Phase II clinical and pharmacokinetic study of plitidepsin 3-hour infusion every two weeks alone or with dexamethasone in relapsed and refractory multiple myeloma.
OBJECTIVE
This trial evaluated the antitumor activity and safety of the marine-derived cyclodepsipeptide plitidepsin in patients with relapsed/refractory multiple myeloma.


METHODS
This was a prospective, multicenter, open-label, single-arm, phase II trial with plitidepsin at 5 mg/m(2) as a 3-hour i.v. infusion every two weeks. The protocol was amended to allow patients with suboptimal response to single-agent plitidepsin to add 20 mg/day on days 1 to 4 of oral dexamethasone every two weeks.


RESULTS
Fifty-one patients started treatment with plitidepsin and 47 were evaluable for efficacy. The overall response rate (complete response plus partial response plus minimal response) was 13% with plitidepsin alone and 22% in the cohort of patients with the addition of dexamethasone (n = 19, 18 evaluable). Both plitidepsin alone and with dexamethasone were feasible and well tolerated. Anemia (29%) and thrombocytopenia (18%) were the most frequent grade 3/4 hematologic toxicities. Fatigue (16%), muscular toxicity (6%), and transient alanine aminotransferase/aspartate aminotransferase (27%) and creatine phosphokinase (23%) increases were the most relevant nonhematologic side effects. A prolonged plasma half-life was observed in responding patients as compared with nonresponding patients (P = 0.009).


CONCLUSIONS
Single-agent plitidepsin has limited but reproducible activity in relapsed/refractory multiple myeloma patients. Activity observed after dexamethasone addition merits further study. Both regimens were well tolerated in this heavily pretreated population.
Mateos
María Victoria
MV
Departamento de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain. mvmateos@usal.es
Cibeira
Maria Teresa
MT
Richardson
Paul G
PG
Prosper
Felipe
F
Oriol
Albert
A
de la Rubia
Javier
J
Lahuerta
Juan José
JJ
García-Sanz
Ramón
R
Extremera
Sonia
S
Szyldergemajn
Sergio
S
Corrado
Claudia
C
Singer
Harald
H
Mitsiades
Constantine S
CS
Anderson
Kenneth C
KC
Bladé
Joan
J
San Miguel
Jesús
J
D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D047630:Depsipeptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003907:Dexamethasone / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D010456:Peptides, Cyclic; D012008:Recurrence
D000970:Antineoplastic Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; D003907:Dexamethasone; C098980:plitidepsin