Minimal Residual Disease Negativity in Multiple Myeloma: One Good Season Is Not Enough

Depth of response has been shown to correlate with long-term disease outcomes for patients with newly diagnosed multiple myeloma (MM) who have undergone autologous hematopoietic stem cell transplantation (ASCT). The aspirational benchmark for optimal depth of response has changed over the past two decades, from complete and stringent complete response (CR) in the 2010s to minimal residual disease (MRD) on bone marrow aspirate by either flow cytometry or next-generation sequencing at 10⁻⁵ in the 2020s. A meta-analysis of several studies confirmed the presence of MRD impacted progression free survival (PFS) and overall survival (OS).¹ 

At 110 National Health Service hospitals in England, Wales, and Scotland, patients enrolled in Myeloma XI, an open-label phase III parallel group adaptive trial, underwent three randomizations — at induction, intensification, and maintenance — that were reported in three prior publications.^2–4  Patients who had achieved at least a minimal response after ASCT underwent the final randomization, which assigned 730 patients to lenalidomide maintenance and 518 patients to observation. Maintenance therapy was continued until disease progression or discontinuation due to toxicity. The primary end points of the overall Myeloma XI study were PFS and OS, and the lenalidomide maintenance randomization showed that maintenance improved PFS from 30 to 57 months compared with observation and three-year OS from 80.2 percent to 87.5 percent.⁴  The current analysis focused on patients who had bone marrow MRD testing at three (ASCT+3) and nine months (ASCT+9) post-ASCT and the impact on PFS and OS.

Flow cytometry with a median sensitivity of 4 ×10⁻⁵ (range, 8×10⁻⁶ – 1×10⁻⁴) was performed at a central laboratory in Leeds to evaluate for MRD. Patients were also defined as high risk or ultra high risk (~3%) if they had one or more of gain(1q), del(17p), t(4;14), t(14;16), or t(14;20), respectively; however, this was missing in 55 to 60 percent of patients. Landmarked analyses from ASCT+3 and ASCT+9 were done to estimate PFS and OS with univariate and multivariate analyses to identify significant factors. Overall, in the lenalidomide maintenance arm, 299 (66%) of 452, 135 (68%) of 200, and 93 (62%) of 151 were MRD negative at ASCT+3, at ASCT+9, and at both timepoints, respectively. In the observation arm, 176 (59%) of 298, 79 (63%) of 126, and 55 (58%) of 94 were MRD negative at ASCT+3, at ASCT+9, and at both timepoints, respectively.

At ASCT+3, 41.8 percent, 52.5 percent, 76.6 percent, and 71 percent of MRD positive patients randomized to lenalidomide or observation, and MRD negative patients randomized to lenalidomide or observation, respectively, were in CR or near CR (nCR). For both PFS and OS, lenalidomide maintenance improved outcomes regardless of MRD status at both ASCT+3 and ASCT+9. PFS improved from 36 to 56 months for patients who were MRD negative at ASCT+3 and from 18 months to 33 months for patients who were MRD positive at ASCT+3 when on lenalidomide maintenance compared to observation, with results similar when only including the patients in CR/nCR. Median OS was not reached but did improve from 75.4 percent to 81.4 percent at three years for patients who received lenalidomide who were MRD positive at ASCT+3. Similarly, at ASCT+9, patients who were MRD positive and continue lenalidomide had a PFS of 47 months versus nine months with observation (p=0.008); OS improved from 75.4 percent with observation to 94.5 percent with lenalidomide. Interestingly, patients who converted from MRD positive at ASCT+3 to MRD negative at ASCT+9 had similar PFS to those with sustained MRD negativity. MRD negativity was not able to overcome the deleterious impact of high-risk disease on PFS. Finally, multivariable models at ASCT+3 showed retained prognostic significance for PFS and OS for MRD status, use of lenalidomide maintenance, and risk status.