Conversion to Minimal Residual Disease Triples With Daratumumab in Relapsed Myeloma

Hervé Avet-Loiseau, MD

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Data from a prospective assessment of minimal residual disease (MRD) from the phase III CASTOR and POLLUX studies demonstrated at least a 3-fold increase in conversion to negative MRD status with the addition of daratumumab (Darzalex) to standard-of-care regimens in the treatment of patients with relapsed/refractory multiple myeloma (RRMM).

The study was the first such evaluation of MRD in the context of RRMM using a randomized, controlled, and prospective analysis, said lead investigator Hervé Avet-Loiseau, MD, at the 2016 ASH Annual Meeting.

“The high rate of MRD negativity and the deep clinical responses induced by daratumumab may lead to improved long-term clinical benefit,” said Avet-Loisseau, from Centre Hospitalier Universitaire Rangueil, Unité de Genomique du Myelome, Toulouse, France. “The magnitude of MRD negativity in the relapsed setting is unprecedented, and for me was not expected.”

MRD is a more sensitive measure of disease burden than traditional definitions of clinical response. “It has been shown in several meta-analyses that achievement of negativity is associated with longer PFS [progression-free survival] and overall survival [OS],” Avet-Loisseau explained. “In the future, MRD might be a primary endpoint for clinical study.”

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The addition of daratumumab to these regimens resulted in significant improvements in median PFS (hazard ratio [HR], 0.37 in POLLUX, 0.33 in CASTOR) when used in combination with lenalidomide/dexamethasone (Rd) and bortezomib/dexamethasone (Vd), respectively.

In both trials, MRD was assessed using bone marrow aspirate samples and evaluated by the ClonoSEQ™ next-generation sequencing—based assay. In POLLUX, MRD was assessed at the time of suspected clinical response (CR), and at 3 and 6 months post-suspected CR for patients who maintained response. In CASTOR, MRD was assessed for patients at the time of suspected CR, and at 6 months and 12 months after the first dose.

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Three MRD sensitivity thresholds were evaluated: 10, 10, and 10. The MRD negativity rate was defined as the proportion of patients with negative MRD results at any point during the studies.

“We used a very stringent and unbiased MRD evaluation, which means that MRD negativity counts were evaluated against the intent-to-treat population, which means that any patient in the overall population who was not determined to be MRD-negative was called MRD-positive,” said Avet-Loisseau.

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Median duration of follow-up was 13.5 months in POLLUX and 7.4 months in CASTOR, respectively. In POLLUX, daratumumab added to Rd improved the percentage of patients who achieved MRD-negative status from 8.8% to 31.8% at the 10threshold, from 5.7% to 24.8% at the 10threshold, and from 2.5% to 11.9% at the 10threshold.

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In CASTOR, daratumumab added to Vd improved the percentage of patients who achieved MRD-negative status from 3.6% to 18.3% at the 10threshold, from 2.4% to 10.4% at the 10threshold, and from 0.8% to 4.4% at the 10threshold.

The MRD-negative rates were consistently higher in patients who achieved a CR or better treated with a daratumumab-containing regimen. In patients who achieved MRD negativity, conversion was rapid in recipients of daratumumab-containing regimens compared with standard of care, and most patients maintained their MRD negativity. The number of MRD-negative patients continued to accumulate over time in both studies.

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When MRD was assessed by cytogenetic risk, “daratumumab allowed high-risk patients to achieve MRD-negative status, which was not possible in the control arm,” said Avet-Loisseau. No conversion to MRD negativity at a threshold of 10was observed in patients with high-risk cytogenetics, defined as either t(4;14), t(14;16), or del17p, in both studies’ control, compared with 10 patients in POLLUX and 14 in CASTOR who were randomized to daratumumab.

Patients with sustained MRD negativity over time showed significantly longer PFS with daratumumab plus Rd or Vd compared with Rd or Vd alone.

References:

1. Avet-Loisseau H, Casneuf T, Chiu C, et al. Evaluation of minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) patients treated with daratumumab in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone. Presented at: American Society of Hematology 58th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 246.
2. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma.N Engl J Med.2016; 375:1319-1331.
3. Palumbo A, Chanan-Khan A, Wesiel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma.N Engl J Med.2016; 375:754-766.