Phase 2 study of dovitinib in patients with relapsed or refractory multiple myeloma with or without t(4;14) translocation.
OBJECTIVE
Approximately 15% of patients with multiple myeloma (MM) exhibit a t(4;14) translocation, which often results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3). This study evaluated the efficacy and safety of dovitinib, an RTK inhibitor with in vitro inhibitory activity against FGFR, in patients with relapsed or refractory MM with or without t(4;14) translocation.


METHODS
Adult patients with relapsed or refractory MM who had received ≥2 prior regimens were enrolled in this multicenter, 2-stage, phase 2 trial. Patients were grouped based on their t(4;14) status. Dovitinib (500 mg/day orally) was administered on a 5-days-on/2-days-off schedule. The primary endpoint was overall response rate by local investigator review (per International Myeloma Working Group criteria). In non-responding patients, treatment could continue with the addition of low-dose dexamethasone.


RESULTS
In total, 43 patients (median age, 63 years) were enrolled (13 t(4;14) positive, 26 t(4;14) negative, and 4 t(4;14) status non-interpretable). Patients had received a median of 5 prior regimens. Median duration of treatment was 8.7 weeks in the t(4;14)-positive group and 3.7 weeks in the t(4;14)-negative group. None of the patients on dovitinib had objective responses. The stable disease rate was 61.5% in the t(4;14)-positive group and 34.6% in the t(4;14)-negative group. Overall, 39 patients (90.7%) had adverse events suspected to be related to study drug, most commonly diarrhea (60.5%), nausea (58.1%), vomiting (46.5%), and fatigue (32.6%).


CONCLUSIONS
Dovitinib showed no single-agent activity in relapsed or refractory MM but may stabilize disease in some t(4;14)-positive patients.
University Hospital of Cologne, Cologne, Germany.
Christof
C
Scheid
Princess Margaret Cancer Centre, Toronto, ON, Canada.
Donna
D
Reece
Ankara University School of Medicine, Ankara, Turkey.
Meral
M
Beksac
Alfred Health-Monash University, Melbourne, Vic., Australia.
Andrew
A
Spencer
University of Wisconsin, Madison, WI, USA.
Natalie
N
Callander
Erasmus Medical Center, Rotterdam, the Netherlands.
Pieter
P
Sonneveld
Novartis Pharmaceuticals, East Hanover, NJ, USA.
Ghulam
G
Kalimi
Novartis Pharmaceuticals, East Hanover, NJ, USA.
Can
C
Cai
Novartis Pharmaceuticals, East Hanover, NJ, USA.
Michael
M
Shi
Novartis Pharmaceuticals, East Hanover, NJ, USA.
Jeffrey W
JW
Scott
Mayo Clinic, Scottsdale, AZ, USA.
A Keith
AK
Stewart
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002883:Chromosomes, Human, Pair 14; D002894:Chromosomes, Human, Pair 4; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012008:Recurrence; D019233:Retreatment; D014178:Translocation, Genetic; D016896:Treatment Outcome
C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D015363:Quinolones
FGFR3; dovitinib; phase 2; relapsed or refractory multiple myeloma; t(4;14) translocation