Pooled Safety Analysis From Phase (Ph) 1 and 2 Studies of Carfilzomib (CFZ) In Patients with Relapsed and/or Refractory Multiple Myeloma (MM)
Authors: Singhal Seema B. , diCapua Siegel David Samuel , Martin Thomas , Vij Ravi , Wang Michael , Jakubowiak Andrzej J , Lonial Sagar , Kukreti Vishal , Zonder Jeffrey A. , Wong Alvin F. , McCulloch Leanne , Kauffman Michael , Badros Ashraf Z. , Niesvizky Ruben , Orlowski Robert Z. , Stewart A. Keith , Jagannath Sundar 
Published: October 2019

Abstract
Abstract 1954

Background:
Carfilzomib (CFZ) is a novel, highly selective epoxyketone proteasome inhibitor that produces potent and sustained proteasome inhibition both in vitro and in vivo. CFZ appears to lack many of the off-target activities frequently associated with bortezomib (BTZ). This lack of off-target activity may account for observed differences in tolerability seen with CFZ including lack of significant neuropathy and minimal neutropenia and diarrhea. To date, single agent CFZ has been evaluated in Ph 1 and 2 studies in >600 patients, and the vast majority of patients treated had relapsed and/or refractory (R/R) MM. In these settings, CFZ has demonstrated durable single-agent activity and was well-tolerated in patients with advanced stage disease with co-morbidities including baseline neuropathy or renal insufficiency. Here we present the results of parallel safety analyses of patients from four Ph 1 and 2 studies with CFZ.

Materials and Methods:
The present safety analyses were based on data accumulated from patients enrolled in the following trials: PX-171-003 A0 (R/R MM), PX-171-003 A1 (R/R MM), PX-171-004 (relapsed MM), and PX-171-005 (R/R MM with varying degrees of renal function). In all studies, the treatment schedule was based on a 28-day cycle, dosing CFZ QDx2 each week for 3 weeks (Days 1, 2, 8, 9, 15, 16) with 12 days of rest. Doses of CFZ ranged from 15–20 mg/m2 in cycle 1 (005 [15 mg/m2], 003 A0 and A1, 004 [20 mg/m2]). In three studies CFZ was escalated to 27 mg/m2 after the first cycle, as tolerated (003- A1, 004-BTZ naïve subset and 005). In PX-171-005, low-dose dexamethasone was added in the majority of patients.

Results:
CFZ was well-tolerated by patients across the 4 studies analyzed. The most common treatment-emergent adverse events (AEs) included fatigue, anemia, nausea, dyspnea, and thrombocytopenia. Detailed descriptions of the incidence of treatment-related AEs (all Grades (G) in ≥25% of pts; ≥G3 in ≥5% of pts) across studies are presented in the table.
Peripheral neuropathy (PN) occurred infrequently across all 4 studies (N= 517), with only 20 patients (3.9%) experiencing PN of any G and only 2 patients (0.4%) with G3 PN. Febrile neutropenia was likewise uncommon, occurring in only 3 patients (0.6%). Serious treatment emergent AEs (SAEs) occurring in ≥1% of patients and considered possibly/probably related to study drug across all 4 studies included: pneumonia (3.5%), congestive cardiac failure (2.5%), acute renal failure (1.7%), pyrexia (1.2%), and dyspnea (1%).

Conclusions:
Despite a substantial disease burden present in the patient populations described here, CFZ was well-tolerated by patients with MM across all studies examined. The excellent safety/tolerability profile of CFZ has permitted prolonged administration (in some cases over 24 mos of continuous therapy including extension study) with minimal dose modifications or discontinuations due to toxicity. The low levels of neuropathy seen with CFZ make this agent a potentially important treatment option for patients with pre-existing neuropathy from either underlying disease or prior neuropathic anti-myeloma therapy.

Disclosures:
Singhal: Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martin:Celgene: Honoraria; Onyx: Consultancy. Vij:Onyx: Honoraria. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotec: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. McCulloch:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Niesvizky:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding. Stewart:Millennium: Consultancy; Celgene: Honoraria. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.