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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Moreau P, Richardson PG, Cavo M, Orlowski RZ, San Miguel JF, Palumbo A, et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood. 2012;120:947–59.

  2. 2.

    Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28:1122–8.

  3. 3.

    Moreau P. How I treat myeloma with new agents. Blood. 2017;130:1507–13.

  4. 4.

    Rajkumar SV, Kumar S. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc. 2016;91:101–19.

  5. 5.

    Kumar SK, Dimopoulos MA, Kastritis E, Terpos E, Nahi H, Goldschmidt H, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017;31:2443–8.

  6. 6.

    Van de Donk NWCJ, Richardson PG, Malavasi F. CD38antibodies in multiple myeloma: back to the future. Blood. 2018;131:13–29.

  7. 7.

    Richter JR, Martin TG, Vij R, Cole C, Atanackovic D, Zonder JA, et al. Updated data from a phase II dose finding trial of single agent isatuximab (SAR650984, anti-CD38 mAb) in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2016;34 15_suppl:8005–8005.

  8. 8.

    Martin T, Baz R, Benson DM, Lendvai N, Wolf J, Munster P, et al. A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma. Blood. 2017;129:3294–303.

  9. 9.

    Martin TG, Mannis GN, Chari A, Munster P, Campana F, Hui A-M, et al. Phase Ib study of isatuximab and carfilzomib in relapse and refractory multiple myeloma. Blood. 2016;128:2111–2111.

  10. 10.

    Mikhael J, Richardson PG, Usmani SZ, Raje NS, Bensinger W, Dubin F, et al. Final results of a phase Ib study of isatuximab (ISA) plus pomalidomide (Pom) and dexamethasone (dex) in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2018;36 15_suppl:8038–8038.

  11. 11.

    Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet (Lond, Engl). 2016;387:1551–60.

  12. 12.

    Chari A, Suvannasankha A, Fay JW, Arnulf B, Kaufman JL, Ifthikharuddin JJ, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130:974–81.

  13. 13.

    Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319–31.

  14. 14.

    Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754–66.

  15. 15.

    Durie BGM, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467. 07/20/online

  16. 16.

    Rajkumar SV, Harousseau J-L, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117:4691–5.

  17. 17.

    Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–81.

  18. 18.

    Nooka AK, Joseph N, Boise LH, Gleason C, Kaufman JL, Lonial S. Clinical efficacy of daratumumab, pomalidomide and dexamethasone in relapsed, refractory myeloma patients: utility of retreatment with daratumumab among refractory patients. Blood. 2016;128:492–492.

  19. 19.

    Chari A, Suvannasankha A, Fay JW, Arnulf B, Kaufman JL, Ifthikharuddin JJ, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130:974–81.

  20. 20.

    Kumar SK, Kapoor P, Laplant B, Muchtar E, Buadi FK, Gonsalves WI, et al. Phase 2 Trial of ixazomib, lenalidomide, dexamethasone and daratumumab in patients with newly diagnosed multiple myeloma. Blood. 2018;132 Suppl 1:304–304.

  21. 21.

    Facon T, Kumar SK, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Blood. 2018;132 Suppl 1:LBA-2–LBA-2.

  22. 22.

    Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018;378:518–28.

  23. 23.

    Raje NS, Berdeja J, Lin Y, Munshi NC, Spigel D, Liedtke M, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. J Clin Oncol. 2018:36:8007. https://doi.org/10.1200/JCO.2018.36.15_suppl.8007

  24. 24.

    Topp MS, Duell J, Zugmaier G, Attal M, Moreau P, Langer C, et al. Treatment with AMG 420, an anti-B-cell maturation antigen (BCMA) bispecific T-cell engager (BiTE®) antibody construct, induces minimal residual disease (MRD) negative complete responses in relapsed and/or refractory (R/R) multiple myeloma (MM) patients: results of a first-in-human (FIH) phase I dose escalation study. Blood. 2018;132 Suppl 1:1010–1010.

  25. 25.

    Trudel S, Lendvai N, Popat R, Voorhees PM, Reeves B, Libby EN, et al. Targeting B-cell maturation antigen with GSK2857916 antibody-drug conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose escalation and expansion phase 1 trial. Lancet Oncol. 2018;19:1641–53.

Download references


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


  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


  1. Search for Ujjawal H. Gandhi in:

  2. Search for Robert F. Cornell in:

  3. Search for Arjun Lakshman in:

  4. Search for Zhubin J. Gahvari in:

  5. Search for Elizabeth McGehee in:

  6. Search for Megan H. Jagosky in:

  7. Search for Ridhi Gupta in:

  8. Search for William Varnado in:

  9. Search for Mark A. Fiala in:

  10. Search for Saurabh Chhabra in:

  11. Search for Ehsan Malek in:

  12. Search for Joshua Mansour in:

  13. Search for Barry Paul in:

  14. Search for Alyssa Barnstead in:

  15. Search for Saranya Kodali in:

  16. Search for Amarendra Neppalli in:

  17. Search for Michaela Liedtke in:

  18. Search for Swapna Narayana in:

  19. Search for Kelly N. Godby in:

  20. Search for Yubin Kang in:

  21. Search for Ankit Kansagra in:

  22. Search for Elvira Umyarova in:

  23. Search for Emma C. Scott in:

  24. Search for Parameswaran Hari in:

  25. Search for Ravi Vij in:

  26. Search for Saad Z. Usmani in:

  27. Search for Natalie S. Callander in:

  28. Search for Shaji K. Kumar in:

  29. Search for Luciano J. Costa in:

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.

Supplementary information

About this article

Publication history