Relapsed/refractory Multiple Myeloma Research Articles

Bispecific antibodies targeting BCMA or GPRC5D are highly effective in relapsed myeloma after CAR T-cell therapy

Despite the astonishing outcomes after chimeric antigen receptor (CAR) T-cell therapy for relapsed refractory multiple myeloma (RRMM), most patients eventually relapse. There are only limited data available on salvage therapies following relapse after BCMA-directed CAR T-cell therapy. Here, we analyzed outcomes of post-CAR T-cell therapy relapse and impact of different salvage strategies in an international cohort of 139 patients (n = 130 ide-cel, n = 9 cilta-cel), receiving talquetamab (n = 28), teclistamab (n = 37), combinations of immunomodulating drugs (IMiDs), proteasome inhibitors (PIs) or CD38 monoclonal antibodies (n = 43), and others (n = 31). The median time to relapse after CAR T-cell therapy was 5 months, 53% had the extramedullary disease (EMD) at relapse, associated with dismal post-relapse outcome (P = 0.005). Overall response and complete response upon salvage therapies were 79% and 39% for talquetamab, 64% and 32% for teclistamab, 30% and 0% for IMiDs/PIs/CD38, and 26% and 3% for others (P < 0.001). Duration of response, as well as median survival, was significantly improved with bispecific antibodies (P < 0.001, respectively). Bispecific antibodies seemed to overcome the poor prognosis associated with early relapse and EMD, and were independent predictors for improved survival in multivariable analysis. In summary, these results suggest bispecific antibodies as the standard of care for relapse after CAR T-cell therapy for RRMM.

Acid ceramidase controls proteasome inhibitor resistance and is a novel therapeutic target for the treatment of relapsed / refractory multiple myeloma.

Multiple myeloma (MM) patients are often refractory to targeted therapies including proteasome inhibitors (PIs). Here, analysis of RNA sequencing data derived from 672 patients with newly diagnosed or relapsed/refractory disease identified the acid ceramidase, ASAH1, as a key regulator of PI resistance. Genetic or pharmacological blockade of ASAH1 remarkably restored PI sensitivity and protected mice from resistant MM progression in vivo. Mechanistically, ASAH1 depletion of ceramide promoted SET inhibition of PP2A phosphatase activity thus facilitating the increased expression and activity of the pro-survival proteins, MCL-1, and BCL-2. We corroborated these findings in human MM datasets, and in ex vivo patient MM cells. These preclinical studies suggest that ASAH1 may be a potential therapeutic target for the treatment of relapsed/refractory MM (RRMM).

A Phase 1/2 study of teclistamab, a humanized BCMA × CD3 bispecific Ab in Japanese patients with relapsed/refractory MM.

We characterized the safety and efficacy of the bispecific antibody teclistamab in Japanese patients with relapsed/refractory multiple myeloma (RRMM). Patients were pretreated with a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 monoclonal antibody (mAb). The primary endpoint was frequency and type of treatment-emergent adverse events (TEAEs) in phase 1, and overall response rate (ORR; ≥ partial response [PR]) in phase 2. In phase 1, 14 patients received once-weekly (QW) subcutaneous teclistamab (0.72mg/kg [n = 5]; 1.5mg/kg [n = 5]; 3mg/kg [n = 4]). No dose-limiting toxicities were observed. As of April 2024, 26 phase-2 patients received the recommended phase-2 dose (QW) (RP2D: 1.5mg/kg) of teclistamab. Biweekly (Q2W) dosing was allowed after maintaining response for ≥ 6months. At a median follow-up of 14.32months, ORR was 76.9% (≥ very good PR: 76.9%; ≥ complete response: 65.4%). Median duration of response, progression-free survival, and overall survival were not reached. Common TEAEs included CRS (grade ≤ 2), neutropenia, and infections. No patient had immune effector cell-associated neurotoxicity syndrome (ICANS) and dose reductions. Teclistamab demonstrated deep and durable responses in Japanese patients with RRMM, consistent with the global pivotal MajesTEC-1 study, supporting the potential for a new standard of care for Japanese RRMM patients.

Clinical impact of [18F]FDG-PET/CT in ARI0002h treatment, a CAR-T against BCMA for relapsed/refractory multiple myeloma

Multiple myeloma (MM) remains incurable, with poor outcomes in heavily pre-treated patients with plasmacytomas. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment option; however, outcomes after such therapy in patients with soft-tissue plasmacytomas and other bone lesions remain poorly understood. Data regarding these parameters is scarce within the specific context of CAR T-cell treatment. This study included 63 patients with relapsed/refractory MM (RRMM), treated either in the CARTBCMA-HCB-01 clinical trial (ARI0002h; academic BCMA-targeted CAR T-cell therapy) or due to compassionate use. The aim was to evaluate the impact of soft-tissue involvement (extramedullary [EMD] and paraskeletal [PS] plasmacytomas) in response, survival and safety. Baseline [18F]FDG-PET/CT from five participating centers were reviewed centrally. Of the 63 patients, 52.4% presented plasmacytomas at the time of inclusion (21 PS, exclusively, and 12 EMD). Per responses, there were no significant differences between patients with and without plasmacytomas. A correlation was present between IMWG responses and those obtained by [18F]FDG-PET/CT at day 100 (Bologna Criteria). No differences were observed in progression-free survival (PFS) or overall survival (OS) between patients with or without plasmacytomas. However, both PFS and OS were significantly shorter in patients with EMD. Interestingly, [18F]FDG-PET/CT response assessed on day 100, in accordance with the Bologna Criteria, was predictive of survival outcomes. A metabolic tumor volume (MTV) of 25 or more at baseline [18F]FDG-PET/CT was associated with earlier disease progression and a shorter OS. These results highlight the importance of EMD evaluation by [18F]FDG-PET/CT before and after CAR T-cell infusion. NCT04309981, and EudraCT, 2019-001472-11.

Real‐world practitioner perceptions of CARTITUDE‐4 results for patients with previously treated multiple myeloma

AbstractIntroductionInitially approved for the fifth‐line or later therapeutic setting, the chimeric antigen receptor (CAR) T‐cell regimen ciltacabtagene autoleucel (cilta‐cel) was recently approved for second‐line (2L) treatment in relapsed/refractory multiple myeloma (RRMM). Oncology practitioners use clinical trials to inform treatment, but real‐world impressions and impact on practice are lacking. We aimed to determine whether presenting CARTITUDE‐4 clinical trial data would impact real‐world preferences/perceptions around CAR T‐cell therapy.MethodsRecruiting from the Cardinal Health Oncology Provider Extended Network (OPEN), we surveyed hematologists/oncologists to investigate fourth‐line (4L) preferences in a hypothetical patient with triple‐class–refractory MM. We posed the same questions and answers before and after the trial presentation and compared pre‐/post‐preferences toward cilta‐cel and sequencing relative to bispecific antibodies (BsAbs). Using the same methodology as described above, we also performed a secondary analysis comparing pre‐/post‐perceptions on the use of CAR T‐cell therapy in earlier lines for patients with triple‐class–refractory MM.ResultsAmong 50 respondents, decision‐making factors before the trial presentation included CAR T‐cell center availability (58%), comorbidities (52%), and center locations (34%). Additionally, 48% of 46 respondents chose 4L cilta‐cel. Among 47, 40% wanted more real‐world/long‐term CAR T‐cell therapy outcomes in any line, 38% wanted more 2L data, and 34% favored 2L/third‐line (3L) use. After the presentation, the preference for cilta‐cel doubled from 48% to 88% (p &lt; 0.001) among 50 respondents and rose from 34% to 55% (p = 0.001) for earlier‐line CAR T‐cell therapy among 49. Moreover, 55% of 49 respondents preferred CAR T‐cell therapy prior to BsAbs.DiscussionWe have shown that making oncology practitioners aware of trials precipitated decision‐making factors and led to notable, significant shifts in future intended practice patterns. Being aware of trial data enables practitioners to make more informed decisions, tailor therapies to individual patients, and ultimately improve outcomes.

Efficacy and safety of daratumumab for the treatment of refractory/relapsed multiple myeloma. A systematic review of meta-analyses.

Several meta-analyses (MAs) of the efficacy and safety of daratumumab in refractory/relapsed multiple myeloma (RRMM) exist. They include different types of populations, Daratumumab regimens, and outcomes. Moreover, there is a wide variation in methodological quality and risk of bias. This study aimed to conduct a systematic review of MAs to summarize the literature on the efficacy and safety profile of daratumumab use in RRMM, and also provide an assessment of the quality and risk of bias of the MAs if sufficient data is available. The literature databases Pubmed, Embase, Web of Science, and Cochrane were searched since inception. The quality of methodology was assessed by the AMSTAR-2 tool, and the risk of bias was assessed by the ROBIS tool. Eight MAs were included in the SR. Most studies reported ORR and CR improvement by adding daratumumab to the chemotherapy regimen. Five MAs reported improvement in PFS in daratumumab-based regimens compared to non- daratumumab-based regimens. Only two MAs reported molecular response, favoring daratumumab. Dara was associated with adverse drug events (ADEs), including pneumonia and diarrhea. Conflicting evidence regarding hematological ADEs association with daratumumab exists. The overall quality of the studies is poor, but the MAs had a low risk of bias overall. Despite including low-quality MAs, this SR provides a summary that simplifies clinicians' access to efficacy and safety outcomes of daratumumab in RRMM patients. Future studies are required to reduce the uncertainty and produce higher-quality Mas, particularly regarding daratumumab's safety.

Outcomes of Ixazomib Treatment in Relapsed and Refractory Multiple Myeloma: Insights from Croatian Cooperative Group for Hematologic Diseases (KROHEM).

Background and Objectives: Ixazomib, used in combination with lenalidomide and dexamethasone (IRd), has shown efficacy in clinical trials for relapsed/refractory multiple myeloma (RRMM). Materials and Methods: This study evaluates the real-world effectiveness and safety of IRd in Croatian RRMM patients. A retrospective analysis was conducted on 164 RRMM patients treated with ixazomib at nine Croatian haematology centres from November 2016 to February 2023. Data on patient demographics, treatment regimens, and outcomes were collected and analysed using Kaplan-Meier survival curves and Cox proportional hazards models in R. The median age at ixazomib initiation was 66 years (range 40-91). Results: The overall response rate (ORR) was 65.8%, with 42% of patients achieving a very good partial response (VGPR) or better. The median progression-free survival (PFS) was 15.4 months, while median overall survival (OS) was 28.2 months. Hematologic toxicities included anaemia (53%), neutropenia (50%), and thrombocytopenia (45%). Infective complications, primarily COVID-19 and pneumonia, were reported in 38% of patients. The safety profile was consistent with previous studies, indicating manageable adverse events. Ixazomib-based therapy is effective and well tolerated in a real-world Croatian RRMM population. Conclusions: The findings align with clinical trial results, demonstrating the applicability of ixazomib in routine clinical practice. Further studies are needed to optimise treatment sequencing and improve patient outcomes.

Retreatment of multiple myeloma with previously refractory drugs

AbstractAs patients with relapsed/refractory multiple myeloma (RRMM) continue to live longer, they might get exposed to most available drugs and drug classes during the disease course. For such late line RRMM or among patients without access to novel therapies, retreatment with a drug that the disease had previously been refractory to might be one option. In this retrospective study, we describe 315 patients with RRMM at our institution who were retreated with a drug that the disease had been previously refractory to. We found an overall response rate of 56.2% and a median progression-free survival (PFS) of 11 months with retreatment. Patients with a longer time on initial therapy with the index drug (>28.4 months) had a superior PFS with retreatment (median PFS, 16.9 vs 8.1 months; P < .001). Similarly, patients with a longer time gap between the initial line of therapy with index drug and retreatment with index drug (>46.1 months) had better PFS with retreatment (28.2 vs 8.9 months; P = .016). In conclusion, retreatment with a previously refractory drug is a viable therapeutic option for RRMM, with the most significant benefit derived in disease demonstrating sensitivity to initial drug exposure and among those with a longer gap between initial drug exposure and retreatment.

Clinical significance of complete remission and measurable residual disease in relapsed/refractory multiple myeloma patients treated with T-cell redirecting immunotherapy.

The impact of measurable residual disease (MRD) in relapse/refractory multiple myeloma (RRMM) patients treated with T-cell redirecting immunotherapy is uncertain. We analyzed MRD dynamics using next-generation flow in 201 patients treated in clinical trials with chimeric antigen receptor (CAR) T cells and T-cell engagers (TCE). Achieving MRD negativity at 10-6 was associated with 89% reduction in the risk of progression and/or death. Survival outcomes were improved in patients with sustained versus transient MRD negativity and were dismal in those who remained MRD positive. The intent-to-treat MRD negative rates were higher in patients treated with CAR T cells versus TCE. However, among patients achieving MRD negativity, there were no differences in survival outcomes when stratified according to treatment with CAR T cells versus TCE. In multivariate analysis including the number of prior lines of treatment, International Staging System, cytogenetic risk, extramedullary disease and type of T-cell redirecting immunotherapy, only the complete remission (CR) and MRD statuses showed independent prognostic value for progression-free and overall survival. In conclusion, our study shows that deep and sustained MRD negative CR is the most relevant prognostic factor and should be considered as the treatment endpoint in RRMM patients treated with CAR T cells and TCE.

Safety and Effectiveness of Elotuzumab in Japanese Patients with Relapsed/Refractory Multiple Myeloma: A Post-marketing Surveillance Study.

Objective Elotuzumab plus lenalidomide and dexamethasone (ELd) was approved in Japan in 2016 for the treatment of relapsed/refractory multiple myeloma (RRMM). This post-marketing surveillance study evaluated the safety and effectiveness of ELd in RRMM patients during routine clinical practice in Japan. Methods Elotuzumab safety was assessed by evaluating adverse drug reactions (ADRs), and effectiveness was assessed primarily by the best overall response. Patients The study enrolled patients with RRMM who received ELd therapy between November 18, 2016, and June 18, 2017. The safety and effectiveness analysis sets included 831 and 755 patients, respectively. Results In the safety analysis set, patients received a median (range) of 12 (1-40) elotuzumab administrations over 108 (1-728) days of treatment. The relative dose intensity of elotuzumab was ≥90% in 74.1% of patients. ADRs and serious ADRs were reported in 41.2% and 15.2% of the patients, respectively. The most common ADR was infection (12.0%), followed by lymphocytopenia (10.1%), infusion reactions (7.5%), secondary malignancies (e.g. gastric cancer and pancreatic carcinoma), cataracts, and interstitial lung disease (0.2% each). While most patients with ADRs recovered, 71 discontinued treatment, and 14 deaths were reported. The presence of comorbidities, particularly cardiovascular disorders, significantly affected the safety. The overall response rate was 41.1%. Conclusion This all-case post-marketing surveillance study showed that ELd had an acceptable tolerability profile and promising clinical activity in Japanese patients with RRMM.

A Short Course of Standard Velcade/Dexamethasone Followed by Unlimited Weekly Maintenance Therapy Is an Effective Treatment in Relapsed/Refractory Multiple Myeloma.

Bortezomib (B), known as Velcade, is a reversible proteasome inhibitor approved for relapsed/refractory multiple myeloma (RRMM) patients (pts). The standard of care protocol includes eight cycles of intravenous push (IVP) injections of B and oral dexamethasone (D), which increases the toxicity. Here, we describe the results of an open-label, phase II clinical trial employing only four cycles of B/D. RRMM pts treated with at least one previous therapy qualified for the trial. Pts were treated with B 1.3 mg/m2 IVP or subcutaneous (SC) on day 1, 4, 8, and 11, followed by a 10-day rest, Q21 days for four cycles; followed by maintenance therapy with once weekly B 1.6 mg/m2 IVP or SC on day 1, 8, 15, and 22, followed by 13 days' rest, repeated Q36 day. Pts received D 20 mg on the days of and days after B. Pts with a complete response (CR) were removed. Those with a partial response (PR) or stable disease (SD) were placed on maintenance therapy until progressive disease (PD), unacceptable toxicity, or pts' decision to stop. A total of 24 pts were enrolled. CR was observed in six pts (25%), PR in eight pts (33%), and SD in nine pts (37.5%). Moreover, 14 of the 24 pts (58.3%) had PR or better. Four pts had PD during induction. The grade 3 toxicities included fatigue (58%), sensory neuropathy (54%), and thrombocytopenia (50%); the grade 4 toxicities were thrombocytopenia (12.5%), fatigue (12.5%), and sensory neuropathy (12.5%). A short course of B/D, plus maintenance with B, is well tolerated in RRMM pts. Long-term maintenance with B/D could become an alternative to new agents.

Efficacy and safety of teclistamab in relapsed or refractory multiple myeloma: a systematic review and meta-analysis.

To synthesize the evidence on the efficacy and safety of teclistamab in treating relapsed/refractory multiple myeloma (RRMM). A systematic search for records published from inception until June 2024 was conducted on PubMed, Web of Science, EMBASE, and Google Scholar databases. Five studies with 661 RRMM patients were included in the analysis. The pooled results showed that teclistamab led to an overall response rate (ORR) of 62.8% (95% Confidence Interval (CI): 58.6-66.8), a ≥ very good partial response or better (VGPR) of 52.1% (95% CI: 46.8-57.3), and a ≥ complete response or better (CR) of 29.5% (95% CI: 21.9-38.4). When the ORR was assessed in different subgroups, we found that patients with extramedullary disease (EMD) had considerably lower ORR than those without EMD (45% vs. 71%, p < 0.0001). The ORR was significantly lower in patients with prior (B-cell maturation antigen) BCMA-directed therapy (OR: 2.24, p = 0.002) and those with stage III disease (OR: 3.69, p = 0.0001). However, the subgroup analyses showed no considerable difference in the ORR between patients with high or standard-risk cytogenetics (OR: 1.05 p = 0.82) and those with penta-drug or triple-class-refractory disease (OR: 0.97 p = 0.89). Regarding the safety of teclistamab, the pooled results showed that the incidence of grade ≥ 3 adverse events was high (90.7%). However, grade ≥ 3 cytokine release syndrome (CRS) and neurotoxic events were low (1.5% and 2.2%, respectively). RRMM patients treated with teclistamab display good response rates.

Long-term safety and efficacy of the fully human CAR-T therapy CT103A in relapsed/refractory multiple myeloma

CT103A is a fully human chimeric antigen receptor T-cell (CAR-T) product for targeting B-cell maturation antigen (BCMA). This study presents the updated safety and efficacy profiles of CT103A in patients with relapsed/refractory multiple myeloma (RRMM) after long-term follow-up. As of July 31, 2023, the median follow-up time after CAR-T-cell infusion was 45.0 months (range, 0.7-58.3 months). During long-term follow-up, the incidence of adverse events gradually decreased over time. One patient had a maximum duration of response of nearly five years. All 18 patients (100%) achieved partial remission or better; 77.8% (14 of 18) of patients eventually exhibited complete response (CR) or stringent complete response (sCR), with response increasing over time. At the time of data cut-off, nine patients were still alive, and seven patients had an sCR status with negative minimal residual disease (MRD). The median progression-free survival (PFS) was 22.6 months, and the median overall survival (OS) was 50.2 months for all 18 patients. The median CAR transgene persistence was 14.0 months (range, 0.7-57.3 months). Long-term follow-up demonstrated that CT103A confers durable clinical benefit for RRMM patients based on the sustained presence of fully human CAR-T cells.

Comparison of CAR T-cell and bispecific antibody as third-line or later-line treatments for multiple myeloma: a meta-analysis

BackgroundCAR-T-cell therapy and bispecific antibody have revolutionized the treatment landscape for multiple myeloma. However, there is currently a lack of studies comparing the efficacy and safety of these two approaches....

Bispecific antibodies as bridging to BCMA CAR-T cell therapy for relapsed/refractory multiple myeloma.

Establishing a strategy for sequencing of T cell redirecting therapies for relapsed/refractory multiple myeloma (RRMM) is a pressing clinical need. We longitudinally tracked the clinical and immunological impact of bispecific T cell engaging antibodies (BsAb) as bridging therapy (BT) to subsequent BCMA-directed CAR-T cell therapies in 52 RRMM patients. BsAbs were a potent and safe option for BT, achieving the highest overall response rate (100%) to BT compared to chemotherapy, anti-CD38 or anti-SLAMF7 antibody based regimens (46%). We observed early CD4+CAR+ and delayed CD8+CAR+ T cell expansion in patients receiving BsAb as BT. In vitro cytotoxicity of CAR-T cells was comparable amongst BT options. Single-cell analyses revealed increased clonality in the CD4+ and CD8+ T cell compartments in patients with previous exposure to BsAbs at leukapheresis and on day 30 after CAR-T infusion. This study demonstrates the feasibility and efficacy of BT with BsAbs for CAR-T cell therapy in RRMM.

Safety and efficacy of standard-of-care ciltacabtagene autoleucel for relapsed/refractory multiple myeloma

AbstractCiltacabtagene autoleucel (cilta-cel) chimeric antigen receptor (CAR) T-cell therapy was approved in 2022 for patients with relapsed/refractory multiple myeloma (RRMM). We report outcomes with cilta-cel in the standard-of-care setting. Patients with RRMM who underwent leukapheresis for cilta-cel manufacturing between 1 March 2022 and 31 December 2022 at 16 US academic medical centers were included. In terms of results, 255 patients underwent leukapheresis and 236 (92.5%) received cilta-cel. Of patients who underwent leukapheresis, 56% would not have met the CARTITUDE-1 trial eligibility criteria. Manufacturing failure rates at first attempt and overall were 6% and 1%, respectively. The median of prior lines of therapy was 6. In treated patients (n = 236), cytokine release syndrome was seen in 75% (grade ≥3, 5%), immune effector cell–associated neurotoxicity syndrome in 14% (grade ≥3, 4%), and delayed neurotoxicity in 10%. Best overall and complete response or better rates were as follows: for patients who received infusion (n = 236), 89% and 70%; patients receiving conforming CAR T-cell product (n = 191), 94% and 74%; and conforming CAR T-cell product with fludarabine/cyclophosphamide lymphodepletion (n = 152), 95% and 76%, respectively. Nonrelapse mortality was 10%, most commonly from infection. After a median follow-up of 13 months from CAR T-cell therapy, the median progression-free survival (PFS) was not reached, with the 12-month estimate being 68% (95% confidence interval, 62-74). High ferritin levels, high-risk cytogenetics, and extramedullary disease were independently associated with inferior PFS, with a signal for prior B-cell maturation antigen–targeted therapy (P = .08). Second primary malignancies excluding nonmelanoma skin cancers were seen in 5.5% and myeloid malignancies/acute leukemia in 1.7%. We observed a favorable efficacy profile of standard-of-care cilta-cel in RRMM, despite more than half the patients not meeting the CARTITUDE-1 eligibility criteria.

B-Cell Maturation Antigen-Directed Immunotherapies for the Treatment of Relapsed/Refractory Multiple Myeloma: A Review of the Literature and Implications for Clinical Practice.

To review the pharmacology, efficacy, safety, dosing and administration, and relevance to patient care and clinical practice of B-cell maturation antigen (BCMA) directed immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies (BsAb), for the management of relapsed/refractory multiple myeloma (RRMM). A literature review of PubMed (1966 to July 2024) was conducted using the keywords idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, elranatamab, and multiple myeloma. Data was also obtained from unpublished meeting abstracts and prescribing information. All relevant published articles, unpublished abstracts, and prescribing information on anti-BCMA immunotherapies for the treatment of RRMM were reviewed. Idecabtagene vicleucel and ciltacabtagene autoleucel are BCMA-directed CAR-T cell therapies that have been compared to standard of care (SOC) regimens for MM in early relapse in the phase III trials KarMMa-3 and CARTITUDE-4, respectively. Both studies demonstrated a significantly improved in response rates, depth of response, and progression-free survival compared to SOC. BsAbs teclistamab and elranatamab have been evaluated in the phase II trials MajesTEC-1 and MagnetisMM-3, respectively. Overall response rates of 63 and 61% were observed with teclistamab and elranatamab, respectively, in a population of patients with heavily pretreated RRMM. BCMA-directed immunotherapies have demonstrated efficacy in the treatment of RRMM. Safety issues with BCMA-directed immunotherapies include cytokine release syndrome, neurotoxicity, infections, and cytopenias. Operational challenges and issues with access to care exist with these therapies as they may be limited to institutions with the infrastructure to safely administer and monitor patients for toxicities. BCMA-directed immunotherapies represent an important advancement in the management of RRMM and have significantly added to the available treatment options for this disease.

Clinical Efficacy of Isatuximab Plus Carfilzomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients.

Isatuximab, a novel anti-CD38 monoclonal antibody, is approved in combination with carfilzomib and dexamethasone (Isa-Kd) in relapsed/refractory multiple myeloma (RRMM) patients. Because of its recent introduction, real-world efficacy and safety are poorly reported. In this Italian multicenter real-life observational retrospective study, efficacy and safety of the Isa-Kd regimen were evaluated in a cohort of 103 RRMM patients. Overall response rate (ORR) was 85%, with stringent (sCR) or complete response (CR) in 18% of cases and very good partial response (VGPR) in 39%. Median PFS and OS were not reached within the study period, while 1-year PFS and OS were 72% and 77%, respectively. Hematological toxicities were observed in 42% of subjects, and cardiac toxicities occurred in 24% of cases. Moreover, we conducted a subanalysis on patients (N = 69) treated with Isa-Kd after one prior line of therapy, showing an ORR of 88%, with sCR + CR in 20% of subjects, VGPR in 46%, and PR in 22% of patients. In this group, median PFS and OS were not reached, while 1-year PFS and OS were 92% and 95%, respectively. In conclusions, our study confirmed Isa-Kd as an effective treatment option for RRMM with a manageable safety profile even in real-life settings.

BCMA-Directed MRD Detection as a Predictor of Relapse after BCMA CAR T in Multiple Myeloma

BackgroundRecent approvals of chimeric antigen receptor T-cells (CAR T) and bispecific antibody therapies offer new hope for relapsed refractory multiple myeloma (RRMM) patients, with superior efficacy over standard regimens observed in clinical trials. However, relapse after BCMA-directed therapy is common and requires further investigation. Patients and MethodsWe conducted a retrospective cohort study on 57 RRMM patients treated with BCMA-directed CAR T. Only the patients who had an initial response and lost BCMA-expressing identified PC following CAR T infusion at Day 30 were included in the analysis. Multicolor flow cytometry (MFC) to detect BCMA + plasma cell (PC) re-emergence was performed on bone marrow samples at defined intervals and clinical responses were assessed using International Myeloma Working Group criteria. ResultsThe majority of patients achieved undetectable BCMA on MFC postinfusion, with subsequent BCMA+ PC re-emergence observed in 55% of cases. Notably, 91% of patients experiencing clinical relapse showed BCMA+ PC re-emergence, often preceding relapse. Early relapse (<6 months) was associated with earlier BCMA re-emergence. ConclusionEarly BCMA+ PC re-emergence may serve as a prognostic marker for clinical relapse post-BCMA CAR T therapy. Monitoring BCMA+ PC levels via MFC offers potential for early relapse detection and informed treatment decisions. Further studies, including novel BCMA-directed minimal residual disease (MRD) detection technologies, are warranted to validate these findings and refine RRMM management strategies.

EASIX-guided risk stratification for complications and outcome after CAR T-cell therapy with ide-cel in relapsed/refractory multiple myeloma

BackgroundChimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release...