KEY TAKEAWAYS
- The phase 2 MASTER trial evaluated the feasibility and outcomes of modulating therapy duration and cessation based on MRD responses in NDMM pts.
- The study showed promising outcomes for many patients, but addressing the therapeutic needs of ultra-high-risk MM patients, particularly those with 2+ HRCA, remains challenging.
- This subset of patients may require alternative treatment strategies, like T-cell redirection, even when provided with quadruplet therapy.
In newly diagnosed multiple myeloma (NDMM) patients, quadruplet enhances the depth and length of treatment response. When given in clinical trials, reaching a state of almost undetectable residual disease (MRD) is tied to better results. However, using MRD to guide NDMM therapy isn’t well-defined.
Researchers carried out a phase 2 trial of MRD response-Adapted Sequential ThERapy (MASTER) in NDMM pts to determine the feasibility and elucidate the outcomes of therapy duration and cessation modulated by MRD responses. This represents the final trial analysis with a median follow-up duration of 42.2 months.
Enrollment criteria prioritized patients with MM characterized by high-risk cytogenetic abnormalities (HRCA). Initial treatment involved a regimen of daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd, for four cycles). This was succeeded by an autologous stem cell transplantation (ASCT), with up to two subsequent consolidation phases using Dara-KRd (comprising four cycles each). At every therapeutic stage, MRD assessment was performed using next-generation sequencing. The continuation of the therapeutic protocol was contingent upon achieving MRD negativity (<10-5) across two successive stages. Upon verifying MRD negativity, patients transitioned to a monitoring phase under MRD surveillance (MRD-SURE); if not, maintenance therapy with lenalidomide was prescribed.
In the MASTER study, a total of 123 pts were enrolled. The cohort consisted of 53, 46, and 24 patients displaying 0, 1, and 2+ HRCA [t(4;14), t(14;16), del(17p), gain/amp 1q], respectively. Among these patients, 20% were aged 70 or older, 20% were classified as R-ISS 3, and 118 (96%) exhibited myeloma identifiable via NGS-MRD. The MRD-negativity rates were 78%, 86%, and 79% for pts with 0, 1, and 2+ HRCA respectively, averaging at 81%. The rates of sustained MRD-negativity (exceeding 12 months) were 64%, 73%, and 46% for these subgroups, respectively. Moreover, MRD levels below 10-6 were observed in 68%, 79%, and 62% of these subgroups, culminating in an overall rate of 71%.
In total, 84 patients (71%) achieved MRD-SURE and subsequently ceased treatment. The progression-free survival (PFS) rates at the 3-year mark for the entire cohort were 88.4%, 78.9%, and 50.0%, and the 3-year overall survival (OS) rates were 94%, 92%, and 75% for patients with 0, 1, and 2+ HRCA respectively. Among the 75 patients who sustained MRD-negativity, the 3-year PFS rate was 82%, in contrast to a rate of 55% for those who did not. Among the 84 patients who achieved MRD-SURE, the median post-treatment cessation follow-up period was 32.7 months. The cumulative 2-year risk of progression for these patients was 9%, 9%, and 47% for the 0, 1, and 2+ HRCA subgroups, respectively. Twenty-three of these patients recommenced treatment due to disease progression (N=16) or MRD reappearance without evident progression (N=7), with an OS rate of 100% recorded 18 months post-reinstatement of therapy. Of the MRD-evaluable cohort, 61 patients (comprising 52% and 73% of MRD-SURE patients) persist in a therapy-free state, maintaining MRD-negativity.
The therapeutic regimen combining Dara-KRd induction, ASCT, followed by MRD-driven post-ASCT consolidation and treatment discontinuation, supplemented with MRD monitoring, demonstrated promising results. This approach offers a potential pathway for halting treatment in a majority of patients with standard or high-risk NDMM. However, addressing the needs of patients with ultra-high-risk MM (2+ HRCA) remains a clinical challenge. Even when using quadruplet therapy, this subgroup might benefit from earlier implementation of alternative modalities, such as T-cell redirection strategies.
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT03224507
Costa, L., Medvedova, E., Chhabra, S., Dholaria, B., Dhakal, B., Godby, K., Silberman, R., Bal, S., D’Souza, A., Giri, S., Schmidt, T., Omel, J., Hari, P., Callander, N. QUADRUPLET INDUCTION THERAPY, ASCT AND MRD-MODULATED CONSOLIDATION AND TREATMENT CESSATION IN NEWLY DIAGNOSED MULTIPLE MYELOMA: FINAL ANALYSIS OF THE MASTER TRIAL. EHA Library. Costa L. 06/08/2023; 387903; S203.
