High-Dose Cyclophosphamide in Highly Refractory Multiple Myeloma Patients As a Bridge to Further Novel Therapies

Background:

Despite major advances in the treatment of multiple myeloma with novel therapies including proteozome inhibitors and immunomodulatory drugs, most patients during the course of their disease will become refractory to all agents. The prognosis of such patients is very poor. Some patients have extensive bone marrow involvement with resulting cytopenias, making them ineligible for clinical trials. The alternative route using aggressive cytoreduction therapies such as VTD-PACE, DCEP, V-DCEP, may have a limited role to serve as debulking agents and as a bridge to a next line of therapy because of their overwheming toxicity. In this pilot study, we chose to treat refractory patients with single agent high dose cyclophosphamide (HDCY), combined with dexamethasone, with the aim to bridge responding patients to a next line of therapy.

Objectives:

Primary outcome: to assess overall response rate (ORR). Secondary outcomes: to assess progression free survival (PFS) and overall survival (OS).

Methods:

Prospective cohort study of patients treated between April 2013 and April 2016 at the Montreal Jewish General Hospital with HDCY, 1.2gr/m2, day 1 and 3, q21days x 4, and dexamethasone, 40mg PO, Q week. All patients received neupogen and levaquin as prophylaxis. PFS was defined as the time between initiation of HDCY and the date of first documented disease progression or death from any cause. Response was assessed by IMWG 2014 criteria. Responders included patients achieving ≥ PR. Kaplan Meier method was used to calculate progression-free and overall survival.

Results:

A total of 18 patients was included in the analysis. The median age was 61years (range, 44-71), median time from diagnosis until HDCY treatment was 57 months (range, 5-108). Patients were heavily pretreated, with median 4 prior lines of therapy (range, 1-7). All patients had been refractory to their last line of therapy. Seventeen patients (94%) were refractory to both bortezomib and lenalidomide containing regimens, and sixteen patients (88%) had an ASCT. Median number of HDCY cycles administered was 4 (range, 2-5). Median follow up was 10 months. ORR to HDCY was 55%, with three patients achieving CR (15%). Twelve patients (67%) went on to further therapies after achieving at least stable disease. Median PFS was 6 months, and median OS was 12 months. This regimen was complicated almost exclusively by hematological toxicity, with 14 out 18 patients experiencing G4 neutropenia. Thirteen patients were admitted for febrile neutropenia. There were no treatment related mortality.

Conclusion:

HDCY with dexamethasone has proven to be in this small prospective study a highly efficient rescue regimen for double refractory, advanced stage disease myeloma patients, providing the opportunity to bridge the majority of these patients to further novel therapies, also including a second ASCT.