Addition of Cyclophosphamide to Pomalidomide and Dexamethasone in Case of Suboptimal Response to Pomalidomide and Dexamethasone Alone in Relapsed and/or Refractory Multiple Myeloma: Results of the GMMG-Perspective Trial

Introduction: Pomalidomide (POM) + dexamethasone (Dex) is a standard treatment in relapsed and refractory multiple myeloma (RRMM) resulting in an overall response rate (ORR) of approximately 30% and a median progression-free survival of 4.0 months (San Miguel et al., Lancet Oncol 2013). Patients responding to POM + Dex show extended progression-free (PFS) and overall survival (OS) (Moreau et al., Leuk Lymphoma 2016). Cyclophosphamide (CY) is an alkylating agent showing anti-myeloma activity with potential synergistic effects to immunomodulating agents as POM and lenalidomide. Previously, it was shown that addition of CY to lenalidomide overcomes lenalidomide-resistance in a marked proportion of patients (Nijhof et al., Blood 2016). The GMMG-PERSPECTIVE trial (Eudra-CT No. 2013‐003678‐29) is a phase II multicenter investigator initiated trial in RRMM patients investigating efficacy when CY is added to POM + Dex standard treatment in case of primary progression or less than partial remission (PR) after 3 treatment cycles of POM + Dex as a tailored treatment strategy. The primary objective of the trial is to demonstrate that the objective response rate (ORR) exceeds 30%, key secondary endpoints are PFS, OS and safety.

Methods: 60 patients with RRMM after at least 2 prior treatment lines including bortezomib and lenalidomide and not or no more responding to the last prior regimen were included. All 60 patients received at least one dose of study medication and were included in safety analyses. 59 patients were eligible for the intention-to-treat (ITT) analysis of the primary and secondary endpoints. Patients received standard dose of POM + Dex (POM 4 mg day 1-21, Dex 40 mg day 1, 8, 15, 22 of a 28-day cycle with age-adjusted reduction of Dex to 20 mg weekly in patients > 75 years of age). In case of no PR or better after 3 cycles and/or disease progression (PD) during cycle 1-3, CY in a dose of 500 mg/m² intravenously day 1 and 15 per cycle was added. Patients were treated until PD or unacceptable toxicity. Planned maximum of cycles with CY was 12. In an early analysis after a median follow-up of 20.1 months, ORR as primary endpoint, PFS from start of CY treatment as secondary endpoint, and safety data were investigated. The final PFS and OS analysis will be presented at the meeting.

Results: From June 2014 to August 2015, 60 patients were included into the trial. Median age was 67.0 (range 47-81) years, median number of prior treatment lines was 3 (2-5). 45% of evaluable patients had cytogenetic high-risk disease defined by one or more of the cytogenetic abnormalities t(4;14), del17p and more than 3 copies of 1q21. ORR (≥ PR) was not significantly ≥30% for the ITT population with an ORR rate of 39.0% but a lower 95% confidence bound of 29.2%. PR was reached in 14 (23.7%), very good partial remission (VGPR) in 7 (11.9%) and complete remission (CR) in 2 (3.4%) patients. In an exploratory analysis of patients who were treated as per protocol, 22/44 patients reached ORR (ORR = 50%, lower 95% confidence bound 38.0%) with PR in 13 (29.6%), VGPR in 7 (15.9%), and CR in 2 (4.5%) patients. 36/59 patients received CY after a median time of 2.9 months (1.1-4.4 months). At the time of addition of CY 16 patients had PD, 15 stable disease (SD) and 5 showed minimal response (MR). 13/36 patients with addition of CY to POM + Dex achieved a response: 8 PR (22.2%), 3 VGPR (8.3%), 2 CR (5.6%). Median PFS from start of CY was 5.0 months. Main hematologic toxicities ≥ grade 3 were neutropenia in 25 (42%), anemia in 16 (27%), leukopenia in 15 (25%) and thrombocytopenia in 9 (15%) patients. Main non-hematologic toxicities ≥ grade 3 were pneumonia in 11 (18%) patients. Final PFS and OS analysis will be presented at the meeting.

Conclusion: In RRMM patients, addition of CY to standard POM + Dex treatment is able to induce deep and durable remissions in a marked proportion of patients not responding to POM + Dex alone. With a favorable toxicity profile of the triple combination, primary addition of CY to POM + Dex should be considered in future to further optimize efficacy and durability of responses in POM standard treatment.