Shaji Kumar, MD, discusses the MAIA trial; key takeaways regarding the long-term safety and efficacy of daratumumab, lenalidomide, and dexamethasone, in transplant-ineligible patients with newly diagnosed multiple myeloma; and the implications of this research on clinical practice.
Data from an updated analysis of the phase 3 MAIA trial (NCT02252172) continued to support the frontline use of the triplet regimen of daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone (D-Rd) in transplant-ineligible patients with newly diagnosed multiple myeloma, according to Shaji Kumar, MD.1
Data presented at the 2022 ASH Annual Meeting showed that at a median follow-up of 64.5 months, patients treated with the triplet (n = 368) experienced a median PFS of 61.9 months compared with 34.4 months in those treated with lenalidomide and dexamethasone (Rd) alone (n = 369; HR, 0.55; 95% CI, 0.45-0.67; P < .0001). Additionally, at a median follow-up of 73.6 months, the median OS was not yet reached for those in the D-Rd arm vs 64.1 months in the Rd arm (HR, 0.65; 95% CI, 0.52-0.80; P < .0001).
In July 2019, the FDA approved D-Rd for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT), based on previous findings from MAIA.2
“The longer-term data support the continued efficacy and safety of this 3-drug combination. It is certainly the go-to, standard-of-care regimen [for transplant-ineligible patients with newly diagnosed multiple myeloma],” Kumar said in an interview with OncLive®. “Of course, the other choice continues to be lenalidomide, bortezomib [Velcade], and dexamethasone [VRd] if you cannot access daratumumab in the newly diagnosed setting.”
In a recent interview, Kumar, who is a consultant and a professor of medicine in the Division of Hematology in the Department of Internal Medicine at the Mayo Clinic in Rochester, Minnesota, further discussed the MAIA trial, key takeaways regarding the long-term safety and efficacy of D-Rd, and the implications of this research on clinical practice.
Kumar: MAIA was a phase 3 trial designed to address whether adding an anti-CD38 monoclonal antibody, such as daratumumab, to Rd would improve outcomes among patients with newly diagnosed multiple myeloma who are not eligible for ASCT.
It is a fairly large trial with  patients. The patients were randomly assigned to get either Rd given until disease progression, or daratumumab with the same dose and schedule of Rd, again, given until disease progression. The trial was intended to look at the older patient population who were not considered eligible for ASCT.
The primary end point for the trial was to assess the improvement in PFS. Additional end points included looking at minimal residual disease [MRD] negativity, and an additional analysis looked at subgroups, including high-risk [patients], those with more frailty, and those who were older.
Daratumumab is an anti-CD38 monoclonal antibody that has been shown to be effective in treating multiple myeloma and was initially explored in the relapsed setting. [Daratumumab] is clearly effective when added to an immunomodulatory drug, and this has been demonstrated with the same regimen of [D-Rd] in the phase 3 POLLUX trial [NCT02076009] done in patients with relapsed/refractory multiple myeloma.
It was logical to explore the same combination in the setting of newly diagnosed multiple myeloma. The combination is being explored both in transplant-eligible and -ineligible patients, with the MAIA trial being representative of the transplant-ineligible population.
At the meeting, we presented an analysis that had longer follow-up, a median follow-up of [64.5] months. [Data] demonstrate that we continue to see a significant improvement in the PFS. The median PFS has been reached at [this point], and it was [61.9 months in the D-Rd arm vs 34.4 months in the Rd arm].
We also have extended follow-up of [73.6] months for OS. Although the median OS has not been reached for D-Rd, we have a 5-year estimated [OS rate] of [66.7%] compared with [53.7%] for Rd [alone].
There have been no new safety signals. Clearly, one of the concerns is the increased risk of infection [with the addition of daratumumab], and we did see more grade 3/4 infections in patients receiving D-Rd vs Rd [alone]. Some of this [increase in infections] is a function of the fact that these patients have been on treatment longer than those getting lenalidomide and dexamethasone.
Nevertheless, we do see significant depletion in the hemoglobin levels and hypogammaglobulinemia in patients who have been on daratumumab for quite a while. Those patients need to be carefully followed up and given intravenous immunoglobulin therapy if they run into problems with recurrent infection. However, that is the main signal that we need to be aware of in patients getting long-term therapy with this [triplet] combination.
For the transplant-ineligible patients, the choice of therapy was VRd, particularly the VRd-lite regimen. [MAIA] gives us an option of another triplet combination that is quite effective. [MAIA] does not allow us to do a direct comparison with VRd; however, the median PFS of more than 5 years observed in the MAIA trial is one of the longest that we have seen in the older patient population.
In frailer patients, we often start treatment with Rd. Other data presented at the 2022 ASH Annual Meeting looked at daratumumab and lenalidomide vs Rd in the frail patient population and showed that [daratumumab plus lenalidomide] also provides comparable benefit.
Potentially in those really frail patients, instead of using a dexamethasone-containing combination, we could use a daratumumab and lenalidomide combination. In effect, it becomes a MAIA regimen, which is less intense in the older patient population.
At the meeting, we also presented findings from the phase 2 ASCENT trial [NCT03289299], which we did in patients with high-risk smoldering myeloma. Here, we used a 4-drug combination [comprised] of daratumumab, carfilzomib [Kyprolis], lenalidomide, and dexamethasone given for a defined duration of 2 years. The results demonstrated good efficacy for this combination with high rates of MRD negativity. [These data] again raised the question: Can we cure some patients with smoldering myeloma?