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K Groen, NWCJ van de Donk, CAM Stege, S Zweegman, IS Nijhof Department of Hematology, VU University Medical Center, Amsterdam, Netherlands Abstract: Although the prognosis of multiple myeloma (MM) patients has dramatically improved during recent years, virtually all patients eventually develop relapsed refractory disease. Several new therapeutics have been developed in the last few years, including carfilzomib, a second-generation proteasome inhibitor (PI) that has been approved by the US Food and Drug Administration (FDA) in the setting of relapsed and/or refractory MM, as a single agent with or without dexamethasone, and in combination with lenalidomide in 2012 and 2015, respectively. Other promising combinations with carfilzomib are being investigated. Carfilzomib has shown superiority over the first-generation PI bortezomib on both efficacy and toxicity. In particular, profoundly lower incidence in polyneuropathy compared to bortezomib has been described. However, carfilzomib has a different toxicity profile, with more cardiovascular adverse events. Therefore, caution should be taken with the use of carfilzomib for elderly and cardiovascularly compromised patients. The once-weekly administration of carfilzomib, recently approved by the FDA in combination with dexamethasone, will lead to a lower burden for the patient and caregivers compared to the twice-weekly schemes that were routinely used until recently. This review has a focus on clinical trial data that has led to drug approval, as well as new promising combination studies, and provides advice for treating physicians who are now prescribing this drug to patients. Keywords: carfilzomib, relapsed, refractory multiple myeloma, proteasome inhibitor

T cell-redirecting bispecific antibodies (BsAb) induce significant responses in heavily pretreated multiple myeloma. BsAbs are currently administered in a dose-dense manner until disease progression. However, continuous therapy is associated with safety concerns, including a high risk of infections and high costs. In addition, chronic exposure to BsAbs, and thus long-term T-cell stimulation, induces T-cell exhaustion, which may contribute to relapse. There is increasing evidence that the strategy of induction treatment followed by maintenance with longer intervals between BsAb doses, or limited treatment duration with cessation of therapy in patients who achieve deep remission, improves the balance between toxicity and efficacy. Significance: There is increasing evidence that after initial debulking, less-frequent BsAb administration mitigates T-cell exhaustion and minimizes the potential for chronic or cumulative toxicity while maintaining durable clinical responses. In addition, specific patient subsets may experience an extended treatment-free period following fixed-duration treatment. Fixed-duration treatment may, therefore, decrease cumulative toxicities and the burden on patients and healthcare systems., (©2024 American Association for Cancer Research.)

Purpose: Therapy resistance is a major clinical hurdle in bone cancer treatment and seems to be largely driven by poorly understood microenvironmental factors. Recent evidence suggests a critical role for a unique subpopulation of mesenchymal stem cells with inflammatory features (iMSC), though their origin and function remained unexplored. We demonstrate that cancer-secreted extracellular vesicles (EV) trigger the development of iMSCs, which hinder therapy response in vivo, and set out to identify strategies to counteract their function., Experimental Design: The role of iMSCs in therapy resistance was evaluated in an orthotopic xenograft mouse model of osteosarcoma. EV-induced alterations of the MSC transcriptome were analyzed and compared with single-cell RNA sequencing data of biopsies from patients with osteosarcoma and multiple myeloma. Functional assays identified EV components driving iMSC development. We assessed the efficacy of clinical drugs in blocking iMSC-induced resistance in vivo., Results: We found that iMSCs are induced by interaction with cancer EVs and completely abrogate the antimetastatic effect of TGFβ signaling inhibition. Importantly, EV-induced iMSCs faithfully recapitulate the inflammatory single-cell RNA signature of stromal cells enriched in biopsies from patients with multiple myeloma and osteosarcoma. Mechanistically, cancer EVs act through two distinct mechanisms. EV-associated TGFβ induces IL6 production, whereas the EV-RNA cargo enhances TLR3-mediated chemokine production. We reveal that simultaneous blockade of downstream EV-activated pathways with ladarixin and tocilizumab disrupts metastasis formation and overcomes iMSC-induced resistance., Conclusions: Our observations establish iMSCs as major contributors to drug resistance, reveal EVs as triggers of iMSC development, and highlight a promising combination strategy to improve therapy response in patients with bone cancer., (©2024 American Association for Cancer Research.)

Background: Talquetamab is a bispecific antibody targeting the multiple myeloma-associated antigen G protein-coupled receptor family C group 5 member D (GPRC5D). In the phase 1/2 MonumenTAL-1 trial (NCT03399799/NCT04634552), overall responses rates were > 71% in patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM). Due to the distribution of the target antigen, a unique pattern of GPRC5D-associated adverse events (AEs) was observed, together with T-cell redirection-associated AEs. Management strategies for talquetamab-associated AEs are described., Discussion: GPRC5D-associated AEs included dermatologic (rash, nonrash, and nail toxicities) and oral AEs (dysgeusia, dysphagia, and dry mouth). The incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were consistent with other T-cell redirection therapies. The incidence of high-grade infections was lower than observed with B-cell maturation antigen-targeting bispecific antibodies, with less frequent use of intravenous immunoglobulin required. GPRC5D-associated AEs were mostly low grade and led to few discontinuations. Skin toxicities were managed with emollients, topical corticosteroids, and oral corticosteroids (for high-grade, persistent, or AEs that progress). Nail toxicities were commonly managed with emollients. Based on investigator experience, dose modification may be effective for controlling oral events. Observation for potential weight changes is required. Infections were managed per standard of care. CRS and ICANS were effectively managed, consistent with other trials of T-cell redirection therapies., Conclusion: Although talquetamab had a distinct safety profile, AEs were considered clinically manageable and mostly low grade. With appropriate education and support, health care practitioners can ensure patients with RRMM maintain quality of life and treatment adherence. VIDEO ABSTRACT., (Copyright © 2024. Published by Elsevier Inc.)

Treatment of relapsed/refractory multiple myeloma (RRMM) is challenging as patients exhaust all available therapies and the disease becomes refractory to standard drug classes. Here we report the final results of LocoMMotion, the first prospective study of real-world clinical practice (RWCP) in triple-class exposed (TCE) patients with RRMM, with a median follow-up of 26.4 months (range, 0.1-35.0). Patients (N  =  248) had received median 4 prior LOT (range, 2-13) at enrollment. 91 unique regimens were used in index LOT. Overall response rate was 31.9% (95% CI, 26.1-38.0), median progression-free survival (PFS) was 4.6 months (95% CI, 3.9-5.6) and median overall survival was 13.8 months (95% CI, 10.8-17.0). 152 patients (61.3%) had subsequent LOTs with 134 unique regimens, of which 78 were used in first subsequent LOT. Median PFS2 (from start of study through first subsequent LOT) was 10.8 months (95% CI, 8.4-13.0). 158 patients died on study, 67.7% due to progressive disease. Additional subgroup analyses and long-term safety summaries are reported. The high number of RWCP treatment regimens utilized and poor clinical outcomes confirm a lack of standardized treatment for TCE patients with RRMM, highlighting the need for new treatments with novel mechanisms., (© 2024. The Author(s).)

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).

Off-the-shelf T-cell-redirecting bispecific antibodies targeting BCMA, GPRC5D, and FcRH5 have high activity in multiple myeloma with a manageable toxicity profile. However, not all patients respond to bispecific antibodies and patients can develop bispecific antibody resistance after an initial response. Mechanisms that contribute to bispecific antibody resistance are multifactorial and include tumour-related factors, such as high tumour burden, expression of T-cell inhibitory ligands, and antigen loss. Resistance due to antigen escape can be prevented by simultaneously targeting two tumour-associated antigens with a trispecific antibody or a combination of two bispecific antibodies. There is also increasing evidence that primary resistance to bispecific antibodies is associated with impaired baseline T-cell function. Long-term exposure to bispecific antibodies with chronic T-cell stimulation further aggravates T-cell dysfunction, which could contribute to failure of disease control. Therapeutic interference with T-cell exhaustion by targeting inhibitory or costimulatory pathways could improve bispecific antibody-mediated antitumour activity. The immunosuppressive microenvironment also contributes to bispecific antibody resistance. CD38-targeting antibodies hold promise as combination partners for bispecific antibodies because of their potential to eliminate CD38 + immune suppressor cells. In conclusion, a better understanding of the mechanisms underlying the absence of disease response has provided novel insights to optimise T-cell activity and bispecific antibody efficacy in multiple myeloma., Competing Interests: Declaration of interests NWCJvdD has received research support, paid to his institution, from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis, and BMS and has been on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Kite Pharma, Merck, Pfizer, AbbVie, and Servier. AC has received research support from Janssen Pharmaceuticals; has received honoraria for lectures from Antengene; and has been a consultant or advisor for AbbVie, Adaptive, Amgen, Antengene, Bristol Myers Squibb, Forus, Genentech–Roche, GlaxoSmithKline, Janssen Pharmaceuticals, Karyopharm Therapeutics, Millennium–Takeda, and Sanofi–Genzyme. MVM has been on advisory boards for Amgen, Bristol Myers Squibb–Celgene, GlaxoSmithKline, Janssen Cilag, Kite Pharma, Oncopeptides, Pfizer, Roche, Sanofi, and Stemline and is a speaker bureau member of Janssen Cilag., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: Teclistamab, an off-the-shelf B-cell maturation antigen (BCMA) × CD3 bispecific antibody that mediates T-cell activation and subsequent lysis of BCMA-expressing myeloma cells, is approved for the treatment of patients with relapsed/refractory multiple myeloma (R/RMM). As a T-cell redirection therapy, clinical outcomes with teclistamab may be influenced by patient immune fitness and tumor antigen expression. We correlated tumor characteristics and baseline immune profiles with clinical response and disease burden in patients with R/RMM from the pivotal phase 1/2 MajesTEC-1 study, focusing on patients treated with 1.5 mg/kg of teclistamab (N = 165). Peripheral blood samples were collected at screening, and bone marrow samples were collected at screening and cycle 3. Better clinical outcomes to teclistamab correlated with higher baseline total T-cell counts in the periphery. In addition, responders (partial response or better) had a lower proportion of immunosuppressive regulatory T cells (Tregs), T cells expressing coinhibitory receptors (CD38, PD-1, and PD-1/TIM-3), and soluble BCMA and a T-cell profile suggestive of a more cytolytic potential, compared with nonresponders. Neither frequency of baseline bone marrow BCMA expression nor BCMA-receptor density was associated with clinical response to teclistamab. Improved progression-free survival was observed in patients with a lower frequency of T cells expressing exhaustion markers and immunosuppressive Tregs. Overall, response to teclistamab was associated with baseline immune fitness; nonresponders had immune profiles suggestive of immune suppression and T-cell dysfunction. These findings illustrate the importance of the contribution of the immune landscape to T-cell redirection therapy response. This trial was registered at www.ClinicalTrials.gov as #NCT03145181/NCT04557098., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Historically, dose selection of anticancer drugs has mainly been based on establishing the maximum tolerated dose in phase 1 clinical trials with a traditional 3 plus 3 design. In the era of targeted therapies and immune-modulating agents, this approach does not necessarily lead to selection of the most favourable dose. This strategy can introduce potentially avoidable toxicity or inconvenience for patients. Multiple changes in drug development could lead to more rational dose selection, such as use of better predictive preclinical models, adaptive and randomised trial design, evaluation of multiple dose levels in late-phase development, assessment of target activity and saturation, and early biomarker use for efficacy and safety evaluation. In this Review, we evaluate the rationale and validation of dose selection in each phase of drug development for anticancer drugs approved by the European Medicines Agency and US Food and Drug Administration from Jan 1, 2020, to June 30, 2023, and give recommendations for dose optimisation to improve safety and patient convenience. In our evaluation, we classified 20 (65%) of the 31 recently registered anticancer agents as potential candidates for dose optimisation, which could be achieved either by reducing the dose (n=10 [32%]) or adjusting the dosage regimen (n=10 [32%]). Dose selection seemed to be adequately justified for nine (29%) of the drugs, whereas the reviewed data were inconclusive for formulating a recommendation on dose optimisation for two (6%) of the drugs., Competing Interests: Declaration of interests NPvE has received research grants from Astellas and Ipsen. NM received consultancy fees from Janssen-Cilag, Bayer, Astellas Pharma, AstraZeneca, Pfizer, and Merck Sharp and Dohme, and research funding (all paid to the institution) from Janssen-Cilag, Astellas Pharma, AstraZeneca/Merck, and Bristol Myers Squibb Foundation. KB received consultancy fees (all paid to the institution) from Merck Sharp and Dohme and Pierre Fabre. HG's institution has received research grants or compensation for patients in studies from Bayer, Boehringer Ingelheim, Deciphera, AmmaxBio, Abbisko, Springworks, Amgen, Pfizer, Novartis, and Servier. GSS received research support (all paid to the institution) from Agendia, AstraZeneca, Merck Sharp and Dohme, Novartis, Roche, and Seagen, and serves on advisory boards for Biovica and Seagen. AJdL reports financial interests and institutional research grants from Bristol Myers Squibb, Merck Sharp and Dohme, Boehringer Ingelheim, and AstraZeneca; and non-financial interests from Merck Serono and Roche. NWCJvdD has received research support (all paid to the institution) from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, Cellectis, and Bristol Myers Squibb; and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, Bristol Myers Squibb, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, AbbVie, and Servier. JJWMJ has received research support (all paid to the institution) from Novartis and Bristol Myers Squibb; serves as president for Apps for Care and Science, a non-profit foundation supported by AbbVie, Alexion, Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Daiichi-Sankyo, Janssen-Cilag, Novartis, Olympus, Incyte, Sanofi Genzyme, Servier, Jazz, and Takeda; and has received honoraria (all paid to the institution) from AbbVie, Novartis, Pfizer, and Incyte. MCM has received research support (all paid to the institution) from Beigene, consultancy fees (all paid to the institution) from Janssen-Cilag, CDR-life, BMC, and GlaxoSmithKline; fees for speakers bureau (all paid to the institution) from Siemens and Janssen-Cilag; and hospitality from Janssen-Cilag. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Frailty in newly-diagnosed multiple myeloma (NDMM) patients is associated with treatment-related toxicity, which negatively affects health-related quality of life (HRQoL). Currently, data on changes in HRQoL of frail and intermediate-fit MM patients during active treatment and post-treatment follow-up are absent., Methods: The HOVON123 study (NTR4244) was a phase II trial in which NDMM patients ≥ 75 years were treated with nine dose-adjusted cycles of Melphalan-Prednisone-Bortezomib (MPV). Two HRQoL instruments (EORTC QLQ-C30 and -MY20) were obtained before start of treatment, after 3 and 9 months of treatment and 6 and 12 months after treatment for patients who did not yet start second-line treatment. HRQoL changes and/or differences in frail and intermediate-fit patients (IMWG frailty score) were reported only when both statistically significant (p < 0.005) and clinically relevant (>MID)., Results: 137 frail and 71 intermediate-fit patients were included in the analysis. Compliance was high and comparable in both groups. At baseline, frail patients reported lower global health status, lower physical functioning scores and more fatigue and pain compared to intermediate-fit patients. Both groups improved in global health status and future perspective; polyneuropathy complaints worsened over time. Frail patients improved over time in physical functioning, fatigue and pain. Improvement in global health status occurred earlier than in intermediate-fit patients., Conclusion: HRQoL improved during anti-myeloma treatment in both intermediate-fit and frail MM patients. In frail patients, improvement occurred faster and, in more domains, which was retained during follow-up. This implies that physicians should not withhold safe and effective therapies from frail patients in fear of HRQoL deterioration., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CAMS serves on advisory boards for Sanofi and Janssen and on speakers' bureaus for Sanofi, Celgene, BMS and Takeda. GJT served as advisor for Novartis. PFY has received payments for lectures from Janssen and Amgen and support for travel expenses from Janssen. RJWK has received support for travel expenses from Novartis and serves on an advisory board of Novartis. PS has received research support from Janssen, Amgen, BMS, Celgene and Karyopharm; and serves on advisory boards for Celgene, Janssen, Amgen, Karyopharm, BMS and Pfizer. NWCJD has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis and BMS, all paid to their institution; and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Adaptive, and Servier, all paid to their institution. HMB serves on an advisory board for Pfizer and has received research support from BMS-Celgene, all paid to their institution. DGJC has received payments for lectures for Takeda, and received financial support for travel expenses from Servier, all outside the submitted work. SZ has received research support from Janssen and the Dutch Cancer Society, all paid to their institution; and serves on advisory boards for Janssen, BMS, Oncopeptides, and Sanofi, all paid to their institution. Others: All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Autologous BCMA-specific CAR T-cell therapies have substantial activity in multiple myeloma (MM). However, due to logistical limitations and BCMA low relapses, there is a need for alternatives. UCARTCS1 cells are 'off-the-shelf' allogeneic CAR T-cells derived from healthy donors targeting SLAMF7 (CS1), which is highly expressed in MM cells. In this study, we evaluated the preclinical activity of UCARTCS1 in MM cell lines, in bone marrow (BM) samples obtained from MM patients and in an MM mouse model., Methods: Luciferase-transduced MM cell lines were incubated with UCARTCS1 cells or control (non-transduced, SLAMF7/TCRαβ double knock-out) T-cells at different effector to target ratios for 24 hours. MM cell lysis was assessed by bioluminescence. Anti-MM activity of UCARTCS1 was also evaluated in 29 BM samples obtained from newly diagnosed patients (n=10), daratumumab-naïve relapsed/refractory patients (n=10) and daratumumab-refractory patients (n=9) in 24-hour flow cytometry-based cytotoxicity assays. Finally, UCARTCS1 activity was assessed in mouse xenograft models., Results: UCARTCS1 cells induced potent CAR-mediated, and dose-dependent lysis of both MM cell lines and primary MM cells. There was no difference in ex vivo activity of UCARTCS1 between heavily pretreated and newly diagnosed patients. In addition, efficacy of UCARTCS1 was not affected by SLAMF7 expression level on MM cells, proportion of tumor cells, or frequency of regulatory T-cells in BM samples obtained from MM patients. UCARTCS1 treatment eliminated SLAMF7 + non-malignant immune cells in a dose-dependent manner, however lysis of normal cells was less pronounced compared to that of MM cells. Additionally, durable anti-MM responses were observed with UCARTCS1 in an MM xenograft model., Conclusions: These results demonstrate that UCARTCS1 has potent anti-MM activity against MM cell lines and primary MM cells, as well as in an MM xenograft model and support the evaluation of UCARTCS1 in patients with advanced MM., Competing Interests: Competing interests: DLC, IC-S and RG are employees of Cellectis SA. MT has received research support from Kite-Gilead, consultancy compensation from Sangamo Therapeutics and is inventor of licensed patents and patent applications related to the development of CARs and CAR-T cells from iPSC. SZ has received research funding from Celgene, Takeda, and Janssen Pharmaceuticals and serves on advisory boards for Janssen Pharmaceuticals, Sanofi, Celgene, Takeda, Amgen and Oncopeptides. No personal funding. TM has received research support from Janssen Pharmaceuticals, Genmab, Takeda, Novartis and ONK Therapeutics. NWCJvdD has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis and BMS and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Pfizer, Kite Pharma, Merck, Abbvie, Adaptive and Servier, all paid to employer., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Sonja Zweegman has received research funding from Celgene, Takeda, and Janssen and serves on advisory boards for Janssen, Takeda, BMS, Oncopeptides, and Sanofi, all paid to the institution. Niels W. C. J. van de Donk has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis, and BMS and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Merck, Roche, Novartis, Bayer, Adaptive, Pfizer, Abbvie, and Servier, all paid to the institution. The remaining authors declare no conflict of interest.

Purpose: Bispecific antibodies (BsAb) directed against B-cell maturation antigen (teclistamab) or the orphan G protein-coupled receptor GPRC5D (talquetamab) induce deep and durable responses in heavily pretreated patients with multiple myeloma. However, mechanisms underlying primary and acquired resistance remain poorly understood., Experimental Design: The anti-multiple myeloma activity of teclistamab and talquetamab was evaluated in bone marrow (BM) samples from patients with multiple myeloma. T-cell phenotype and function were assessed in BM/peripheral blood samples obtained from patients with multiple myeloma who were treated with these BsAb., Results: In ex vivo killing assays with 41 BM samples from BsAb-naive patients with multiple myeloma, teclistamab- and talquetamab-mediated multiple myeloma lysis was strongly correlated (r = 0.73, P < 0.0001). Both BsAb exhibited poor activity in samples with high regulatory T-cell (Treg) numbers and a low T-cell/multiple myeloma cell ratio. Furthermore, comprehensive phenotyping of BM samples derived from patients treated with teclistamab or talquetamab revealed that high frequencies of PD-1+ CD4+ T cells, CTLA4+ CD4+ T cells, and CD38+ CD4+ T cells were associated with primary resistance. Although this lack of response was linked to a modest increase in the expression of inhibitory receptors, increasing T-cell/multiple myeloma cell ratios by adding extra T cells enhanced sensitivity to BsAb. Further, treatment with BsAb resulted in an increased proportion of T cells expressing exhaustion markers (PD-1, TIGIT, and TIM-3), which was accompanied by reduced T-cell proliferative potential and cytokine secretion, as well as impaired antitumor efficacy in ex vivo experiments., Conclusions: Primary resistance is characterized by a low T-cell/multiple myeloma cell ratio and Treg-driven immunosuppression, whereas reduced T-cell fitness due to continuous BsAb-mediated T-cell activation may contribute to the development of acquired resistance., (©2024 American Association for Cancer Research.)

Competing Interests: Kazimierz Groen: BMS and Beigene: speakers bureau (no personal funding). Febe Smits: No conflicts of interest. Kazem Nasserinejad: No conflicts of interest. Mark‐David Levin: Support for attending meetings and/or travel: Janssen, Takeda. Josien C. Regelink: No conflicts of interest. Gert‐Jan Timmers: Participation on an Advisory Board: Novartis; Travel, Accommodations, Expenses; Novartis, Janssen. Esther G. M. de Waal: No conflicts of interest. Matthijs Westerman: No conflicts of interest. Gerjo A. Velders: No conflicts of interest. Koen de Heer: No conflicts of interest. Rineke B. L. Leys: No conflicts of interest. Roel J. W. van Kampen: No conflicts of interest. Claudia A. M. Stege: Speaker's Bureau: Sanofi, Celgene/Bristol Myers Squibb, Takeda; Consulting or Advisory Role: Sanofi, Janssen. Maarten R. Seefat: No conflicts of interest. Inger S. Nijhof: Payment or honoraria for lectures, presentations, or educational events: Janssen, Celgene/Bristol Myers Squibb, Sanofi. Ellen van der Spek: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Janssen. Saskia K. Klein: No conflicts of interest. Niels W. C. J. van de Donk: Consulting or Advisory Role: Janssen, Celgene, Bristol Myers Squibb, Novartis, Amgen, Servier, Takeda, Bayer, Roche, Pfizer, Abbvie, Adaptive (no personal funding); Research Funding: Janssen, Celgene, Amgen, Novartis, Bristol Myers Squibb, Cellectis. Paula F. Ypma: Payment or honoraria for presentations: Janssen; Support for attending meetings and/or travel: Janssen. Sonja Zweegman: Consulting or Advisory Role: Janssen‐Cilag, Takeda, Celgene/Bristol Myers Squibb, Sanofi, Oncopeptides (no personal funding); Research Funding: Janssen, Takeda.

Iberdomide is a next-generation cereblon (CRBN)-modulating agent in the clinical development in multiple myeloma (MM). The analysis of biomarker samples from relapsed/refractory patients enrolled in CC-220-MM-001 (ClinicalTrials.gov: NCT02773030), a phase 1/2 study, shows that iberdomide treatment induces significant target substrate degradation in tumors, including in immunomodulatory agent (IMiD)-refractory patients or those with low CRBN levels. Additionally, some patients with CRBN genetic dysregulation who responded to iberdomide have a similar median progression-free survival (PFS) (10.9 months) and duration of response (DOR) (9.5 months) to those without CRBN dysregulation (11.2 month PFS, 9.4 month DOR). Iberdomide treatment promotes a cyclical pattern of immune stimulation without causing exhaustion, inducing a functional shift in T cells toward an activated/effector memory phenotype, including in triple-class refractory patients and those receiving IMiDs as a last line of therapy. This analysis demonstrates that iberdomide's clinical mechanisms of action are driven by both its cell-autonomous effects overcoming CRBN dysregulation in MM cells, and potent immune stimulation that augments anti-tumor immunity., Competing Interests: Declaration of interests M.A., E.F., M.W., M.O., N.S., P.M., T.P., P.R., and A.T. report equity ownership in Bristol Myers Squib. M.A., E.F., N.S., M.W., M.O., P.M., T.P., and P.R. are current employees of Bristol Myers Squib. A.T. is a former employee of Bristol Myers Squibb. Funding for data generation, processing, and storage was provided by Bristol Myers Squib. S.L. reports consulting fees from AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Janssen Pharmaceuticals, and Takeda; institution grants or contracts from Bristol Myers Squibb, Janssen, and Takeda; membership on an entity’s board of directors or advisory committees for TG Therapeutics; and stock ownership in TG Therapeutics. N.W.C.J.v.d.D. reports institution grants or contracts from Amgen, Cellectis, and Janssen Pharmaceuticals and membership on an entity’s board of directors or advisory committees for Adaptive Biotechnologies, Amgen, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis, Roche Sanofi, and Takeda. S.P. reports consulting fees from Foundation Medicine and research funding from Bristol Myers Squibb (Celgene), Karyopharm, and Amgen. P.R. reports shares in Doloromics., (Copyright © 2024. Published by Elsevier Inc.)

Immunotherapeutic strategies, specifically T-cell-redirected therapies, have been transformative in the context of multiple myeloma (MM). With the approval of two chimeric antigen receptor T-cell (CAR-T) drug products and three bispecific antibodies/T-cell engagers (bsAbs/TCEs) in relapsed/refractory MM (RRMM), the 20th annual IMS meeting dedicated a session to the practical aspects of these therapies. Here, we highlight the discussion during this session, including the role of CAR-T and bsAb therapies in frontline MM treatment, management of acute toxicities, prevention and management of infections, and finally treatment sequencing of T-cell redirected therapies., Competing Interests: Disclosure NSR declares consulting/advisory board participation for Bristol Myers Squibb, J and J, Pfizer, Abbvie, Genentech, GlaxoSmithKline, Immuneel, Kite, Caribou, and Kelonia Therapeutics, and research funding from 2Seventy Bio and Pfizer. ADC declares consulting/advisory board participation for Bristol Myers Squibb, Janssen Pharmaceuticals, Pfizer, Abbvie, Genentech/Roche, GlaxoSmithKline, Legend Biotech, iTeos, and Ichnos, and research funding from GlaxoSmithKline, Genentech, and Novartis. KKP declares consultancy/advisory board participation for Bristol Myers Squibb, Janssen Pharmaceuticals, Legend Biotech, Pfizer, AstraZeneca, Merck, Abbvie, Genentech, Regeneron, Takeda, and Karyopharm; is on the Speakers Bureau for Bristol Myers Squibb, Janssen Pharmaceuticals, and Legend Biotech; and has received research support from Nektar, Bristol Myers Squibb, and Allogene. NWCJvdD has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis, and Bristol Myers Squibb, and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, Bristol Myers Squibb, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, Abbvie, and Servier, all paid to the institution. JR declares consultancy/advisory board participation for Janssen Pharmaceuticals, Bristol Myers Squibb, Pfizer, Karyopharm, Sanofi, Takeda, Genentech, Abbvie, and Regeneron, and is on the Speakers Bureau for Janssen Pharmaceuticals, Bristol Myers Squibb, Sanofi, and Adaptive Biotechnologies. JS-M declares participation on advisory boards and consulting services, on behalf of his institution, for Abbvie, AMGEN, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Haemalogix, Janssen-Cilag, Karyopharm, MSD, Novartis, Pfizer, Takeda, Regeneron, Roche, Sanofi, and SecuraBio., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: A decline in physical function may be an early predictor for complications of cancer treatment. This study examined whether repeated objective smartphone measurements of physical activity and exercise capacity in patients with cancer are feasible during early-phase clinical trials (EPCTs) and whether a decline in physical function is associated with clinical outcomes., Methods: Physical activity (steps/day) and exercise capacity (6-minute walk test [6MWT]) were measured with a smartphone before EPCT start (T0) and after 4 weeks (T1) and 8 weeks (T2). Univariable logistic regression analyzed associations between a decline in step count (≥20%), 6MWT distance (≥10%), or deterioration of ECOG performance status (PS) and trial discontinuation at 8 weeks and 90 days. Cox proportional hazards models were used to examine associations with progression-free survival (PFS) and overall survival (OS), adjusting for trial phase (I vs II), cancer type (hematologic malignancy vs solid tumor), and PS (0 vs ≥1)., Results: Among 117 included patients, valid step count and 6MWT measurements were available for 96.6% and 76.7% of patients at T0, 74.4% and 53.3% at T1, and 89.7% and 54.4% at T2, respectively. Patients experiencing step count decline between T0 and T1 had higher odds of trial discontinuation at 8 weeks (odds ratio, 8.67; 95% CI, 1.94-61.43), and decline between T1 and T2 was associated with discontinuation at 90 days (odds ratio, 5.20; 95% CI, 1.43-21.14). Step count decline was significantly associated with shorter PFS (hazard ratio, 3.54; 95% CI, 2.06-6.08) and OS (hazard ratio, 2.31; 95% CI, 1.26-4.23). Declines in 6MWT distance or deterioration in ECOG PS were not associated with trial discontinuation or survival., Conclusions: Repeated smartphone measurements of physical activity are feasible in patients participating in EPCTs. Additionally, physical activity decline is significantly associated with trial discontinuation, PFS, and OS. Hence, we envision that objective smartphone measurements of physical activity will contribute to optimal treatment development for patients with cancer.

Multiple myeloma remains an incurable disease, despite the development of numerous drug classes and combinations that have contributed to improved overall survival. Immunotherapies directed against cancer cell-surface antigens, such as chimeric antigen receptor (CAR) T-cell therapy and T-cell-redirecting bispecific antibodies, have recently received regulatory approvals and shown unprecedented efficacy. However, these immunotherapies have unique mechanisms of action and toxicities that are different to previous treatments for myeloma, so experiences from clinical trials and early access programmes are essential for providing specific recommendations for management of patients, especially as these agents become available across many parts of the world. Here, we provide expert consensus clinical practice guidelines for the use of bispecific antibodies for the treatment of myeloma. The International Myeloma Working Group is also involved in the collection of prospective real-time data of patients treated with such immunotherapies, with the aim of learning continuously and adapting clinical practices to optimise the management of patients receiving immunotherapies., Competing Interests: Declaration of interests PR-O reports personal fees derived from consulting or advisory board roles from Celgene-BMS, Janssen, Roche, AbbVie, Pfizer, GSK, Sanofi, and H3Biomedicine; steering committee membership from Celgene-BMS, Regeneron, and Janssen; speaker's bureau fess from Janssen, Celgene-BMS, GSK, Sanofi, and AbbVie; and a travel grant from Pfizer. SU reports grants and personal fees from AbbVie, Amgen, BMS, EdoPharma, Genentech, Gilead, GSK, Merck, Sanofi, and Seagen; speakers’ bureau fees, consulting and advisory board participation, and steering committee membership from Janssen; participation on advisory boards from Karyopharm Therapeutics, Oncopeptides, Secura Bio, SkylineDx, and Takeda; and grants from Moderna, TeneoBio, and Pharmacyclics, outside the submitted work. ADC reports personal fees and participation on advisory boards from GSK; personal fees from Bristol Myers Squibb, Janssen, AbbVie, Pfizer, iTeos, Ichnos, Arcellx, and Legend; personal fees and participation on advisory boards from Genentech/Roche; participation on advisory boards from Novartis, outside the submitted work; and has a patent licensed for Novartis. NWCJvdD reports personal fees from Janssen Pharmaceuticals, Amgen, Celgene, Novartis, Cellectis, Bristol Myers Squibb/Celgene, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, AbbVie, and Servier, outside the submitted work. JGP-L reports personal fees from Janssen and GSK, outside the submitted work. MVM reports personal fees from Janssen, Celgene/Bristol Myers Squibb, Novartis, GSK, Sanofi, Amgen, Pfizer, AbbVie, and Regeneron, outside the submitted work. HE reports personal fees and research support from Bristol Myers Squibb/Celgene, Janssen, Sanofi, and GSK; and personal fees from Amgen, Takeda, and Novartis; outside the submitted work. MM reports personal fees from Janssen, Bristol Myers Squibb, WebMD global, GSK, and CDR-Life; and research funding from Siemens and BeiGene; outside the submitted work. BAD reports advisory board participation and consulting fees from COTA and Janssen; personal fees from Multiple Myeloma Research Foundation; honoraria for CME-related activities from Plexus Communications; research funding from Amgen and GSK; and involvement as an independent reviewer of a clinical trial for BMS; outside the submitted work. NP reports research funding and accomodation expenses from Amgen, Bristol Myers Squibb, Janssen, Takeda, and The Binding Site; research funding from Sanofi, and personal fees from Pfizer, outside the submitted work. PJH reports personal fees from Antengene, Gilead, iTeos Therapeutics, Janssen, Novartis, and Pfizer, outside the submitted work. W-JC reports personal fees from AbbVie, Amgen, Pfizer, Sanofi, Regeneron, GSK, and Novartis; and grants and personal fees from Bristol Myers Squibb, Janssen, and Novartis, outside the submitted work. GG reports personal fees from and is a shareholder of XNK Therapeutics Sweden, and personal fees from Fujimoto Pharmaceutical corporation, outside the submitted work. FS reports personal fees from AbbVie, GSK, Celgene, Takeda, Janssen, Oncopeptides, Sanofi, BMS, Novartis, SkyliteDX, Pfizer, and Daiki-Sankyo, outside the submitted work. JCY reports personal fees from Janssen, Sanofi, BMS, Regeneron, GSK, Pfizer, Menarini, outside the submitted work. EZ reports personal fees from Janssen, Bristol Myers Squibb, Amgen, and Takeda, outside the submitted work. RP reports personal fees and travel support from GSK and Janssen; and personal fees from Pfizer, AbbVie, Bristol Myers Squibb, and Sanofi, outside the submitted work. CN reports personal fees and participation on advisory boards from Janssen; personal fees from Bristol Myers Squibb, Sanofi, GSK, Pfizer, AstraZeneca, and DKSH; and personal fees and participation on advisory boards from Amgen, outside the submitted work. YL reports grants and personal fees from Janssen; personal fees from Sanofi, NexImmune, Caribou, Bristol Myers Squibb, Regeneron, and Genentech; and personal fees and participation on data safety monitoring boards from Pfizer, outside the submitted work. AC reports personal fees from AbbVie, Adaptive, Amgen, Antengene, Bristol Myers Squibb, Forus, Genetech/Roche, GSK, Janssen, Karyopharm, Millenium/Takeda, and Sanofi/Genzyme, outside the submitted work. JM reports personal fees from Amgen, Sanofi, Bristol Myers Squibb, Janssen, and Takeda, outside the submitted work. MC reports personal fees from Janssen, Celgene/Bristol Myers Squibb, GSK, Sanofi, Amgen, Menarini-Stemline, AbbVie, and Pfizer, outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: N.W.C.J.v.d.D. has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis, and BMS and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Adaptive, Pfizer, Abbvie, and Servier, all paid to the institution. C.H. and M.D. declare no conflicts of interest.

The incorporation of monoclonal antibodies into backbone regimens has substantially improved the clinical outcomes of patients with newly diagnosed and relapsed/refractory multiple myeloma (MM). Although the SLAMF7-targeting antibody elotuzumab has no single- agent activity, there is clinical synergy between elotuzumab and immunomodulatory drugs in patients with relapsed/refractory disease. Daratumumab and isatuximab are CD38-targeting antibodies which have single-agent activity and a favorable safety profile, which make these agents an attractive component of combination regimens. Monoclonal antibodies may cause infusion-related reactions, but with subcutaneous administration these are less frequently observed. All therapeutic antibodies may interfere with assessment of complete response. Next-generation Fc-engineered monoclonal antibodies are in development with the potential to further improve the outcome of patients with MM., Competing Interests: Disclosure N.W.C.J. van.de.Donk has received research support from Janssen Pharmaceuticals, United States, Amgen, United States, Celgene, United States, Novartis, Switzerland, Cellectis and BMS, and serves in advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Abbvie, Novartis, Bayer, Adaptive, and Servier, all paid to institution; S. Zweegman. has received research funding from Celgene, Takeda, Janssen, United States, and serves in advisory boards for Janssen, Takeda, BMS, Oncopeptides and Sanofi, all paid to institution; no funding received for this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Talquetamab, a bispecific antibody targeting GPRC5D × CD3, is approved for the treatment of patients with triple-class -exposed (TCE) relapsed/refractory multiple myeloma (RRMM) on the basis of the results from the phase I/II MonumenTAL-1 trial. The relative effectiveness of talquetamab vs. real-world physician's choice of therapy (RWPC) was assessed using adjusted comparisons., Methods: An external control arm for MonumenTAL-1 (subcutaneously administered talquetamab 0.4 mg/kg weekly [QW] and 0.8 mg/kg every other week [Q2W]) was created from two observational real-world studies: LocoMMotion and MoMMent. Imbalances in baseline covariates were adjusted using inverse probability weighting. The relative effectiveness of talquetamab vs. RWPC was estimated for overall response rate (ORR), ≥ very good partial response (VGPR), and ≥ complete response (CR); odds ratios and relative response ratios (RRs) were derived from weighted logistic regression. Hazard ratios (HRs) for duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) were estimated using a weighted Cox proportional hazards model., Results: After reweighting, baseline characteristics were balanced across cohorts. In adjusted comparisons, patients treated with talquetamab QW (n = 143) had significantly improved outcomes vs. RWPC; RRs were ORR 2.67, p < 0.0001; ≥ VGPR 4.70, p < 0.0001; ≥ CR 78.05, p = 0.0002; and HRs were PFS 0.52, p < 0.0001; TTNT 0.48, p < 0.0001; OS 0.36, p < 0.0001. Patients treated with talquetamab Q2W (n = 145) also had significantly improved outcomes vs. RWPC; RRs were ORR 2.62, p < 0.0001; ≥ VGPR 5.04, p < 0.0001; ≥ CR 101.14, p = 0.0002; and HRs were PFS 0.40, p < 0.0001; TTNT 0.39, p < 0.0001; OS 0.37, p < 0.0001., Conclusion: Effectiveness of talquetamab for both schedules was significantly better than RWPC for ORR, ≥ VGPR, ≥ CR, PFS, OS, and TTNT, highlighting its clinical benefit for patients with TCE RRMM., Trial Registration: MonumenTAL-1, ClinicalTrials.gov identifier NCT03399799/NCT04634552; LocoMMotion, ClinicalTrials.gov identifier NCT04035226; MoMMent, ClinicalTrials.gov identifier NCT05160584., (© 2024. The Author(s).)

Background: Patients with relapsed/refractory multiple myeloma are at increased risk of infection. Infections during treatment with teclistamab, the first B-cell maturation antigen-directed bispecific antibody approved for triple-class-exposed relapsed/refractory multiple myeloma, was examined in the phase 1/2 MajesTEC-1 study., Methods: Patients (N = 165) received subcutaneous teclistamab 1.5 mg/kg weekly after a step-up dosing schedule (0.06 mg/kg and 0.3 mg/kg, each separated by 2-4 days). Patients were monitored frequently for infections; prophylaxis and management were per institutional guidelines., Results: At a median follow-up of 22.8 months (range, 0.3-33.6), infections were reported in 132 patients (80.0%). Grade 3/4 infections occurred in 91 patients (55.2%), including COVID-19 (21.2%), respiratory infections (19.4%), Pneumocystis jirovecii pneumonia (4.2%), viral infections (4.2%), and gastrointestinal infections (1.2%). Twenty-one patients died from infections (18 from COVID-19). Median time to first onset of any-grade and grade 3 to 5 infections was 1.7 and 4.2 months, respectively. Overall, 70.9% of patients had ≥1 postbaseline immunoglobulin G (IgG) level <400 mg/dL; median time to IgG <400 mg/dL was 1.2 months (range, 0.2-19.8) and 46.1% received ≥1 dose of IgG replacement. Grade 3/4 neutropenia occurred in 65.5% of patients (median time to grade ≥3 neutropenia/febrile neutropenia was 2.3 months [range, 0-18.1])., Conclusion: Based on the infection profile of B-cell maturation antigen-targeted bispecific antibodies such as teclistamab, it is recommended that clinicians and patients remain vigilant for a range of infection types throughout treatment to facilitate prompt intervention. Appropriate screening, prophylaxis, and management of infections, hypogammaglobulinemia, and neutropenia are important., Clinical Trial Registration: NCT03145181/NCT04557098 (ClinicalTrials.gov) PLAIN LANGUAGE SUMMARY: Before starting teclistamab, patients should be up to date with vaccinations (including COVID-19) and screened for hepatitis B and C and HIV. Teclistamab should not be given to patients with any active infections. Prophylactic antimicrobials should be administered per institutional guidelines. Prophylaxis for Pneumocystis jirovecii pneumonia and herpes simplex/varicella zoster virus is recommended during teclistamab treatment. Close monitoring of infections and immunoglobulin G (IgG) levels should continue throughout teclistamab treatment. IgG replacement (administered every 3-6 weeks) should be used to maintain IgG ≥400 mg/dL. Growth factors should be considered for grade ≥3 neutropenia with infection/fever and grade 4 neutropenia., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Novel therapies for multiple myeloma (MM) have improved patient survival, but their high costs strain healthcare budgets. End-of-life phases of treatment are generally the most expensive, however, these high costs may be less justifiable in the context of a less pronounced clinical benefit. To manage drug expenses effectively, detailed information on end-of-life drug administration and costs are crucial. In this retrospective study, we analysed treatment sequences and drug costs from 96 MM patients in the Netherlands who died between January 2017 and July 2019. Patients received up to 16 lines of therapy (median overall survival: 56.5 months), with average lifetime costs of €209 871 (€3111/month; range: €3942-€776 185) for anti-MM drugs. About 85% of patients received anti-MM treatment in the last 3 months before death, incurring costs of €20 761 (range: €70-€50 122; 10% of total). Half of the patients received anti-MM treatment in the last 14 days, mainly fully oral regimens (66%). End-of-life treatment costs are substantial despite limited survival benefits. The use of expensive treatment options is expected to increase costs further. These data serve as a reference point for future cost studies, and further research is needed to identify factors predicting the efficacy and clinical benefit of continuing end-of-life therapy., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Introduction: Patients with relapsed or refractory multiple myeloma (RRMM) report significantly lower HRQoL compared with patients with newly diagnosed MM and experience further deterioration in HRQoL with each relapse and subsequent treatment. Therefore, consideration of the impact of treatment on HRQoL in addition to clinical outcomes is vital., Patients and Methods: In the phase I/II MajesTEC-1 (NCT03145181, NCT04557098) study, patients with RRMM who received teclistamab, an off-the-shelf, T-cell redirecting BCMA × CD3 bispecific antibody, had deep and durable responses with manageable safety. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30-item and the EuroQol 5 Dimension 5 Level descriptive questionnaire. Changes over time from baseline were measured with a repeated measures mixed-effects model. Proportions of patients with clinically meaningful improvement after starting treatment and time to clinically meaningful worsening were assessed., Results: Compliance was maintained throughout the study. Compared with baseline, positive changes were observed for pain, global health status, and emotional functioning with treatment; other assessments were largely unchanged from baseline. Post hoc analysis showed patients with deeper clinical response generally reported improved HRQoL outcomes. Following an initial decline in HRQoL in some scales, the proportion of patients reporting clinically meaningful improvements increased, while the proportion reporting clinically meaningful worsening decreased over time. Clinically meaningful improvements in pain were reported in ≥40% of patients at most assessment time points., Conclusions: These results complement previously reported clinical benefits and support teclistamab as a promising therapeutic option for patients with RRMM., (Copyright © 2023. Published by Elsevier Inc.)

Multiple myeloma is a genetically complex and heterogenous malignancy with a 5-year survival rate of approximately 60%. Despite advances in therapy, patients experience cycles of remission and relapse, with each successive line of therapy associated with poorer outcomes; therefore, therapies with different mechanisms of action against new myeloma antigens are needed. G protein-coupled receptor class C group 5 member D (GPRC5D) has emerged as a novel therapeutic target for the treatment of multiple myeloma. We review the biology and target validation of GPRC5D, and clinical data from early phase trials of GPRC5D-targeting bispecific antibodies, talquetamab and forimtamig, and chimeric antigen receptor T cell (CAR-T) therapies, MCARH109, OriCAR-017, and BMS-986393. In addition to adverse events (AEs) associated with T-cell-redirection therapies irrespective of target, a consistent pattern of dermatologic and oral AEs has been reported across several trials of GPRC5D-targeting bispecific antibodies, as well as rare cerebellar events with CAR-T therapy. Additional studies are needed to understand the underlying mechanisms involved in the development of skin- and oral-related toxicities. We review the strategies that have been used to manage these GPRC5D-related toxicities. Preliminary efficacy data showed overall response rates for GPRC5D-targeting T-cell-redirecting therapies were ≥64%; most responders achieved a very good partial response or better. Pharmacokinetics/pharmacodynamics showed that these therapies led to cytokine release and T-cell activation. In conclusion, results from early phase trials of GPRC5D-targeting T-cell-redirecting agents have shown promising efficacy and manageable safety profiles, including lower infection rates compared with B-cell maturation antigen- and Fc receptor-like protein 5-targeting bispecific antibodies. Further clinical trials, including those investigating GPRC5D-targeting T-cell-redirecting agents in combination with other anti-myeloma therapies and with different treatment modalities, may help to elucidate the future optimal treatment regimen and sequence for patients with multiple myeloma and improve survival outcomes. Video Summary., (© 2024. The Author(s).)

Introduction: Teclistamab is the first approved B cell maturation antigen × CD3 bispecific antibody with precision dosing for the treatment of triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM). We compared the effectiveness of teclistamab in MajesTEC-1 versus real-world physician's choice of therapy (RWPC) in patients from the prospective, non-interventional LocoMMotion and MoMMent studies., Methods: Patients treated with teclistamab from MajesTEC-1 (N = 165) were compared with an external control arm from LocoMMotion (N = 248) or LocoMMotion + MoMMent pooled (N = 302). Inverse probability of treatment weighting adjusted for imbalances in prognostic baseline characteristics. The relative effect of teclistamab versus RWPC for overall response rate (ORR), very good partial response or better (≥ VGPR) rate, and complete response or better (≥ CR) rate was estimated with an odds ratio using weighted logistic regression transformed into a response-rate ratio (RR) and 95% confidence interval (CI). Weighted proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for duration of response (DOR), progression-free survival (PFS), and overall survival (OS)., Results: Baseline characteristics were well balanced between treatment cohorts after reweighting. Patients treated with teclistamab had significantly improved outcomes versus RWPC in LocoMMotion: ORR (RR [95% CI], 2.44 [1.79-3.33]; p < 0.0001), ≥ VGPR (RR 5.78 [3.74-8.93]; p < 0.0001), ≥ CR (RR 113.73 [15.68-825.13]; p < 0.0001), DOR (HR 0.39 [0.24-0.64]; p = 0.0002), PFS (HR 0.48 [0.35-0.64]; p < 0.0001), and OS (HR 0.64 [0.46-0.88]; p = 0.0055). Teclistamab versus RWPC in LocoMMotion + MoMMent also had significantly improved outcomes: ORR (RR 2.41 [1.80-3.23]; p < 0.0001), ≥ VGPR (RR 5.91 [3.93-8.88]; p < 0.0001), ≥ CR (RR 132.32 [19.06-918.47]; p < 0.0001), DOR (HR 0.43 [0.26-0.71]; p = 0.0011), PFS (HR 0.49 [0.37-0.66]; p < 0.0001), and OS (HR 0.69 [0.50-0.95]; p = 0.0247)., Conclusion: Teclistamab demonstrated significantly improved effectiveness over RWPC in LocoMMotion ± MoMMent, emphasizing its clinical benefit as a highly effective treatment for patients with TCE RRMM., Trial Registration: MajesTEC-1, ClinicalTrials.gov NCT03145181 (phase 1) and NCT04557098 (phase 2); LocoMMotion, ClinicalTrials.gov NCT04035226; MoMMent, ClinicalTrials.gov NCT05160584., (© 2023. The Author(s).)