Myeloma: a sky full of MRD stars Free

In this issue of Blood, Corre et al¹ present the final, long-term minimal residual disease (MRD) and progression-free survival (PFS) results from the multifaceted CASSIOPEIA clinical trial. This comprehensive analysis is an invaluable contribution to the field and sets the stage for future research questions about the use of MRD to individualize treatment of patients with multiple myeloma (MM).

CASSIOPEIA was a 2-part, randomized, phase 3 trial that investigated treatment of transplant-eligible patients newly diagnosed with MM with induction and consolidation using daratumumab plus bortezomib, thalidomide, dexamethasone (D-VTd) vs VTd before and after autologous stem-cell transplant, followed by a second randomization to daratumumab maintenance or observation.² With a median follow-up of 80 months from the first randomization, D-VTd induction and consolidation significantly improved PFS and overall survival compared with VTd, and daratumumab maintenance significantly improved PFS vs observation, although the benefit was stronger in patients unexposed to daratumumab during induction and consolidation.² The use of the anti-CD38 monoclonal antibody across the treatment continuum resulted in the highest and most durable rates of MRD negativity at 10⁻⁵ and 10⁻⁶.² The CASSIOPEIA trial was already known to be a good demonstration of how the efficacy of the new regimens resulting in deeper and durable MRD responses correlated with prolonged survival in MM.^3,4 In the present study, Corre and colleagues report additional results supporting the importance of MRD in MM, including data on the techniques used to determine MRD.

This is probably the largest comparison between multiparameter flow cytometry (based on EuroFlow next-generation flow,⁵ though not exactly the same protocol) and the next-generation sequencing clonoSEQ assay. These techniques were performed on 3237 samples and showed a Pearson coefficient of 0.90. These results confirm previous reports⁵ and provide unequivocal evidence of high concordance between the methods in patients treated with anti-CD38 antibodies, which despite altering the expression of CD38 on the surface of plasma cells did not compromise the performance of flow cytometry provided multiepitope CD38 monoclonal antibodies were used. Interestingly, samples classified as positive by one method and negative by the other often reported MRD results >0.001% (supplemental Figure 1 in the article by Corre et al). Thus, it appears that reasons other than sensitivity (eg, sample collection and distribution, cell death, phenotype of clonotypic cells) might explain the few discordances. From the compliance standpoint, the authors should be praised for the study design that included MRD assessments at predefined time points regardless of patients’ response, which led to high compliance rates (ie, >90% during induction and consolidation, ∼80% during maintenance, and ∼60% during follow-up).

One interesting finding was that the rates of MRD negativity at 10⁻⁶ decreased when adjusting for the complete remission (CR) status, except in patients who were not exposed to daratumumab (ie, VTd and observation). In the other 3 arms of the trial, MRD⁻ rates (at 10⁻⁵ and 10⁻⁶) were inferior if linked to the achievement of CR (Figure 2 in the article by Corre et al). Because immunofixation reflex assays were used to confirm CR if daratumumab interference with serum M-protein was suspected,² there results are most likely linked to the lag between the achievement of a deep MRD response and the clearance of the M-protein due to its long half-life.⁶ The authors should be commended for reporting MRD⁻ rates with and without CR, and maybe future response criteria should include the 2 definitions of MRD negativity to foster the reporting of both rates in future clinical trials.

High-risk patients carrying t(4;14) or del(17p) who received daratumumab maintenance achieved a cumulative rate of MRD negativity at 10⁻⁶ of 79%, which was the highest rate across the subgroups. There was also significant improvement in PFS with daratumumab treatment in high-risk patients, which in the maintenance phase led to outcomes similar to those observed in standard-risk patients. Although differences in PFS were still noted between MRD⁻ patients with high- vs standard-risk cytogenetics (supplemental Figures 5 and 6 in the article by Corre et al), it is not known if differences in PFS disappeared among MRD⁻ patients who received daratumumab continuously (ie, the D-VTd/daratumumab arm of the CASSIOPEIA trial).

Contrary to previous reports,⁷ the PFS of patients converting from MRD⁺ before high-dose therapy to MRD⁻ after consolidation was significantly inferior to that of patients who achieved MRD⁻ status with induction and maintained the response during consolidation (supplemental Figure 4 in the article by Corre et al). The authors carefully investigated this finding by segregating patients according to the second randomization and showed that this phenomenon was mainly observed in patients allocated to the observation arm. Once again, these results highlight the importance of prolonging treatment after the achievement of best response,⁸ particularly if the latter occurred only after intensification.

In the maintenance phase, patients who were randomly assigned to intravenous daratumumab (16 mg/kg) received it every 8 weeks for a maximum of 2 years.² The estimated PFS rate at 6 years after the second randomization was 72.1% among MRD⁻ patients (at 10⁻⁵) treated with daratumumab maintenance. These impressive results are similar to those reported in the GEM2014MAIN trial of a PFS rate at 4 years of 82.8% among MRD⁻ patients (at 10⁻⁶).⁹ These studies suggest that many patients can sustain deep MRD responses without the need for indefinite maintenance until (a putative) disease progression. Studies like PERSEUS¹⁰ may answer the question whether resuming daratumumab after confirmed loss of CR without disease progression or after the recurrence of MRD during lenalidomide maintenance can reduce patients’ exposure to therapy without impairing survival.

This multipronged Corre et al study demonstrated that deeper and durable MRD responses strongly correlate with prolonged PFS in transplant-eligible patients with MM and exemplifies how MRD should be assessed and reported in clinical trials. MM has its sky full of MRD stars!

Conflict-of-interest disclosure: B.P. reports honoraria for lectures from and participation on advisory boards for Adaptive Biotech, Amgen, Becton Dickinson, Bristol Myers Squibb (BMS)/Celgene, Gilead, GSK, Janssen, Oncopeptides, Roche, Sanofi, Takeda, and The Binding Site; has received unrestricted grants from BMS/Celgene, EngMab, GSK, Roche, Sanofi, and Takeda; and has acted as a consultant for BMS/Celgene, Janssen, and Sanofi. J.F.S.-M. reports consulting or advisory roles for AbbVie, Amgen, BMS, Celgene, GSK, HaemaLogiX, Janssen, Karyopharm Therapeutics, MSD, Novartis, Regeneron, Roche, Sanofi, Secura Bio, and Takeda.