Mechanisms and salvage treatments in patients with multiple myeloma relapsed post-BCMA CAR-T cell therapy.

Chimeric antigen receptor T-cell (CAR-T) therapy has ushered in a new era for the treatment of multiple myeloma (MM). Numerous clinical studies, especially those involving B-cell maturation antigen (BCMA)-directed CAR-T, have shown remarkable efficacy in patients with relapsed or refractory multiple myeloma (R/R MM). However, a considerable number of patients still experience disease recurrence or progression after BCMA CAR-T treatment, which is attributed to various factors, including antigen escape, CAR-T manufacturing factors, T cell exhaustion, inhibitory effects of tumor microenvironment and impact of prior treatments. The scarcity of effective treatment options following post-CAR-T disease recurrence, coupled with the lack of well-established salvage regimens, leaves patients who do relapse facing a bleak prognosis. In recent years, some academic institutions have achieved certain results in salvage treatments of patients with relapse after BCMA CAR-T treatment through secondary infusion of BCMA CAR-T, changing to non-BCMA-directed CAR-T, double-target CAR-T, bispecific antibodies or other novel therapies. This review summarizes the mechanisms of resistance or relapse after BCMA CAR-T administration and the available data on current salvage treatments, hoping to provide ideas for optimizing clinical salvage therapies.

T-cell redirecting bispecific antibody treatment in multiple myeloma: current knowledge and future strategies for sustained T-cell engagement.

INTRODUCTION: T-cell redirecting bispecific antibodies (BsAbs), targeting B-cell maturation antigen (BCMA) or G-protein - coupled receptor class C group 5 member D (GPRC5D), are efficacious new agents for the treatment of patients with relapsed or refractory MM. AREAS COVERED: This review discusses the pharmacokinetic properties, efficacy, and safety profile of T-cell redirecting BsAbs in MM, with a special focus on their optimal dosing schedule, resistance mechanisms and future strategies to enhance efficacy, reduce toxicity, and maximize duration of response. EXPERT OPINION: To further improve the efficacy of BsAbs, ongoing studies are investigating whether combination therapy can enhance depth and duration of response. An important open question is also to what extent response to BsAbs can be improved when these agents are used in earlier lines of therapy. In addition, more evidence is needed on rational de-intensification strategies of BsAb dosing upon achieving a sufficient response, and if (temporary) treatment cessation is possible in patients who have achieved a deep remission (e.g. complete response or minimal residual disease-negative status).

Just scratching the surface: novel treatment approaches for multiple myeloma targeting cell membrane proteins.

A better understanding of the roles of the adaptive and innate immune systems in the oncogenesis of cancers including multiple myeloma (MM) has led to the development of novel immune-based therapies. B cell maturation antigen (BCMA), G protein-coupled receptor family C group 5 member D (GPRC5D) and Fc receptor-like protein 5 (FcRL5, also known as FcRH5) are cell-surface transmembrane proteins expressed by plasma cells, and have been identified as prominent immunotherapeutic targets in MM, with promising activity demonstrated in patients with heavily pretreated relapsed and/or refractory disease. Indeed, since 2020, antibody-drug conjugates, bispecific T cell engagers and autologous chimeric antigen receptor T cells targeting BCMA or GPRC5D have been approved for the treatment of relapsed and/or refractory MM. However, responses to these therapies are not universal, and acquired resistance invariably occurs. In this Review, we discuss the various immunotherapeutic approaches targeting BCMA, GPRC5D and FcRL5 that are currently either available or in clinical development for patients with MM. We also review the mechanisms underlying resistance to such therapies, and discuss potential strategies to overcome these mechanisms and improve patient outcomes.

Clinical features associated with poor response and early relapse following BCMA-directed therapies in multiple myeloma.

Three classes of BCMA-directed therapy (BDT) exist: antibody drug-conjugates (ADCs), CAR-T, and T-cell engagers (TCEs), each with distinct strengths and weaknesses. To aid clinicians in selecting between BDTs, we reviewed myeloma patients treated at Mayo Clinic with commercial or investigational BDT between 2018-2023. We identified 339 individuals (1-exposure = 297, 2-exposures = 38, 3-exposures = 4) who received 385 BDTs (ADC = 59, TCE = 134, CAR-T = 192), with median follow-up of 21-months. ADC recipients were older, with more lines of therapy (LOT), and penta-refractory disease. Compared to ADCs, CAR-T (aHR = 0.29, 95%CI = 0.20-0.43) and TCEs (aHR = 0.62, 95%CI = 0.43-0.91) had better progression-free survival (PFS) on analysis adjusted for age, the presence of extramedullary (EMD), penta-refractory disease, multi-hit high-risk cytogenetics, prior BDT, and the number of LOT in the preceding 1-year. Likewise, compared to ADCs, CAR-T (aHR = 0.28, 95%CI = 0.18-0.44) and TCEs (aHR = 0.60, 95%CI = 0.39-0.93) had superior overall survival. Prior BDT exposure negatively impacted all classes but was most striking in CAR-T, ORR 86% vs. 50% and median PFS 13-months vs. 3-months. Of relapses, 54% were extramedullary in nature, and a quarter of these cases had no history of EMD. CAR-T demonstrates superior efficacy and where feasible, should be the initial BDT. However, for patients with prior BDT or rapidly progressive disease, an alternative approach may be preferable.

B-Cell Maturation Antigen/CD19 Dual-Targeting Immunotherapy in Newly Diagnosed Multiple Myeloma.

Importance: Patients with high-risk newly diagnosed multiple myeloma (NDMM) often have poor outcomes with standard treatments, necessitating novel effective frontline therapies to enhance clinical outcomes. GC012F, a B-cell maturation antigen/CD19 dual-targeting chimeric antigen receptor (CAR) T-cell therapy, has been developed on the novel FasTCAR platform. Notably, its use as a frontline therapy for patients with high-risk NDMM who are eligible for transplant has not been thoroughly explored. Objective: To examine the safety, pharmacokinetics, and patient health and survival outcomes associated with GC012F in individuals with NDMM. Design, Setting, and Participants: Patients were enrolled in this single-arm, open-label phase 1 cohort study between June 28, 2021, and June 1, 2023 (the data cutoff date). All patients included in this study were treated at a single center, Shanghai Changzheng Hospital. The patients in the efficacy evaluation were followed up for a minimum period of 3 months. Intervention: Patients underwent 2 cycles of induction therapy, followed by GC012F infusion (at 1 × 105 cells/kg, 2 × 105 cells/kg, or 3 × 105 cells/kg). Main Outcomes and Measures: The primary goals were to assess the safety, efficacy, and pharmacokinetics of GC012F at various dose levels. Results: Of 22 patients receiving GC012F treatment, 6 experienced mild to moderate cytokine release syndrome (grade 1-2) and none experienced neurotoxic effects. Nineteen patients were included in the efficacy evaluation, and all 19 patients showed stringent complete responses and achieved minimal residual disease negativity. The treatment's effectiveness was consistent across different dose levels. GC012F demonstrated a rapid response, with a median time to first stringent complete response of 84 days (range, 26-267 days) and achieving minimal residual disease negativity within 28 days (range, 23-135 days). The CAR T-cell expansion was robust, with a median peak copy number of 60 652 copies/µg genomic DNA (range, 8754-331 159 copies/µg genomic DNA), and the median time to median peak copy number was 10 days (range, 9-14 days). Conclusions and Relevance: The findings of this single-arm, open-label phase 1 cohort study suggest that GC012F may be a safe treatment associated with positive health and survival outcomes for patients with high-risk NDMM eligible for transplant. Owing to the small sample size, further studies with larger cohorts and longer follow-up durations are needed.

Linvoseltamab for Treatment of Relapsed/Refractory Multiple Myeloma.

PURPOSE: We present a phase I/II first-in-human trial evaluating the safety and efficacy of 50 mg and 200 mg doses of linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody in relapsed/refractory multiple myeloma (RRMM). METHODS: Phase II eligible patients had RRMM that either progressed on/after ≥three lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody or was triple-class (PI/IMiD/anti-CD38) refractory. Phase II treatment was once a week through week 14 and then once every 2 weeks. Phase II 200 mg patients who achieved a ≥very good partial response by week 24 received linvoseltamab once every 4 weeks. The primary end point in phase II was overall response rate (ORR). RESULTS: Among the 117 patients treated with 200 mg, the median age was 70 years, 39% had high-risk cytogenetics, and 28% had penta-refractory disease. At a median follow-up of 14.3 months, the ORR was 71%, with 50% achieving ≥complete response (CR). In 104 patients treated with 50 mg at a median follow-up of 7.4 months, the ORR was 48%, with 21% achieving ≥CR. The median duration of response (DOR) for 200 mg patients (n = 83) was 29.4 months (95% CI, 19.2 to not evaluable). Among 200 mg patients, the most common adverse events included cytokine release syndrome (35.0% Gr1, 10.3% Gr2, 0.9% Gr3), neutropenia (0.9% Gr2, 18.8% Gr3, 23.1% Gr4), and anemia (3.4% Gr1, 4.3% Gr2, 30.8% Gr3). Immune effector cell-associated neurotoxicity syndrome occurred in 7.7% of patients (2.6% each Gr1, Gr2, Gr3). Infections were reported in 74.4% of patients (33.3% Gr3, 2.6% Gr4); infection frequency and severity declined over time. CONCLUSION: Linvoseltamab 200 mg induced deep and durable responses, with a median DOR of 29.4 months, in patients with RRMM with an acceptable safety profile.

Beyond BCMA: newer immune targets in myeloma.

ABSTRACT: The identification and targeting of B-cell maturation antigen (BCMA) through immunotherapeutic strategies such as antibody-drug conjugates, chimeric antigen receptor T cells, and T-cell engagers have revolutionized the care of patients with multiple myeloma (MM). These treatment modalities have improved the survival outcomes of patients with relapsed and/or refractory MM compared with previously established strategies and are moving into earlier lines of therapy. Despite their efficacy, the majority of patients eventually relapse, necessitating additional therapeutic targets for salvage. G-protein-coupled receptor class 5 member D, Fc receptor-homolog 5, and SLAMF7 are some examples of novel targets in development. This expanding armamentarium of immunotherapeutic agents will be crucial to address the unmet need for relapses after BCMA-targeting therapies, particularly antigen-negative relapses. The utilization of sequential T-cell redirective therapies including agents targeting different tumor-associated antigens and combination therapies appears feasible, paving the way for effective chemotherapy-free regimes. Deliberate consideration of treatment timing, preserving T-cell health, overcoming antigenic loss, and comprehension of the complex tumor microenvironment would be key to maximizing therapeutic benefits and minimizing adverse effects. This review summarizes novel targets in development for myeloma beyond BCMA, presenting pivotal safety and efficacy data derived from clinical trials when available and the considerations vital for navigating this expanding landscape of immunotherapeutic options.

Anti-BCMA CAR-T cell-based therapies and bispecific antibodies in the immunotherapy era: are we ready for this?

INTRODUCTION: Therapeutic strategies against multiple myeloma (MM) have evolved dramatically in recent decades, with unprecedent results in the treatment landscape, culminating in the recent incorporation of novel agents in the anti-myeloma armamentarium. AREAS COVERED: BCMA represents one of the most promising targets in MM and currently available immune approaches, either approved or under active investigation, are clearly showing their greater potential over standard regimens. In this context, immunotherapies based on chimeric antigen receptor (CAR)-engineered T-cells and bispecific antibodies (BsAbs) have taken center stage, being the ones that are yielding the most promising results in clinical trials. This review focuses on the current landscape of BsAbs and CAR-T, summarizing the latest advances and possible future developments. EXPERT OPINION: CAR-T and BsAbs anti-BCMA strategies represent breakthrough therapies against MM. However, their inclusion in clinical practice is almost feared, due to the associated limitations, some of which have been addressed here. Meanwhile, all the efforts should be focused on individualizing and choosing the most suitable candidates for each treatment and to understand how to combine, or sequence, these therapies to improve efficacy and minimize toxicity, especially for those patients with limited available treatment options.

FDA Approval Summary: Ciltacabtagene Autoleucel for Relapsed or Refractory Multiple Myeloma.

In February 2022, the FDA approved ciltacabtagene autoleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting the B-cell maturation antigen, for adult patients with relapsed/refractory multiple myeloma after ≥4 lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Approval was based on overall response rate (ORR), complete response (CR) rate, and duration of response (DoR) in 97 adult patients in a single-arm, open-label, multicenter phase 2 trial (CARTITUDE-1 [NCT03548207]). Patients received a single infusion of ciltacabtagene autoleucel, preceded by lymphodepleting chemotherapy. Of the 97 patients evaluable, ORR was 97.9% [95% confidence interval (CI), 92.7-99.7] with a stringent CR rate of 78.4% (95% CI, 68.8-86.1). After median follow-up of 18 months, the median DoR was 21.8 months (95% CI, 21.8-not estimable [NE]) in responders (PR or better) and NE (95% CI, 21.8 months-NE) in patients who achieved stringent CR. Serious adverse reactions occurred in 55% of the 97 patients evaluated for safety. Grade 3 or higher cytokine release syndrome (CRS) and neurologic toxicities occurred in 5% and 11% of the patients, respectively, leading to a Risk Evaluation and Mitigation Strategy. Neurologic toxicities included immune effector cell-associated neurologic syndrome, typically seen with CAR-T products, parkinsonism, peripheral neuropathy, cranial nerve palsies, and Guillain-Barré syndrome. One fatal case of hemophagocytic lymphohistiocytosis/macrophage activation syndrome occurred. Prolonged and recurrent grade 3 or 4 cytopenias occurred; a single patient required hematopoietic stem-cell rescue.

Clinical evaluation and determinants of response to HBI0101 (BCMA CART) therapy in relapsed/refractory multiple myeloma.

ABSTRACT: HBI0101 is an academic chimeric antigen receptor T-cell (CART)-targeted to B-cell maturation antigen (BCMA) for the treatment of relapsed and refractory multiple myeloma (R/RMM) and light chain amyloidosis. Herein, we present the phase 1b/2 results of 50 heavily pretreated patients with R/RMM dosed with 800 × 106 CART cells. Inclusion criteria were relatively permissive (i.e., performance status and baseline organ function) and consequently, approximately half of the enrolled patients would have been ineligible for pivotal clinical trials. The median time elapsed from patient enrollment until CART delivery was 25 days (range, 14-65). HBI0101-related toxicities included grade 1 to 3 cytokine release syndrome, grade 3 to 4 hematologic toxicities, and grade 1 to 2 immune effector cell-associated neurotoxicity syndrome. Responses were achieved in 90% of the patients, 56% achieved stringent and complete response, and 70% reached a minimal residual disease negativity. Within a median follow-up of 12.3 months, the median progression-free survival (PFS) was 11.0 months (95% confidence interval [CI], 6.2-14.6), and the overall survival was not reached (95% CI, 13.3 to not reached). Multivariable analysis on patient/disease and CART-related characteristics revealed that high-risk cytogenetic, extramedullary disease, and increased number of effector-memory T cells in CART products were independently associated with inferior PFS. In conclusion, comprehensive analyses of the parameters affecting the response to CART therapy are essential for improving patients' outcome. This trial was registered at www.ClinicalTrials.gov as #NCT04720313.

Effectiveness and infectious complications of BCMA T-cell engagers in treating multiple myeloma: Real-world evidence from Sweden.

BACKGROUND: Multiple myeloma (MM), an incurable disease characterized by frequent relapses and a need for multiple treatments, often progresses to a relapse/refractory status resistant to all available drugs and drug classes. Bispecific antibodies, specifically BCMA T-cell engagers, have emerged as effective treatments for MM, demonstrating impressive efficacy. However, these treatments can adversely affect the immune system, increasing vulnerability to infections. METHODS/RESULTS: This study evaluated the efficacy and safety of BCMA T-cell engagers in 58 Swedish patients with poor MM prognosis. The patients exhibited a 69% overall response rate, with 69% survival and 60% progression-free survival at 15 months. CONCLUSIONS: Despite the risk of infectious complications, the prognosis of MM patients can be significantly improved with vigilant monitoring and proactive management of infections. This real-world data highlight the potential of BCMA T-cell engagers in treating MM, emphasizing the need for careful patient monitoring to mitigate infection risks.

Patterns of CRS with teclistamab in relapsed/refractory multiple myeloma with or without prior T-cell redirection therapy.

ABSTRACT: Teclistamab (Tec) is a first-in-class BCMA × CD3 bispecific T-cell engager antibody approved for treating multiple myeloma progressing after at least 4 lines of therapy. The objective of this study was to evaluate the rate of cytokine release syndrome (CRS) in patients who were treated with commercial Tec and had prior exposure to other T-cell redirection therapies. A retrospective chart review was performed to identify patients who completed the Tec step-up dosing phase between November 2022 and November 2023. Patients were divided into 2 cohorts based on prior exposure to T-cell redirection therapy (cohort 1: T-cell redirection therapy experienced; cohort 2: T-cell redirection therapy naïve). The primary objective was to compare the differences in the rates of CRS between the 2 cohorts. Univariate and multivariate logistic regression analyses were performed to assess the association between CRS rates with Tec and prior treatment with T-cell redirection therapy. A total of 72 patients were included in the analysis (27 in cohort 1 and 45 in cohort 2). The CRS rates were significantly lower in cohort 1 (37%, n = 10) compared with cohort 2 (80%, n = 36; P = .0004). Based on multivariate logistic regression analysis, patients without prior exposure to T-cell redirection therapy (cohort 2) had about a fourfold increase in the incidence of CRS (95% confidence interval, 1.40-14.90; P = .0002) with Tec. In our study, prior exposure to T-cell redirection therapy reduced the risk of CRS with Tec during the step-up dosing phase. This observation will allow for the optimization of CRS prophylactic strategies for Tec.

Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma.

PURPOSE: B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial. PATIENTS AND METHODS: We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes. RESULTS: At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2-37.1), overall response rate in the first 3 months was 95% [95% confidence interval (CI), 89.5-100]; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5-22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse. CONCLUSIONS: Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.

Salvage therapies including retreatment with BCMA-directed approaches after BCMA CAR-T relapses for multiple myeloma.

ABSTRACT: For patients with relapsed/refractory multiple myeloma with a relapse after B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell therapy (CAR-T), optimal salvage treatment strategies remain unclear. BCMA-directed CAR-T and bispecific antibodies (BsAbs) are now commercially available, and the outcomes for retreatment with BCMA-directed approaches are not well studied. We performed a retrospective analysis of 68 patients with relapsed disease after BCMA-directed CAR-T to evaluate outcomes and responses to salvage therapies. With a median follow-up of 13.5 months, median overall survival from time of relapse until death was 18 months (95% confidence interval [CI], 13.2 to not reached [NR]). Fifty-eight patients received subsequent myeloma-directed therapies, with a total of 265 lines of therapy (LOTs). The overall response rate for firstline salvage therapy was 41% (95% CI, 28-55). Among all LOTs, high response rates were observed among those receiving another BCMA-directed CAR-T (89%), BCMA-directed BsAbs (60%), CD38-directed combinations (80% when combined with BsAb; 50% when combined with immunomodulatory drugs and/or proteasome inhibitors), and alkylator-combinations (50% overall; 69% with high-dose alkylators). Thirty-four patients received at least 1 line of salvage BCMA-directed therapy; median progression-free survival was 8.3 months (95% CI, 7.9 to NR), 3.6 months (95% CI, 1.4 to NR), and 1 month (95% CI, 0.9 to NR) with median duration of response (DOR) of 8 months, 4.4 months, and 2.8 months for subsequent BCMA-directed CAR-T, BsAb, and belantamab mafadotin, respectively. Retreatment with BCMA-directed CAR-T and BsAbs can be effective salvage options after BCMA-directed CAR-T relapse; however, DORs appear limited, and further studies with new combinations and alternative targets are warranted.

A matching-adjusted indirect comparison of the efficacy of elranatamab versus teclistamab in patients with triple-class exposed/refractory multiple myeloma.

For patients with triple-class exposed/refractory multiple myeloma (TCE/RMM), where effective treatments options are limited, B-cell maturation antigen and CD3-directed bispecific antibodies offer a promising new approach. Teclistamab gained conditional approval in Europe and accelerated Food and Drug Administration (FDA) approval based on the MajesTEC-1 trial (NCT03145181). Elranatamab, approved by the FDA demonstrated its safety and efficacy in the MagnetisMM-3 trial (NCT04649359). Given the absence of head-to-head trials, an unanchored matching-adjusted indirect comparison (MAIC) was conducted to assess their relative efficacy. Key baseline characteristics were adjusted to be comparable between the two trials. In the MAIC, elranatamab demonstrated significantly better objective response rate and progression-free survival (PFS) than teclistamab, and numerically better complete response, duration of response, and overall survival (OS). These results suggest that elranatamab is an efficacious option for treating patients with TCE/R MM.