Abstract

In this phase I/II trial, a triplet regimen of ixazomib (Ixa: 3 or 4 mg), pomalidomide (Pom: 4 mg), and dexamethasone (Dex: 40 mg) was administered to 32 lenalidomide-refractory multiple myeloma (MM) patients; 31 were evaluable for response and toxicity. At dose level 1 (DL1, 3 mg Ixa), 1/3 patients experienced grade 3 fatigue, grade 3 lung infection, grade 4 neutropenia, and grade 4 thrombocytopenia; all were considered dose-limiting. Per 3 + 3 phase I design, an additional three patients were enrolled to DL1, with no further dose-limiting toxicity (DLT). At dose level 2 (DL2, 4 mg Ixa), 1/3 patients had dose-limiting febrile neutropenia, neutropenia, and thrombocytopenia (grade 4 each). DL2 was expanded to enroll three additional patients with no further DLT, establishing the recommended phase II dose (RP2D). In phase II, 19 additional patients were treated at RP2D. With a median follow-up of 11.9 months, 48% achieved  ≥ partial response (PR), with 5 patients (20%) achieving very good partial response (VGPR) and 76% experiencing ≥ stable disease. The most common adverse events (≥grade 2) were anemia, neutropenia, thrombocytopenia, and infections. Peripheral neuropathy was infrequent. In summary, Ixa/Pom/Dex is a well-tolerated and effective oral combination therapy for patients with relapsed/refractory MM.

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Acknowledgements

We thank all of the research participants and their families, the Briskin family, the Multiple Myeloma Research Foundation, and the physicians, study nurses, research associates, and protocol staff at all participating sites. Support was received from NIH P30 CA033572 (Biostatistics and Pathology Cores) and the Tom Klemens Family Foundation.

Author contributions

Conception and design: A.K., J.P., S.F., and J.B. Collection and assembly of data: A.K., P.K., J.P., N.T., S.K., S.L., M.H., C.K., N.N., M.R., F.S., G.S., L.D., and JB. Data analysis and interpretation: A.K., J.P., N.T., L.D., J.S., and D.A. Manuscript writing: all authors. Final approval of manuscript: all authors.

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Affiliations

  1. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA

    • Amrita Krishnan
    • , Myo Htut
    • , Chatchada Karanes
    • , Nitya Nathwani
    • , Michael Rosenzweig
    • , George Somlo
    • , James F. Sanchez
    •  & Stephen J. Forman
  2. Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA, USA

    • Amrita Krishnan
    • , Myo Htut
    • , Chatchada Karanes
    • , Nitya Nathwani
    • , Michael Rosenzweig
    • , George Somlo
    • , Lupe Duarte
    •  & James F. Sanchez
  3. Department of Hematology, Mayo Clinic, Rochester, MN, USA

    • Prashant Kapoor
    •  & Shaji Kumar
  4. Department of Biostatistics, City of Hope, Duarte, CA, USA

    • Joycelynne M. Palmer
    • , Ni-Chun Tsai
    •  & Lupe Duarte
  5. Winship Cancer Institute, Emory University, Atlanta, GA, USA

    • Sagar Lonial
  6. Southern California Kaiser Permanente Bone Marrow Transplant Program, Los Angeles, CA, USA

    • Firoozeh Sahebi
  7. Multiple Myeloma Research Foundation, Norwalk, CT, USA

    • Daniel Auclair
  8. Sarah Cannon Research Institute, Nashville, TN, USA

    • Jesus G. Berdeja

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Conflict of interest

Dr. Krishnan serves on the speakers’ bureau for Janssen, Celgene, Takeda, and Onyx, is a consultant for Janssen and Celgene, and has stock ownership in Celgene. Dr. Kapoor is a principal investigator on studies funded by Takeda, Celgene, and Amgen. Dr. Kumar has participated in advisory boards for Takeda, Celgene, Amgen, Janssen, Abbvie, Merck, and SkylineDX, and receives clinical trial funding from Takeda, Janssen, Abbvie, Merck, Celgene, Sanofi, Roche, and Sanofi. Dr. Lonial is a consultant for Millennium, Celgene, Novartis, BMS, Onyx, and Janssen. Dr. Karanes has research funding from Celgene. Dr. Rosenzweig serves on the speakers’ bureau for Celgene. Dr. Somlo serves on the speakers’ bureau for Takeda, is a consultant for Pfizer, AstraZeneca, Abbvie, Puma, Novartis, and Celgene, and receives research support from Merck, Celgene, and Genentech. Dr. Forman has license agreements with and receives research support from Mustang Therapeutics Inc. Dr. Berdeja has received institutional funding from Takeda, Teva, Celgene, Acetylon, MEI, BMS, Amgen, Janssen, Novartis, Abbvie, Curis, Array, Constellation, and Bluebird Bio. The remaining authors declare no competing financial interests.

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Correspondence to Amrita Krishnan.

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https://doi.org/10.1038/s41375-018-0038-8