New Analysis Affirms Value of MRD in Multiple Myeloma

Minimal residual disease (MRD) negativity and its duration led to significantly better progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma, new analyses of two randomized trials showed.

MRD-negative rates increased significantly with the addition of daratumumab (Darzalex) to standard therapy, from 6.7% with lenalidomide (Revlimid) and dexamethasone (Rd) to 32.5% with the addition of the anti-CD38 antibody (DRd) and from 1.6% with bortezomib (Velcade)-dexamethasone (Vd) to 15.1% with daratumumab-VD (DVd). The proportion of patients who had MRD-negative status for 6 months or longer increased about 10-fold when daratumumab was added to Rd or Vd.

Progression-free survival (PFS) increased with MRD-negativity and its duration, Hervé Avet-Loiseau, MD, of University Cancer Institute-Oncopole in Toulouse, France, and co-authors reported in the Journal of Clinical Oncology.

“Our data represent the largest dataset analyzed to date, but other studies have highlighted the role of sustained MRD negativity in MM [multiple myeloma] and its association with survival outcomes,” the authors stated. “Taken together, these findings support the utility of sustained MRD assessment in MM.”

“Patients in the RR [relapsed/refractory] MM setting who achieved CR [complete response] or better and MRD-negative status had prolonged PFS compared with patients who did not,” the researchers said. “In addition, daratumumab-based regimens enabled many patients with RRMM to attain deep and sustained MRD-negative responses, resulting in longer periods without disease progression.”

The data add to existing evidence about the importance of MRD and probably support the clinical opinion of many myeloma specialists, according to co-author Sagar Lonial, MD, of Winship Cancer Institute and Emory University in Atlanta.

“This retrospective analysis proves what I think many of us have been saying: It is not just the depth of response (MRD-negative) that matters, but more intense therapy can impact the duration of that depth,” he told MedPage Today by email. “Thus, combination therapy not only improves the MRD rate, it also improves the duration of sustained MRD, which is a more clinically meaningful endpoint.”

“Duration of MRD negativity is very important,” Lonial continued. “The longer the duration, the more the clinical benefit a patient receives from therapy. It is not dissimilar to a decade ago when we were talking about sustained CR vs just achieving CR. This to me really supports the concept of using the best therapy we can (combination) to achieve a deep response, and that deep response usually results in a more durable CR than using a doublet. This to me is the main point and should further support the use of three drugs over two in the relapsed setting.”

Multiple studies and analysis have shown that MRD negativity is associated with improved PFS and overall survival [OS] in newly diagnosed multiple myeloma, the authors noted. Ongoing studies are evaluating MRD as a potential surrogate for more established endpoints in myeloma, including PFS and OS.

The International Myeloma Working Group guidelines for assessing MRD negativity state that sustained MRD negativity, measured serially, can support more meaningful assessments of disease control. However, sustained MRD negativity had not been evaluated prospectively in large trials of relapsed/refractory myeloma.

Two recent randomized trials of relapsed/refractory myeloma included assessment of MRD negativity and its duration. The POLLUX trial evaluated Rd and DRd, and the CASTOR trial compared Vd and DVd. In both studies, the addition of daratumumab met the primary endpoint of improved PFS.

Avet-Loiseau and co-authors examined the relationship between MRD negativity and PFS in the intention-to-treat populations of the trials. Data analysis included 569 patients from the POLLUX trial and 498 from CASTOR.

In POLLUX, five times as many patients attained MRD negativity with the DRd regimen (P<0.000001). MRD-negative status persisted for at least 6 months in 20.3% of patients treated with DRd vs 2.1% of those allocated to Rd (P<0.0001), and 12-month MRD-negativity rates were 16.1% vs 1.4% (P<0.0001).

In CASTOR, MRD-negative rates were 15.1% with DVd and 1.6% with Vd (P<0.000001), including 6 or more months of MRD negativity in 10.4% vs 1.2 and 12 or more month rates of 6.8% vs 0.0% (P<0.0001 for both comparisons).

Among patients who attained CR or better as best response, more than half of the patients treated with daratumumab attained MRD-negative status in each trial, as compared with 29.2% for Rd in POLLUX and 17.4% with Vd in CASTOR.

In both trials, MRD negativity was associated with improved PFS. Further improvement in PFS was observed with longer duration of MRD negativity.

Additionally, time to next treatment and second PFS increased with MRD negativity and its duration. Patients who attained CR or better response plus MRD negativity with DRd or DVd had almost a 50% reduction in the hazard ratio (HR) for disease progression or death as compared with patients who received Rd or Vd (HR 0.51, 95% CI 0.27-0.96, P=0.0358).