Oral Weekly Cyclophosphamide in Combination with Pomalidomide and Dexamethasone for Relapsed and Refractory Myeloma: Report of the Dose Escalation Cohort

The response rate (partial remission and better) of pomalidomide and low dose dexamethasone in myeloma patients who received prior lenalidomide and bortezomib was 34% (Richardson P, Blood 2011, 118; abs 634). In order to augment the response rate of a pomalidomide based therapy, we conducted a phase I trial to evaluate the safety of the addition of oral weekly cyclophosphamide to pomalidomide and a more frequent dose of dexamethasone and plan a phase II randomized trial to assess the efficacy of this strategy in relapsed and refractory myeloma.

Eligible patients had relapsed and refractory myeloma after at least 2 prior therapies and were lenalidomide refractory. Patients received pomalidomide 4mg PO D1–21, dexamethasone 40 mg PO D1–4; 15–19 (20mg if older than 75 years) and oral cyclophosphamide on D1, 8, 15 of a 28 days cycle. Three cyclophosphamide dose levels (300 mg, 400mg and 500mg) were planned in this dose escalation. A dose limiting toxicity (DLT) was defined as one of the following toxicities occurring in cycle 1: febrile neutropenia, grade 3/4 non hematologic toxicity at least possibly related to pomalidomide or cyclophosphamide, grade 4 thrombocytopenia or neutropenia lasting more than 7 days or more than 7 days delay in starting cycle 2 for toxicities. Given the significant tumor burden and/or multiple prior therapies these patients were exposed to, Granulocyte colony stimulating factor support was allowed and encouraged during the phase I portion of the trial including the DLT period consistent with routine medical care. Responses were assessed per the IMWG criteria with the addition of minimal remission (>25% decrease in serum component). This study was approved by the institutional review board.

Between 12/2011 and 6/2012, ten patients were enrolled in the phase I portion. The median age was 69 (range 48–73) years, and 7 were males (70%). The median time from diagnosis to current therapy was 6 years (range 6 months – 15 years). The median number of prior therapies was 5 (range 3–10) and 9/10 patients were bortezomib refractory and all were lenalidomide refractory. In dose level 1, no DLT was noted and 1 patient achieved a very good partial remission (VGPR) and 1 a MR. In dose level 2, 1 patient developed an upper extremity DVT (DLT) and 1 patient developed diverticular rupture in cycle 2. Another patient with a history of colitis had a flare of his colitis which required IV antibiotics during cycle 1 but that was not felt to be related to study drugs. In dose level 2, 1 patient had a VGPR, 2 a partial remission (PR), 1 a MR and 2 stable disease (SD). 6/10 patients had dexamethasone dose reductions and none had pomalidomide or cyclophosphamide dose reductions. Grade 3/4 neutropenia, and thrombocytopenia occurred in 5 (50%), 3 (30%) patients. 1 patient had febrile neutropenia. Based on the above, further dose escalation of cyclophosphamide was not planned and the recommended phase II dose (RP2D) of cyclophosphamide was 400 mg PO D1, 8, 15 in combination with pomalidomide and low dose dexamethasone.

The recommended phase II dose of cyclophosphamide in combination with pomalidomide and dexamethasone was 400 mg PO D1, 8, 15. Toxicities are manageable and the regimen has evidence of preliminary efficacy. Enrollment on the randomized phase II study is ongoing and updated safety data will be presented at the meeting.

[a] 1 patient was not evaluable for DLT in the first cycle and was replaced because she took 50 mg of oral cyclophosphamide instead of 300 mg weekly in error.

[b] 1 patient developed an upper extremity DVT which was considered a DLT. In addition, 1 patient with a history of colitis had a flare of his colitis which was not felt to be treatment related. 1 patient developed diverticular rupture in cycle 2.

Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Off Label Use: Pomalidomide for relapsed multiple myeloma. Alsina:Millenium: Consultancy, Research Funding. Martin:celgene: Consultancy.