ASH 2018 | Triplet combination of venetoclax, carfilzomib, and dexamethasone for relapsed/refractory multiple myeloma

The 60th American Society of Hematology (ASH) Annual Meeting was held in San Diego, California, from 1–4 December 2018. On Sunday 2 December 2018, an oral abstract session was held entitled: Myeloma: Therapy, excluding Transplantation: Novel Targeted Combinations in Myeloma, which focused on updates of clinical trials using novel combination regimens for patients with multiple myeloma (MM).

Luciano J Costa from the University of Alabama at Birmingham, Vestavia, US, presented results of an ongoing phase II clinical trial that examines the safety and efficacy of the triplet combination of venetoclax (Ven) with carfilzomib and dexamethasone (Ven-Kd) for patients with relapsed/refractory (R/R) MM.

Both venetoclax and carfilzomib target the anti-apoptotic machinery of MM cells, by inhibiting the function of the pro-survival proteins BCL-2 and MCL-1, respectively.

Study Design:

• Key inclusion criteria:
  • R/R MM (1-3 prior lines of treatment)
  • Measurable disease: M-protein ≥ 0.5 g/dL (serum) and/or ≥ 200 mg/24 h (urine); serum free-light chains ≥ 10 mg/dL
  • ECOG score ≤ 2
  • Adequate organ function
• Key exclusion criteria:
  • Prior treatment with carfilzomib
  • Grade 3/4 peripheral neuropathy
  • Significant cardiovascular disease
• Dose-escalation study: First part = dose escalation with four trialed doses; second part = expansion with the selected dose
• Treatment: Given for up to 18 cycles with the option to continue on venetoclax or until disease progression (DP) or unacceptable toxicity; 28-day cycles
  • Cohort 1: Venetoclax, 400 mg/day orally; carfilzomib, 27 mg/m² intravenously (IV) on days 1, 2, 8, 9, 15, and 16; dexamethasone, 40 mg orally on days 1, 8, 15, and 22 (N = 4 patients)
  • Cohort 2: Venetoclax, 800 mg/day orally; carfilzomib and dexamethasone as for cohort 1 (N= 3 patients)
  • Cohort 3: Venetoclax, 800 mg/day orally; carfilzomib 70 mg/m² IV on days 1, 8, and 15; dexamethasone, 40 mg orally on days 1, 8, 15, and 22 (N = 6 patients)
  • Cohort 4: Venetoclax, 800 mg/day orally; carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16; dexamethasone, 40 mg orally on days 1, 2, 8, 9, 15, 16, 22, and 23 (N = 7 patients)
  • Carfilzomib was administered at 20 mg/m² on cycle 1, days 1 and 2

Key Data:

• Data cut-off: 17 September 2018
• Time on study = 8.0 months (range, 0.9–19.5)
• Number of participants = 42; 26 (62%), still active; 16 (38%), discontinued
• Age = 67 years (range, 37–79)
• International Staging System (ISS) stage: ISS I = 36%; ISS II/III = 62%; unknown = 2%
• Cytogenetic abnormalities: Standard risk = 69%; high-risk [t(4;14); t(4;16); del17p] = 29%; t(11;14) = 19%
• Prior therapies = 2 (range, 1–3); stem cell transplant, 48%; refractory to a proteasome inhibitor (PI), 50%; refractory to an immunomodulatory drug (IMiD), 62%; double refractory, 33% of patients
• Reasons for treatment discontinuation:
  • DP, N = 6 patients
  • Physician decision/lack of efficacy, N = 3
  • Adverse events (AE), N = 2
  • Withdrawal of consent, N = 2
  • Deaths: N = 3
• AEs: All patients experienced at least one AE; 33 patients (79%) experienced a grade 3/4 AE
• AEs, grade 3/4:
  • Lymphopenia = 31%
  • Neutropenia = 17%
  • Leukopenia = 10%
  • Hypertension = 14%
• Serious AEs: 15 patients (36%) experienced at least one serious AE
  • Pneumonia = 12%
  • Influenza = 7%
  • Acute kidney injury = 5%
  • Congestive heart failure = 5%
• All doses tested in the four cohorts were found tolerable; the dosing used in cohort 3 was selected for expansion based not only on safety and tolerability, but also on dose convenience (N = 22 patients)
• Overall response rate (ORR) = 79%
• Complete response or better (≥ CR) = 38%
• Very good partial response or better (≥ VGPR) rate = 59%
• Similar response rates were obtained when patients were analyzed based on their refractory status (PI, IMiD, or double refractory)
• Patients with t(11;14) (N = 8) showed: 100% ORR; 63% ≥ CR; 88% ≥ VGPR rate
• Patients without t(11;14) (N = 34) showed: 74% ORR; 32% ≥ CR; 53% ≥ VGPR rate
• Median follow-up = 8.0 months (range, 6.0–9.79)
• Progression-free survival (PFS) events = 12 (10, DP; 2, death)

Conclusions

These results show that treatment with Ven-Kd is safe and efficacious and provide the basis for future studies with this triplet combination for patients with R/R MM. The study is ongoing and expanded with 60 additional patients.

References

Costa L.J. et al. Phase 2 Study of Venetoclax Plus Carfilzomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. 2018 Dec 2; Oral Abstract #303: ASH 60th Annual Meeting and Exposition, San Diego, CA.