In an updated analysis of the phase III MAIA trial, the addition of the monoclonal antibody daratumumab to the immunomodulatory agent lenalidomide and the corticosteroid dexamethasone (D-Rd) significantly improved overall survival over lenalidomide/dexamethasone alone in patients newly diagnosed with multiple myeloma and ineligible for autologous stem cell transplantation.1 The previous analysis had shown a progression-free survival benefit alone.2
Thierry Facon, MD
At the European Hematology Association (EHA) 2021 Virtual Congress, the late-breaking abstract was presented by Thierry Facon, MD, Professor of Hematology at Lille University Hospital, France. “These results strongly support upfront daratumumab with lenalidomide and dexamethasone as a new standard of care for patients with transplant-ineligible newly diagnosed multiple myeloma,” Dr. Facon said.
In the previous MAIA update, which was reported at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, D-Rd prolonged progression-free survival and second progression-free survival, but the overall survival data were not mature.2 Dr. Facon reported updated efficacy and safety results from a prespecified interim overall survival analysis, after a median follow-up of approximately 56 months.
The estimated 5-year overall survival rate at this time was 66.3% with D-Rd compared with 53.1% with Rd (hazard ratio [HR] = 0.68; P = .0013). Benefit was demonstrated despite a 46% crossover rate from Rd to D-Rd upon disease progression; median survival was not reached in either arm. The risk of disease progression or death was reduced by 47% (P < .0001), he reported.
“These data provide a new progression-free survival benchmark in patients with newly diagnosed multiple myeloma who are transplant-ineligible,” Dr. Facon commented.
The benefits are even more meaningful because the study population was elderly—mostly aged 75 to 90, said Dr. Facon, who emphasized that 50% or more of nontransplant elderly patients never receive subsequent therapy. “This suggests the most effective therapy should be used upfront and not saved for relapse, at which time additional genetic mutations conferring resistance may have been acquired,” he said.
Numerous Outcomes Improved
Numerous outcomes were significantly improved with the addition of daratumumab, as shown for D-Rd vs Rd:
- Median overall survival: not reached in either arm; the 5-year rates were 66.3% vs 53.1% (HR = 0.68; P = .0013).
- Median progression-free survival: not reached vs 34.4 months; the 5-year rates were 52.5% vs 28.7% (HR = 0.53; P < .0001).
- Median time to next treatment: not reached vs 42.4 months (HR = 0.47; P < .0001).
- Objective response rate: 93% vs 82%.
“Daratumumab plus lenalidomide/dexamethasone induced deeper responses with significantly higher rates of complete responses or very good partial responses or better,” Dr. Facon said. “With 28 months or more of additional follow-up, responses deepened with continued daratumumab therapy.”
Comparing Results With Past Studies
Dr. Facon put the results into context with past studies of this and other regimens in newly diagnosed patients not slated for immediate transplantation. The phase III MAIA and ALCYONE3 studies both established a progression-free survival benefit with daratumumab maintenance alone or in combination with lenalidomide. ALCYONE also established, for the first time, an overall survival benefit. The CASSIOPEIA trial4 established the progression-free survival benefit of daratumumab alone as maintenance therapy following autologous stem cell transplantation in newly diagnosed, transplant-eligible patients.
KEY POINTS
- The phase III MAIA trial compared daratumumab plus lenalidomide/dexamethasone (D-Rd) with lenalidomide/dexamethasone (Rd) alone in patients with newly diagnosed multiple myeloma who are ineligible for transplantation.
- In the updated analysis, the estimated 5-year overall survival was 66.3% with D-Rd compared with 53.1% with Rd (hazard ratio = 0.68; P = .0013).
- Numerous outcomes were improved with the addition of daratumumab, which was given until disease progression.
Specifically in the elderly, the phase III SWOG S0777 trial5 established bortezomib plus lenalidomide/dexamethasone (V-Rd) as the standard of care. In fact, its population was much younger than that of MAIA’s, Dr. Facon pointed out: “In SWOG S077, 43% of patients were ≥ 65, and very few were older than 75. In MAIA, 99% were older than 65, and 44% were aged 75 to 90.”
“In an analysis of benefit with V-Rd for patients older than age 65, median progression-free survival was 34 months in SWOG S0777. With MAIA, in an equivalent population, with D-Rd it will be about 5 years,” he noted. “I would say that’s a great difference.”
About MAIA
From 2015 to 2017, MAIA enrolled 737 patients with newly diagnosed multiple myeloma (median age, 73) who were ineligible for high-dose chemotherapy and stem cell transplantation. Patients were randomly assigned to receive D-Rd or Rd alone in 28-day cycles. In the D-Rd arm, patients received daratumumab at 16 mg/kg weekly for cycles 1 to 2, every 2 weeks for cycles 3 to 6, and every 4 weeks for cycle 7 onward. In both arms, patients received lenalidomide at 25 mg on days 1 to 21 of each cycle and dexamethasone at 40 mg weekly. Patients continued treatment until disease progression.
At the time of the analysis, 42% of the D-Rd arm remained on treatment compared with 18% of the Rd arm. The median duration of the study treatment was 47.5 months and 22.6 months, respectively.
There were no new safety signals observed with continuous therapy and follow-up. The most common grade 3 or 4 adverse event in the D-Rd and Rd arms was neutropenia, seen in 54% vs 37%, respectively. Of note, a lower percentage of grade 3 or 4 and serious treatment-emergent adverse events occurred after 24 months, compared with the first 24 months, in both treatment arms. More patients discontinued Rd because of toxicity (23% vs 13%).
Earlier results from MAIA supported the U.S. Food and Drug Administration approval of this combination.
DISCLOSURE: Dr. Facon has served as a consultant or advisor to Amgen, Celgene, Janssen, Karyopharm, Oncopeptides, Roche, Sanofi, and Takeda; and has participated in a speakers bureau for Celgene, Janssen, and Takeda.
REFERENCES
1. Facon T, Kumar SK, Plesner T, et al: Overall survival results with daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: Phase 3 MAIA study. EHA 2021 Virtual Congress. Abstract LB1901. Presented June 12, 2021.
2. Kumar SK, Facon T, Usmani SZ, et al: Updated analysis of daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with transplant-ineligible newly diagnosed multiple myeloma: The phase 3 MAIA study. 2020 ASH Annual Meeting & Exposition. Abstract 2276. Presented December 6, 2020.
3. Mateos MV, Cavo M, Blade J, et al: Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): A randomised, open-label, phase 3 trial. Lancet 395:132-141, 2020.
4. Moreau P, Sonneveld P, for the CASSIOPEIA Study Investigators: Daratumumab maintenance or observation after treatment with bortezomib, thalidomide and dexamethasone with or without daratumumab and autologous stem cell transplant in patients with newly diagnosed multiple myeloma: CASSIOPEIA Part 2. 2021 ASCO Annual Meeting. Abstract 8004. Presented June 8, 2021.
5. Durie BGM, Hoering A, Abidi MH, et al: Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial. Lancet 389:519-527, 2017.
