Real-world prognostic significance of attaining minimal residual disease negativity in newly diagnosed multiple myeloma

Multiple myeloma (MM) is an incurable plasma cell disorder that usually produces monoclonal immunoglobulins (M-protein or monoclonal component). Therapeutic improvement over the last two decades made it possible for unprecedented response rates in myeloma patients leading to long-time survival. But even myeloma patients with such good responses still relapse due to the presence of residual tumor cells in the bone marrow. Conventional complete remission (CR) and subsequent attempts of stringent CR (sCR) were used to describe the depth of the response. The requirement of achieving deep responses with modern therapy led to the definition of negative minimal residual disease (MRD) which enable a higher prediction ability. MRD status has been shown a good surrogate marker for progression-free survival (PFS) and overall survival (OS) in a number of trials and meta-analyses [1‐3]. The International Myeloma Working Group (IMWG) revised the MM response criteria in 2015 and introduced the definition of MRD in patients who have achieved a CR as an indication of long-term outcomes. However, results are conflicting regarding achievement of CR and minimal residual disease negativity. The percentage of patients with undetectable MRD showing positive immunofixation after induction was 22.5% by multiparameter flow cytometry(MFC), at a sensitivity level of ≤ 10⁻⁴ to 10⁻⁵ [4]. Even using next-generation sequencing(NGS), of which sensitivity was 10^–6, the rates of discordance were 20% during treatment in the IFM-2009 clinical trial [5]. Besides, whether MRD negativity could overcome the initial molecular risk status and treatment remains controversial. IFM 2009 trial showed significantly longer PFS in those achieving MRD negativity irrespective of the treatment received (transplantation or VRD-only arms) or molecular risk status or ISS stage [5]. While in Myeloma XI, achieving MRD negativity was not able to overcome the adverse PFS associated with genetic high risk [6]. And meta-analysis confirmed that achieving MRD negativity in patients who had only achieved VGPR or better was associated with superior outcomes [2]. Sustained MRD negativity represents a deeper level of remission with a higher prognostic value [7, 8], especially lasting more than 1 year as IMWG recommended [9]. It remains unclear whether there are differences in clinical features and prognosis among MRD-negative patients who attain this status in different subgroups, such as those with high-risk cytogenetics, autologous stem cell transplantation (ASCT), or clinical response. In this article, we examined the MRD value in the real-world setting under different circumstances.

CR by this conventional definition was not precise enough to reflect disease control, subsequent attempts to improve response assessment using MRD negativity may be a more robust evaluation of disease control in the novel agent era. MRD evaluation is now a fundamental surrogate for survival in NDMM for redefining the goal of therapy, focusing on long-term control, quality of life, and even a cure [11]. We found higher rates of MRD negativity among patients who underwent transplantation than among those who didn’t. Moreover, the value of CR is intrinsically related to a high proportion of patients who were MRD-negative. Age was found to be a contributing factor with respect to achieving an MRD-negative status. Age < 65 years, clinical response ≥ CR and ASCT were associated with achieving an MRD-negative status.

In our study, we confirmed the prognostic role of MRD negativity in a large cohort of NDMM patients with ≥ VGPR status. Our results are consistent with previous publications showing that MRD negativity is associated with improved PFS and OS for multiple myeloma and also was found to confer a more than 50% relative risk reduction in both progression and mortality [2, 12]. Besides, we also explored the applicability of these findings to various subgroups of patients with MM. PFS and OS were prolonged in both high- and standard-risk myeloma patients who were MRD-negative than in those who are MRD-positive. This result was consistent with those presented in previous studies [13‐16]. However, whether achieving MRD negativity can thoroughly ameliorate adverse risk factors identified at diagnosis? Our results showed that compared to standard-risk myeloma patients with MRD negativity, high-risk myeloma patients with MRD negativity showed similar survival outcome. Thus, achieving MRD negativity may be associated with superior outcomes in patients even with high-risk cytogenetics. Furthermore, we also explore the MRD impact in the transplantation and non-transplantation subgroups. The best PFS and OS were seen in post-ASCT MRD-negative patients. OS in MRD-negative patients in the transplantation group was superior to that in patients in the non-transplantation group with the same MRD status. Of note, in cases where MRD negativity was not attained after ASCT, the survival outcomes were comparable to those who did not undergo ASCT. It seems possible that MRD monitoring could identify patients who might benefit from ASCT. Further intensify therapy may be added in post-transplantation MRD-positive patients. Moreover, patients who were MRD-negative despite persistent M component showed PFS and overall survival were as favorable as those of MRD-negative patients in CR. Similar findings were reported in the clinical trials [17‐19]. This unexpected discordance may be driven by long half live of immunoglobulins or oligoclonal responses after treatment [4, 20, 21].

Our study has shown that MRD status is a robust and independent prognostic indicator for both PFS and OS, with particular significance observed in the OS analysis, where it was the only prognostic marker found to be significant in multivariate analysis. Interestingly, our study did not find high-risk cytogenetics or ASCT, which are typically considered to be important factors, to be significant predictors of survival outcomes. In 2016, IMWG recommended the concept of sustained MRD negativity, defined as MRD negativity lasting for a duration of more than 1 year [9]. Our current analysis demonstrated that patients with sustained MRD negativity lasting either ≥ 12 or ≥ 24 months had a longer time to progression and death. Sustained MRD negativity lasting ≥ 24 months was even associated with a longer PFS than lasting for ≥ 12 months. Clinical decisions such as discontinuation, intensification or initiation of a new therapy based on measurable residual disease treatment were confirmed to improve PFS [22]. Thus, more clinical trials might bring us the endpoint of maintenance [23].

With the advances in therapy targeting the myeloma cell, achieving minimal residual disease states is now possible. Data clearly support the robust evaluation of disease control if sustained over time, with patients achieving an MRD-negative status having improved PFS and OS. Consequently, our findings suggest that MRD negativity can be a valuable endpoint in informing treatment decisions and providing significant reassurance for myeloma patients who achieve this status, regardless of their cytogenetic risk or previous treatment or clinical response.