Pomalidomide (Pom) Dexamethasone (D) With Or Without Oral Weekly Cyclophosphamide (Cy) For Lenalidomide Refractory Multiple Myeloma (LRMM): A Multicenter Randomized Phase II Trial

PomD results in an overall response rate of 30% and median PFS of 3.8 months in patients with prior lenalidomide (L) and bortezomib (Vij et al. ASCO 2012). We thought to investigate the addition of oral weekly Cy to PomD in patients with LRMM. We have previously reported that the recommended phase II dose of Cy with standard dose Pom D was 400 mg PO D1, 8, 15. We herein report aggregated results of the phase I/II trial.

Eligible patients had relapsed and refractory myeloma after at least 2 prior therapies and were L refractory. Patients had a platelet count≥50,000/ mm3 and ANC≥1,000/mm3 (patients with ≥50% bone marrow plasmacytosis were allowed if platelet count ≥30,000/mm3 and ANC could be supported with GCSF during screening and therapy). In the phase II portion, patients were randomized (1:1) to receive pomalidomide 4mg PO D1-21, dexamethasone 40 mg PO D1,8,15,22 (20mg if older than 75 years) with or without oral cyclophosphamide 400 mg PO D1, 8, 15 of a 28 days cycle. Patients randomized to PomD were allowed to cross over to the PomCyD in the event of disease progression. Thromboprophylaxis was mandated with aspirin, warfarin or LMWH. Responses were assessed per the IMWG criteria with the addition of minimal response (MR, ≥25% decrease in serum component).

Between 1/2012 and 7/2013, 70 patients were enrolled (10 in the phase I portion) and 30 patients were randomized to the PomCyD and 30 to PomD. The median age was 65 years (range 44-80) and 41 (58%) were male. The median number of prior therapies was 5 (range 2-14). All patients were lenalidomide refractory and 55 (79%) were refractory to proteasome inhibitors. 19 patients (27%) had high risk cytogenetics (del 17p, t(4;14), t(14;16)) of which 12 patients (17%) had del 17p. In addition, 15 (21%) had 1q21 trisomy or tetrasomy. Aggregated responses are reported for the cohort. Of the 66 patients evaluable for response, 1 achieved a CR, 10 achieved a VGPR (15%), 21 achieved a PR (32%), 13 achieved a MR (20%) and 11 achieved SD (16%). The overall response rate (PR and better) was 48.5% and the clinical benefit rate (MR and better) was 68.2%. The median progression free survival (PFS) was 6.4 months (95% CI 2.6-10.2). Patients with ≥PR had a median duration of response of 10.4 months (95% CI 6.1-14.7). The most common grade ¾ adverse event regardless of attribution were neutropenia (30% of patients), febrile neutropenia (13%), pneumonia (13%), thrombocytopenia (11%) while grade 3/4 thromboembolic events were noted in 4%.

The aggregate response rates (≥PR in 48%) and PFS of this all oral regimen compare favorably with published results using PomD in LRMM. Enrollment on the randomized phase II trial continues. Per protocol and to avoid alpha-spending, non-aggregated results of the two arms will be presented at the meeting.

Baz:Sanofi: Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Off Label Use: pomalidomide dexamethasone in combination with cyclophosphamide for relapsed refractory myeloma. Alsina:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Shain:Celgene: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Wolf:Celgene: Honoraria, Research Funding; Millenium: Honoraria; Onyx: Honoraria. Mahindra:millenium: Membership on an entity’s Board of Directors or advisory committees. Chari:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Jagannath:Millennium: Honoraria; Celgene: Honoraria.