Infectious Complications Following Venetoclax-Proteasome Inhibitor Based Regimens in Relapsed Myeloma: A Single Center Retrospective Analysis
Authors: Sauter Christopher Tor , Bernabei Luca L , Waxman Adam , Cohen Adam D. , Garfall Alfred L. , Vogl Dan T. , Whittington, Sara , Erb Colleen Harker , Mangan Patricia , Sanchez Mary , Stadtmauer Edward A. 
Published: November 2019

Introduction: Venetoclax is an oral BCL2 inhibitor, effective in CLL and under investigation in multiple clinical trials to treat relapsed or refractory multiple myeloma (RRMM) in combination with a proteasome inhibitor (VPI) - either carfilzomib or bortezomib (Moreau P, 2017; Kumar S, 2017). VPI has shown promising initial results in a phase 2 trial with an overall response rate of 78% and a very good partial response or better (≥VGPR) rate of 56% (Costa L J, 2018; Terpos E, 2019). However, a separate phase 3 trial evaluating bortezomib given with venetoclax or placebo found improved response rates and progression free survival but a decrease in overall survival rate in the venetoclax arm of the study (data not published). The primary association with increased mortality was infection. Better characterizing infections in patients treated with VPI may give insight into the pathophysiology and suggest strategies for safe and effective use of this therapy in RRMM.
Methods: We retrospectively reviewed charts of patients treated with VPI for infectious complications from initiation of treatment until one month after progression treated at the Hospital of the University of Pennsylvania. Infections were classified by site, pathogen and severity of infection. Additional data collected included demographics, blood cell counts, quantitative immunoglobulins, SPEP M-spike, light chain analysis, cytogenetics, prior lines of therapy, prophylactic antibiotics and IVIG use. We determined non-monoclonal IgG (NM-IgG) via the difference between serum M-spike and IgG for IgG patients. The two-sample Wilcoxon rank-sum was used to compare different subgroups within our study population.
Results: We identified 18 patients treated with a VPI combination regimen of which 78% were male. The median age was 64.5 years (range 47-76) and a median of 3 (1-10) prior regimens. 14 were treated with carfilzomib and 4 with bortezomib combinations. 4 patients progressed by the time of data collection. 8 patients were positive for t(11;14). 11 patients experienced 35 discrete infectious episodes resulting in 4 hospitalizations. Respiratory infections predominated (29/35) with 24 upper respiratory infections or sinusitis. 4 were lower respiratory infections and comprised all the hospitalizations. Among respiratory infections, viruses were the only pathogens identified, including influenza, rhinovirus, coronavirus and RSV. Other sites of infection were gastrointestinal (including recurrent C. difficile) and urinary tract. No CNS, blood, or intra-abdominal infections were identified. Reductions in lymphocyte counts and non-monoclonal IgG were near universal but significant reductions in neutrophil counts were not observed. A greater proportional reduction of NM-IgG was noted in good-responders, defined as CR and VGPR (≥VGPR, n=9), with a mean of 78% decrease compared to 47% in poor-responders (PR/MR/SD/PD, n=4, p=0.045). Importantly, treatment of those with t(11;14) positive status demonstrated no significant difference in NM-IgG. Additionally, there was a relative risk ratio favoring a reduction in infections among those with t(11;14).
Conclusion: Patients with RRMM treated with VPI experience frequent infectious complications, some severe, with sustained reductions in serum IgG and lymphocyte counts, but without neutropenia. Reduction in NM-IgG is associated with improved response depth. This phenomenon could explain the paradoxical improvement of response rate and progression free survival with concomitant reduction in overall survival due to infections noted by other reports. Interestingly, the presence of t(11;14) in this analysis was not associated with as great a drop in NM-IgG, as was seen in responders as whole, indicating a more differential effect. The absence of significant reduction in NM-IgG is a potential mechanism for relative reduction of infections in this subgroup. Suggestions of survival benefit among t(11;14) positive subgroups in other reports may be related to this preservation of NM-IgG. Replenishing NM-IgG with IVIG is a hypothetical mitigating strategy that could be of benefit in other subgroups treated with this combination of therapy.

Disclosures
Cohen: Poseida Therapeutics, Inc.: Research Funding. Garfall:Surface Oncology: Consultancy; Novartis: Patents & Royalties: inventor on patents related to tisagenlecleucel (CTL019) and CART-BCMA, Research Funding; Janssen: Research Funding; Amgen: Research Funding; Tmunity: Honoraria, Research Funding. Vogl:Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Active Biotech: Consultancy. Mangan:janssen: Speakers Bureau; celgene: Speakers Bureau; takeda: Speakers Bureau; amgen: Speakers Bureau. Stadtmauer:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Abbvie: Research Funding.

OffLabel Disclosure:
venetoclax for myeloma