Relapsed/refractory patients

Patient outcomes in multiple myeloma refractory to CD38 monoclonal antibodies 

The development of daratumumab and isatuximab, anti-CD38 monoclonal antibodies (MoABs), has created a new class of agents for the treatment of multiple myeloma (MM). These have proven efficacy both as single-agent monotherapy and in combination with proteasome inhibitors (PIs) and/or immunomodulatory drugs (IMiDs).

Notably, anti-CD38 MoABs have significant activity in patients who have been heavily pre-treated and are refractory/resistant (RR) to PIs and IMiDs. Daratumumab was the first anti-CD38 MoAB approved by the U.S. Food and Drug Administration, initially in combination and now as monotherapy in specific settings.1 Isatuximab is another anti-CD38 MoAB, currently being investigated in a phase III trial (NCT02990338), which recently met its primary endpoint of improving progression-free survival (PFS) in patients with RRMM in combination with pomalidomide and dexamethasone.2

Since the outcomes of patients who are refractory to these MoABs has not, to date, been investigated, Ujjawal H Gandhi, Vanderbilt University Medical Center, Nashville, TN, and colleagues conducted the, “monoclonal antibodies in multiple myeloma: outcomes after therapy failure” (MAMMOTH) study. The results were recently published in Leukemia. It was hypothesized that patients who are refractory to anti-CD38 MoABs would have very few effective treatment options and would represent a new population for whom novel treatments are required.3

Study design and patient characteristics

This retrospective study identified patients with active MM who were refractory to daratumumab or isatuximab as a single-agent or in combination (index regimen). The index regimen must have been part of the management of RRMM, have been used for at least 4 weeks, and with evidence of progressive disease (PD). The time between a diagnosis of MM and refractoriness to CD38 MoAB was termed T0.

  • Based on their refractory status, patients (N = 275) were classified into three groups:
    • Penta-refractory (n = 70)
      • Refractory to: 1 CD38 MoAB, 2 PIs and 2 IMiDs
    • Triple- and quad-refractory (n = 148)
      • Refractory to: 1 CD38 MoAB, 1 PI and 1 or 2 IMiDs or
      • Refractory to: 1 CD38 MoAB, 1 or 2 PIs and 1 IMiD
    • Not triple refractory (n = 57)
      • Refractory to: 1 CD38 MoAB and 1 PI or 1 IMiD
  • Median age at T0: 65 years (27–90)
  • Median interval from diagnosis of MM to T0: 50.1 months (2.5–230.1)
  • Median prior lines of therapy before index regimen: 4 (1–16)
  • Cytogenetics (high risk vs standard risk vs not available): 29.1% vs 63.6% vs 7.3%
  • Refractory status (daratumumab vs lenalidomide vs pomalidomide vs bortezomib): 93% vs 77% vs 65% vs 68%
  • Overall response rate (ORR) was calculated as partial response (PR) + very good partial response or better (≥VGPR)
Key findings
  • Median follow-up (from T0) of survivors: 10.6 months (1.9–42.3)
  • Median OS (mOS): 8.6 months (95% CI, 7.2–9.9)
    • Refractory status (not triple refractory vs triple- or quad-refractory vs penta-refractory): 11.2 months (95% CI, 5.4–17.1) vs 9.2 months (95% CI, 7.1–11.2) vs 5.6 months (95% CI, 3.5–7.8)
    • Cytogenetic risk (standard vs high risk): 10.1 months vs 5.6 months
    • Lactate dehydrogenase (LDH) (normal vs elevated): 10.0 months vs 6.4 months
    • Renal function (creatinine ≤2 mg/dL vs >2 mg/dL): 9.0 months vs 3.7 months
    • Multivariate analysis:
      • Associated with OS: refractory status, cytogenetic risk, LDH and renal function
      • Not associated with OS: age, sex and CD38 MoAB in index regimen

 

  • After T0, 90% of patients (n = 249) received a further treatment regimen
    • Median number of additional therapies after T0: 2 (1–10)
    • Median PFS (mPFS) in patients receiving ≥1 additional therapy: 3.4 months
    • mOS (patients receiving ≥1 additional therapy vs no further therapy): 9.3 months (95% CI, 8.1–10.6) vs 1.3 months (95% CI, 0.6–1.9)
    • ORR to first regimen after T0: 31%
      • ORR by refractory status (not triple refractory vs triple- or quad-refractory vs penta-refractory): 38% vs 29% vs 30%
      • ORR decreased with subsequent regimens
      • Fifth subsequent line ORR: 18%
    • Depth of response predicted response duration and survival (≥VGPR vs PR vs stable disease [SD] vs progressive disease [PD])
      • mPFS: 9 months vs 5.1 months vs 4.5 months vs 1.5 months
      • mOS: 14.8 months vs 11.4 months vs 11.9 months vs 4.8 months

 

  • Patients were then classified based on the first agent they received after T0
    • Most commonly used: alkylator (excluding high-dose melphalan conditioning, n = 90), carfilzomib (n = 68) and daratumumab (n = 57)
    • Results given as carflizomib-based (n = 68) vs alkylator-based (n = 90) vs daratumumab-based (n = 57) regimens:
      • ORR: 32% vs 44% vs 25%
      • mPFS: 4.2 months vs 3.2 months vs 3.9 months
      • mOS: 10.9 months vs 7.7 months vs 11.4 months
      • Specifically, carfilzomib + alkylator regimens provided an improved ORR, mPFS and mOS when compared to carfilzomib-based regimens as a whole
    • PFS was statistically better with carfilzomib-based regimens: HR: 0.60, P = 0.004
    • Multivariate analysis on objective response (OR) and PFS to first therapy after T0:
      • Factors associated with predicting OR: high cytogenetic risk and an alkylator-based regimen
      • Factors associated with reducing the risk of progression/death: carflizomib-based therapy and daratumumab + IMiD regimens
Conclusion

Firstly, the MAMMOTH study has identified a group of patients for whom there is a significant unmet need for effective treatments. These patients, who are refractory to CD38 MoABs, regardless of sensitivity to PIs and IMiDs, have an unfavorable prognosis. This study represents a benchmark for the comparison of outcomes of newer clinical trials involving novel therapies such as CAR T-cell therapies, bispecific antibodies and antibody-drug conjugates.

Secondly, the analysis of outcomes to subsequent therapy regimens provides some evidence for clinical decisions in this setting. Carfilzomib-based regimens provided the most favorable PFS and OS rates whilst daratumumab-IMiD combination regimens may provide better results in patients refractory to single-agent CD38 MoAB.

References
  1. U.S. Food and Drug Administration: Daratumumab (DARZALEX): https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm530249.htmhtm [accessed 2019 March 21]
  2. Phase III Isatuximab Trial Meets Primary Endpoint of Improving PFS in Relapsed/Refractory Myeloma https://www.targetedonc.com/news/phase-iii-isatuximab-trial-meets-primary-endpoint-of-improving-pfs-in-relapsedrefractory-myeloma [accessed 2019 March 21]
  3. Ghandi U.H. et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019 March 11. DOI: 10.1038/s41375-019-0435-7
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