Raje, Noopur S

Abstract Chimeric antigen receptor (CAR) T-cell therapy enriched for a memory-like phenotype may persist and function longer than a nonenriched product, thereby improving duration of response (DOR). We conducted a phase I study with bb21217 (NCT03274219), an anti–B-cell maturation antigen CAR T-cell therapy manufactured in the presence of the phosphoinositide 3-kinase inhibitor bb007 to enrich for T cells with a memory-like phenotype, in patients with relapsed/refractory multiple myeloma (N = 72). No new safety concerns were raised with bb21217 therapy (three cases each of grade ≥3 cytokine release syndrome and grade ≥3 neurotoxicity were observed). The objective response rate was 69.4% and the median DOR was 23.8 (95% confidence interval, 16.8–34.8) months. Analysis of the drug product established an association between early memory phenotype and robust expansion and depth of response. Examination of baseline characteristics indicated that tumor burden and prior therapies influenced DOR. The data indicate that generation of CAR T cells early in a disease course when tumor burden is lower and source material exhibits a more naïve phenotype may maximize the clinical benefit potential of the drug product.

Despite significant improvements in survival of patients with multiple myeloma (MM), outcomes remain heterogeneous, and a significant proportion of patients experience suboptimal outcomes. Importantly, traditional prognostic factors based on data from patients treated with older therapies no longer capture prognosis accurately in the contemporary era of novel triplet or quadruplet therapies. Therefore, risk stratification requires refinement in the context of available and investigational treatment options in routine practice and clinical trials, respectively. The current identification of high-risk MM (HRMM) in routine practice is based on the Revised International Staging System, which stratifies patients using a combination of widely available serum biomarkers and chromosomal abnormalities assessed via fluorescence in situ hybridization. In recent years, a substantial body of evidence concerning additional clinical, biological, and molecular/genomic prognostic factors has accumulated, along with new MM risk stratification tools and consensus reports. The International Myeloma Society, along with the International Myeloma Working Group, convened an Expert Panel with the primary aim of revisiting the definition of HRMM and formulating a practical and data-driven consensus definition, based on new evidence from molecular/genomic assays, updated clinical data, and contemporary risk stratification concepts. The Panel proposes the following Consensus Genomic Staging (CGS) of HRMM which relies upon the presence of at least one of these abnormalities: (1) del(17p), with a cutoff of >20% clonal fraction, and/or TP53 mutation; (2) an IgH translocation including t(4;14), t(14;16), or t(14;20) along with 1q+ and/or del(1p32); (3) monoallelic del(1p32) along with 1q+ or biallelic del(1p32); or (4) β2 microglobulin ≥5.5 mg/L with normal creatinine (<1.2 mg/dL).

CARTITUDE-1 evaluated ciltacabtagene autoleucel (cilta-cel) in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM). We describe overall survival (OS), ≥5-year progression-free outcomes, associated biomarkers, and safety, with a median study follow-up of 61.3 months. For the 97 treated patients, median OS was 60.7 months (95% CI, 41.9 to not estimable). One third (32/97) of patients remain alive and progression-free for ≥5 years after a single cilta-cel infusion, without maintenance treatment. Twelve of these patients treated at a single center underwent serial minimal residual disease (MRD) and positron emission tomography-computed tomography assessments, and all (100%) were MRD-negative (at least 10 −5 threshold) and imaging-negative at year 5 or later after cilta-cel. Baseline characteristics, including the presence of high-risk cytogenetics and extramedullary disease, were generally comparable for the 32 patients who were progression-free for ≥5 years versus patients who had progressive disease by year 5. A trend of lower baseline tumor burden, higher fraction of naïve T-cells in the cilta-cel drug product, higher T cell-to-neutrophil ratio, higher hemoglobin and platelets at baseline, and higher effector-to-target ratio were associated with ≥5-year progression-free status. The safety profile of cilta-cel remained consistent with previous reports. To our knowledge, our data provide the first evidence that cilta-cel is potentially curative in patients with RRMM.

Abstract The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics during the first year after idecabtagene vicleucel (ide-cel) infusion in 125 relapsed/refractory multiple myeloma patients enrolled in KarMMa. At month 1 after ide-cel, there were no differences in progression-free survival (PFS) between patients in less than complete response (CR) versus those in CR; only MRD status was predictive of significantly different PFS at this landmark. In patients with undetectable MRD at 3 months and beyond, PFS was longer in those achieving CR versus &lt;CR. Persistent MRD in the 10−6 logarithmic range and reappearance of normal plasma cells in MRD-negative patients were associated with inferior PFS. This study unveils different prognostic implications of serological and MRD response dynamics after ide-cel and suggests the potential value of studying the reappearance of normal plasma cells as a surrogate of loss of CAR T-cell functionality. Significance: This is one of the first studies evaluating the impact of CR and MRD dynamics after CAR T therapy in relapsed/refractory multiple myeloma. These data help interpret the prognostic significance of serological and MRD responses at early and late time points after CAR T-cell infusion. See related commentary by Landgren and Kazandjian, p. 346 . This article is featured in Selected Articles from This Issue, p. 337