Phase 2 Trial of Ixazomib, Cyclophosphamide and Dexamethasone in Relapsed Multiple Myeloma
Authors: Buadi Francis K. , Lacy Martha Q. , Laplant Betsy , Wolfe Eric , Gertz Morie A. , Ailawadhi Sikander , Hayman Suzanne R. , Go Ronald S. , Helgeson Dania Kaehlyn , Roy Vivek , Reeder Craig B. , Fonder Amie , Hwa Yi L. , Hobbs Miriam A. , Bergsagel P. Leif , Fonseca Rafael , Dingli David , Gonsalves Wilson I , Kapoor Prashant , Chanan-Khan Asher A. , Kourelis Taxiarchis , Larsen Jeremy , Russell Stephen J , Lust John A. , Sher Taimur , Siddiqui Mustaqeem A. , Stewart A. Keith , Warsame Rahma M , Rajkumar S. Vincent , Kyle Robert A. , Kumar Shaji K. 
Published: November 2019

Background: Combinations of alkylating agents with proteasome inhibitors have demonstrated efficacy in newly diagnosed and relapsed multiple myeloma (MM), with melphalan or cyclophosphamide combinations being some of the commonly used regimens for initial treatment of MM. Ixazomib (Ixa) is an oral proteasome inhibitor that is approved for use in combination with lenalidomide for patients with relapsed MM. We examined if Ixa can be effectively combined with cyclophosphamide (Ctx) in order to develop a less expensive, all oral regimen for patients with relapsed MM.
Patients and Methods: Patients with relapsed MM, who were proteasome inhibitor naïve OR have received less than 6 cycles of therapy with bortezomib and had a better than PR with no progression at the time of discontinuation, were enrolled. The primary objective was to determine overall response rate (ORR). Treatment consisted of Ixa 4mg PO days 1, 8, 15; Ctx 300 mg/m2 PO days 1, 8, 15, 22 and dexamethasone (Dex) 40 mg PO weekly in a 28-day cycle. Overall, 37 patients were accrued; data on 33 eligible patients were available for analysis as of July 18, 2019.
Results: The median age was 71 (48-89), 61% were male and the median duration from diagnosis was 46 months (mos). Median number of prior lines of therapy was 4 (range 1-5), 76%, 42% and 67% respectively had a prior IMiD, proteasome inhibitor or stem cell transplant, respectively. At data cutoff, 22 (67%) had progressed, 4 (12%) had died and the median follow up of those alive was 21.3 mos. Fourteen patients are still receiving treatment, with median of 8.5 cycles. Most common reason for treatment discontinuation was disease progression (10 pts; 53%). The ORR was 60% including 6% CR and 24% VGPR. The median event free survival was 11.3 mos (95%CI: 9.0 - 26.8). Overall, 401 cycles have been administered across the study, with dose modifications/ hold required for Ixa, Ctx, and Dex in 9 (27%), 14 (42%), and 22 (67%) patients respectively, the most common reason being hematologic toxicity. A grade 3 or higher adverse event at least possibly attributed to the study drugs was seen in 77% of patients, hematologic in 67% and non-hematologic in 30%. (Table 1) The most commonly observed hematologic toxicities included thrombocytopenia, neutropenia, lymphopenia and anemia; for non-hematologic was nausea, diarrhea, peripheral neuropathy toxicity and fatigue.
Conclusions: The combination of Ixa, Ctx and Dex (ICd) offers a convenient, all oral regimen for treatment of relapsed disease not refractory to proteasome inhibitors. The regimen has good efficacy in this group f heavily pretreated patients, with an acceptable toxicity profile.

Disclosures
Lacy: Celgene: Research Funding. Gertz:Ionis: Honoraria; Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria. Ailawadhi:Takeda: Consultancy; Janssen: Consultancy, Research Funding; Cellectar: Research Funding; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy. Bergsagel:Janssen Pharmaceuticals: Consultancy; Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy. Fonseca:AbbVie, Amgen, Bayer, Celgene, Kite, Janssen, Juno, Merck, Pharmacylics, Sanofi, Takeda: Other: Consultant/Advisor; Prognosticatin of MM based on Genetic Categorization by FISH: Patents & Royalties; Adaptive Biotechnologies: Other: Scientific Advisory Board. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Honoraria, Research Funding; Glaxo Smith Kline: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding. Chanan-Khan:AbbVie: Research Funding; Pharmacyclics: Research Funding; Xencor: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding. Larsen:Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Russell:Imanis: Equity Ownership. Stewart:Roche: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; Ionis: Consultancy; Janssen: Consultancy, Research Funding; Oncopeptides: Consultancy; Ono: Consultancy; Amgen: Consultancy, Research Funding; Bristol Myers-Squibb: Consultancy; Celgene: Consultancy, Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.