Relapsed/refractory Multiple Myeloma Research Articles

Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis.

We previously demonstrated that reduced intrinsic electron transport chain (ETC) activity predicts and promotes sensitivity to the BCL-2 antagonist, venetoclax (Ven) in multiple myeloma (MM). Heme, an iron-containing prosthetic group, and metabolite is fundamental to maintaining ETC activity. Interrogation of the CD2 subgroup of MM from the CoMMpass trial (NCT01454297), which can be used as a proxy for Ven-sensitive MM (VS MM), shows reduced expression of the conserved heme biosynthesis pathway gene signature. Consistent with this, we identified that VS MM exhibit reduced heme biosynthesis and curiously elevated hemin (oxidized heme) uptake. Supplementation with hemin or protoporphyrin IX (heme lacking iron) promotes Ven resistance while targeting ferrochetalase, the penultimate enzyme involved in heme biosynthesis, increases Ven sensitivity in cell lines and primary MM cells. Mechanistically, heme-mediated activation of pro-survival RAS-RAF-MEK signaling and metabolic rewiring, increasing de novo purine synthesis, were found to contribute to heme-induced Ven resistance. Co-targeting BCL-2 and MCL-1 suppresses heme-induced Ven resistance. Interrogation of the MMRF CoMMpass study of patients shows increased purine and pyrimidine biosynthesis to corelate with poor progression free survival and overall survival. Elevated heme and purine biosynthesis gene signatures were also observed in matched relapse refractory MM, underscoring the relevance of heme metabolism in therapy refractory MM. Overall, our findings reveal for the first time a role for extrinsic heme, a physiologically relevant metabolite, in modulating proximity to the apoptotic threshold with translational implications for BCL-2 antagonism in MM therapy.

Treatment adherence and effectiveness in patients treated with carfilzomib-based therapy combinations for relapsed/refractory multiple myeloma in Germany: interim results from the non-interventional CARO study

Therapy adherence can significantly influence the outcome of cancer patients. The prospective, non-interventional CARO study (NCT02970747) investigated adherence, effectiveness, and safety of carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) in the German real-world setting. In total, 359 patients were included at 69 sites. Data on carfilzomib combination regimens were evaluated for three treatment cohorts: carfilzomib with lenalidomide and dexamethasone (KRd), with dexamethasone only (Kd) or with daratumumab and dexamethasone (KdD). Encouragingly, patients maintained levels of treatment adherence ≥95% to carfilzomib across cohorts. The effectiveness outcomes of CARO were in line with previous data. Median PFS (95% CI) was 17.5 months (14.5, 24.7 [KRd]), 13.4 months (7.0, 18.1 [Kd]), and 15.6 months (9.9, NA [KdD]), respectively. Median OS was 38.9 months (31.5, 53.9 [KRd]), 24.2 months (17.3, 36.8 [Kd]), and not reached (KdD). Overall, the CARO study impressively demonstrates efficacy and safety of KRd, Kd, and KdD regimen in real-world.

Venetoclax in the Treatment of Multiple Myeloma: A Retrospective Analysis of 79 Patients.

Venetoclax, the first-in-class BCL-2 inhibitor, has shown efficacy in multiple myeloma (MM), particularly in patients with the t(11;14) translocation. This single-center retrospective analysis included MM patients treated with venetoclax from November 2017 to March 2023. Data encompassed demographics, disease characteristics, treatment regimens, and outcomes using median progression-free-survival (mPFS). Eligibility required patients to be aged 21 and older and to have received at least one venetoclax cycle. Seventy-nine patients (median age 61, 58.2% female) were included, with 31.6% having t(11;14). Patients had received a median of 5 lines of therapy (LOT) before venetoclax. The mPFS was 3.4 months, with a significant difference between t(11;14) positive (7.8 months) and negative patients (2.4 months, p < 0.01). Patients achieving a very good partial response or better had a mPFS of 7.1 months. Common adverse events included fatigue (31.6%), diarrhea (26.5%), and respiratory infections (30.3%). Univariable and multivariable analyses identified sex, disease response, and t(11;14) presence as significant survival predictors. Our real-world study suggests that venetoclax demonstrates moderate efficacy in heavily pretreated patients with relapsed/refractory MM (RRMM), compared to previous studies where patients received 1-3 prior LOT, such as the BELLINI study (mPFS of 22.4 months). Notably, the efficacy was higher in patients with t(11;14). Despite the heavily pretreated nature of our cohort, venetoclax was well tolerated, with a manageable safety profile and low incidence of severe infections, largely due to effective prophylactic measures. Venetoclax should be carefully considered in heavily pretreated populations, and further multicenter research is essential to better define its role in RRMM.

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.

Visualizing immunotherapy for multiple myeloma worldwide from 2013 to 2023: A bibliometric analysis

ABSTRACT Multiple myeloma (MM) is a malignant, clonal proliferative disease of plasma cells that remains incurable. This paper aims to analyze the current research status and emerging trends in immunotherapy for MM through bibliometric methods, thereby providing valuable references and guidance for future research and clinical practice. This study presents a bibliometric analysis of 1,018 English-language publications related to MM immunotherapy, which were published in the Web of Science (WoS) Core Collection database from 2013 to 2023. VOSviewer and CiteSpace were employed to visualize the research hotspots and trends within the field of MM immunotherapy. The United States had the highest number of publications (n = 432, 42.44%), followed by China (n = 177, 17.39%). Harvard University was the institution with the most publications (n = 85), while Anderson KC (n = 27) was the most prolific researcher in the field. The highly cited literature mainly focuses on the treatment regimen based on daratumumab, the application of BCMA CAR-T therapy and the management of relapsed/refractory MM (RRMM), which represent the current research hotspots in this field. Burst detection highlights that bispecific antibodies and preclinical activity as key areas of interest. The cooperation among countries, institutions, and authors in this field should be strengthened. The treatment regimen utilizing daratumumab, the implementation of BCMA CAR-T therapy, and the management of RRMM represent significant research focal points in this field. Additionally, the development and application of bispecific antibodies have emerged as a frontier in recent years.

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).

Tumor Lysis Syndrome with Venetoclax/Carfilzomib/Dexamethasone for Relapsed/Refractory Multiple Myeloma: A Case Report

Background and Clinical Significance: Tumor lysis syndrome (TLS) is a rare occurrence in patients treated with venetoclax mono- or combination therapy, and clear protocols guiding TLS prophylaxis are lacking. Case Presentation: We present a 53-year-old male with a history of relapsed refractory multiple myeloma (RRMM) with t(11;14) treated with venetoclax, carfilzomib and dexamethasone (VenKd), resulting in TLS with subsequent renal failure. Repeat marrow biopsy showed no monoclonal plasma cells but extensive fibrosis. Venetoclax was reintroduced after two months with marrow recovery. Venetoclax was titrated from 200 to 400 mg daily alongside IV fluids and allopurinol without TLS recurrence. Conclusions: Here, we highlight the importance of risk stratification, dose titration, and TLS prophylaxis with venetoclax use in 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.

Initially 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. Recruiting 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. Among 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<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. We 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.

Nivolumab As an Adjunctive Therapy in Relapsed Refractory Multiple Myeloma Patients with Sub-Optimal Response to Idecabtagene Vicleucel

Background: Idecabtagene vicleucel (ide-cel) is a chimeric antigen receptor T-cell (CAR-T) targeting B-cell maturation antigen (BCMA) approved in the US for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) after two or more prior lines of therapy, including an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody. Prior studies of ide-cel have shown that depth of response (DOR) correlates with progression free survival (PFS). Specifically, median PFS was 20.2 months in patients who achieved a CR/sCR compared to only 11.3 and 5.4 months in patients who achieved a VGPR or PR as best response respectively. Nivolumab is a fully human anti-programmed death 1 (PD-1) antibody which has been shown to restore the function of existing antitumor T cells and enhance antitumor immunity through direct or indirect immune-system activation in multiple malignancies. Our study evaluates fixed duration nivolumab starting within 60 days post-ide-cel in RRMM patients who achieved a sub-optimal response to ide-cel (defined as a VGPR, PR, MR, or SD) on initial restaging-approximately 30-days post-CAR-T infusion-a timepoint when CAR-T cells should still be present in most patients. Study Objective: Our study aims to determine if adjuvant nivolumab administered within 8 weeks of CAR-T infusion in patients with RRMM who achieve a sub-optimal response to ide-cel (as defined as VGPR, PR, MR, or SD) at 30-day response assessment will improve DOR, PFS, and CAR-T cell expansion, and persistence, while maintaining manageable toxicity compared to historical controls. Study Design and Methods: This is a single arm, two-stage, phase II study designed to assess for deepening of response with nivolumab as an adjunctive therapy in patients with RRMM who achieved a sub-optimal response after treatment with ide-cel. The estimated enrollment is 50. The study will enroll adult patients with RRMM who have been treated with &amp;gt;= 2 prior lines of therapy and are refractory to or intolerant of at least one IMiD, PI, and anti-CD38 antibody who achieved a sub-optimal response (defined as a VGPR, PR, MR, or SD by IMWG 2016 criteria) to ide-cel. Key exclusion criteria include any evidence of residual cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) at time of screening and active autoimmune disease (except well-controlled type 1 diabetes mellitus or hypothyroidism). Enrolled subjects will receive 2 cycles of nivolumab at a dose of 480 mg on day 1 of each 28-day cycle. The primary endpoint is the CR/sCR rate with adjuvant nivolumab. Key secondary endpoints are PFS, DOR, MRD negativity rate, and OS. Safety and tolerability will be evaluated from the first dose of nivolumab administration through the end of the 100-day safety follow up period. Key translational endpoints include sequential assessments of CAR-T expansion, persistence, and fitness. We also plan to characterize the mechanism(s) of immune exhaustion and T cell dysfunction in RRMM patients. These translational endpoints are aimed to determine patients who would be at highest likelihood to derive benefit from adjuvant nivolumab in future studies. Statistical Considerations: Historically, 12% of patients with a suboptimal response to ide-cel at 30-days subsequently achieve a CR/sCR without additional therapy. Stage 1 of our study will enroll 21 patients; if at least 3 response evaluable patients achieve a CR/sCR in stage 1 the trial will enroll an additional 29 patients in stage 2 for a total of 50 patients. Based on a 1-sided alpha=0.10 significance level, 50 patients will provide 90% power to detect a post-adjuvant nivolumab treatment CR/sCR rate of 25%. Conclusion: This Phase II study will evaluate the safety, tolerability, and efficacy of a short course of adjuvant nivolumab given soon after ide-cel infusion. The study will be open soon and will be enrolling at 5 centers in the United States This study is registered with ClinicalTrials (NCT06523621)

Depletion of Mature B Cells and of Normal Plasma Cells (PC) behind the Higher Incidence of Infections after Anti-BCMA VS Anti-GPRC5D Bispecific Antibodies (bsAb) in Relapsed Refractory Multiple Myeloma (RRMM)

Depletion of Mature B Cells and of Normal Plasma Cells (PC) behind the Higher Incidence of Infections after Anti-BCMA VS Anti-GPRC5D Bispecific Antibodies (bsAb) in Relapsed Refractory Multiple Myeloma (RRMM)

First Results from the Dose Escalation Part of the Phase 1 Study of KTX1001, an Oral, First-in-Class, Potent Inhibitor of MMSET/NSD2 for Relapsed/Refractory Multiple Myeloma (RRMM)

First Results from the Dose Escalation Part of the Phase 1 Study of KTX1001, an Oral, First-in-Class, Potent Inhibitor of MMSET/NSD2 for Relapsed/Refractory Multiple Myeloma (RRMM)