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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.

Abstract Infection is the leading cause of death in multiple myeloma (MM). However, the cellular composition associated with immune dysfunction is not defined. We analyzed immune profiles in the peripheral blood of patients with MM (n = 28) and B-cell chronic lymphoproliferative disorders (n = 53) vs. health care practitioners (n = 96), using multidimensional and computational flow cytometry. MM patients displayed altered distribution of most cell types (41/56, 73%), particularly within the B-cell (17/17) and T-cell (20/30) compartments. Using COVID-19 as a case study, we compared the immune response to vaccination based on 64,304 data points generated from the analysis of 1099 longitudinal samples. MM patients showed limited B-cell expansion linked to lower anti-RBD and anti-S antibody titers after the first two doses and booster. The percentages of B cells and CD4+ T cells in the blood, as well as the absolute counts of B cells and dendritic cells, predicted vaccine immunogenicity at different time points. In contrast with the humoral response, the percentage and antigen-dependent differentiation of SARS-CoV-2-specific CD8+ T cells was not altered in MM patients. Taken together, this study defined the cellular composition associated with immune dysfunction in MM and provided biomarkers such as the B-cell percentage and absolute count to individualize vaccination calendars.

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The treatment of relapsed and refractory multiple myeloma has improved substantially in the last 5–10 years based on the development and use of several novel classes of drugs and drug combinations. These advances have led to improvements in progression-free and overall survival as well as quality of life. The general tendency has been to advance drugs/combinations that have performed well in advanced disease to the earlier line settings (frontline, first/early relapse). There are several triplet drug combinations that, when used as part of first or early relapse, can provide remission durations of 3 years or longer. More recently, impressive responses have been seen with the use of targeted immunotherapeutics (chimeric antigen receptor T-cells and bispecific antibodies) in heavily pretreated patients with MM. These treatments, however, have been associated with some new and occasionally severe toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and severe infections, including opportunistic infections and profound cytopenias. These potential toxicities bring into question whether these immune-targeting drugs should remain as late-line therapeutics or whether the high single-agent overall response rates mandate that these agents be used in earlier line settings. Herein, the authors provide a point and counterpoint about the future use of these agents.

Abstract Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.

Abstract 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

Abstract Overall outcomes for multiple myeloma have improved due to the availability of new therapies, but patients with relapsed/refractory multiple myeloma harbouring certain factors continue to pose a therapeutic challenge. These challenging features include high‐risk cytogenetics, renal impairment, patient characteristics such as age and frailty, and extramedullary disease. Prior refractory status and number of prior lines add further complexity to the treatment of these patients. While newer regimens are available and have suggested efficacy in these patient populations through subgroup analyses, differences in trial definitions and cut‐offs make meaningful comparisons difficult. This review aims to examine the available clinical trial data for patients with high‐risk cytogenetics, renal impairment, age and frailty and extramedullary disease.

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Patients with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed (to an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody) have limited treatment options and there is no standard of care. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T-cell therapy, demonstrated efficacy in triple-class exposed RRMM patients in the KarMMa trial (NCT03361748). In this retrospective study (KarMMa-RW), patient-level data from triple-class exposed RRMM patients were merged into a single data model and compared with KarMMa using trimmed stabilized inverse probability of treatment weighting. Endpoints included overall response rate (ORR; primary), rate of very good partial response or better (≥VGPR), progression-free survival (PFS), and overall survival (OS). Of 1949 real-world triple-class exposed RRMM patients, 190 received subsequent (index) line of therapy and met KarMMa eligibility criteria (Eligible RRMM cohort). With a median follow-up of 13.3 months in KarMMa and 10.2 months in Eligible RRMM, ORR, and ≥VGPR were significantly improved in KarMMa versus Eligible RRMM (ORR, 76.4% vs 32.2%; ≥VGPR, 57.9% vs 13.7%; both P

In this work, an efficient synthesis of bionanohybrids as artificial metalloenzymes (Cu, Pd, Ag, Mn) based on the application of an enzyme as a scaffold was described. Here we evaluated the effect of changing the metal, pH of the medium, and the amount of enzyme in the synthesis of these artificial metalloenzymes, where changes in the metal species and the size of the nanoparticles occur. These nanozymes were applied in the degradation of hydrogen peroxide for their evaluation as mimetics of catalase activity, the best being the Mn@CALB-H2O, which presented MnO2 nanostructures, with three-fold improved activity compared to Cu2O species, CuNPs@CALB-P, and free catalase.

Lipid metabolism regulates stem cell states and differentiation. Here, the authors demonstrate a requirement in planarians for Apolipoprotein B-mediated neutral lipid transport from intestinal stores to stem cells and their progeny during differentiation and whole-body regeneration.

Abstract There is evidence of reduced SARS-CoV-2 vaccine effectiveness in patients with hematological malignancies. We hypothesized that tumor and treatment-related immunosuppression can be depicted in peripheral blood, and that immune profiling prior to vaccination can help predict immunogenicity. We performed a comprehensive immunological characterization of 83 hematological patients before vaccination and measured IgM, IgG, and IgA antibody response to four viral antigens at day +7 after second-dose COVID-19 vaccination using multidimensional and computational flow cytometry. Health care practitioners of similar age were the control group (n = 102). Forty-four out of 59 immune cell types were significantly altered in patients; those with monoclonal gammopathies showed greater immunosuppression than patients with B-cell disorders and Hodgkin lymphoma. Immune dysregulation emerged before treatment, peaked while on-therapy, and did not return to normalcy after stopping treatment. We identified an immunotype that was significantly associated with poor antibody response and uncovered that the frequency of neutrophils, classical monocytes, CD4, and CD8 effector memory CD127low T cells, as well as naive CD21+ and IgM+D+ memory B cells, were independently associated with immunogenicity. Thus, we provide novel immune biomarkers to predict COVID-19 vaccine effectiveness in hematological patients, which are complementary to treatment-related factors and may help tailoring possible vaccine boosters.

Abstract Patients with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed (to an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody) have limited treatment options and there is no standard of care. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T-cell therapy, demonstrated efficacy in triple-class exposed RRMM patients in the KarMMa trial (NCT03361748). In this retrospective study (KarMMa-RW), patient-level data from triple-class exposed RRMM patients were merged into a single data model and compared with KarMMa using trimmed stabilized inverse probability of treatment weighting. Endpoints included overall response rate (ORR; primary), rate of very good partial response or better (≥VGPR), progression-free survival (PFS), and overall survival (OS). Of 1949 real-world triple-class exposed RRMM patients, 190 received subsequent (index) line of therapy and met KarMMa eligibility criteria (Eligible RRMM cohort). With a median follow-up of 13.3 months in KarMMa and 10.2 months in Eligible RRMM, ORR, and ≥VGPR were significantly improved in KarMMa versus Eligible RRMM (ORR, 76.4% vs 32.2%; ≥VGPR, 57.9% vs 13.7%; both P

Not available.

There is accumulating evidence of BCMA and GPRC5D loss after treatment with T-cell redirecting therapies in patients with relapsed/refractory multiple myeloma (RRMM). While complete CD38 loss is not observed upon relapses after treatment with anti-CD38 monoclonal antibodies (mAb), there is downregulation of surface CD38 expression and decreased number and function of NK cells, which renders these patients resistant to retreatment with anti-CD38 mAb. Here, we provide preclinical evidence that RRMM patients previously exposed to anti-CD38 mAb could benefit from T-cell-based immunotherapy that depend less on CD38 antigen density and NK-cell activity, such as the novel CD38/CD3xCD28 trispecific T-cell engager, SAR442257., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Outcomes are poor in triple-class-exposed (TCE) relapsed/refractory multiple myeloma (RRMM). In the phase 3 KarMMa-3 (clinicaltrials.gov; NCT03651128) trial, patients with TCE RRMM and 2-4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary endpoint; 13.3 vs 4.4 months; P<.0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio (HR), 0.49; 95% confidence interval (CI), 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median (95% CI) was 41.4 (30.9-not reached [NR]) vs 37.9 (23.4-NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE RRMM. NCT03651128., (Copyright © 2024 American Society of Hematology.)

Competing Interests: Michael H. Tomasson: consulting or advisory roles for Janssen. Shinsuke Iida: honoraria from Bristol Myers Squibb, Celgene, Janssen, Pfizer, Sanofi, and Takeda; consulting or advisory roles for Janssen, Sanofi, and Takeda; and research funding from AbbVie, Amgen, Bristol Myers Squibb, Caelum Biosciences, Celgene, Daiichi Sankyo, Janssen, Ono, Otsuka, Sanofi, and Takeda. Ruben Niesvizky: consulting or advisory roles for Bristol Myers Squibb, GSK, Janssen, Karyopharm Therapeutics, and Takeda and research funding from Bristol Myers Squibb, GSK, Janssen, Karyopharm Therapeutics, and Takeda. Mohamad Mohty: honoraria from Amgen, Celgene; consulting or advisory roles for Adaptive Biotechnologies, GSK, Jazz Pharmaceuticals, MaaT Pharma, Novartis, Sanofi, and Xenikos; personal fees from Amgen, Astellas, Bristol Myers Squibb, Celgene, Pfizer, Stemline‐Menarini and Takeda; and speakers bureau roles for Janssen, Jazz Pharmaceuticals, and Sanofi. Nizar J. Bahlis: honoraria from AbbVie, Amgen, Celgene, Genentech/Roche, GSK, Janssen, Karyopharm Therapeutics, Sanofi, and Takeda; consulting or advisory roles for Amgen, Celgene, Janssen, Karyopharm Therapeutics, Pfizer, Sanofi, and Takeda; personal fees from AbbVie, Amgen, Celgene, Genentech/Roche, GSK, Janssen, Karyopharm Therapeutics, Sanofi, and Takeda; and patents, royalties, and/or other intellectual property interests with Celgene and Janssen. Joaquin Martinez‐Lopez: consulting or advisory roles for Bristol Myers Squibb, Janssen, and Novartis; research funding from Astellas and Bristol Myers Squibb; and speakers bureau roles for Bristol Myers Squibb, Janssen‐Cilag, and Roche. Paula Rodriguez‐Otero: consulting or advisory roles for AbbVie, Bristol Myers Squibb, GSK, Janssen, Pfizer, and Sanofi; personal fees from AbbVie, Celgene, GSK, H3 Biomedicine, Janssen, Pfizer, and Sanofi; travel and accommodations expenses paid by Pfizer; and speakers bureau roles for Bristol Myers Squibb, GSK, Janssen, and Sanofi. Alexander M. Lesokhin: honoraria from iTeos Therapeutics, Janssen, Legend Biotech, Pfizer, Sanofi, and Trillium Therapeutics; consulting or advisory roles for Pfizer, Trillium Therapeutics, and Arcellx; personal fees from iTeos Therapeutics, Janssen, Legend Biotech, Pfizer, Sanofi, and Trillium Therapeutics; research funding from Bristol Myers Squibb, Genentech, Janssen, Pfizer, Sanofi, and Trillium Therapeutics; and patents, royalties and/or other intellectual property interests with Serametrix. Andrea Viqueira, Eric Leip, Umberto Conte, and Sharon T. Sullivan: employment and stock ownership at Pfizer. Guenther Koehne: has no conflicts of interest.