Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma

Abstract

Importance Numerous studies have evaluated the prognostic value of minimal residual disease (MRD) in multiple myeloma (MM). Most studies were small and varied in terms of patient population, treatment, and MRD assessment methods. Objective To evaluate the utility of MRD detection in patients with newly diagnosed MM. Data Sources A Medline search was conducted for articles published in English between January 1990 and January 2016. Study Selection Eligible studies reported MRD status and progression-free survival (PFS) or overall survival (OS) in ≥ 20 patients following treatment. Among 405 articles identified, 21 met the initial eligibility criteria and were included in the analysis. Data Extraction and Synthesis Information on patient characteristics, treatment, MRD assessment, and outcomes were extracted using a standard form. Main Outcome Measures The impact of MRD status on PFS and OS was assessed by pooling data from relevant trials. Data were adjusted to allow for different proportions of patients with MRD in different studies, and analyzed using the Peto method. Forest plots were created based on Cox model analysis. Other pre-specified research questions were addressed qualitatively. Results Fourteen studies (n = 1,273) provided data on the impact of MRD on PFS, and 12 studies (n = 1,100) on OS. Results were reported specifically in patients who had achieved conventional complete response (CR) in 5 studies for PFS (n = 574) and 6 studies for OS (n = 616). MRD-negative status was associated with significantly better PFS overall (Hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.36–0.48; P < .0001) and in studies specifically looking at CR patients (HR 0.44; 95% CI 0.34–0.56; P < .0001). OS was also favorable in MRD-negative patients overall (HR 0.57; 95% CI 0.46–0.71; P < .0001) and in CR patients (HR 0.47; 95% CI 0.33–0.67; P < .0001). Tests of heterogeneity found no significant differences among the studies for PFS and OS. Conclusions and Relevance MRD-negative status after treatment for newly diagnosed MM is associated with long-term survival. These findings provide quantitative evidence to support the integration of MRD assessment as an endpoint in clinical trials of MM.

A look backward and forward in the regulatory and treatment history of multiple myeloma: Approval of novel-novel agents, new drug development, and longer patient survival

“…This has been important because newer therapies have achieved higher response rates that in many instances have been “deeper” in nature. 2 With the importance of MRD as a marker of long-term clinical benefit established by two independent groups 3,4 the International Myeloma Working Group (IMWG) recently revised the MM response criteria by adding “MRD negativity” as a deeper and more stringent response than stringent complete response. 5 These advances have contributed to the longer overall survival (OS) of patients diagnosed with MM in the past decade and an expectation of further improvement in the coming decade with rapid approval of drugs by the US Food and Drug administration (FDA) and the European Medicines Agency (EMA).…”

How I treat myeloma with new agents

“…Nevertheless, recent data show that minimal residual disease (MRD)-negative status has a favorable prognostic impact, and it is known that frontline ASCT is associated with the higher rate of MRD negativity. 7,9 Based on response rates, depth of response, and PFS as surrogate markers for outcome, 3-drug combinations, including bortezomib and dexamethasone, are currently the standard of care as induction therapy prior to ASCT, but only limited data from prospective phase III trials are available to demonstrate that one combination is superior to the other. 1,4,10,11 Four to six courses of induction are recommended before proceeding to stem cell collection.…”

Should minimal residual disease negativity not be the end point of myeloma therapy?

“…2 A recent metaanalysis has confirmed that MRD-negative disease status is associated with prolonged survival. 18 Should MRD negativity not be the standard end point of MM therapy?…”