Sustained minimal residual disease in myeloma

In this issue of Blood, San-Miguel et al¹ report on the prognostic impact of sustained minimal residual disease (MRD) negativity in newly diagnosed, transplant-ineligible multiple myeloma (MM) patients treated with daratumumab-containing regimens. The authors analyzed progression-free survival (PFS) according to MRD status as assessed at a single time point, vs sustained MRD negativity over a period of 6 or 12 months in patients enrolled in the randomized, phase 3 trials, MAIA and ALCYONE. In these studies, patients were treated with lenalidomide and dexamethasone alone (Rd) or in combination with daratumumab (Dara-Rd); or with bortezomib, melphalan, and prednisone alone (VMP), or with daratumumab (Dara-VMP), respectively.^2,3

This work outlines two important points: (1) sustained MRD negativity over a period of 6 or 12 months translated to improved PFS and provides better prognostic granularity compared with a static, one-time MRD assessment; and (2) Dara-containing regimens outperformed the control arms in frequency of MRD⁻ status, persistence of MRD⁻ status over time, and PFS regardless of MRD status (visual abstract).

This is the first study to evaluate the impact of dynamic assessment of MRD via next-generation sequencing at 10⁻⁵ sensitivity at distinct time points during remission in >1400 patients enrolled in the two trials. The authors found that MRD negativity sustained over a period of 12 months translated to superior PFS as compared with not only MRD positivity but also MRD negativity not maintained over a 12-month period, regardless of treatment arm and across both studies. As expected, compared with the control arms, patients receiving Dara-containing regimens had a higher rate of MRD negativity sustained over 6 (14.9% for Dara-Rd vs 4.3% for Rd and 15.7% for Dara-VMP vs 4.5% for VMP) and 12 months (10.9% for Dara-Rd vs 2.4% for Rd and 14% for Dara-VMP vs 2.8% for VMP).

Interestingly, across both studies, the negative impact on PFS of MRD positivity and/or loss of MRD negativity over a 12-month period was ameliorated by the use of Dara. It is important to point out that in both studies Dara was used both in induction and during maintenance until disease progression, making it impossible to establish whether the addition of Dara in the induction setting or rather its prolonged use as maintenance strategy drove the positive prognostic impact. In ALCYONE, patients in the control arm did not receive any maintenance after VMP induction, whereas patients in the control arm of MAIA received Rd until disease progression. Although cross-trial comparison is not recommended, this study offers the opportunity to speculate on the intrinsic mitigating value of maintenance in patients with suboptimal response to therapy (MRD⁺ patients and/or patients with nonsustained MRD negativity). In fact, patients who did not receive any maintenance appear to suffer a disproportionately worse prognosis as compared with patients who received any type of maintenance. These data are consistent with prior reports of lenalidomide maintenance attenuating the adverse prognostic significance of MRD positivity.⁴ 

Several large, randomized clinical trials have established the prognostic impact of MRD negativity on PFS in MM, supporting its use as a surrogate end point of PFS in clinical trials.^5,6 The Food and Drug Administration approval of next-generation sequencing MRD assessment has facilitated the routine incorporation of MRD as an endpoint in research studies and boosted its use in routine clinical practice.⁷ However, in the absence of scientific data justifying the use of MRD to guide clinical decision making, currently MRD assessment in MM has solely a prognostic role.⁸ As an extra layer of complexity, this study now sets a new standard for the use of MRD not as a fixed, one-time snapshot but rather as a continuous variable subjected to change over time and the impact of which pertains more to longitudinal sustainability rather than mere achievement at one point.

There are several major questions left unanswered by this study. First, does sustained MRD negativity translate to prolonged overall survival? Second, is sustained MRD negativity the result of intensification of induction treatment or rather of maintenance? Third, can maintenance treatment be deintensified/discontinued based on sustained MRD⁻ status without compromising PFS or overall survival? If so, where should we set the threshold for sufficiently sustained MRD negativity to trigger discontinuation of maintenance? Lastly, are the data observed in MAIA and ALCYONE applicable to real-world patients treated with induction and maintenance regimens other than the ones used in these studies?

A growing number of clinical trials are evaluating MRD as a tool to guide therapeutic decisions in MM, such as treatment intensification or deintensification, further personalizing patient care. It is a sobering reality in MM that staging systems and cytogenetics do not faithfully capture the biological heterogeneity and complexity of this disease and are insufficient tools to adequately prognosticate outcome and predict treatment response. The use of functional and dynamic measures that also account for MM response to therapy is thus critical to adequately counsel and treat our patients. Recently, Saussele and colleagues reported high rates of molecular relapse-free survival in patients with chronic phase, chronic myeloid leukemia who discontinued tyrosine kinase inhibitors after achieving sustained molecular response, paving the way to the use of high-sensitivity molecular studies to guide clinical practice in this setting.⁹ The jury remains out as to whether such an approach may be feasible in MM, a disease characterized by pervasive genomic instability and clonal heterogeneity, but an effort to address this question is critical now that the tools are available.