the Safety and Efficacy of Pomalidomide in Combination with Cyclophosphamide and Dexamethasone (PCD) in the Transplant-Ineligible Patients with Relapsed and/or Refractory Multiple Myeloma (MM) Who Had Lenalidomide Plus Dexamethasone (LD) Following Frontline Bortezomib Combined Chemotherapy, Open-Labeled, Multicenter Phase II Study

Background : Bortezomib, melphalan and prednison is most commonly used as frontline treatment in patients with newly diagnosed multiple myeloma (MM) who were ineligible for high-dose therapy in Korea. The second-line lenalidomide plus dexamethasone can be tried when the bortezomib-containing treatment failed to salvage the patients. Patients who have relapsed MM after exposure to the above agents and have progressive disease have a short life expectancy. Tolerable third-line therapy is needed for retrieving elderly patients hereafter. Therefore, a clinical trial in which the efficacy and safety of the completely oral regimen, pomalidomide, cyclophosphamide and prednisone (PCD) were combined for treatment failure in both bortezomib and lenalidomide was conducted in Korea.

Methods : This clinical trials began in June 2015 and the study protocol was approved by the institutional review board of each participating fourteen hospital. The treatment scheme was pomalidomide 4mg day 1-21, dexamethasone 40mg once weekly and oral cyclophosphamide 400mg day 1, 8, 15. And then the dose of dexamethasone can be reduced when at least a minimal response is achieved after 3 months of treatment with the initial dose. Three months later (6 months after the initial treatment), the response remains in stable disease, second dose reduction (dexamethasone 10mg or prednisone 50mg) will be carried out. The first objective of the study is progression free survival (PFS), and the second is overall survival (OS), overall response rates (ORR), duration of response, toxicities. The enrolled patients were ineligible for autologous stem cell transplantation and must be relapse refractory to initial therapy with bortezomib, melphalan and prednison and then lenalidomide plus dexamethasone.

Results : This study is currently underway and 49 out of 55 target registered subjects (89%) are registered. During this time, 6 died, and 14 patients were discontinued due to progression of disease. Four patients had discontinued medication due to side effects, and three patients had withdrawal of consent and failed follow-up. Currently, 19 patients are taking clinical trial drugs. Six deaths were reported: 2 septic shocks, 1 heart failure, 1 colonic perforation, and 2 pneumonia. However, the number of death-related events was associated with the severity of neutropenia associated with the initial cyclophosphamide doses at the beginning of the study and the deaths due to sepsis or pneumonia. Subsequently, the doses of cyclophosphamide were actively reduced according to the blood test results, and Since then, there have been few deaths. To date, the results of the intermediate response evaluation were confirmed as CR (10.4%), VGPR (8.3%), PR (37.5%) and MR (14.5%). The ORR including PR was 56.2% and the ORR including MR was 70.7%. The survival analysis results of this study have not yet been confirmed.

Conclusions : The Phase 2 clinical trials are ongoing to confirm the efficacy and safety of PCD in relapsed and/or refractory MM. The results of the response evaluation and the survival analysis will be reported with the final analysis results after the completion of the further study.