Randomized phase III study (ADMYRE) of plitidepsin in combination with dexamethasone vs. dexamethasone alone in relapsed/refractory multiple myeloma: Results for patients aged < 75 years

Abstract The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma (r/r MM) in patients exposed to proteasome inhibitors and immunomodulatory drugs. ADMYRE met its primary endpoint, progression-free survival by Independent Review Committee, showing a statistically significant 35% reduction in the risk of progression or death (Spicka et al. Ann Hematol 2019;98(9):2139-50). Age subgroup analysis was pre-planned in the Statistical Analysis Plan of the ADMYRE study. Results from the subgroup of patients aged < 75 years are shown here: 145 patients (plitidepsin plus DXM arm) and 71 patients (DXM arm). Compared to the overall population, higher reduction was found with plitidepsin plus DXM in the risk of progression or death in the primary endpoint: 47.7% vs. 35.0% (HR=0.523 vs. HR=0.650). Higher reduction in the risk of death in overall survival was also found: 28.9% vs. 20.3% (HR=0.711 vs. HR=0.797). A difference in median overall survival of about 5 months (13.0 months vs. 8.1 months; p=0.0350) is clinically meaningful in this heavily pretreated patient population. The safety profile of plitidepsin plus DXM in patients aged < 75 years was similar than that observed in the overall population of patients treated in the ADMYRE study and better than patients aged ≥75 years. The most common adverse events (all grades) related to the study treatment in patients < 75 years were fatigue (39.2% of patients), gastrointestinal (nausea, 39.2%; vomiting, 19.6%; diarrhea, 14.7%) and myalgia (14.0%). Since the design of ADMYRE, new evidence has demonstrated that in regimens in combination with DXM, adjustments of the starting dose of DXM from 40 to 20 mg are required in patients ≥75 years to increase tolerability and extend survival. Of note, DXM dose reduction was not done in ADMYRE trial in patients ≥ 75 years, which might have improved the tolerance and allowed the patient to receive more treatment and to increase benefit. Tolerance to treatment was also evaluated by the time to performance status deterioration or death, indicative of patient general status, which was 5.7 months (95%CI, 3.8-9.0 months) for the plitidepsin plus DXM arm and 2.1 months (95%CI, 1.4-3.8 months) for the DXM arm (HR=0.5680; 95%CI, 0.394-0.820; p=0.0021). In conclusion, larger differences in efficacy outcomes while maintaining a similar safety profile together with a novel mechanism of action suggest that this combination can be a valid option for patients with r/r MM aged < 75 years.