Minimal residual disease more prognostic than remission in myeloma

Achieving minimal residual disease-negative status surpasses the prognostic value of complete remission and should be considered a relevant endpoint for transplant-eligible and fit elderly patients with multiple myeloma, according to a study published in Journal of Clinical Oncology.

“On the basis of our findings from a large series of patients with multiple myeloma with lengthy follow-up, we demonstrated that minimal residual disease (MRD) negativity surpasses complete remission as a prognostic marker for PFS and OS across the spectrum of patients with multiple myeloma,” Jesus F. San-Miguel, MD, PhD, a clinical researcher at Clinica Universidad de Navarra.

Although the treatment landscape for multiple myeloma has experienced drastic improvements, response criteria and clinical endpoints have not changed. Further, the clinical utility of complete remission has been questioned, because rates do not always predict outcomes, and some patients without complete remission may still achieve long-term survival.

Previous studies showed that MRD status — which is determined by the number of cancer cells that remain in a patient following treatment — is one of the most relevant independent prognostic factors in multiple myeloma and that persistence of MRD is consistently a predictor for inferior PFS.

San-Miguel and colleagues performed a critical analysis on the impact of depth of response.

They analyzed data from 609 patients enrolled in the Grupo Espanol de Mieloma 2000 (n = 256) and 2005 (n = 226) studies for transplant-eligible patients, and the 2010 (n = 127) clinical trial for elderly patients. Patients had MRD assessments 9 months after study enrollment.

PFS and OS calculated from 9 months after study enrollment served as primary endpoints. Median follow-up was 71 months.

Researchers measured MRD with either four-color or eight-color flow cytometry with a sensitivity of 10^-4 to 10^-5.

Achievement of complete remission without MRD-negative status did not prolong PFS or OS.

Patients with complete remission demonstrated similar outcomes as those with near-complete remission and partial response for PFS (27 months vs. 27 months vs. 29 months) and OS (59 months vs. 64 months vs. 65 months).

However, MRD-negative status appeared strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall, as well as in subgroups for prior transplantation, disease stage and cytogenetics. The prognostic superiority of MRD negativity was particularly evident in patients with high-risk cytogenetics.

Further, MRD negativity surpassed complete remission in reduced risk for PFS (HR = 0.42 vs. 0.67) and OS (HR = 0.33 vs. 0.58) in both transplant-eligible and ineligible patients in stage I, II and III disease, as well as in standard- and high-risk cytogenetics subgroups.

Rates of MRD negativity varied with different induction regimens before transplant, from 11% with VBMCP/VBAD (vincristine, carmustine, cyclophosphamide, prednisone/vincristine, carmustine, doxorubicin and dexamethasone) to 50% with VTD (bortezomib [Velcade, Takeda], thalidomide and dexamethasone). Median PFS and OS appeared similar in patients with MRD positivity or negativity before but MRD negativity after transplant, but were inferior in patients with MRD positivity before and after transplant.

Among 34 MRD-negative patients with a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of “operational cure” appeared high, with a median PFS of 12 years and a 10-year OS rate of 94%.

Researchers noted their findings do not establish a role for MRD evaluation in tailoring patients’ treatments; however, the results do indicate possible value of MRD assessments at additional time points beyond the current 100-day mark after transplant.

“On the basis of the remarkable reduction in risk [for] progression and/or death, our results support MRD negativity being considered as one of the most relevant clinical endpoints and an aim of multiple myeloma treatment of transplant-eligible and elderly patients who can tolerate intensive therapies,” San-Miguel and colleagues wrote.

Although the prognostic impact of MRD negativity is clear, the study did not include the use of eight- or 10-color flow cytometry or next-generation sequencing, which can detect MRD with greater sensitivity, Jean-Luc Harousseau, MD, professor of hematology at University of Nantes, and Herve Avet-Loiseau, MD, professor of myeloma genomics at University Cancer Center in Toulouse, noted in an accompanying editorial.

“An important clinical question is determining whether patients with positive MRD after treatment should be retreated, and, if so, how,” Harousseau and Avet-Loiseau wrote. “Another practical question is how to define the optimal number and sequencing of MRD assessments across the different therapeutic strategies. ... Efforts should be made to include next-generation flow or next-generation sequencing in future trials to better define their optimal use before extending these methods to daily practice.”– by Chuck Gormley

Disclosure: Cooperative Research Thematic Network of the Red de Cancer funded this study. San-Miguel reports he is a consultant for Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Takeda. Harousseau reports he is a consultant with and receives honoraria from Janssen and MaaT Pharma. Please see the full study for a list of all other researchers’ relevant financial disclosures.