Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone (D-KRd), Autologous Transplantation, and MRD Response–Adapted Treatment Modification in NDMM

These results indicate that quadruplet induction therapy with daratumumab plus carfilzomib, lenalidomide, and dexamethasone (D-KRd); ASCT; and MRD response–adapted D-KRd consolidation therapy yielded high MRD negativity rates in patients with NDMM.

This trial evaluated patients with newly diagnosed multiple myeloma (NDMM) who were receiving the quadruplet combination regimen of the anti-CD38 monoclonal antibody daratumumab plus carfilzomib, lenalidomide, and dexamethasone (D-KRd) as induction/consolidation therapy following autologous stem-cell transplantation (ASCT); minimal/measurable residual disease (MRD), as assessed by next-generation sequencing, was utilized to guide the use and modify D-KRd duration post-ASCT. Results of this analysis were presented at the 2021 International Myeloma Workshop and summarized here.

The study enrolled patients with NDMM, with creatinine clearance ≥40 mL/min, adequate organ function, Eastern Cooperative Oncology Group performance status 0-2, no age limit, and enrichment for patients with high-risk cytogenetic abnormalities (HRCA). Eligible patients were receiving daratumumab (16 mg/kg intravenously [IV] on days 1, 8, 15, and 22; reduction in frequency with subsequent cycles), carfilzomib (56 mg/m2 IV on days 1, 8, and 15), lenalidomide (25 mg on days 1-21), and dexamethasone (40 mg orally or IV on days 1, 8, 15, and 22) repeated every 28 days. Patients received 4 cycles of D-KRd as induction, followed by ASCT, and 0, 4, or 8 cycles of D-KRd as consolidation based on MRD status. MRD was evaluated by next-generation sequencing (ClonoSEQ) in all patients at the end of induction, post-ASCT, and during each 4 cycles of D-KRd consolidation. The primary end point was MRD negativity (sensitivity threshold <10–5) rate in the intent-to-treat population. Patients received therapy until achievement of 2 consecutive MRD <10–5 (confirmed MRD negativity). Patients with confirmed MRD negativity were under observation and MRD surveillance (“MRD-SURE” phase; 6 months after treatment cessation and yearly thereafter). Patients who did not achieve confirmed MRD negativity received standard lenalidomide maintenance.

A total of 123 patients were enrolled in the study. The median age was 60 years; 20% had Eastern Cooperative Oncology Group performance status of 2, 21% had high lactate dehydrogenase, and 20% had Revised Multiple Myeloma International Staging System stage III. A total of 46 (37%) patients had 1 and 24 (20%) had ≥2 HRCA (gain1q, t[4;14], t[14;16], t[14;20], or del17p).

At a median follow-up of 25.1 months, MRD status was evaluable in 96% of patients. In the intent-to-treat population, MRD negativity <10–5 was achieved by 80% of patients. By HRCA status, MRD negativity <10–5 was achieved by 78% of patients with 0 HRCA, 82% of patients with 1 HRCA, and 79% of patients with ≥2 HRCA. Overall, MRD negativity <10–6 was achieved by 65% of all patients; 62% of patients with 0 HRCA, 73% of patients with 1 HRCA, and 58% of patients with ≥2 HRCA. Increased depth of response over time was noted; MRD negativity was achieved in 38% of patients after D-KRd induction, 65% post-ASCT, and 80% after MRD-directed D-KRd consolidation. Complete response or better was achieved in 86% of patients. Overall, confirmed MRD negativity was achieved by 71% of patients, entering MRD surveillance or MRD-SURE phase as an alternative to indefinite maintenance. Most common severe adverse events reported during study treatment were pneumonia (N = 8) and venous thromboembolism (N = 3).

These results indicate that quadruplet induction therapy with D-KRd, ASCT, and MRD response–adapted D-KRd consolidation therapy yielded high MRD negativity rates in patients with NDMM. However, the ability to discontinue therapy remains unknown as with short follow-up in the high-risk cohort, there were relapses noted. Limited duration therapy based on MRD assessment at short intervals remains a research question.

Source: Costa L, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd), autologous transplantation and MRD response-adapted treatment duration and cessation in newly diagnosed multiple myeloma (NDMM). Clin Lymphoma Myeloma Leuk. 2021;21(suppl 2):S33.

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