Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma.
Thalidomide (Thal) can overcome drug resistance in multiple myeloma (MM) but is associated with somnolence, constipation, and neuropathy. In previous in vitro studies, we have shown that the potent immunomodulatory derivative of thalidomide (IMiD) CC-5013 induces apoptosis or growth arrest even in resistant MM cell lines and patient cells, decreases binding of MM cells to bone marrow stromal cells (BMSCs), inhibits the production in the BM milieu of cytokines (interleukin-6 [IL-6], vascular endothelial growth factor [VEGF], tumor necrosis factor-alpha [TNF-alpha]) mediating growth and survival of MM cells, blocks angiogenesis, and stimulates host anti-MM natural killer (NK) cell immunity. Moreover, CC-5013 also inhibits tumor growth, decreases angiogenesis, and prolongs host survival in a human plasmacytoma mouse model. In the present study, we carried out a phase 1 CC-5013 dose-escalation (5 mg/d, 10 mg/d, 25 mg/d, and 50 mg/d) study in 27 patients (median age 57 years; range, 40-71 years) with relapsed and refractory relapsed MM. They received a median of 3 prior regimens (range, 2-6 regimens), including autologous stem cell transplantation and Thal in 15 and 16 patients, respectively. In 24 evaluable patients, no dose-limiting toxicity (DLT) was observed in patients treated at any dose level within the first 28 days; however, grade 3 myelosuppression developed after day 28 in all 13 patients treated with 50 mg/d CC-5013. In 12 patients, dose reduction to 25 mg/d was well tolerated and therefore considered the maximal tolerated dose (MTD). Importantly, no significant somnolence, constipation, or neuropathy has been seen in any cohort. Best responses of at least 25% reduction in paraprotein occurred in 17 (71%) of 24 patients (90% confidence interval [CI], 52%-85%), including 11 (46%) patients who had received prior Thal. Stable disease (less than 25% reduction in paraprotein) was observed in an additional 2 (8%) patients. Therefore, 17 (71%) of 24 patients (90% CI, 52%-85%) demonstrated benefit from treatment. Our study therefore provides the basis for the evaluation of CC-5013, either alone or in combination, to treat patients with MM at earlier stages of disease.
Richardson
Paul G
PG
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Schlossman
Robert L
RL
Weller
Edie
E
Hideshima
Teru
T
Mitsiades
Constantine
C
Davies
Faith
F
LeBlanc
Richard
R
Catley
Laurence P
LP
Doss
Deborah
D
Kelly
Kathleen
K
McKenney
Mary
M
Mechlowicz
Julie
J
Freeman
Andrea
A
Deocampo
Reggie
R
Rich
Rebecca
R
Ryoo
Joan J
JJ
Chauhan
Dharminder
D
Balinski
Kathe
K
Zeldis
Jerome
J
Anderson
Kenneth C
KC
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D003131:Combined Modality Therapy; D003248:Constipation / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology; D009194:Myeloma Proteins / Q000032:analysis; D009422:Nervous System Diseases / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D036102:Peripheral Blood Stem Cell Transplantation; D012074:Remission Induction; D012449:Safety; D016879:Salvage Therapy; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced; D014182:Transplantation, Autologous; D016896:Treatment Outcome
D000276:Adjuvants, Immunologic; D009194:Myeloma Proteins; D013792:Thalidomide; D000077269:Lenalidomide