/MEL) (n = 52) or a variant of DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin) (n = 28). Median time to neutrophil recovery was 10 days and was significantly lower with DCEP (8 days) compared to MEL and BCNU/MEL (10-11 days) (p = 0.0047). Time to progression, progression-free survival and overall survival were 3.19, 2.7 and 8.38 months, respectively. The BCNU/MEL group had the highest response rate of 85% (p = 0.05), clinical benefit rate of 94% (p = 0.0014), progression-free survival of 3.3 months (p = 0.4) and overall survival of 8.7 months (p = 0.5). Sixty-six patients (69%) were bridged to new lines of therapy, including clinical trials. Non-myeloablative chemotherapy with SCB provides rapid disease control and marrow recovery with potential to receive further therapy.

Sequencing T-cell redirection therapies leads to deep and durable responses in patients with relapsed/refractory myeloma.

T-cell redirection therapy using chimeric antigen receptor (CAR) T cells and bispecific antibodies (BiAbs) has shown promising efficacy in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), leading to the approval of 2 CAR T-cell products and numerous BiAb trials. Data on the outcomes after relapse following BiAbs are urgently required to develop strategies for sequencing salvage therapies. We identified 58 patients progressing after a BiAb trial at Mount Sinai Hospital. Progression-free survival (PFS) to the first salvage (PFS1), second salvage therapy (PFS2), and overall survival (OS) were estimated using the Kaplan-Meier method. The median age of the patients was 67 years, and 78% had high-risk cytogenetics. They had a median of 6 prior therapy lines, 89% were triple-class refractory, and 44% were penta-drug refractory. After the BiAb trial, patients were followed for a median of 30.5 months and received a median of 2 additional salvage therapies (range, 1-9). The most common first salvage was T-cell redirection in 19 patients (10 BiAb and 9 CAR T cells). Ten patients underwent T-cell redirection as a second salvage treatment. T-cell redirection therapy as first or second salvage was feasible and associated with a median PFS1 of 28.9 months, PFS2 of 30.9 months, and an OS of 62% at 2 years. The sequential use of different T-cell redirection therapies is possible and may lead to deep and durable responses following the relapse after BiAb therapy in RRMM.

Interventions and outcomes of patients with multiple myeloma receiving salvage therapy after BCMA-directed CAR T therapy.

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR T) therapy has demonstrated remarkable efficacy in patients with relapsed/refractory multiple myeloma, and now there are two US Food and Drug Administration-approved BCMA-directed CAR T products. However, despite high initial response rates, most patients eventually relapse. The outcomes of patients with disease recurrence after BCMA-directed CAR T have not been comprehensively studied, and such an analysis would help define optimal treatment strategies. We analyzed the salvage treatments and outcomes of 79 patients with multiple myeloma from two academic institutions, who had progression of disease after treatment with BCMA-directed CAR T. A total of 237 post-CAR T salvage treatment lines were used, and patients received a median of 2 (range, 1-10) treatment lines. The median overall survival from the date of relapse post-CAR T therapy was 17.9 months (95% confidence interval [CI], 14.0 non-estimable). The overall response rate to the first salvage regimen was 43.4%, with a median progression-free survival of 3.5 months (CI, 2.5-4.6). Thirty-five patients (44.3%) received a T-cell-engaging therapy (bispecific antibody or subsequent CAR T) as salvage treatment. The overall survival in patients who received subsequent T-cell-engaging therapy was not reached after a median follow up of 21.3 months. Patients with multiple myeloma who relapse after BCMA-directed CAR T have a limited prognosis but can be potentially treated with multiple lines of salvage therapy. T-cell-engaging therapies appear to maintain pronounced clinical activity in this setting.

No needles needed: All-oral therapy options for relapsed and refractory multiple myeloma.

Immense progress has been made for the treatment of multiple myeloma over the past two decades, with patient outcomes improving dramatically as a result. Patient quality of life, however, is constantly challenged by complications of the disease, side effects of therapy and the overall burden receiving continuous treatment. Compared to parenteral agents, all-oral regimens can provide logistically favorable alternatives and are associated with improved quality of life. Here, we review the currently available and investigational oral therapies for relapsed and refractory multiple myeloma and provide a practical clinical reference tool. We explore the factors that dictate the selection of therapy, such as prior drug refractoriness, disease biology and patient-specific considerations. Regimens with their respective supporting clinical data are organized by the degree of prior treatment, from lenalidomide-sensitive to heavily pretreated patients. We explore common challenges such as renal insufficiency and cytopenias. Lastly, we review investigational oral agents.

The Safety and Efficacy of Radiation Therapy with Concurrent Dexamethasone, Cyclophosphamide, Etoposide, and Cisplatin-Based Systemic Therapy for Multiple Myeloma.

INTRODUCTION: The concurrent delivery of radiation therapy (RT) with salvage chemotherapies in the management of relapsed and refractory multiple myeloma (MM) is an area of ongoing investigation. This study examined the safety and efficacy of palliative RT given in the setting of concurrent dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP). PATIENTS AND METHODS: Fifty-five patients with MM received RT to 64 different sites within three weeks of receiving DCEP from 2010 to 2020. A median dose of 20 Gray (range 8-32.5 Gy) was delivered in a median of 5 fractions (range 1-15). Patients received a median of 1 cycle (range 1-5) of DCEP. Rates of hematologic and RT toxicity were recorded along with pain, radiographic, and laboratory responses to treatment. RESULTS: RT was completed in 98% of patients. 21% of patients experienced RTOG grade 3+ hematologic toxicity before RT, which increased to 35% one-month post-RT (P = .13) before decreasing to 12% at 3 to 6 months (P = .02). The most common toxicity experienced was thrombocytopenia. Grade 1 to 2 non-hematologic RT-related toxicity was reported in 15% of patients while on treatment and fell to 6% one-month after completing RT. Pain resolved in 94% of patients with symptomatic lesions at baseline. Stable disease or better was observed in 34/39 (87%) of the targeted lesions on surveillance imaging. CONCLUSION: RT administered concurrently with DCEP was well-tolerated by most of the patients in this series, with low rates of hematologic and RT-related toxicity. RT was also very effective, with the vast majority of patients demonstrating resolution of their pain and a significant response on follow-up imaging.

Bispecific Antibodies in Multiple Myeloma: Present and Future.

Despite many recent advances in therapy, there is still no plateau in overall survival curves in multiple myeloma. Bispecific antibodies are a novel immunotherapeutic approach designed to bind antigens on malignant plasma cells and cytotoxic immune effector cells. Early-phase clinical trials targeting B-cell maturation antigen (BCMA), GPRC5D, and FcRH5 have demonstrated a favorable safety profile, with mainly low-grade cytokine release syndrome, cytopenias, and infections. Although dose escalation is ongoing in several studies, early efficacy data show response rates in the most active dose cohorts between 61% and 83% with many deep responses; however, durability remains to be established. Further clinical trial data are eagerly anticipated. SIGNIFICANCE: Overall survival of triple-class refractory multiple myeloma remains poor. Bispecific antibodies are a novel immunotherapeutic modality with a favorable safety profile and impressive preliminary efficacy in heavily treated patients. Although more data are needed, bispecifics will likely become an integral part of the multiple myeloma treatment paradigm in the near future. Studies in earlier lines of therapy and in combination with other active anti-multiple myeloma agents will help further define the role of bispecifics in multiple myeloma.

Strategies to Overcome High-Risk Multiple Myeloma.

ABSTRACT: Multiple myeloma (MM) patients with high-risk cytogenetics continue to have inferior outcomes despite recent advances in the treatment of MM. As defined by the International Myeloma Working Group, the presence of t(4;14), t(14;16), del(17p), t(14;20) and amplification of 1q are considered to be high-risk chromosomal abnormalities associated with poor survival. Despite the use of immunomodulatory agents, proteasome inhibitors, autologous stem cell transplantation, and anti-CD38 monoclonal antibodies, clinical trials of current therapies have not shown strong statistical evidence of being able to overcome the poor prognosis of high-risk disease. Novel treatment approaches are urgently needed to improve survival in this subset of MM patients.

B-cell maturation antigen (BCMA) in multiple myeloma: the new frontier of targeted therapies.

Outcomes of patients with multiple myeloma (MM) who become refractory to standard therapies are particularly poor and novel agents are greatly needed to improve outcomes in such patients. B-cell maturation antigen (BCMA) has become an important therapeutic target in MM with three modalities of treatment in development including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BITEs), and chimeric antigen receptor (CAR) T-cell therapies. Early clinical trials of anti-BCMA immunotherapeutics have demonstrated extremely promising results in heavily pretreated patients with relapsed/refractory MM (RRMM). Recently, belantamab mafodotin was the first anti-BCMA therapy to obtain approval in relapsed/refractory MM. This review summarizes the most updated efficacy and safety data from clinical studies of BCMA-targeted therapies with a focus on ADCs and BITEs. Additionally, important differences among the BCMA-targeted treatment modalities and their clinical implications are discussed.

Subcutaneous daratumumab and hyaluronidase-fihj in newly diagnosed or relapsed/refractory multiple myeloma.

Daratumumab, a human immunoglobulin G1 kappa monoclonal antibody that targets CD38, is currently approved as monotherapy and in varying combinations with approved anti-myeloma regimens in both newly diagnosed multiple myeloma and relapsed refractory multiple myeloma. Originally developed for intravenous administration, the subcutaneous formulation of daratumumab (daratumumab and hyaluronidase-fihj) was recently approved by the US Federal Drug Administration and European Commission in 2020. In clinical trials, compared with the intravenous formulation, subcutaneous daratumumab (Dara-SC) has significantly shorter administration time (median first dose 7 h versus 3-5 min, respectively), lower rates of infusion-related reactions (median first dose 50% versus less than 10%, respectively), and lower volume of infusion (median 500-1000 ml versus 15 ml, respectively). Otherwise, the pharmacokinetics, safety profile, and efficacy are comparable. This review summarizes the pivotal trials that led to the approval of Dara-SC, highlights important clinical considerations for the use of Dara-SC, and provides practical guidelines for the administration of Dara-SC in the clinic.

Renal failure among multiple myeloma patients utilizing carfilzomib and associated factors in the "real world".

Carfilzomib, a next-generation proteasome inhibitor, improves outcomes in patients with multiple myeloma (MM); however, a proportion of those treated develop renal failure due to adverse event, comorbidity, or myeloma progression. The rate of renal failure and associated risk factors remains unknown in real-world populations. Adults with relapsed/refractory MM who received carfilzomib between the years 2013 and 2016 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases. Renal failure was defined using the corresponding International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnostic codes and procedure codes for dialysis. Patients with a pre-existing diagnosis of renal failure were excluded to distinguish an adverse event from comorbidity. Multivariate cox regression analysis was performed to identify the variables independently associated with the development of renal failure among MM patients utilizing carfilzomib. A total of 1950 patients were included in the analysis. Renal failure developed in 22% of patients during the study period. The median time to development of renal failure from first carfilzomib administration was 1.6 months (range < 0.1-23.3). Increasing age (adjusted hazard ratio [aHR] 1.01 per year, p = 0.018), pre-existing heart failure (aHR 1.50, p = 0.005), and pre-existing chronic kidney disease (aHR 2.00, p < 0.001) were associated with a higher risk of developing renal failure. Renal failure occurred in up to 22% of patients on carfilzomib therapy. The exact cause and mechanism of renal failure cannot be determined from our study and may be multifactorial. Future studies are needed to further understand the cause of renal failure among patients on carfilzomib and devise strategies to mitigate the risk.

Prevalence and Survival Impact of Self-Reported Symptom and Psychological Distress Among Patients With Multiple Myeloma.

BACKGROUND: Advances in the management of multiple myeloma (MM) have extended survival and reduced painful skeletal-related events. As MM is evolving toward a chronic disease, we sought to determine the prevalence of self-reported symptom burden and psychological distress, and to determine the association of distress with survival. METHODS: The CPASS-7 patient-reported outcome instrument was administered to a convenience sample of MM patients at 7 outpatient cancer centers. RESULTS: A total of 239 patients completed the CPASS-7 between September 2015 and October 2016%; 57% of respondents were male, and median age was 67 years. Forty-eight percent were concerned that they could not do the things they wanted to do, with 33% reporting decreased performance status. Financial toxicity concerns were self-reported by 44%, with family burdens noted in 24%. Although depression was reported by only 15%, 41% noted lack of pleasure. Pain was a concern in 36%. With a median follow-up of 316 days since CPASS-7 completion, 13% of patients had died. A high total distress score was noted in 57 (24%) and trended toward an association with a decreased survival rate compared to the 182 patients (76%) with a low total distress score (P = .066). The 6-month survival rates for patients with high and low distress scores were 86% and 96%, respectively, and 12-month survival rates were 76% and 87%, respectively. CONCLUSION: Despite dramatic improvements in survival among patients with MM, symptom, financial, and psychosocial concerns continue to be major patient concerns. As MM becomes a chronic disease, additional attention to addressing these issues is required.

Immunomodulatory drug- and proteasome inhibitor-backbone regimens in the treatment of relapsed multiple myeloma: an evidence-based review.

INTRODUCTION: Recent advances and drug approvals in the last decade have substantially changed the landscape of relapsed and refractory multiple myeloma (RRMM), which not only improved outcomes for patients but also increased complexity of treatment decisions. The approvals are based on randomized studies of novel agents added to an immunomodulatory drug- (IMiD) or proteasome inhibitor (PI)-backbone showing an improvement in outcomes. However, differences in enrolled patient populations/study designs limit comparisons of results, making the choice and sequencing of agents challenging. AREAS COVERED: This review summarizes the latest updates of key clinical trials of IMiD- and PI-backbone regimens in RRMM. Additionally, it highlights carfilzomib dosing strategies and toxicity profiles of varying carfilzomib combination regimens and provides a clinical guideline for the use of carfilzomib therapy. PubMed and relevant meeting (ASH, ASCO, EHA, IMW) databases from 2010 to 2020, as well as clinicaltrials.gov, were queried for this review. EXPERT OPINION: The choice of therapy for RRMM requires careful consideration of patient factors (age/frailty and comorbidities), disease factors (symptom burden/biology), and treatment-related factors (toxicities/responses to prior therapies). Importantly, a critical factor in selecting an agent based on the published data is a patient's sensitivity to lenalidomide and bortezomib at the time of relapse.

Therapeutic potential of isatuximab in the treatment of multiple myeloma: Evidence to date.

Management of multiple myeloma represents an ever changing paradigm with monoclonal antibodies adding the ability to treat patients with 3 and 4 drug regimens with acceptable toxicity profiles. In recent years, we have seen the FDA approve a number of regimens with both elotuzumab and daratumumab in combination with the standard approaches of immunomodulatory drugs, proteasome inhibitors, and steroids. Isatuximab is a naked, humanized IgG1 monoclonal antibody directed against CD38. With the recent FDA approval in March 2020, we seek to summarize the presented data to date and where this drug will fit into the future gestalt of myeloma therapy.