SummaryBackgroundAddition of daratumumab to lenalidomide, bortezomib, and dexamethasone (D-RVd) in the GRIFFIN study improved the stringent complete response rate by the end of consolidation in transplantation-eligible patients with newly diagnosed multiple myeloma. Here, we report the findings of the predefined final analysis.
MethodsGRIFFIN was an open-label, randomised, active-controlled, phase 2 trial done in 35 research centres in the USA. Patients had newly diagnosed multiple myeloma with measurable disease by M protein or free light chain, were aged 18每70 years, had an ECOG performance score of 0每2, and were eligible for autologous haematopoietic stem-cell transplantation (HSCT). Patients were randomly assigned (1:1) to four D-RVd or RVd induction cycles, autologous HSCT, two D-RVd or RVd consolidation cycles, and lenalidomide with or without daratumumab maintenance therapy for 2 years. Patients received 21-day cycles of oral lenalidomide (25 mg on days 1每14), subcutaneous bortezomib (1﹞3 mg/m2 on days 1, 4, 8, and 11), oral dexamethasone (40 mg weekly) with or without intravenous daratumumab (16 mg/kg weekly, cycles 1每4; day 1, cycles 5每6). Maintenance therapy (28-day cycles) was oral lenalidomide (10 mg on days 1每21) with or without daratumumab (16 mg/kg intravenously every 4 or 8 weeks, or 1800 mg subcutaneously monthly). Patients could continue lenalidomide maintenance after study treatment completion. The primary endpoint was stringent complete response rate by the end of consolidation in the response-evaluable population, and has already been reported. Here we report updated stringent complete response rates and secondary outcomes including progression-free survival and overall survival. The trial is registered with ClinicalTrials.gov (NCT02874742) and ended on April 8, 2022.
FindingsBetween Dec 20, 2016, and April 10, 2018, 104 patients were randomly assigned to the D-RVd group and 103 were randomly assigned to the RVd group; most patients were White (85 [82%] in the D-RVd group and 76 [74%] in the RVd group) and male (58 [56%] in the D-RVd group and 60 [58%] in the RVd group). At a median follow-up of 49﹞6 months (IQR 47﹞4每52﹞1), D-RVd improved rates of stringent complete response (67 [67%] of 100] vs 47 [48%] of 98]; odds ratio 2﹞18 [95% CI 1﹞22每3﹞89], p=0﹞0079), and 4-year progression-free survival was 87﹞2% (95% CI 77﹞9每92﹞8) for D-RVd versus 70﹞0% (95% CI 55﹞9每80﹞3) for RVd, with a hazard ratio (HR) of 0﹞45 (95% CI 0﹞21每0﹞95, p=0﹞032) for risk of disease progression or death with D-RVd. Median overall survival was not reached for either group (HR 0﹞90 [95% CI 0﹞31每2﹞56], p=0﹞84). The most common grade 3每4 treatment-emergent adverse events in the D-RVd versus RVd groups were neutropenia (46 [46%] of 99 vs 23 [23%] of 102), lymphopenia (23 [23%] vs 23 [23%]), leukopenia (17 [17%] vs eight [8%]), thrombocytopenia (16 [16%] vs nine [9%]), pneumonia (12 [12%] vs 14 [14%]), and hypophosphataemia (ten [10%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 46 (46%) of 99 patients in the D-RVd group and in 53 (52%) of 102 patients in the RVd group. One patient in each treatment group reported a treatment-emergent adverse event that resulted in death (bronchopneumonia in the D-RVd group; cause unknown in the RVd group); neither was related to study treatment. No new safety concerns occurred with maintenance therapy.
InterpretationAddition of daratumumab to RVd improved the depth of response and progression-free survival in transplantation-eligible patients with newly diagnosed multiple myeloma. These results justify further evaluation in phase 3 studies.
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Validation Study of the MDS Criteria for the Diagnosis
