New disease assessment methods are needed to serve as surrogate endpoints with more expedient read-out for newly diagnosed multiple myeloma patients. By analysing the data of the phase III MAIA and ALCYONE trials, it becomes clear that daratumumab-based therapies are associated with higher MRD rates and durability, and that durable MRD negativity is associated with improved progression-free survival.
EXPERT OPINION OF PROF. DR. DOMINIQUE BRON, HAEMATOLOGIST, INSTITUT JULES BORDET
“Daratumumab-based therapy improved rates of MRD negativity lasting ≥12 months (D-Rd, 10.9% vs. Rd, 2.4%; D-VMP, 14.0% vs. VMP, 2.8%). Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes.”
Recent treatment advances have improved long-term outcomes among patients with newly diagnosed multiple myeloma (NDMM). However, as the duration until read-out of clinical trials is long for traditionally used endpoints such as progression-free survival (PFS) and overall survival (OS), it can take a long time until these advances can be incorporated into clinical practice. Therefore, new disease assessment methods are needed to serve as surrogate endpoints with more expedient read-out. Minimal residual disease (MRD) is a sensitive measure of tumour cells in bone marrow that reflects remission status. Many studies have demonstrated that MRD-negative status is associated with improved PFS and OS. Daratumumab is a human immunoglobulin GK monoclonal antibody targeting CD38. Both the MAIA and ALCYONE trials demonstrated that daratumumab-based regimens improved outcomes compared with standard of care for NDMM. In addition, they showed that achievement of MRD negativity was associated with longer PFS, irrespective of trial treatments. By analysing the data of these two trials, this study is the first to assess the prognostic value of sustained MRD negativity lasting ≥ 6 or ≥ 12 months in NDMM.
Briefly, MAIA and ALCYONE evaluated daratumumab plus lenalidomide and dexamethasone (D-Rd) or bortezomib, melphalan, and prednisone (D-VMP), respectively, in patients with transplant-ineligible NDMM. In MAIA, patients in the D-Rd group received daratumumab (16 mg/kg) weekly for cycles 1 and 2, every other week for cycles 3 to 6, and every 4 weeks thereafter. In ALCYONE, patients in the D-VMP group, received daratumumab (16 mg/kg intravenously) weekly in cycle 1, every 3 weeks in cycles 2 to 9, and every 4 weeks thereafter. In both trials, study treatment was continued until progressive disease or unacceptable toxicity.
For MAIA and ALCYONE, the primary endpoint was PFS. MRD assessments were to occur in patients who achieved complete response or better (≥CR). For patients who achieved ≥CR, additional MRD assessments occurred at 12, 18, 24, and 30 months after the first dose. MRD was assessed from bone marrow aspirates and evaluated with next-generation sequencing. The MRD negativity rate was defined as the proportion of patients who achieved ≥CR with negative MRD test results at any time during treatment.
In total, 737 patients in MAIA (D-Rd, N= 368; Rd, N= 369) and 706 patients in ALCYONE (D-VMP, N= 350; VMP, N= 356) were randomised to the daratumumab and control groups. The median follow-up duration was 36.4 and 40.1 months in MAIA and ALCYONE, respectively. In both MAIA and ALCYONE, daratumumab-based therapy improved rates of MRD negativity (10-5 threshold) compared to the standard treatment (28.8% vs. 9.2%, and 26.9% vs. 7.0%, in the MAIA and ALCYONE trial, respectively). MRD durability was assessed among patients achieving ≥2 MRD negative results lasting ≥6 or ≥12 months with no MRD positive result in between. Daratumumab-based therapy improved rates of MRD negativity compared to the standard treatment, lasting ≥6 months (14.9% vs. 4.3% in the MAIA trial, and 15.7% vs. 4.5% in the ALCYONE trial) and ≥12 months (10.9% vs. 2.4% in the MAIA trial; 14.0% vs. 2.8% in the ALCYONE trial). In the intention-to-treat (ITT) population of both trials, MRD-negative patients had improved PFS compared with MRD-positive patients (MAIA: HR[95%CI]: 0.15[0.09-0.26]; p< 0.0001); ALCYONE: HR[95%CI]: 0.21[0.15-0.30]; p< 0.0001). Consistent with these findings, PFS was also improved for patients who achieved sustained MRD negativity lasting ≥ 6 and ≥ 12 months, regardless of the treatment arm.
A combined analysis of patients from MAIA and ALCYONE compared patients who achieved MRD negativity (N= 259) with patients who were MRD positive (N= 1,184). Patients who were MRD negative had improved PFS compared with patients who were MRD positive (HR[95%]: 0.19[0.14-0.26]; p< 0.0001). This trend was maintained irrespective of the therapy regimen. Among patients achieving MRD negativity, daratumumab-containing regimens improved PFS compared with standard of care (HR[95%CI]: 0.51[0.28-0.92]; p< 0.0253).
This analysis from two phase III studies of daratumumab plus standard-of-care regimens for the treatment of transplant-ineligible NDMM provides evidence that MRD negativity is associated with longer PFS, and that this benefit is improved for patients who reach durable MRD negativity. These results indicate that durable MRD negativity lasting ≥6 or ≥12 months may represent yet a deeper level of response with a higher prognostic value. MRD negativity and durability were associated with improved PFS regardless of treatment regimen; however, daratumumab-based therapies drove more patients to achieve MRD-negative status and maintain MRD negativity for ≥6 and ≥12 months.
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