Cyclophosphamide Maintenance Therapy Is a Safe and Effective Alternative In Multiple Myeloma Patients Who Undergo Autologous Stem Cell Transplantation
Authors: Byrne Michael T. , Moreb Jan S 
Published: October 2019

Background
In spite of recent improvements in survival, multiple myeloma (MM) remains an incurable disease. Following autologous stem cell transplantation (ASCT), maintenance therapy has been shown to improve progression free survival (PFS) but data on overall survival (OS) is mixed. The expense of therapy is significant and a substantial number of patients are unable to tolerate its toxicity. In this study, we report our experience with the use of oral cyclophosphamide ± prednisone (CY) as an alternative for these patients.

Methods
From January of 2000 to December of 2010, we retrospectively evaluated all patients with MM who underwent ASCT at our institution and separated them into four groups depending on maintenance therapy: No maintenance, interferon ± prednisone (IFN/Pd), IMIDs, and CY. Patients who received maintenance after their first relapse were analyzed separately for tolerability, PFS, and OS. Survival data was analyzed by logrank test and the group characteristics were compared using an unpaired t-test.

Results
A total of 288 patients underwent ASCT at our institution from 2000 to 2010. Of these patients, 8 were excluded due to insufficient follow-up. 1 patient who received bortezomib was also excluded. The median age at diagnosis was 58.0 years and the median time from diagnosis to ASCT was 8.3 months. Collectively, this cohort included 193 Caucasians, 64 African Americans, 16 Hispanics, 4 Asian and 2 unknown race; 55.7% were men and 44.3% were women. Following ASCT, 112 patients received no maintenance therapy, 74 of them (66.1%) had documented relapses with a median PFS of 18.2 months. 78 patients received IFN/Pd; 55 of them (70.5%) relapsed with a median PFS of 18.4 months. Alternatively, 79 patients were treated with IMIDs with 40 known relapses (50.6%) and a median PFS of 22.5 months. CY maintenance was used in 10 patients; six patients relapsed within a median time of 20.4 months. Collectively, maintenance therapy was associated with a significant improvement in PFS (22.5 vs. 18.2 months, p=0.037) but no difference in OS (45.5 vs. 43.9 months, p=0.29). Among patients treated with maintenance therapy, PFS was superior in the group treated with IMIDs compared to IFN/Pd (22.5 vs. 18.4 months, p <0.001) however there was no improvement in OS (43.1 vs. 46.5 months, p=0.29). PFS was equivocal between CY and all other maintenance (20.4 vs. 22.5 months, p=0.19). OS of first-remission CY vs. other maintenance therapy cannot be calculated due to small sample size. 34.6-38.8% of patients who received non-CY maintenance therapy had toxicity requiring dose reductions or discontinuation whereas 10% of CY patients developed toxicity (Table 1). Following relapse and salvage therapy, 78 patients received non-CY second-remission maintenance therapy with a median PFS of 9.2 months whereas those treated with second-remission CY (n=25) had a median PFS of 11.7 months (p=0.89). OS was comparable between the two groups (69.2 vs. 79.8 months, p=0.44). Patients who received CY, however, had a significantly longer OS compared to those who did not receive second-remission maintenance therapy (79.8 vs. 41.2 months, p<0.001) and a trend toward improved OS compared to other forms of second remission maintenance (p=0.085). 5.0% of patients in this study developed secondary malignancies: 4 in non-maintenance group, 3 in the IFN/Pd group, 6 in the IMID group, and 1 in the CY group (Table 2).

Conclusions
CY is well tolerated with comparable efficacy to other maintenance drugs in MM, particularly in the second maintenance setting. Our data corroborates published experience that maintenance therapy improves PFS but often fails to impact OS. Such improvement in PFS with conventional maintenance therapy is associated with a high rate of toxicity and an increase in secondary malignancies.

Disclosures:
No relevant conflicts of interest to declare.