ASH 2017 | LBA-4: Phase III ALCYONE clinical trial: daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) in NDMM patients ineligible for transplant

The MM Hub are delighted to be present at the 59th American Society of Hematology (ASH) Annual Meeting held in Atlanta, Georgia, from 9-12 December 2017. On Tuesday 12 December, the Late-Breaking Abstracts (LBA) session was held and an oral abstract was presented by Maria-Victoria Mateos from the University Hospital of Salamanca/IBSAL, Salamanca, Spain, entitled (LBA-4): Phase 3 Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE). This article is based on data from the presentation and may supersede that presented in the published abstract.

Dr. Mateos began her talk by setting the scene for the work. Currently, outside of the US, bortezomib, melphalan, and prednisone (VMP) is a standard of care (SOC) regimen for Newly Diagnosed Multiple Myeloma (NDMM) patients that are ineligible for autologous stem cell transplantation (ASCT). In the VISTA trial – the VMP registration study, the addition of V to MP improved efficacy but at the cost of added toxicity. The PETHEMA/GEM2005MAS65 and GINEMA studies optimized VMP by reducing toxicity and maintaining cumulative bortezomib dose and efficacy. Promising results with the addition of daratumumab, an anti-CD38 monoclonal antibody, to SOC regimens in the relapsed setting prompted a study to assess its efficacy in frontline treatment of patients that are ineligible for transplantation. The phase I safety study of daratumumab in combination with VMP was well tolerated in transplant-ineligible NDMM patients

Therefore, in the ALCYONE study, daratumumab (D) was added to VMP in patients (pts) aged 56 years or older who were ineligible for high-dose chemotherapy with ASCT. Patients were randomized 1:1 to receive either VMP or D-VMP, and stratified according to the International Staging System (ISS I, II, III), the region they were from (Europe or other) and age (<75 or ≥75 years). The primary endpoint was progression free survival (PFS) and key secondary endpoints were overall response rate (ORR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, rate of negativity of minimal residual disease (MRD), overall survival (OS), and safety.

Key Data:

• Pts received up to a maximum of nine 6-week cycles of VMP:
  • V: 1.3 mg/m² SC on Days 1, 4, 8, 11, 22, 25, 29, 32 (Cycle 1) and Days 1, 8, 22, and 29 (Cycles 2–9); M: 9 mg/m² PO and P: 60 mg/m² PO on Days 1–4 (Cycles 1–9)
  • D-VMP: D = 16 mg/kg IV QW for Cycle 1, Q3W for Cycles 2–9, and Q4W for Cycles 10+ (post VMP-treatment phase) until disease progression.
• Pts (n = 706) were randomized: D-VMP = 350, VMP = 356
• Median age = 71 (range 40–93) years; 29.9% were ≥75 years; 46.3% were male
• FISH/karyotyping cytogenetic analysis (616 pts evaluable); standard risk: 84.1%; high-risk (positive for del17p, t[14;16], t[4;14]):15.9%

Data is given as: D-VMP vs VMP:

• Median number of treatment cycles (after 231 PFS events): 12 (1-24) vs 9 (1-9); cutoff date for interim analysis = 12 June, 2017
• Percentage of pts still on treatment = 71% vs 5%; 229 (66%) of pts in the D-VMP arm were receiving daratumumab monotherapy
• Progressive disease (PD): 23 pts (9%) vs 47 pts (13%) for 1-9 cycles and D-VMP 10+ cycles = 30 pts (12%)
• Adverse Event (AE): 17 pts (5%) vs 33pts (9%) for 1-9 cycles and D-VMP 10+ cycles = no AEs
• At a median follow-up of 16.5 months (range, 0.1-28.1 months), HR for PFS = 0.50 (95% CI, 0.38-0.65, P <0.0001)
• Median PFS was not reached vs 18.1 months
• PFS benefit for D-VMP = consistent across all subgroups (age ≥75 years, ISS stage III, and high-risk cytogenetics)
• ORR = 91% vs 74%, P < 0.0001
• PR = 20 vs 24; ≥VGPR = 71% vs 50%, ≥CR = 42.6% vs 24.4%
• MRD-negativity rate (NGS; 10^-5 sensitivity threshold) = 22.3% vs 6.2%; (P < 0.0001)
• OS data were immature after a total of 93 deaths (45 vs 48)
• Most common treatment emergent adverse events (TEAE): neutropenia = 50% vs 53%, thrombocytopenia = 48.8% vs 53.7%, anemia = 28% vs 38%, peripheral sensory neuropathy = 28% vs 34%, upper respiratory tract infection = 26% vs 14%
• Most common grade 3-4 TEAE: neutropenia = 39.9% vs 38.7%, thrombocytopenia = 34.4% vs 37.6%), anemia (15.9% vs 19.8%), and pneumonia = 11.3% vs 4.0% (1 pt in each arm discontinued due to pneumonia)
• The rates of grade 3/4 infections were 23.1% vs 14.7% and treatment discontinuations due to infections were 0.9% vs 1.4%
• Deaths due to treatment-emergent AEs (TEAEs) = 19 pts in both arms: 6% vs 5%
• Daratumumab-associated infusion-related reactions (IRRs) = 28 pts (most grade 1-2) 96%; most occurred during the first infusion
• Discontinuation due to AEs = 5 pts (1.4%) but Montelukast was used as a premedication in <5% of pts

The talk was concluded by re-affirming the significant (50%) reduction in the risk of progression or death with daratumumab (HR = 0.5). This was attributed to patients achieving deeper responses and a tripling of the rate of MRD-negativity. The safety assessments were also discussed with the important finding that the addition of daratumumab did not lead to any additional AEs to those already reported for the background regimen. The infusion reactions were noted in general as very manageable. Other ongoing studies were mentioned (phase III studies: MAIA (D-Rd), CASSIOPEIA (D-VTd) and phase II studies: GRIFFIN (D-VRd) and LYRA (D-CyBorD)). The results reported here have been used in recent applications to both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) to extend the marketing authorization for daratumumab – see MM Hub article and strongly support D-VMP as a SOC for transplant-ineligible NDMM patients. The talk was well received with enthusiastic questioning regarding other daratumumab combinations.