Treatment Efficacy for Relapsed/Refractory Multiple Myeloma Patients with Gain/Amplification of 1q21

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Treatment Efficacy for Relapsed/Refractory Multiple Myeloma Patients with Gain/Amplification of 1q21
Authors: Xia Zhou1, Hongying Wu1, Lumei Hao1, Liyan Wei1, Xuemei Li1, Junjing Yin1, Qianru Yu1, Zhanzhi Xie2, Yuping Zhong1
Affiliations:
1 Hematology Department, Qingdao Hospital, University of Health and Rehabilitation Science (Qingdao Municipal Hospital), Qingdao, Shandong 266011, China;
2 Sanofi-Aventis China Investment Co., Ltd., Beijing 100124, China.
Correspondence to: Yuping Zhong, Hematology Department, Qingdao Hospital, University of Health and Rehabilitation Science (Qingdao Municipal Hospital), Qingdao, Shandong 266011, China.
E-Mail: zhongyp3352@126.com

Introduction

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of plasma cells in the bone marrow. In China, MM has a crude prevalence of 7 per 100,000 population and an incidence of 1.6 per 100,000 population. The disease is often associated with genetic abnormalities, including gain or amplification of the 1q21 region of chromosome 1 (1q21+). This abnormality is linked to poor prognosis, drug resistance, and disease progression in both newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). Despite its clinical significance, treatment options specifically targeting 1q21+ patients remain limited due to a lack of robust clinical data. This study aimed to evaluate the efficacy of various treatment regimens for RRMM patients with 1q21+ and to review relevant studies to fill this critical gap in the literature.

Methods

The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA 2020) guidelines and was registered in the PROSPERO database (No. CRD42023401904). A comprehensive search was conducted on September 8, 2022, using PubMed, EMBASE, and the Cochrane CENTRAL Database. The inclusion criteria focused on randomized controlled trials (RCTs) involving patients aged 18 years or older with RRMM and 1q21+. The interventions included single or combined pharmacological therapies, such as anti-CD38 monoclonal antibodies (e.g., daratumumab and isatuximab), exportin-1 inhibitors (e.g., selinexor), antibody-drug conjugates (e.g., belantamab), anti-SLAMF7 monoclonal antibodies (e.g., elotuzumab), proteasome inhibitors (e.g., ixazomib and carfilzomib), immunomodulatory drugs (e.g., pomalidomide), and combinations like bortezomib plus lenalidomide plus dexamethasone.

The primary outcome was progression-free survival (PFS), while secondary outcomes included overall survival (OS), overall response rate (ORR), duration of response (DOR), and time to progression (TTP). Data extraction and quality assessment were performed independently by two reviewers using the Cochrane Collaboration Risk of Bias 2.0 tool. Statistical analyses were conducted using RevMan 5.3 and R version 4.1.0, with a fixed-effects model employed for data synthesis. Heterogeneity was addressed through subgroup analysis and, where necessary, a random-effects model.

Results

Five RCTs involving 2094 patients were included, with 926 (44.2%) patients identified as having 1q21+. The analysis revealed the following key findings:

  1. Overall Survival (OS):

    • No significant differences were observed in OS between elotuzumab plus lenalidomide plus dexamethasone (ERd) and Rd (HR 0.81, 95% CI 0.61–1.06) or between ixazomib plus lenalidomide plus dexamethasone (IRd) and Rd (HR 0.86, 95% CI 0.66–1.12).
    • Similarly, isatuximab-based regimens (IsaPd or IsaKd) showed no significant OS benefit compared to Pd or Kd alone (HR 0.76, 95% CI 0.56–1.04).

  2. Progression-Free Survival (PFS):

    • The addition of isatuximab to Pd or Kd significantly reduced the risk of progression or death by 54% compared to Pd or Kd alone (HR 0.46, 95% CI 0.33–0.66).
    • Elotuzumab-based regimens lowered the risk by 29% compared to Pd or Rd alone (HR 0.71, 95% CI 0.55–0.93).
    • Ixazomib-based regimens showed a 22% reduction in risk compared to Rd alone (HR 0.78, 95% CI 0.49–1.24).

  3. Overall Response Rate (ORR) and Very Good Partial Response (VGPR):

    • IsaPd demonstrated a significantly higher ORR (51.9% vs. 9.5%, P = 0.0011) and VGPR (33.3% vs. 0%, P = 0.0018) compared to Pd alone.
    • The CR rate, DOR, and TTP were also reported for IRd compared to Rd, with favorable outcomes for the ixazomib-based regimen.

  4. Comparative Efficacy:

    • The lowest proportion of disease progression or death was observed for IsaKd (35%), followed by IRd (45%), Kd (50%), IsaPd (54%), EPd, ERd, and Rd (60%), and Pd (75%).

Discussion

The study highlights the potential benefits of isatuximab-based regimens for RRMM patients with 1q21+, particularly in improving PFS, ORR, and VGPR. However, no significant OS benefits were observed for isatuximab, ixazomib, or elotuzumab-based therapies. These findings suggest that 1q21+ status may serve as a prognostic factor for relapse/refractory patients, and targeted therapies like isatuximab could mitigate the adverse outcomes associated with this genetic abnormality.

Notably, the study did not include RCTs involving daratumumab, another anti-CD38 monoclonal antibody. Previous studies have reported mixed outcomes for daratumumab-based regimens in 1q21+ patients, with some indicating improved PFS and others suggesting no significant benefit. This underscores the need for further research to validate the efficacy of daratumumab and other emerging therapies in this patient population.

The variation in baseline characteristics, such as age and prior treatments, may have influenced the study outcomes. For instance, younger patients enrolled in some studies may have contributed to better responses. Additionally, the efficacy of lenalidomide and pomalidomide, either alone or in combination, may have played a role in the observed differences in ORR and VGPR.

Conclusion

This systematic review and meta-analysis provide valuable insights into the treatment of RRMM patients with 1q21+. The addition of isatuximab to Pd or Kd significantly improves PFS, ORR, and VGPR, making it a promising option for this difficult-to-treat subgroup. However, further studies are needed to confirm these findings and explore the efficacy of other therapies, such as daratumumab, in this patient population.

Conflicts of Interest

Zhanzhi Xie is an employee of Sanofi and may hold shares and/or stock options in the company. This work was supported by Sanofi.

References

  1. Wang S, Xu L, Feng J, Liu Y, Liu L, Wang J, et al. Prevalence and incidence of multiple myeloma in urban area in China: a national population-based analysis. Front Oncol 2020;9:1513.
  2. An, G, Li Z, Tai YT, Acharya C, Li Q, Qin X, et al. The impact of clone size on the prognostic value of chromosome aberrations by fluorescence in situ hybridization in multiple myeloma. Clin Cancer Res 2015;21:2148–2156.
  3. Moreau P, Dimopoulos M-A, Mikhael J, Yong K, Capra M, Facon T, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet 2021;397:2361–2371.
  4. Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med 2018;379:1811–1822.
  5. Harrison SJ, Perrot A, Alegre A, Simpson D, Wang MC, Spencer A, et al. Subgroup analysis of ICARIA-MM study in relapsed/refractory multiple myeloma patients with high-risk cytogenetics. Br J Haematol 2021;194:120–131.
  6. Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med 2015;373:621–631.
  7. Avet-Loiseau H, Bahlis NJ, Chng WJ, Masszi T, Viterbo L, Pour L, et al. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood 2017;130:2610–2618.
  8. Dimopoulos MA, Lonial S, White D, Moreau P, Weisel K, San-Miguel J, et al. Elotuzumab, lenalidomide, and dexamethasone in RRMM: final overall survival results from the phase 3 randomized ELOQUENT-2 study. Blood Cancer J 2020;10:91.
  9. Richardson PG, Kumar SK, Masszi T, Grzasko N, Bahlis NJ, Hansson M, et al. Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma. J Clin Oncol 2021;39:2430–2442.
  10. Martin T, Richardson PG, Facon T, Moreau P, Perrot A, Spicka I, et al. Primary outcomes by 1q21+ status for isatuximab-treated patients with relapsed/refractory multiple myeloma: Subgroup analyses from ICARIA-MM and IKEMA. Haematologica 2022;107:2485.
  11. Yong K, Martin T, Dimopoulos MA, Mikhael J, Capra M, Facon T, et al. Isatuximab plus carfilzomib-dexamethasone versus carfilzomib-dexamethasone in patients with relapsed multiple myeloma (IKEMA): overall survival analysis of a phase 3, randomised, controlled trial. Lancet Haematol 2024;11:e741–e750.
  12. Mohan M, Weinhold N, Schinke C, Thanedrarajan S, Rasche L, Sawyer JR, et al. Daratumumab in high-risk relapsed/refractory multiple myeloma patients: adverse effect of chromosome 1q21 gain/amplification and GEP70 status on outcome. Br J Haematol 2020;189:67–71.
  13. Parrondo RD, Gardner LB, Alhaj Moustafa M, Roy V, Sher T, Rasheed A, et al. Therapeutic Outcomes of Relapsed-Refractory Multiple Myeloma Patients with 1q21+Treated with Daratumumab-Based Regimens: A retrospective analysis. Blood 2022;140:7237–7238.
  14. Moreau P, Joshua D, Chng WJ, Palumbo A, Goldschmidt H, Hájek R, et al. Impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study. Leukemia 2017;31:115–122.

DOI: doi.org/10.1097/CM9.0000000000003435

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