MRD Negativity Plus Complete Response or Better Associated With Improved PFS in Myeloma

Take-aways:

• Regardless of treatment regimen, MRD negativity with CR or better was associated with improved progression-free survival in patients with relapsed/refractory and transplant-ineligible newly diagnosed myeloma.
• Patients treated with daratumumab-based therapies achieved higher rates of CR or better with MRD negativity, compared with those who received standard of care.
• These findings support the use of MRD negativity as a prognostic tool to measure deep response, leading to improved PFS in patients who achieve CR or better.

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Compared with standard of care, daratumumab-based treatment regimens increased rates of measurable residual disease (MRD) negativity and reduced the risk of disease progression or death in patients with relapsed/refractory and transplant-ineligible newly diagnosed multiple myeloma (MM), according to an analysis of 4 phase III studies that was recently published in Blood. Additionally, patients who achieved MRD negativity with complete response (CR) or better (CR) had greater progression-free survival (PFS) regardless of therapy received.

In this analysis, researchers, led by Michele Cavo, MD, of the University of Bologna in Italy, focused on MRD as an alternative disease assessment because it allows for evaluation of novel therapies’ efficacy at earlier timepoints. These types of earlier assessments are needed as long-term outcomes continue to improve and the duration of time to data maturity for clinically meaningful patient benefits, such as PFS and overall survival (OS), continues to lengthen, the authors explained.

This large-scale pooled analysis explored data on MRD in 2,510 patients with relapsed/refractory MM and transplant-ineligible newly diagnosed MM. Patients had received one of the following treatment regimens as part of a phase III trial:

• DRd (daratumumab, lenalidomide, and dexamethasone)
• Rd (lenalidomide plus dexamethasone)
• DVd (daratumumab, bortezomib, and dexamethasone)
• Vd (bortezomib plus dexamethasone)
• DVMP (daratumumab, bortezomib, melphalan, and prednisone)
• VMP (bortezomib, melphalan, and prednisone)

Patients were enrolled in one of the following phase III trials:

• POLLUX: DRd (n, 286) versus Rd (n, 283)
• CASTOR: DVd (n, 251) versus Vd (n, 247)
• ALCYONE: DVMP (n, 350) versus VMP (n, 356)
• MAIA: DRd (n, 368) versus Rd (n, 369)

To briefly summarize common inclusion and exclusion criteria, POLLUX excluded patients with lenalidomide-
refractory disease, CASTOR excluded patients with disease that was refractory to bortezomib or another proteasome inhibitor, and ALCYONE and MAIA included patients who were ineligible for high-dose chemotherapy and stem cell transplantation due to age or certain comorbidities.

To perform a uniform assessment of MRD across the trials, Dr. Cavo and colleagues used the International Myeloma Working Group (IMWG) criteria, which state that MRD should be assessed during CR and with a minimum sensitivity threshold of 10⁻⁵, by either next-generation sequencing (NGS) or next-generation flow cytometry.

Median follow-up durations were: 54.8 months in POLLUX, 50.2 months in CASTOR, 40.1 months in ALCYONE, and 36.4 months in MAIA.

Across all studies, 16.7% of patients (n, 418) achieved MRD-negative status. One-third (34%; n, 854) achieved a CR or better, of whom nearly half (48.4%) achieved MRD negativity.

Looking specifically at patients who received daratumumab-based regimens, the MRD-negativity rate was 26.8%, compared with 6.5% in the control groups. Nearly half of daratumumab-treated patients (45.9%) achieved CR or better, compared with 22.2% in the control groups. Of this group, 57.5% were MRD negative, compared with 29.5% in the control groups. Therapy combinations containing daratumumab led to higher rates of MRD negativity than standard of care in both the intention-to-treat populations and among patients who achieved ≥CR within each of the 4 studies (Tables 1 and 2).

Overall, the 413 patients across studies in the pooled analysis who achieved deep responses (MRD-negative CR or better) had improved 48-month PFS rates, at 70.4%, while the rate for patients who were MRD-positive or achieved very good partial response or lower was 23.9%. This translated to an 80% reduction in the risk of disease progression or death for patients with at least a CR and MRD negativity, irrespective of therapy or disease setting (hazard ratio [HR], 0.20; 95% CI, 0.16-0.24; P < .0001). “These data highlight the importance of assessing MRD status even in patients with a deep response according to conventionally defined criteria,” the authors wrote.

Moreover, patients treated with daratumumab-based regimens with a CR or better had even greater improvements in PFS compared with control groups, regardless of MRD status.

“One possible explanation for these observations is that daratumumab may induce longer periods of sustained MRD negativity and deeper responses compared with standard of care,” the authors wrote. “It is also possible that the improved outcomes associated with daratumumab-based regimens may be affected by continued daratumumab therapy that was given until progression, versus standard of care that was given for a fixed number of cycles in 2 of 4 studies,” they added.

Disclosures: The included studies were supported by Janssen Research & Development, LLC. Study authors report relationships with Janssen, the manufacturer of daratumumab.

Reference

Cavo M, San-Miguel J, Usmani SZ, et al. Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA. Blood. 2022;139(6):835-844.