Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA

Abstract

We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (≥CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10-5 sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received ≤2 prior lines of therapy (≤2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved ≥CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2 PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172.

Graphical abstract

Figure 1.

PFS by response and MRD status. PFS by response and MRD status (10⁻⁵) among patients who achieved CR or better and were MRD negative (≥CR and MRD negative) or who achieved a response less than CR or were MRD positive (≤VGPR or MRD positive) for patients pooled from POLLUX, CASTOR, ALCYONE, and MAIA (A) and patients in POLLUX and CASTOR with ≤2 PL pooled with all patients from ALCYONE and MAIA (B). Shown are Kaplan-Meier estimates of PFS among patients in the ITT population based on the absence of MRD as measured using the threshold of 1 tumor cell per 10⁵ white cells and response categories according to IMWG criteria.

Figure 2.

PFS by response and MRD status among patients who received daratumumab-based regimens vs control regimens. PFS by response and MRD status (10⁻⁵) among patients in the pooled daratumumab-combination groups vs the pooled control groups from POLLUX, CASTOR, ALCYONE, and MAIA who achieved CR or better and were MRD negative (≥CR and MRD negative) or who achieved a response less than CR or were MRD positive (≤VGPR or MRD positive) for all patients combined (A) and patients in POLLUX and CASTOR with ≤2 PL pooled with all patients from ALCYONE and MAIA (B). Shown are Kaplan-Meier estimates of PFS among patients in the ITT population based on the absence of MRD as measured using the threshold of 1 tumor cell per 10⁵ white cells and response categories according to IMWG criteria. In CASTOR and ALCYONE, standard of care was given for a fixed number of cycles and daratumumab was given until disease progression. In POLLUX and MAIA, patients who received standard of care or daratumumab-based regimens received study treatment until disease progression or unacceptable toxicity. Dara, daratumumab.

Figure 3.

PFS by MRD status among patients who achieved ≥CR. PFS by MRD status (10⁻⁵) among all patients who achieved ≥CR (A) and patients in the pooled daratumumab-combination groups vs the pooled control groups (B) from POLLUX, CASTOR, ALCYONE, and MAIA. Shown are Kaplan-Meier estimates of PFS based on MRD status (MRD negative or positive) as measured using the threshold of 1 tumor cell per 10⁵ white cells among patients in the ITT population who achieved ≥CR according to IMWG criteria. In CASTOR and ALCYONE, standard of care was given for a fixed number of cycles, and daratumumab was given until disease progression. In POLLUX and MAIA, patients who received standard of care or daratumumab-based regimens received study treatment until disease progression or unacceptable toxicity.