ClaPD (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma

The addition of clarithromycin has been reported to enhance anti-myeloma activity of lenalidomide+dexamethasone in the upfront treatment of multiple myeloma (MM). Pomalidomide is a distinct IMiD^® immunomodulatory agent with a significant response rate in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide treatment. We have shown initial results that clarithromycin may similarly enhance the activity of pomalidomide + dexamethasone in patients with RRMM after prior lenalidomide therapy (Rossi et al, ASCO 2012). We now report updated results from a phase 2 trial of large group of patients treated with ClaPD in RRMM.

One hundred patients with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPD. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; pomalidomide 4mg for days 1–21 of a 28-day cycle, and dexamethasone 40mg on days 1,8,15,22. All subjects had thromboprophylaxis with 81mg aspirin daily. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patient until disease progression.

Ninety-seven patients had completed at least 1 cycle of ClaPD and were eligible for disease response and safety analysis. Patients had undergone a median of 5 (range 3–15) prior lines of therapy. The proportion of patients who were refractory to lenalidomide, refractory to bortezomib, and double (lenalidomide +bortezomib) refractory were 73%, 70%, and 64% respectively. The median number of ClaPD cycles received was 4 (range 1–23). Response to ClaPD was progressive disease (PD): 9.3%, stable disease (SD): 32%, minimal response (MR): 5.2%, partial response (PR): 32%, very good partial response (VGPR): 17.5%, stringent complete remission (sCR): 4.1%, giving an overall response rate (ORR, ≥PR) of 53.6% and a ≥VGPR rate of 21.6%. Clinical benefit (≥SD) was achieved in 90.7%. Median time to PR and maximum response was 1 (range 1–7) and 2 (range 1–14) cycles, respectively. After a mean follow up time of 10.1 months, 41 patients (42%) remain on study free from disease progression, with a median progression free survival of 8.2 months (95% CI: 5.1, 10.3). Median overall survival has not been reached with 72 patients (74%) alive at last follow-up. The most common grade 3 and 4 toxicities included anemia (25%), neutropenia (40%), hyperglycemia (11%), and fatigue (6%). Febrile neutropenia was uncommon at 2%. There were 4 cases of lower extremity venous thrombosis (4.1%, 1 at grade 1, 3 at grade 2) and no instances of pulmonary embolism. There was no treatment related mortality.

ClaPD is a highly effective regimen for heavily treated RRMM that has progressed after prior treatments. Response to ClaPD is rapid and sustained at > 8 months in the majority of subjects. The tolerability profile is comparable to lenalidomide and incidence of thromboembolic events was low with low-dose aspirin prophylaxis. These data support the use of pomalidomide therapy in RRMM that has progressed after lenalidomide.

Mark:Celgene Corp: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium Inc.: Speakers Bureau. Off Label Use: Pomalidomide is not indicated to treat multiple myeloma. This drug is a next-generation immunomodulatory agent. We are investigating its activity and safety for use in relapsed or refractory myeloma. Zafar:Celgene Corp: Speakers Bureau. Pekle:Celgene Corp: Speakers Bureau. Coleman:Celgene Corp: Speakers Bureau. Niesvizky:Onyx, Millenium, Celgene. Speakers bureau: Millenium and Celgene: Consultancy, Research Funding.