Antimyeloma Efficacy of Plitidepsin (Aplidin®): From Bench to the Bedside.
Authors: Ocio Enrique M. , Mitsiades Constantine , Mateos M. Victoria , Maiso Patricia , Mollinedo Faustino , Garayoa Mercedes , Gajate Consuelo , Blade Joan , Prosper Felipe , Lahuerta Juan José , Mitsiades Nicholas , McMullan Ciaran J. , Munshi Nikhil C. , Hideshima Teru , Chauhan Dharminder , Cuevas Carmen , Avilés Pablo , Faircloth Glynn , Richardson Paul G. , Pandiella Atanasio , Anderson Kenneth C. , Miguel J.F. San 
Published: October 2019

Abstract
Introduction Plitidepsin is a cyclic depsipeptide isolated from the marine tunicate, Aplidium albicans with promising antitumor activity. This work represents a comprehensive study (in vitro, in vivo and clinical) of its antimyeloma efficacy.
Material & Methods In vitro studies were performed in 23 multiple myeloma (MM) cell lines and in cells from 16 MM patients. For the in vivo analysis a human plasmocytoma model in CB17-SCID mouse was used. Mice were randomized to receive Aplidin® 100 μg/Kg ip x 7 days/week (n=9), Aplidin® 140 μg/Kg ip x 5 days/week (n=7) or vehicle alone (n=9). The clinical efficacy of Aplidin® in relapsed/refractory patients was evaluated in a non-randomized two-stage Phase II, multicenter, clinical trial. Dosage of Aplidin® was 5 mg/m2 every 2 weeks.
Results Aplidin® showed clear in vitro efficacy (IC50:1–10 nM) in the 23 cell lines tested including those resistant to dexamethasone, melphalan or doxorubicin. It was also active in the presence of microenvironment (IL-6, IGF-1 and BMSCs). Thirteen out of the 16 patient samples were sensitive to Aplidin® with >80% cell death in 8 cases and 60–80% in the remaining ones without significant toxicity in non tumor cells. Combination of Aplidin® with dexamethasone, bortezomib or lenalidomide showed clear potentiation. Aplidin® acts by inducing apoptosis with caspase−3, −7, −8, −9 and PARP cleavage. It also involves the activation of p38 and JNK signalling, Fas/CD95 translocation to lipid rafts and downregulation of Mcl-1 and myc. In mice studies, both schedules of treatment reduced tumor growth and increased survival with statistical differences in the group receiving 140 μg/Kg x 5d/week (p=0.04, Log Rank p=0.02). No significant toxicity was observed. These data provided the rationale for a clinical trial that has included 31 patients with relapsed/refractory MM. Median age was 65 years (47–82) and the median number of prior lines of therapy was 4 (range: 1–9) including autologous stem cell transplant (60%), thalidomide (58%) and bortezomib (48%). Out of the 26 evaluable patients, 2 (8%) achieved PR and 3 (12%) MR. Eight patients (31%) remained in stable disease (SD). Due to the synergism with dexamethasone observed in the in vitro studies, the protocol was amended to allow the addition of this agent in pts progressing after 3 cycles or with SD after 4 cycles. With a median follow-up of 14 months (range: 6.8–16.3), the time to progression in responding pts was 5.8 months (4.9–7.6). The most common G3-4 adverse events were fatigue (7%), serum creatine phosphokinase increase (7%), muscle toxicity (10%) and hepatic toxicity (10%). No significant hematologic toxicity or neuropathy was observed.
Conclusion Aplidin® is effective both as a single agent and in combination with dexamethasone in the in vitro and in vivo settings. Its activity in relapsed/refractory MM patients is promising with an acceptable toxicity profile.