High Dose Fractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (mHyperCVAD) Is an Active Regimen in Heavily Pretreated Relapsed/Refractory Multiple Myeloma, Enabling Access to Experimental Therapies

Background

Therapeutic advancements and deeper understanding of disease biology have helped improve the outcomes of multiple myeloma (MM). However, there is no consensus regarding the optimal management of patients whose disease becomes refractory to the three main class of drugs [proteasome inhibitors (PI), immunomodulatory drug (IMiD), and monoclonal antibodies (mab)] or among those presenting with complications secondary to rapidly progressive disease. While chimeric antigen receptor T-cell (CAR-T) and bispecific T-cell engagers have yielded high rates of durable responses, access to these therapies in clinical trials is often hindered by high disease burden compromising eligibility. We evaluated the use of a combination of cytotoxic agents (cyclophosphamide, doxorubicin, vincristine, and dexamethasone; mHyperCVAD) in this challenging population.

Methods

This is a retrospective, single center study evaluating the safety/tolerability and efficacy of mHyperCVAD in relapsed and refractory MM (RRMM). The regimen consists of cyclophosphamide 300 mg/m2 IV every 12 hours on D1-4 (total 2400 mg/m2), vincristine 0.4 mg/day IV continuous infusion D1-4 (total 1.6 mg), doxorubicin 9 mg/m2/day IV continuous infusion D1-4 hours (total 36 mg/m2) and dexamethasone 40 mg PO daily D1-4. Adult patients with RRMM were included if they received ≥1 cycle of mHyperCVAD between 2019-2021. Patients with primary plasma cell leukemia were excluded. Response was assessed by International Myeloma Working Group Uniform Criteria. Overall response rate (ORR) and disease control rate (DCR) were defined as ≥ partial response and ≥ stable disease, respectively. Patients were censored for progression free survival (PFS) at the last follow-up date if neither progression nor death occurred. All patients received growth factors, and infectious disease prophylaxis per institutional standard. Toxicities were graded using CTCAE v5.0 up to 30 days post therapy.

Results

Between 1/2019 and 7/2021, 39 patients met the inclusion criteria and received 44 courses of mHyperCVAD (four patients received mHyperCVAD at more than one timepoint). The median age was 54 years (range 32-71), 56% male. 36% patient had ISS stage III disease and 56% had high risk disease [t(4;14), t(14;16), del17p, +1q]. The median lines of therapy prior to mHyperCVAD were 3 (range 1-12) with 93% triple class refractory (refractory to PI, IMID and mab) and 64% penta-refractory (refractory to 2 PI, 2 IMiDs and mab) and 76% had received a prior autologous transplant. The median number of mHyperCVAD cycles per course was 1 (range 1-8). Baseline characteristics are summarized in Table. Eleven courses (25%) were administered as bridge after lymphocyte collection for the manufacture of CAR-T cells and prior to lymphodepletion chemotherapy (100% triple class refractory and 91% penta-refractory) with ORR 18% and DCR 72%. Thirty-three courses (75%) were used as salvage for rapid disease control. The most common toxicities with mHyperCVAD were hematologic (65% grade 3/4 toxicities) with 20% incidence of febrile neutropenia. Four patients died during mHyperCVAD therapy due to rapidly progressive disease and one patient died due to sepsis.

For the entire cohort, the ORR is 50% (≥VGPR 30%) with a DCR 82%. Additionally, 39% could proceed with experimental CAR-T cells and/or bispecific T cell engagers. The median progression free survival is 3.6 months, and the median overall survival is 8 months from start of mHyperCVAD with 10.5 months median follow up. The most common cause of death was progressive disease (39%).

Conclusion

mHyperCVAD is an efficacious cytotoxic chemotherapy regimen which can achieve rapid disease control allowing patients an opportunity to proceed with additional therapies, including investigational agents on clinical trials. It can also be used as an effective bridging strategy among heavily treated, triple class and penta-refractory MM awaiting manufacturing of CAR-T cells with manageable and expected toxicities.

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