Final Analysis of IFM2009 Trial Confirms Predictive Value of Minimal Residual Disease in Myeloma

Because survival for patients with multiple myeloma (MM) has significantly improved within the past decade, complete response (CR) rates may no longer be a clinically meaningful endpoint. According to a final analysis of the IFM2009 trial presented at the 2017 ASH Annual Meeting, minimal residual disease (MRD) could be considered a surrogate biomarker in clinical trials of anti-myeloma therapies.

“We used a very sensitive technique – immunoglobulin next-generation sequencing – in a prospective trial to [measure] MRD and to correlate with progression-free and overall survival (OS),” said lead author Hervé Avet-Loiseau, MD, PhD, of IUCT-Oncopole in Toulouse, France, during his presentation of the results. He added that MRD monitoring should be “included in all upcoming trials [and] could become the primary endpoint of future trials.”

IFM2009 included 700 patients with MM who were randomized to receive induction therapy with RVD (lenalidomide, bortezomib, dexamethasone) with or without high-dose melphalan. All patients also received 12 months of lenalidomide as maintenance therapy. MRD was assessed before and after maintenance therapy using the clonoSEQ kit, which can detect disease at a level of 1×10-6.

MRD was evaluated in 269 patients who achieved at least a very good partial response (VGPR). If patients did not achieve VGPR, they were considered MRD-positive, and MRD negativity was defined as <1×10-6.

Using this cutoff, at a median follow-up of 55 months (range not provided), the median progression-free survival (PFS) among patients who achieved MRD negativity was not met, compared with 29 months for patients who remained MRD-positive (ranges and p values not provided). OS was also longer in patients who achieved MRD negativity.

“We found that sensitivity is very important,” Dr. Avet-Loiseau and co-authors added. “Patients with an MRD level below 10-6 presenting a [significantly] better PFS than patients not achieving this level.”

Also, patients who achieved MRD negativity had similar survival rates regardless of whether they underwent hematopoietic cell transplantation.

MRD negativity also appeared to be a more powerful predictor of survival outcome than cytogenetics: Participants with high-risk cytogenetics who achieved MRD negativity had better outcomes than patients with standard-risk cytogenetics who did not achieve MRD negativity. This suggests that “high-risk cytogenetics is a dynamic concept that should be reevaluated during treatment,” the researchers wrote.

MRD should be considered a novel surrogate biomarker for trial evaluation, the researchers concluded. These findings demonstrate that “the best sensitivity is associated with the best discrimination in PFS and OS, and 10-6 should be [used as] the optimal cutoff.”

Dr. Avet-Loiseau noted several questions that remain, including the role of imaging techniques and the role of circulating cell-free tumor DNA in these evaluations.

The authors report financial relationships with Celgene, Janssen, Amgen, Takeda, and Bristol-Myers Squibb.


Avet-Loiseau H, Lauwers-Cances V, Corre J, et al. Minimal residual disease in multiple myeloma: final analysis of the IFM2009 trial. Abstract #435. Presented at the 2017 American Society of Hematology Annual Meeting, December 10, 2017; Atlanta, GA.