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.