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DETERMINATION: the addition of ASCT to lenalidomide, bortezomib, and dexamethasone provides a PFS advantage for patients with newly diagnosed multiple myeloma

For decades, autologous stem cell transplants (ASCTs) with high-dose chemotherapy has been the standard of care for patients with newly diagnosed multiple myeloma (MM). However, treatment is associated with hospitalization and severe toxicities. Additional advances in novel therapeutics, specifically immunomodulatory drugs and proteosome inhibitors, combined with dexamethasone have yielded improved survival rates in patients both eligible and ineligible for ASCT. The benefit of this combination introduces questions surrounding whether ASCT provides an advantage to this treatment combination in newly diagnosed MM and whether it can be withheld.1

The Phase III DETERMINATION (NCT01208662) trial was designed to establish the effect of early and delayed addition of ASCT to the triplet regimen lenalidomide, bortezomib, and dexamethasone (RVD) for newly diagnosed patients with MM. Transplant-eligible patients with newly diagnosed MM were randomized to receive 3 cycles of RVD, stem cell mobilization, followed by 5 additional RVD cycles (Arm A; n = 357) or melphalan plus ASCT and 2 cycles of RVD (Arm B; n = 365). Both arms received lenalidomide maintenance until progression (n = 291 and 290, respectively). The primary endpoint was progression-free survival (PFS). 2

After a median follow-up of 76 months, median PFS was 46.2 versus 67.6 months in Arm A versus Arm B (HR 1.53; 95% CI, 1.23–1.91; p < .0001). Best response in patients assessed to date in Arms A and B, respectively, were complete response (CR) or better in 52% and 62%; very good partial response (VGPR) or better in 79% and 83%; and partial response (PR) or better in 94% and 96%. Five-year overall survival (OS) was similar between the two arms ((HR 1.10, 95% CI [0.73, 1.65]; P = .99)). 28% of patients in Arm A had ASCT as salvage therapy and the remaining patients received other therapies including immunomodulatory drugs and proteosome inhibitors, which likely contributed to the lack in OS difference between the two treatment arms.9 Significantly more grade 3 or higher hematologic adverse events were reported in Arm B (89.9%) compared to Arm A (60.5%; P < .001).

The association between rate of minimal residual disease (MRD) negativity and PFS was explored via samples collected at the start of maintenance treatment from 108 patients in Arm A and 90 patients in Arm B. The rate of MRD negativity was 54.4% versus 39.8%, respectively, within 1 year of maintenance (odds ratio 0.55, unadjusted 95% CI [0.30, 1.01]). Five-year PFS in patients with MRD negativity was similar regardless of treatment (59.2% without ASCT vs 53.5% with ASCT; HR 0.91, 95% CI [0.46, 1.79]). Moreover, patients with MRD detection following RVD had increased PFS rates with early transplant versus delayed, suggesting an advantage to MRD-directed personalized therapy for newly diagnosed MM.3

Overall, ASCT was demonstrated to improve PFS in newly diagnosed patients with MM. No difference in OS observed between the different treatment arms suggests salvage transplantation is viable and the timing of ASCT can be individualized without detriment to survival.

References

  1. US Food and Drug Administration. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-car-t-cell-therapy-treat-adults-certain-types-large-b-cell-lymphoma (Last accessed 31/05/22).
  2. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. The New England Journal of Medicine. 2022 February 17; 386:640-654.
  3. Kamdar M, Solomon SR, Arnason JE, et al. Lisocabtagene Maraleucel (liso-cel), a CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy, Versus Standard of Care (SOC) with Salvage Chemotherapy (CT) Followed By Autologous Stem Cell Transplantation (ASCT) As Second-Line (2L) Treatment in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Results from the Randomized Phase 3 Transform Study. Blood. 2021 November 23; 138(1), 91.
  4. Bishop MR, Dickinson M, Purtill D, et al. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. The New England Journal of Medicine. 2022 February 17. 386:629-639
  5. US Food and Drug Administration. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. Available from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-axicabtagene-ciloleucel-second-line-treatment-large-b-cell-lymphoma#:~:text=B%2Dcell%20lymphoma-,FDA%20approves%20axicabtagene%20ciloleucel%20for%20second%2Dline,of%20large%20B%2Dcell%20lymphoma&text=On%20April%201%2C%202022%2C%20the,%2C%20Kite%20Pharma%2C%20Inc (Last accessed 31/05/22).
  6. Business Wire. U.S. FDA Approves New Label Update for CAR T-Cell Therapy Yescarta® Showing Prophylactic Steriod Use Improves Management of Cytokine Release Syndrome. Available from https://www.businesswire.com/news/home/20220131005477/en/ (Last accessed 31/05/22).
  7. Oluwole OO, Forcade E, Muñoz J, et al. Prophylactic Corticosteroid Use with Axicabtagene Ciloleucel (Axi-Cel) in Patients (Pts) with Relapsed/Refractory Large B-Cell Lymphoma (R/R LBCL): One-Year Follow-up of ZUMA-1 Cohort 6 (C6). Blood. 2021 December 24; 138 (1), 2832
  8. Neelapu SS, Dickinson M, Muñoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nature Medicine. 2022 March 21; 28, 735–742

Written by Ellie Jackson

Edited by Sol Yohannes