KarMMa-4: Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T-Cell Therapy, in High-Risk Newly Diagnosed Multiple Myeloma

BACKGROUND: Despite the introduction of novel agents, patients with high-risk (Revised International Staging System [R-ISS] stage III) newly diagnosed multiple myeloma (NDMM) have a poor prognosis (median progression-free survival [PFS], 29 months), highlighting the need for novel disease-targeting approaches (Palumbo A, et al. J Clin Oncol. 2015;33:2863-2869). The BCMA-directed CAR T cell therapy ide-cel demonstrated deep, durable responses in heavily pretreated patients with relapsed and refractory MM (RRMM; Raje N, et al. N Engl J Med. 2019;380:1726-1737; Munshi NC, et al. J Clin Oncol. 2020;38[suppl] [abstract 8503]), including those with high-risk (R-ISS stage III) RRMM. Earlier use in this population-where there is potentially more bone marrow reserve, more healthy peripheral blood mononuclear cells, a less compromised immune status, and less extensive disease to debulk before cell therapy-may result in improved outcomes and offer an opportunity to replace transplant with CAR T cell therapy. KarMMa-4 is a multicenter, open-label, phase 1, single-arm study of ide-cel in patients with high-risk NDMM (R-ISS stage III disease per International Myeloma Working Group criteria).

STUDY DESIGN: KarMMa-4 is enrolling patients with NDMM who have high-risk disease, defined as R-ISS stage III (ISS stage III [serum b2 microglobulin ≥ 5.5 mg/L] and cytogenetic abnormalities t(4;14), del(17p), and/or t(14;16) by interphase fluorescence in situ hybridization; or ISS stage III and serum lactate dehydrogenase > upper limit of normal). Patients must have received ≤ 3 cycles of the induction regimens listed below, be aged ≥ 18 years, and have Eastern Cooperative Oncology Group performance status 0-1. Patients with nonsecretory myeloma or central nervous system involvement are excluded.

Patients can enroll between cycle 1 and cycle 3 of induction. Permitted induction regimens for cycle 1 are carfilzomib + lenalidomide + dexamethasone ± daratumumab (KRd ± DARA), lenalidomide + bortezomib + dexamethasone ± daratumumab (RVd ± DARA), or cyclophosphamide + bortezomib + dexamethasone (CyBorD). Induction regimens for cycles 2-4 are limited to KRd or RVd, with dexamethasone omitted during cycle 3. All patients will undergo leukapheresis for T cell collection after cycle 3, and ide-cel will be manufactured during cycle 4 of induction. Stem cell collection for future use may be conducted after cycle 3 (following leukapheresis) or cycle 4 (before lymphodepletion). Ide-cel is infused after 2 days of rest following lymphodepletion with 3 days of fludarabine 30 mg/m² + cyclophosphamide 300 mg/m². Lenalidomide-based maintenance may be provided upon bone marrow recovery or 90 days after ide-cel infusion, whichever is later.

The primary endpoints are dose-limiting toxicity and safety. Secondary endpoints include complete response rate and overall response rate, duration of response, time to complete response, time to start of maintenance, feasibility of initiating maintenance, PFS, overall survival, and pharmacokinetics. Exploratory endpoints include safety of lenalidomide maintenance therapy, minimal residual disease, immunogenicity and biomarkers.

The starting ide-cel target dose is 450 × 10⁶ CAR+ T cells, with dose escalation/de-escalation (150, 300, and 800 × 10⁶ CAR+ T cells). After identification of the optimal target dose, 12 patients will be enrolled in the dose-expansion phase. KarMMa-4 is registered at ClinicalTrials.gov: NCT04196491.