Retrospective Analysis of Modified Hyper-CVAD Therapy Combined with Proteasome Inhibition for Patients with Multiple Myeloma and Renal Insufficiency or Renal Failure
Authors: Galligan Derek , Narayan Rupa , Kim Sarah , Lazar Ann , Tan Marisela , Fong Richard , Lo Mimi , Shah Nina , Arora Shagun , Wong Sandy W. , Martin Thomas G. , Wolf Jeffrey Lee 
Published: October 2019

Abstract
Background: While novel agents have allowed for successful outpatient treatment of patients with multiple myeloma (MM), multi-agent infusional chemotherapy regimens continue to have a role, particularly in high burden disease states. However, the use of platinum-based regimens is limited in patients with renal insufficiency and renal failure. We have been using a modified hyperCVAD regimen, termed HyperCD (Table 1), with omission of vincristine, and inclusion of a proteasome inhibitor (PI, either bortezomib or carfilzomib) in these aggressive clinical presentations for rapid tumor reduction. Here we present our experience with this treatment modality, with analysis of treatment outcomes and toxicities in the renal insufficiency subset.
Methods:We performed a single-center chart review of all MM patients at our institution with available electronic medical records who received at least one HyperCD cycle in the setting of concurrent renal insufficiency (defined by estimated eGFR <50mL/min by CKD-EPI at treatment start) between 01/2012 and 12/2016. Data on demographics and disease characteristics were collected. Response was determined by IMWG criteria. Progression free survival (PFS) and overall survival (OS) were calculated by Kaplan Meier method, with PFS including progression or death from any cause and censoring at last known follow-up for live patients.
Results: Baseline characteristics: Sixty-seven patients were included in this analysis (Table 2), including 46 non-dialysis dependent and 21 dialysis dependent patients. Median age was 62 years (range 29 - 85). 19% had known prior high-risk cytogenetics defined by t(4;14), t(14;16) and/or 17p(del). Median number of prior lines of therapy was 2 (range 0-14). 34% had prior autologous transplantation. Prior therapies included alkylator therapy in 67%, immunomodulator in 64%, anti-CD38 antibody therapy in 13%, and PI in 87%. Reasons for HyperCD administration included rapidly progressive disease (63%), hypercalcemia (30%), extensive bony (16%) or soft tissue disease (9%), primary (4%) or secondary plasma cell leukemia (7%), and stem cell mobilization (22%). Disease status at time of treatment included new diagnosis (13%), insufficient prior response (18%), and relapsed/refractory or relapsed disease (69%). The median number of cycles administered per patient was 1 (range 1-4), with 55% receiving 1 cycle and 45% receiving 2 or more cycles. The median creatinine at therapy start was 2.93 (range 1.15-8.98).
Responses: Of 23 patients on dialysis, 8 (35%) were able to discontinue either during or sometime after therapy. Median percent improvement in creatinine after therapy among non-dialysis patients was 24% (p=0.0001 by wilcoxon signed rank). The overall response rate (ORR) was 69% (46/67), with 1% complete responses (CR), 28% very good partial responses (VGPR), and 39% partial responses (PR). The median time to PR or better was 1.1 months, with a median PFS of 5.1 months, and median OS of 21 months. 87% of patients were able to bridge to other therapy including autologous transplantation (22%). 81% of patients have progressed or died at last follow-up, with disease being the most common cause of death (29/34, 85%).
Therapy related toxicities: Median duration of severe neutropenia (ANC</=500/µl) was 4 days (range 0-17) and severe thrombocytopenia (platelets </= 50,000/µl) 7 days (range 0-29), per cycle. 24% of patients had neutropenic fever with documented infections in 37%. Other toxicities included severe bleeding (4%), deep vein thrombosis (7%), and cardiac events (25%), including tachyarrhythmia (9%), demand ischemia (3%), heart failure (2%), pulmonary hypertension (3%), and volume overload (9%). One patient (2%) had potential treatment related mortality (TRM) approximately 3 months after therapy and 1 patient (2%) died within 30 days from progressive disease.
Conclusion: HyperCD-based regimens yielded relatively high response rates in MM patients with renal insufficiency, including renal failure. Several patients discontinued dialysis, with improvement in renal function also seen in non-dialysis patients. While TRM was low, hematologic, infectious, and cardiac toxicities were common. The majority of patients were able to successfully bridge to other therapy. HyperCD-based regimens may thus be a potential alternative to platinum based therapies in myeloma patients requiring intensive infusional chemotherapy.

Disclosures
Shah: Nekktar: Consultancy; Teneobio: Consultancy; Amgen: Consultancy; Sutro Biopharma: Research Funding; Janssen: Research Funding; Nkarta: Consultancy; Indapta Therapeutics: Equity Ownership; Takeda: Consultancy; Celgene: Research Funding; Indapta Therapeutics: Consultancy; Bluebird: Research Funding; University of California San Francisco: Employment; Kite: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy. Wong:Janssen: Research Funding; Roche: Research Funding. Martin:Sanofi: Research Funding; Amgen: Research Funding; Roche: Consultancy. Wolf:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy.