Original Articles
Vol. 13 No. 1 (2021): Mediterranean Journal of Hematology and Infectious Diseases, Volume 13, 2021
REAL-WORLD OUTCOME IN THE PRE-CAR-T ERA OF MYELOMA PATIENTS QUALIFYING FOR CAR-T CELL THERAPY
Real-world Assessment of Myeloma Patients as Candidates for CAR-T Therapy
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Received: September 23, 2020
Accepted: November 16, 2020
Accepted: November 16, 2020
Versions
- 2021-01-01 (2)
- 2020-12-31 (1)
1644
Views
558
Downloads
169
HTML
Authors
Introduction: CAR-T cell therapy is likely to be introduced starting from 2021 in patients with relapsed/refractory myeloma (r/r MM) in Europe. In order to qualify for commercial CAR-T treatment, it is assumed that r/r MM patients will have to be exposed to at least three lines of previous treatments including lenalidomide, bortezomib and anti-CD38 treatment. However, the outcome of this particular subgroup of r/r MM patients is largely unknown whereas this knowledge is crucial to estimate the possible benefit of eventual CAR-T treatment.
Methods: In this non-interventional, retrospective single-center study, we analyzed all subsequent r/r MM patients treated between 01/2016 (when anti-CD38 treatment was commercially introduced in Switzerland) and 04/2020 at the University Hospital of Bern. Patients were eligible for the study if they had received at least three lines of treatment including one proteasome inhibitor (PI), one immunomodulatory drug (IMID) and one anti-CD38 antibody, and if they were in need of subsequent treatment and effectively received further lines of treatment.
Results: Among 56 patients fulfilling the criteria of at least three lines of treatment including PI, IMID and anti-CD38 treatment, only 34 (60%) effectively received subsequent further therapy. This suggests that 40% of r/r MM patients never receive additional treatment after at least three lines of treatment including PI, IMID and anti-CD38 treatment. For patients receiving further treatment, the median number of previous lines of treatment was 4.5 (range 2-12), including autologous stem cell transplantation in 31 (91%) patients. 13 (37%) patients were penta-refractory. The most frequently used treatment options were IMID/dexamethasone treatment in 11 (32%) patients, followed by PI/dexamethasone in 10 (29%) patients. 21 (62%) patients received two or more additional lines of therapy. The median PFS was 6.6 months (range 0–36.6 months), the median TTNT was 7.5 months (range 1.4-24.5 months) and the median OS was 13.5 months, (range 0.1-38 months) for the first subsequent treatment. The overall response rate (ORR) to the first subsequent treatment was 41%, with a median duration of the response of 5 months (range 1-37 months). 12% of the patients achieved VGPR or better, with a median duration of response of 8 months (range 3-37 months).
Conclusion: Myeloma patients refractory after at least three lines of anti-CD38/PI/IMID treatment have a poor prognosis with a PFS of 6.6 months and OS of 13.5 months. These data may serve as reference to compare the potential benefit of CAR-T treatment in this group of myeloma patients when available in the near future.
Downloads
Download data is not yet available.
Citations
Bundesamt für Statistik. Schweizerischer Krebsbericht 2015 Multiples
Myelom. Neuchâtel; 2017. Available from:
Krebsliga Schweiz. Multiples Myelom - Plasmazellmyelom - Eine Information der Krebsliga. Bern, Krebsliga Schweiz 2018. Available from: https://www.krebsliga.ch/ueber-krebs/krebsarten/multiplesmyelom-plasmazellmyelom/
Brudno JN, Maric I, Hartman SD, et al. T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. JCO2018;36(22):2267-80.
https://doi.org/10.1200/JCO.2018.77.8084 PMid:29812997 PMCid:PMC6067798
Palumbo A, Anderson K. Multiple Myeloma. N Engl J Med 2011;364(11):1046-60. https://doi.org/10.1056/NEJMra1011442 PMid:21410373
Laubach J, Garderet L, Mahindra A, et al. Management of relapsed multiple myeloma: recommendations of the international myeloma working group. Leukemia 2016;30(5):1005-17. https://doi.org/10.1038/leu.2015.356
PMid:26710887
Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood 2017;130(24): 2594-02. https://doi.org/10.1182/blood-2017-06-793869 PMid:28928126 PMCid:PMC5731088
Sonneveld P. Management of multiple myeloma in the relapsed/refractory patient. Hematology 2017;2017(1):508-17.
https://doi.org/10.1182/asheducation-2017.1.508 PMid:29222299 PMCid:PMC6142583
Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia
;26(1):149-57. https://doi.org/10.1038/leu.2011.196 PMid:21799510 PMCid:PMC4109061
Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med 2019;380(18):1726-37. https://doi.org/10.1056/NEJMoa1817226 PMid:31042825
Kumar S. Treatment of newly diagnosed multiple myeloma in transplanteligible patients. Current Hematologic Malignancy Reports 2011;6(2):104-12. https://doi.org/10.1007/s11899-011-0083-0 PMid:21394431
Nijhof IS, van de Donk NWCJ, Zweegman S, Lokhorst HM. Current and new therapeutic strategies for relapsed and refractory multiple myeloma: an update. Drugs 2018;78(1):19-37. https://doi.org/10.1007/s40265-017-0841-y
PMid:29188449 PMCid:PMC5756574
Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor dexamethasone for triple-class refractory multiple myeloma. N Engl J Med 2019;381(8):727-38. https://doi.org/10.1056/NEJMoa1903455 PMid:31433920
Vogl DT, Dingli D, Cornell RF, et al. Selective inhibition of nuclear
export with oral selinexor for treatment of relapsed or refractory multiple myeloma. JCO 2018;36(9):859-66.
https://doi.org/10.1200/JCO.2017.75.5207 PMid:29381435 PMCid:PMC6905485
Chen C, Siegel D, Gutierrez M, et al. Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia. Blood 2018;131(8):855-63. https://doi.org/10.1182/blood-2017-08-797886
PMid:29203585
Driessen C, Kraus M, Joerger M, et al. treatment with the HIV protease inhibitor nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: a phase I trial (SAKK 65/08). Haematologica 2016;101(3):346-55. https://doi.org/10.3324/haematol.2015.135780 PMid:26659919 PMCid:PMC4815726
Hitz F, Kraus M, et al. Nelfinavir and lenalidomide/dexamethasone in patients with lenalidomide-refractory multiple myeloma. a phase I/II trial (SAKK 39/10). Blood Cancer J 2019;9(9):70. https://doi.org/10.1038/s41408-019-0228-2
PMid:31455773 PMCid:PMC6711992
Bazarbachi AH, Al Hamed R, Malard F, Harousseau J-L, Mohty M. Relapsed refractory multiple myeloma: a comprehensive overview. Leukemia 2019;33(10):2343-57. https://doi.org/10.1038/s41375-019-0561-2
PMid:31455853
Turtle CJ, Hanafi L-A, Berger C, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. Journal of Clinical Investigation 2016;126(6):2123-38. https://doi.org/10.1172/JCI85309 PMid:27111235 PMCid:PMC4887159
Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014;371(16):1507-17. https://doi.org/10.1056/NEJMoa1407222 PMid:25317870 PMCid:PMC4267531
Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing
CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. The Lancet 2015;385(9967):517-28. https://doi.org/10.1016/S0140-6736(14)61403-3
Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Science Translational Medicine 2014;6(224):224-25. https://doi.org/10.1126/scitranslmed.3008226 PMid:24553386 PMCid:PMC4684949
Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Science Translational Medicine 2013;5(177ra38):1-9.
Turtle CJ, Hanafi L-A, Berger C, et al. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8 + and CD4 + CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med
;8(355ra116):1-12. https://doi.org/10.1126/scitranslmed.aaf8621 PMid:27605551 PMCid:PMC5045301
Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapyrefractory diffuse large B-cell lymphoma and indolent B-cellmalignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. JCO 2015;33(6):540-9. https://doi.org/10.1200/JCO.2014.56.2025 PMid:25154820 PMCid:PMC4322257
Kochenderfer JN, Somerville RPT, Lu T, et al. Long-duration complete remissions of diffuse large B cell lymphoma after anti-CD19 chimeric antigen receptor T cell therapy. Molecular Therapy 2017;25(10):2245-53.
https://doi.org/10.1016/j.ymthe.2017.07.004 PMid:28803861 PMCid:PMC5628864
Kochenderfer JN, Somerville RPT, Lu T, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. JCO 2017;35(16):1803-13. https://doi.org/10.1200/JCO.2016.71.3024
PMid:28291388 PMCid:PMC5455597
Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 2010;116(20):4099-102.
https://doi.org/10.1182/blood-2010-04-281931 PMid:20668228 PMCid:PMC2993617
Makita S, Yoshimura K, Tobinai K. Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. Cancer Sci 2017;108(6):1109-18. https://doi.org/10.1111/cas.13239
PMid:28301076 PMCid:PMC5480083
Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med 2018;378(5):449-59. https://doi.org/10.1056/NEJMoa1709919 PMid:29385376 PMCid:PMC6637939
Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017;377(26):2531-44. https://doi.org/10.1056/NEJMoa1707447 PMid:29226797 PMCid:PMC5882485
Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 2018;378(5):439-48. https://doi.org/10.1056/NEJMoa1709866 PMid:29385370 PMCid:PMC5996391
Jain MD, Bachmeier CA, Phuoc VH, Chavez JC. Axicabtagene ciloleucel (KTE-C19), an anti-CD19 CAR T therapy for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin's lymphoma. Ther Clin Risk Manag 2018;14:1007-17.
https://doi.org/10.2147/TCRM.S145039 PMid:29910620 PMCid:PMC5987753
Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Molecular Therapy 2017;25(1):285-95. https://doi.org/10.1016/j.ymthe.2016.10.020
PMid:28129122 PMCid:PMC5363293
Carpenter RO, Evbuomwan MO, Pittaluga S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clinical Cancer Research 2013;19(8):2048-60. https://doi.org/10.1158/1078-0432.CCR-12-2422 PMid:23344265 PMCid:PMC3630268
Ali SA, Shi V, Maric I, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 2016;128(13):1688-700. https://doi.org/10.1182/blood-2016-04-711903
PMid:27412889 PMCid:PMC5043125
Novak AJ, Darce JR, Arendt BK, et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood 2004;103(2):689-94. https://doi.org/10.1182/blood-2003-06-2043 PMid:14512299
Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation: annotation. British Journal of Haematology 1998;102(5):1115-23. https://doi.org/10.1046/j.1365-2141.1998.00930.x PMid:9753033
Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised international staging system for multiple myeloma: a report from international myeloma working group. JCO 2015;33(26):2863-9. https://doi.org/10.1200/JCO.2015.61.2267
PMid:26240224 PMCid:PMC4846284
Samaras P, Bargetzi M, Betticher DC, et al. Updated recommendations for diagnosis and treatment of plasma cell myeloma in Switzerland [Internet] Swiss Med Wkly. 2019 [cited 2020 Apr 16]; Available from: https://doi.emh.ch/smw.2019.20031 https://doi.org/10.4414/smw.2019.20031 PMid:30943308
Rajkumar SV, Kumar S. Multiple myeloma: diagnosis and treatment. Mayo Clinic Proceedings 2016;91(1):101-19.
https://doi.org/10.1016/j.mayocp.2015.11.007 PMid:26763514 PMCid:PMC5223450
Kumar SK, Callander NS, Hillengass J, et al. NCCN guidelines insights: multiple myeloma, version 1.2020. Journal of the National Comprehensive Cancer Network 2019;17(10):1154-65. https://doi.org/10.6004/jnccn.2019.0049
PMid:31590151
Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 2016;375(8):754-66. https://doi.org/10.1056/NEJMoa1606038 PMid:27557302
Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood 2017;130(8):974-81. https://doi.org/10.1182/blood-2017-05-785246 PMid:28637662 PMCid:PMC5570682
Tzogani K, Penninga E, Schougaard Christiansen ML, et al. EMA review of daratumumab for the treatment of adult patients with multiple myeloma. The Oncologist 2018;23(5):594-602. https://doi.org/10.1634/theoncologist.2017-0328
PMid:29371479 PMCid:PMC5947446
Pick M, Vainstein V, Goldschmidt N, et al. Daratumumab resistance is frequent in advanced-stage multiple myeloma patients irrespective of CD38 expression and is related to dismal prognosis. Eur J Haematol 2018;100(5):494-501.
https://doi.org/10.1111/ejh.13046 PMid:29453884
Oostvogels R, Jak M, Raymakers R, Mous R, Minnema MC. Efficacy of retreatment with immunomodulatory drugs and proteasome inhibitors following daratumumab monotherapy in relapsed and refractory multiple myeloma patients. Br J Haematol 2018;183(1):60-7. https://doi.org/10.1111/bjh.15504 PMid:30080247 PMCid:PMC6220946
Trudel S, Lendvai N, Popat R, 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. The Lancet Oncology 2018;19(12):1641-53. https://doi.org/10.1016/S1470-2045(18)30576-X
Lakshman A, Abeykoon JP, Kumar SK, et al. Efficacy of daratumumab-based therapies in patients with relapsed, refractory multiple myeloma treated outside of clinical trials. Am J Hematol 2017;92(11):1146-55.
https://doi.org/10.1002/ajh.24883 PMid:28799231
Swissmedic. DARZALEX [Internet]. Compendium.ch. [cited 2020 April 21]; Available from:
Seckinger A, Delgado JA, Moser S, et al. Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody EM801 for multiple myeloma treatment. Cancer Cell 2017;31(3):396-410.
https://doi.org/10.1016/j.ccell.2017.02.002 PMid:28262554
Shah N, Chari A, Scott E, Mezzi K, Usmani SZ. B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia 2020;34(4):985-1005. https://doi.org/10.1038/s41375-020-0734-z PMid:32055000 PMCid:PMC7214244
Cohen AD. Myeloma: next generation immunotherapy. Hematology 2019;2019(1):266-72.
https://doi.org/10.1182/hematology.2019000068 PMid:31808859 PMCid:PMC6913481
Pillarisetti K, Edavettal S, Mendonça M, et al. A T-cell-redirecting bispecific G-protein-coupled receptor class 5 member D x CD3 antibody to treat multiple myeloma. Blood 2020;135(15):1232-43. https://doi.org/10.1182/blood.2019003342 PMid:32040549 PMCid:PMC7146017
How to Cite
“REAL-WORLD OUTCOME IN THE PRE-CAR-T ERA OF MYELOMA PATIENTS QUALIFYING FOR CAR-T CELL THERAPY: Real-world Assessment of Myeloma Patients as Candidates for CAR-T Therapy” (2021) Mediterranean Journal of Hematology and Infectious Diseases, 13(1), p. e2021012. doi:10.4084/mjhid.2021.012.
Copyright (c) 2020 Ulrike Bacher, Simon Brechbühl, Barbara Jeker, Thomas Pabst
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
