Abstract

The introduction of CD38-targeting monoclonal antibodies (CD38 MoABs), daratumumab and isatuximab, has significantly impacted the management of patients with multiple myeloma (MM). Outcomes of patients with MM refractory to CD38 MoABs have not been described. We analyzed outcomes of 275 MM patients at 14 academic centers with disease refractory to CD38 MoABs. Median interval between MM diagnosis and refractoriness to CD38 MoAB (T0) was 50.1 months. The median overall survival (OS) from T0 for the entire cohort was 8.6 [95% C.I. 7.5–9.9] months, ranging from 11.2 months for patients not simultaneously refractory to an immunomodulatory (IMiD) agent and a proteasome inhibitor (PI) to 5.6 months for “penta-refractory” patients (refractory to CD38 MoAB, 2 PIs and 2 IMiDs). At least one subsequent treatment regimen was employed after T0 in 249 (90%) patients. Overall response rate to first regimen after T0 was 31% with median progression-free survival (PFS) and OS of 3.4 and 9.3 months, respectively. PFS was best achieved with combinations of carfilzomib and alkylator (median 5.7 months), and daratumumab and IMiD (median 4.5 months). Patients with MM refractory to CD38 MoAB have poor prognosis and this study provides benchmark for new therapies to be tested in this population.

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Acknowledgements

We are thankful to the Institutional Review Boards and hospital staff at each participating academic center, REDCap IT support at Vanderbilt University Medical Center, and all the patients and their families. This study was not funded commercially.

Author information

Author notes

  1. These authors contributed equally: Ujjawal H. Gandhi and Robert F. Cornell

Affiliations

  1. Department of Medicine, Division of Hematology & Oncology, Vanderbilt University Medical Center, Nashville, TN, USA

    • Ujjawal H. Gandhi
    •  & Robert F. Cornell
  2. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    • Arjun Lakshman
    •  & Shaji K. Kumar
  3. University of Wisconsin, Madison, WI, USA

    • Zhubin J. Gahvari
    •  & Natalie S. Callander
  4. University of Texas Southwestern Medical Center, Dallas, TX, USA

    • Elizabeth McGehee
    •  & Ankit Kansagra
  5. Department of Hematologic Oncology & Blood Disorders Levine Cancer Institute/Carolinas Health Care, Charlotte, NC, USA

    • Megan H. Jagosky
    •  & Saad Z. Usmani
  6. Stanford Cancer Institute, Stanford, CA, USA

    • Ridhi Gupta
    •  & Michaela Liedtke
  7. Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

    • William Varnado
    • , Kelly N. Godby
    •  & Luciano J. Costa
  8. Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA

    • Mark A. Fiala
    •  & Ravi Vij
  9. Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

    • Saurabh Chhabra
    • , Swapna Narayana
    •  & Parameswaran Hari
  10. Adult Hematologic Malignancies & Stem Cell Transplant Section, Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH, USA

    • Ehsan Malek
  11. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA

    • Joshua Mansour
    •  & Amarendra Neppalli
  12. Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke University School of Medicine, Durham, NC, USA

    • Barry Paul
    •  & Yubin Kang
  13. Oregon Health & Science University, Portland, OR, USA

    • Alyssa Barnstead
    •  & Emma C. Scott
  14. University of Vermont, College of Medicine, Burlington, VT, USA

    • Saranya Kodali
    •  & Elvira Umyarova

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Conflict of interest

EhM: Consultancy and Speakers Bureau (Takeda, Celgene, Amgen, Janssen); BP: Stock and pension plan (Bristol Myer Squibb); AN: Consultancy (Celgene, Amgen); ML: Consultancy (Amgen/Onyx), Honoraria (Amgen/Onyx, Pfizer, Prothena, Takeda), Research Funding (Amgen/Onyx, BlueBirdBio, Celgene, Genentech/Roche, Gilead, Pfizer, Prothena, Takeda), Membership on an entity’s Board of Directors or advisory committees (Caelum, Pfizer, Prothena, Takeda); PH: Consultancy and Research Funding (Amgen, Celgene), Honoraria (Celgene); RV: Honoraria (Celgene, Bristol Myers Squibb, Takeda, Amgen, Janssen, Karyopharma, Jazz), Research Funding (Celgene, Bristol Myers Squibb, Takeda); SU: Consultancy (Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Seattle Genetics), Research Funding (Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics, Takeda), Membership on an entity’s Board of Directors or advisory committees (Sanofi); ShK: Consultancy (AbbVie, Celgene, Janssen, Kite Pharma, Merck, Takeda); LC: Honoraria (Amgen, Celgene, AbbVie), Research Funding (Amgen, Celgene, Janssen). The remaining authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Luciano J. Costa.

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DOI

https://doi.org/10.1038/s41375-019-0435-7