Positive results from MAIA study of Darzalex + Revlimid and dexamethasone in multiple myeloma patients ineligible for transplant.- Genmab + Janssen Biotech

Genmab A/S announced that data from the Phase III MAIA study of daratumumab in front line multiple myeloma, which was submitted by its collaboration partner Janssen Biotech, Inc., was accepted as a late-breaking abstract for oral presentation at the 60th Annual Meeting of the American Society of Hematology (ASH). The abstract is now published online on the ASH website:BA-2: "Phase III Randomized Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant (MAIA)".

Abstract:Introduction: Lenalidomide-based therapies are a standard of care for patients with newly diagnosed, transplant-ineligible MM. Daratumumab (DARA) is a human, CD38-targeted, IgG1k monoclonal antibody which has single-agent activity in heavily pretreated MM patients. As previously reported in 3 phase III studies, the addition of DARA to standards of care in both relapsed refractory (D-Rd, DARA plus bortezomib and dexamethasone [D-Vd]) or transplant-ineligible NDMM (DARA plus bortezomib, melphalan, and prednisone [D-VMP]) resulted in a greater than 50% reduction in the risk of disease progression or death (Palumbo A, et al. N Engl J Med 2016;375:754-766; Dimopoulos MA, et al. N Engl J Med 2016;375:1319-1331; Mateos MV, et al. N Engl J Med 2018;378:518-528). Of these, the POLLUX study with D-Rd showed the greatest benefit with a 63% reduction in risk of disease progression or death in patients with MM who had at least one prior line of therapy. Based on the efficacy and tolerable safety profile of D-Rd, we conducted a phase III study (MAIA) to evaluate D-Rd vs Rd in transplant-ineligible NDMM. Here we report the prespecified interim analysis of the MAIA study.

Methods; Patients ineligible for high-dose chemotherapy with autologous stem cell transplantation due to age greater than 65 years or comorbidities were randomized 1:1 to Rd � DARA. Stratification was based on International Staging System stage (ISS [I, II, III]), region (North America vs other), and age (<75 vs greater than 75 years. all patients received 28-day cycles of treatment with rd dara. r: 25 mg oral qd on days 1- 21 d: 40 mg oral on days 1 8 15 and 22. in the d-rd arm dara was given at 16 mg kg intravenously qw for cycles 1-2 q2w for cycles 3-6 and q4w thereafter. in both arms patients were treated until disease progression or unacceptable toxicity. the primary endpoint was progression-free survival pfs. key secondary endpoints included overall response rate orr minimal residual disease mrd-negativity rate 10-5 sensitivity clonoseq version 2.0 and safety.>

Results : This international study randomized 737 patients (368 to D-Rd; 369 to Rd) from 14 countries. Key baseline characteristics were well balanced between the two arms. The median (range) age was 73 (45-90) years with 44% of patients greater than 75 years, and 52% were male. Two thirds of patients had ECOG scores greater than 1: ECOG score 0, 34%; 1, 50%; greater than 2, 17%. Overall, 27%, 43%, and 29% were ISS stage I, II, and III, respectively. Of 642 patients evaluable for FISH/karyotyping analysis, 86% and 14% were standard and high cytogenetic risk, respectively. The prespecified interim analysis occurred after 239 PFS events on 24 September 2018 with a median follow up of 28 months. For the primary endpoint, the hazard ratio was 0.55 (95% CI, 0.43 to 0.72; P <0.0001), representing a 45 reduction in the risk of progression or death in patients treated with d-rd . the median pfs for the rd arm was 31.9 months and not reached for the d-rd arm. adding dara to rd resulted in deeper responses with a complete response cr or better rate of 47.6 in the d-rd arm compared with 24.7 in the rd arm odds ratio or 2.75 95 ci 2.01 to 3.76 p><0.0001). the very good partial response vgpr or better rate was 79.3 in the d-rd arm compared with 53.1 in the rd arm or 3.4 95 ci 2.45 to 4.72 p><0.0001). a total of 19 of patients have died and the hr for os was 0.78 95 ci 0.56 to 1.1 follow-up is ongoing. higher rates 5 or more difference of grade 3 4 pneumonia neutropenia and leukopenia were observed in the d-rd arm. the safety profile is consistent with previously reported dara studies. the complete topline data set will be presented with additional efficacy endpoints including mrd negativity rate.>

Conclusion: The addition of DARA to Rd in patients with transplant-ineligible NDMM significantly reduced the risk of progression or death by 45%. There are no new safety signals using DARA plus Rd in NDMM. These data together with the phase III ALCYONE study (D-VMP vs VMP) support the addition of DARA to standard of care combinations in patients with NDMM ineligible for transplant.

Comment: A summary is that adding Darzalex to dexamethasone and lenalidomide (Revlimid) cut the risk of death or disease progression by 45% for newly diagnosed multiple myeloma patients ineligible for transplants. The study arm that received Darzalex saw a higher complete response rate than the patients that did not take Darzalex at 47.6% versus 24.7%, respectively.