Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma.
Dysregulation of cyclin-dependent kinases is a hallmark of myeloma, and specifically, cdk5 inhibition can enhance the activity of proteasome inhibitors in vitro. Dinaciclib is a novel potent small molecule inhibitor of cyclin-dependent kinases (CDK)1, CDK2, CDK5, and CDK9. Patients with relapsed multiple myeloma and ≤5 prior lines of therapy, with measurable disease, were enrolled. Dinaciclib was administered on day 1 of a 21-day cycle at doses of 30 to 50 mg/m(2). Overall, 27 evaluable patients were accrued; the median number of prior therapies was 4. The dose level of 50 mg/m(2) was determined to be the maximally tolerated dose. The overall confirmed partial response rate (PR) was 3 of 27 (11%), including 1 patient at the 30 mg/m(2) dose (1 very good PR [VGPR]) and 2 patients at the 40 mg/m(2) dose (1 VGPR and 1 PR). In addition, 2 patients at the 50 mg/mg(2) dose achieved a minimal response (clinical benefit rate, 19%). Leukopenia, thrombocytopenia, gastrointestinal symptoms, alopecia, and fatigue were the most common adverse events. The current study demonstrates single agent activity of dinaciclib in relapsed myeloma, with 2 patients achieving a deep response (VGPR) and 10 patients obtaining some degree of M protein stabilization or decrease. This trial was registered at www.clinicaltrials.gov as #NCT01096342.
Division of Hematology and.
Shaji K
http://orcid.org/0000-0001-5392-9284
SK
Kumar
Department of Biostatistics, Mayo Clinic, Rochester, MN;
Betsy
B
LaPlant
Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore;
Wee Joo
WJ
Chng
Karmanos Cancer Center, Detroit, MI;
Jeffrey
J
Zonder
Section of Hematology and Bone Marrow Transplant, University of Wisconsin, Madison, WI;
Natalie
N
Callander
Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ;
Rafael
R
Fonseca
Department of Biostatistics, Mayo Clinic, Rochester, MN;
Briant
B
Fruth
Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL; and.
Vivek
V
Roy
Division of Medical Oncology, Mayo Clinic, Rochester, MN.
Charles
C
Erlichman
Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ;
A Keith
AK
Stewart
D000368:Aged; D000369:Aged, 80 and over; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007212:Indolizines; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011726:Pyridinium Compounds / Q000627:therapeutic use*; D015996:Survival Rate
D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D007212:Indolizines; D047428:Protein Kinase Inhibitors; D011726:Pyridinium Compounds; C553669:dinaciclib; D018844:Cyclin-Dependent Kinases