Baseline Peripheral Neuropathy Does Not Impact the Efficacy and Tolerability of the Novel Proteasome Inhibitor Carfilzomib (CFZ): Results of a Subset Analysis of a Phase 2 Trial In Patients with Relapsed and Refractory Multiple Myeloma (R/R MM)

Treatment-induced peripheral neuropathy (TIPN) can be a debilitating side-effect as well as a therapy-limiting complication in multiple myeloma (MM). Thalidomide (THAL) and bortezomib (BTZ) are two therapies frequently associated with TIPN in MM. Carfilzomib (CFZ) is a novel and highly selective epoxyketone proteasome inhibitor that differs from BTZ both structurally and mechanistically. CFZ overcomes BTZ-resistance in vitro, lacks the off-target activities of BTZ in preclinical studies, and does not cause neurotoxicity in long-term (6–9 month) chronic animal toxicology studies (Kirk et al. Blood, 2008). Single-agent CFZ produces durable responses in relapsed or refractory (R/R) MM without dose-limiting PN. Here we report on the clinical experience with single-agent CFZ in the Ph 2b PX-171-003-A1 trial in patients (pts) with R/R MM and Grade (G) 1/2 PN at study entry.

Pts received CFZ at 20 mg/m² IV, on Days 1, 2, 8, 9, 15, and 16 in a 28-day cycle (C) for the first C followed by 27 mg/m² thereafter for up to 12 C. Pts completing 12 C were eligible to enter an extension study. Responses and progression were determined according to the International Myeloma Working Group (IMWG) criteria and were assessed by an Independent Review Committee (IRC). PN data were collected for all pts on study and included neuropathy history, neurological physical exam and PN-related quality of life data (FACT-GOG/NTx v 4.0 scores) collected at screening. Prospective neurological exams and subjective reporting of PN occurred every 2 cycles until study discontinuation to proactively assess for PN. Adverse event (AE) data were also collected, with AEs reported as ‘neuropathy peripheral', ‘neuropathic pain', ‘neuropathy', and ‘peripheral sensory neuropathy' included as PN. AE reports of ‘paraesthesias' and ‘dysesthesias' were counted separately.

Of the 266 pts with R/R MM in PX-171-003-A1, 237 (89%) had a history of PN which was attributable to prior anti-myeloma therapy, including THAL (108 pts/41%), BTZ (134 pts/50%), or both BTZ and THAL (17 pts/6.4%). 206 of the 266 (77%) had G1/2 PN at baseline and a median disease duration of 5.9 years. This subset with active PN at baseline had received a median of 5 prior lines of therapy (range 1–20), with a median 13 anti-myeloma agents, and a median of 2 prior BTZ- and 1 prior THAL- containing regimens. Prior therapies included 100% BTZ, and 100% either THAL (77%) or prior lenalidomide (95%). Responses in the subset of pts with baseline PN were nearly identical to those seen in the full study population with an overall response rate (ORR; ≥ partial response [PR]) of 24% and a clinical benefit response rate (CBR; ≥ minimal response [MR]) of 36%.

The median duration of response (≥PR) was 7.4 mo (95% CI 5.6–not reached) and median duration of MR was 6.3 months in both the overall and PN-baseline cohorts. OS and TTP data will also be reported. The most common treatment-emergent ≥G3 adverse events regardless of relationship to study drug were primarily hematologic and were as follows: thrombocytopenia (24%), anemia (21%), lymphopenia (11%), pneumonia (9%), neutropenia (9%), fatigue (7%), hypercalcemia (7%), and hyponatremia (6%). Although 77% of pts had G1/2 PN at baseline, new onset PN was infrequent with PN AEs of any grade reported in 31 (15%) pts and G3 PN reported in only 1 (0.4%) pt. New onset or worsening of paraesthesias (6.8%) and dysesthesias (0%) was also infrequent.

Analysis of the subset of pts (77%) with active PN (G1/2) in this single-agent Ph 2 trial of CFZ in pts with R/R MM demonstrated that PN has no impact on depth or durability of responses, or on the tolerability of CFZ, in heavily pretreated pts with multiply relapsed and refractory MM. Reports of new or worsening PN were very uncommon, and paraesthesias and dysesthesia were generally infrequent and mild. CFZ can be given to pts with baseline PN with little risk of exacerbation; prolonged therapy is possible in this population.

Martin:Celgene: Honoraria; Onyx: Consultancy. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding. Vij:Onyx: Honoraria. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: 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. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: 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. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. Vallone:Onyx Pharmaceuticals: Employment. Chang:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.