An Observational, Retrospective Analysis of Retreatment with Carfilzomib in the Management of Patients with Multiple Myeloma
Authors: Peterson Tim J , Korde Neha , Hassoun Hani , Mailankody Sham , Lesokhin Alexander M. , Hultcrantz Malin , Shah Urvi A , Smith Eric L , Lu Sydney X , Landau Heather J , Shah Gunjan L. , Scordo Michael , Lahoud Oscar B , Giralt Sergio A , Landgren Ola 
Published: November 2019

Background: Several studies have indicated that the depth and duration of treatment response in multiple myeloma are both reduced in the relapsed setting. With further lines of therapy, responses continue to weaken in depth and shorten in duration. The National Comprehensive Cancer Network (NCCN) Guidelines suggest that regimens may be repeated in the relapsed setting if there has been a duration of at least 6 months since that regimen was given; however, there is limited information regarding treatment response and duration in the setting of re-treating patients with agents previously utilized. Moreover, preliminary data has suggested that carfilzomib-based regimens in the frontline may be able to attain deeper and longer responses than alternative therapies, which has led to carfilzomib being used more frequently in the frontline. This motivated us to investigate the treatment response, depth, and safety of re-challenging patients with carfilzomib in the relapsed setting.
Methods: In this retrospective chart review, we identified all patients who were treated with multiple courses of carfilzomib-based regimens at Memorial Sloan Kettering Cancer Center between January 1, 2014 and November 30, 2018. Our primary objectives were to assess the response, duration of response and treatment, and safety of re-exposure to carfilzomib-based regimens. Responses were assessed as per IMWG 2016 consensus criteria (Lancet Oncol 2016). In this review we describe the clinical course, safety, and efficacy of re-challenging patients with carfilzomib in the relapsed and refractory settings.
Results: Fifteen patients were identified as having received multiple, independent lines of carfilzomib-based therapy. The median age of the cohort was 58 years (49-76) with 53% male (8); two patients had R-ISS stage 1, eight stage 2, and five stage 3 disease. Five of these patients received their initial carfilzomib in the frontline as part of KRD; four of whom attained a sCR with the fifth attaining a VGPR. The remaining ten patients received their initial carfilzomib in the second-line (4) or 3rd and subsequent lines (6). Upon re-exposure to carfilzomib, patients were heavily treated with a median of four lines of therapy (2-15). All but three patients had at least one adverse cytogenetic abnormality; eight with 17p-, five with 13q-, three with t4;14, and six with 1q+. Regimens utilized in the relapsed setting included KRD (N=4), KPD (N=3), Cyklone (N=2), KD + HDAC inhibitor (N=3), KD (N=1), KCD (N=1), and KRD + daratumumab (N=1). Four patients received carfilzomib at a dose of 27 mg/m2 while the remaining 10 received > 36 mg/m2. Responses were seen in all but four patients (two VGPR, five PR, and four MR), with one patient experiencing progression during carfilzomib with no response; notably, this patient only attained a MR to primary carfilzomib therapy and their second exposure was the 15th line of therapy. The median time to next therapy was 4.8 months (1.9-19.4) with one patient being bridged to autologous hematopoietic cell transplantation (HCT), one to allogeneic HCT, and three are currently receiving ongoing carfilzomib treatment (13.9, 2.8, 2.5 months with VGPR, MR, and PR, respectively). Exacerbation of baseline hypertension was identified in three patients, but these instances were treated successfully with standard medications with no further complications. No additional cardiovascular events were identified in the frontline or re-treatment settings.
Conclusions: We report that in a heavily pre-treated, high risk patient cohort, patients previously treated with carfilzomib-based regimens may be safely re-challenged with carfilzomib. Importantly, none of these patients experienced cardiovascular adverse effects other than exacerbation of underlying hypertension, further supporting the ability to safely re-treat a select group of patients with carfilzomib. We conclude that depending on the patient and treatment history, re-challenging with carfilzomib at relapse may be appropriate salvage therapy, particularly as a bridge towards HCT and/or clinical trials.

Disclosures
Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Lesokhin:Genentech: Research Funding; Serametrix Inc.: Patents & Royalties; Janssen: Research Funding; GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landau:Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Giralt:Amgen: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Miltenyi: Research Funding; Jazz Pharmaceuticals: Consultancy; Actinium: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Kite: Consultancy. Landgren:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Merck: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.