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What Is This Summary About?: This is a summary of a phase 3 clinical trial called CARTITUDE-4. This trial compared the anti-cancer therapy ciltacabtagene autoleucel (or cilta-cel) with standard therapies in people who have multiple myeloma, a cancer that affects specific kinds of blood cells called plasma cells. The people in the study had been treated with 1 to 3 previous treatments for multiple myeloma, including a common anti-myeloma treatment called lenalidomide, but their multiple myeloma did not get better., How Was the Study in This Summary Conducted?: About half of the 419 participants in this study received cilta-cel, while the other half received standard therapies, or therapies that are commonly used to treat multiple myeloma. Participants who received cilta-cel had a type of immune cell called T cells collected from their blood and genetically modified to recognize a specific protein found on myeloma cells. These modified T cells, which comprise cilta-cel, were then infused back into the bloodstream., What Were the Results of the Study?: After approximately 1 year in the study, more participants were alive without their cancer getting worse in the cilta-cel group (76%) than in the standard therapies group (49%). The most common side effects in both groups were infections and low blood cell counts. Cytokine release syndrome (a potentially serious side effect caused by overactivation of the immune system) was common but mostly mild. Neurotoxicities (including immune effector cell-associated neurotoxicity syndrome, which can cause symptoms such as headaches, changes in consciousness, and difficulty with memory, attention, speaking, or understanding others) were less common and were reported in 20.5% of participants treated with cilta-cel., What Were the Main Conclusions Reported by the Researchers?: In CARTITUDE-4, more participants treated with cilta-cel showed improvements and were alive with control of their disease 12 months after receiving cilta-cel compared with participants who received standard therapies. Clinical Trial Registration: NCT04181827 (CARTITUDE-4) (ClinicalTrials.gov).

Background: Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequate persistence of the modified T cells in the body. IL15, known for its pro-survival and proliferative properties, has been suggested for incorporation into the fourth generation of CAR-T cells to enhance their persistence. However, the potential systemic toxicity associated with this cytokine warrants further evaluation., Methods: We analyzed the persistence, antitumor efficacy and potential toxicity of anti-mouse CD19 CAR-T cells which express a membrane-bound IL15-IL15Rα chimeric protein (CD19/mbIL15q CAR-T), in BALB/c mice challenged with A20 tumor cells as well as in NSG mice., Results: Conventional CD19 CAR-T cells showed low persistence and poor efficacy in BALB/c mice treated with mild lymphodepletion regimens (total body irradiation (TBI) of 1 Gy). CD19/mbIL15q CAR-T exhibits prolonged persistence and enhanced in vivo efficacy, effectively eliminating established A20 B cell lymphoma. However, this CD19/mbIL15q CAR-T displays important long-term toxicities, with marked splenomegaly, weight loss, transaminase elevations, and significant inflammatory findings in some tissues. Mice survival is highly compromised after CD19/mbIL15q CAR-T cell transfer, particularly if a high TBI regimen is applied before CAR-T cell transfer., Conclusion: Tethered IL15-IL15Rα augments the antitumor activity of CD19 CAR-T cells but displays long-term toxicity in immunocompetent mice. Inducible systems to regulate IL15-IL15Rα expression could be considered to control this toxicity., Competing Interests: Competing interests: None declared., (© 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.)

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.)

Immunoparesis (IP) in multiple myeloma (MM) patients can be measured by classic assessment of immunoglobulin (Ig) levels or by analysis of the uninvolved heavy/light chain pair of the same immunoglobulin (uHLC) by the Hevylite® assay. In this study we evaluate the prognostic value of recovery from IP measured by classic total Ig and uHLC assessment in newly diagnosed MM transplant-eligible (NDMM-TE) patients with intensive treatment and its association with minimal residual disease (MRD). Patients were enrolled and treated in the PETHEMA/GEM2012MENOS65 trial and continued in the PETHEMA /GEM2014MAIN trial. Total Ig (IgG, IgA and IgM) and uHLC were analyzed in a central laboratory at diagnosis, after consolidation treatment and after the first year of maintenance. MRD was analyzed by next-generation flow cytometry after consolidation (sensitivity level 2x10-6). We found no differences in progression-free survival (PFS) between patients who recovered and patients who didn't recover from IP after consolidation when examining classic total Ig and uHLC. However, after the first year of maintenance, in contrast to patients with classic IP, patients with recovery from uHLC IP had longer PFS than patients without recovery, with hazard ratio of 0.42 (95% confidence interval [CI]: 0.21-0.81; P=0.008). Multivariate analysis with Cox proportional-hazards regression models confirmed recovery from uHLC IP after the first year of maintenance as an independent prognostic factor for PFS, with an increase in C-statistic of 0.05 (95% CI: -0.04 to 0.14; P<0.001) when adding uHLC IP recovery. Moreover, we observed that MRD status and uHLC IP recovery affords complementary information for risk stratification. In conclusion, recovery from uHLC IP after 1 year of maintenance is an independent prognostic factor for PFS in NDMM-TE patients who receive intensive treatment. Immune reconstitution, measured as recovery from uHLC IP, provides complementary prognostic information to MRD assessment (clinicaltrials gov. Identifiers: NCT01916252 and NCT02406144).

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., (© 2024. The Author(s).)