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Multiple myeloma gammopathies

Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy

Leukemia volume 33, pages 2266–2275 (2019)Cite this article

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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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References

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Google Scholar 

  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.

    Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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

    Article  Google Scholar 

  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.

    Google Scholar 

  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.

    Article  CAS  Google Scholar 

Download references

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.

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Author notes

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

Authors and 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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  1. Ujjawal H. Gandhi
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  2. Robert F. Cornell
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  23. Emma C. Scott
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  26. Saad Z. Usmani
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  28. Shaji K. Kumar
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  29. Luciano J. Costa
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Corresponding author

Correspondence to Luciano J. Costa.

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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.

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Gandhi, U.H., Cornell, R.F., Lakshman, A. et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia 33, 2266–2275 (2019). https://doi.org/10.1038/s41375-019-0435-7

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

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