Berdeja, Jesús G.

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 <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

8009 Background: Heavily pretreated patients (pts) with relapsed/refractory multiple myeloma (RRMM) treated with standard of care therapy have median overall survival (OS) of ~12 months (mo). In the single-arm, phase 1b/2 CARTITUDE-1 study (NCT03548207), pts received a single infusion of ciltacabtagene autoleucel (cilta-cel), a CAR-T cell therapy targeting BCMA. At the final protocol-specified analysis (27.7-mo median follow-up [MFU]), overall response rate (ORR) was 98%, with 83% stringent complete response (CR); 27-mo rates of progression-free survival (PFS) and OS were 55% and 70%, respectively. Here, we report study closeout results. Methods: Eligible pts received ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD); and had received prior PI, IMiD, and anti-CD38 antibody therapy. Primary endpoint was ORR and safety; secondary endpoints included PFS, OS, and minimal residual disease (MRD) negativity at 10-5. Results: 97 pts received cilta-cel (median age 61 years [y]; median 6 prior LOT; 42% penta-drug refractory; 88% triple-class refractory; 99% refractory to last LOT). As of October 14, 2022, MFU was 33.4 mo (range, 1.5-45.2). Median (m) duration of response was 33.9 mo (95% CI, 25.5–not estimable [NE]). mPFS was 34.9 mo (95% CI, 25.2–NE), with an estimated 47.5% progression free and alive at 36 mo. mOS was not reached (NR), with an estimated 62.9% survival at 36 mo. Of 49 MRD-evaluable pts, 26 had MRD negativity sustained for ≥12 mo, of which 20 had sustained MRD-negative ≥CR. mPFS was NR in these subgroups (Table). 18 pts were MRD negative with ≥CR at 24 mo post infusion. No new safety signals and no new neurotoxicity events were reported since the 27.7-mo MFU. 6 new cases of second primary malignancy were reported, including 2 cases of basal cell carcinoma and 1 case each of myelodysplastic syndrome, B-cell lymphoma, melanoma, and prostate cancer. 5 additional deaths occurred (progressive disease [PD], n=3; pneumonia and sepsis, n=1 each [both unrelated to cilta-cel]), for a total of 35 (PD, n=17; unrelated to cilta-cel, n=12; related, n=6). Conclusions: Longer mPFS was observed after a single infusion of cilta-cel than any previously reported therapy in heavily pretreated pts with RRMM. Achieving CR and/or sustained MRD negativity was associated with prolonged PFS. Pts continue to be followed for safety and survival in the 15-y CARTINUE long-term study (NCT05201781; MMY4002). Clinical trial information: NCT03548207 . [Table: see text]

TPS8064 Background: Multiple myeloma (MM) remains an incurable disease. Combinations of established agents, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 antibodies, are used in all lines of therapy, but re-exposure to previously received classes of therapy is associated with decreasing response rates and duration of response (Moreau et al. 2021). BCMA-targeted agents have recently been approved for the treatment of patients with RRMM whose disease has been exposed or become refractory to PIs, IMIDs and anti-CD38 antibodies (triple-class exposed or refractory MM). Although effective, the majority of patients who respond to anti-BCMA agents eventually relapse. Proven salvage therapies for these patients are currently lacking and represent a new unmet medical need. Cevostamab is an immunoglobulin G1-based T-cell-engaging bispecific antibody that targets Fc receptor-homolog 5 (FcRH5) on myeloma cells and CD3 on T cells. Dual binding results in T-cell activation and potent killing of MM cells. In an ongoing Phase I study (GO39775; NCT03275103), cevostamab monotherapy showed promising activity in heavily pre-treated patients with RRMM, including those with prior exposure to anti-BCMA agents (Trudel et al. 2021). Methods: CAMMA 2 (CO43476; NCT05535244) is an open-label, multicenter Phase I/II trial evaluating cevostamab monotherapy in patients with RRMM who are triple-class refractory and have previously received an anti-BCMA agent. Prior anti-BCMA antibody-drug conjugates or chimeric antigen receptor (CAR) T cells are permitted in Cohorts A1 and B1, while prior anti-BCMA bispecific antibodies are allowed in Cohorts A2 and B2. In A1 and A2, cevostamab is administered by intravenous infusion and is initiated with step dosing (0.3mg on Cycle [C] 1 Day [D] 1 and 3.3mg on C1D2, D3, or D4 depending on the emergence and resolution of cytokine release syndrome [CRS] after the initial administration), with the target dose of 160mg given on C1D8 and on D1 of each subsequent 21-day cycle. Patients are hospitalized for the C1 administrations only and treatment is continued until disease progression or unacceptable toxicity occurs. CRS is managed per protocol based on the clinical presentation and may involve corticosteroid and tocilizumab treatment. Primary objectives are evaluation of efficacy (primary endpoint: objective response rate by investigator assessment using IMWG criteria) and safety. Secondary objectives include assessment of quality of life, pharmacokinetics, pharmacodynamics, and immunogenicity. Cohorts B1 and B2 will evaluate the efficacy and safety of cevostamab at the recommended Phase II dose in this setting. As of February 2023, enrolment into Cohorts A1 and A2 is ongoing. Clinical trial information: NCT05535244 .