Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma

Blood. 2017 Nov 30;130(22):2401-2409. doi: 10.1182/blood-2017-06-788786. Epub 2017 Oct 10.

Abstract

Venetoclax is a selective, orally bioavailable BCL-2 inhibitor that induces cell death in multiple myeloma (MM) cells, particularly in those harboring t(11;14), which express high levels of BCL-2 relative to BCL-XL and MCL-1. In this phase 1 study, patients with relapsed/refractory MM received venetoclax monotherapy. After a 2-week lead-in with weekly dose escalation, daily venetoclax was given at 300, 600, 900, or 1200 mg in dose-escalation cohorts and 1200 mg in the safety expansion. Dexamethasone could be added on progression during treatment. Sixty-six patients were enrolled (30, dose-escalation cohorts; 36, safety expansion). Patients received a median of 5 prior therapies (range, 1-15); 61% were bortezomib and lenalidomide double refractory, and 46% had t(11;14). Venetoclax was generally well tolerated. Most common adverse events included mild gastrointestinal symptoms (nausea [47%], diarrhea [36%], vomiting [21%]). Cytopenias were the most common grade 3/4 events, with thrombocytopenia (32%), neutropenia (27%), anemia (23%), and leukopenia (23%) reported. The overall response rate (ORR) was 21% (14/66), and 15% achieved very good partial response or better (≥VGPR). Most responses (12/14 [86%]) were reported in patients with t(11;14). In this group, ORR was 40%, with 27% of patients achieving ≥VGPR. Biomarker analysis confirmed that response to venetoclax correlated with higher BCL2:BCL2L1 and BCL2:MCL1 mRNA expression ratios. Venetoclax monotherapy at a daily dose up to 1200 mg has an acceptable safety profile and evidence of single-agent antimyeloma activity in patients with relapsed/refractory MM, predominantly in patients with t(11;14) abnormality and those with a favorable BCL2 family profile. Registered at www.clinicaltrials.gov: #NCT01794520.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Bridged Bicyclo Compounds, Heterocyclic / adverse effects
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Multiple Myeloma / drug therapy*
  • Neoplasm Recurrence, Local / drug therapy
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / therapeutic use*

Substances

  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Sulfonamides
  • venetoclax

Associated data

  • ClinicalTrials.gov/NCT01794520
  • ClinicalTrials.gov/NCT01794520