DISCUSSION
myalgia, MM, diarrhea, fatigue, thrombocytopenia, hematological toxicity, muscular toxicity, vomiting, anemia, hematological abnormality, muscular weakness, nausea,
DISEASE, THROMBOCYTOPENIA, RELAPSED/REFRACTORY MULTIPLE MYELOMA, ANEMIA, EVENTS
The RD for phase II studies for this triple combination was plitidepsin 5.0 mg/mThe most common hematological abnormality (all grades) was anemia, which occurred in all patients (grade ≥ 3 in 33% at the RD). Most cases were grade 1/2, and at the RD the majority of patients with grade ≥ 3 anemia while on treatment already had grade 2 anemia at baseline. The most common severe hematological toxicity at the RD was thrombocytopenia, which was grade ≥ 3 in half of patients with most of them (6 of 11) already having grade ≥ 2 thrombocytopenia at baseline. Lower rates of severe thrombocytopenia (21%–22%) have been previously observed in patients with r/r MM treated with the double combination of plitidepsin 5.0 mg/mThe most common biochemical abnormality was transaminase increases. Grade 3 ALT increase was most frequent at the RD (26% of patients), but it was transient and manageable with dose delays, omissions, or reductions.Treatment‐related AEs at the RD for this triple combination were mostly mild/moderate; grade 3 diarrhea, nausea, vomiting, or fatigue were observed in less than 10% of patients. Severe muscular toxicity was not observed with the triple combination in this study. In contrast, incidences of 5.4% and 3.6% were reported for severe myalgia and muscular weakness, respectively, in MM patients treated with plitidepsin plus DXM.At the RD cohort, only three patients discontinued treatment due to treatment‐related events, thereby suggesting an acceptable safety profile for plitidepsin combined with BTZ and DXM in this heavily pretreated r/r MM population (pretreated with a median of five prior lines, HSCT in 44% and refractory disease in 59%).This triple combination showed modest antitumor activity (ORR of 35.7% at all dose levels; 22.2% at the RD) in this population of heavily pretreated r/r MM patients, most of them having received BTZ and with disease refractory to the last prior therapy. Comparing the efficacy of the 18 evaluable patients during the escalation stage with an ORR of 55.6% (data presented at the ASCO 2016 Annual Meeting),The antitumor activity found in patients treated with the combination of plitidepsin, BTZ, and DXM (ORR of 35.7% at all dose levels, and 22.2% at the RD) was higher than that observed in the ADMYRE trial evaluating plitidepsin plus DXM (ORR: 13.8%),Results of the VISTA trial were further supported by those of phase II trials: RETRIEVE (ORR: 40%) and SUMMIT (ORR: 35%, including minimal response while on BTZ treatment), and of the phase III APEX trial (crossover from DXM to BTZ), in which the overall and complete response rates with BTZ were 43% and 9%, respectively.Of note, the median DoR (14.4 months at all dose levels; 12.3 months at the RD) was longer than that observed with most other BTZ and DXM‐containing combinations, including panobinostat (6.0 months),The similarity of PK parameters found in the present study compared to reference values, and the lack of overlapping metabolic routes of plitidepsin and BTZ, suggest that no major PK interaction between these two drugs is expected. Compared to the values reported herein, patients with MM treated with plitidepsin in other trials had a similar median CL (4.4 L/h) and a somewhat larger median peripheral volume (513 L) (unpublished data). The plitidepsin concentrations found in this study fitted within the 90% prediction interval simulated for patients with MM, although most were above the 50th percentile for the typical values expected during the first 48 hours after dosing (Figure Typical plitidepsin exposure in patients with in relapsed/refractory multiple myeloma patients and observed plitidepsin concentrations. Dots represent observations from the current study, lines represent the 5th, 50th, and 95th percentile of the simulated concentrations, and the shaded area represents the 90% prediction interval of plitidepsin whole blood concentrationsIn summary, the triple combination of plitidepsin 5.0 mg/m