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Phase I/II Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Dexamethasone As Targeted Therapy for Patients with t(11;14) Relapsed/Refractory Multiple Myeloma

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Kaufman, JL; Gasparetto, C; Schjesvold, FH; Moreau, P; Touzeau, C; Facon, T; Boise, LH; Alzate, S; Macartney, T; Pesko, J; Salem, AH; Ross, JA ...
Published in: Blood
November 13, 2019

BackgroundVenetoclax (Ven) is a selective, small molecule inhibitor of anti-apoptosis protein Bcl-2 that has antitumoral activity against multiple myeloma (MM), notably those with translocation t(11;14). Dexamethasone (d) has shown to enhance the expression of BCL-2 and pro-apoptotic protein Bim, shifting its binding towards Bcl-2 and sensitizing MM cells to Ven. This Phase 1/2 open-label trial is evaluating the safety and efficacy of the combination of Ven+d as a therapeutic approach to improve clinical outcomes in patients with t(11;14) Relapsed/Refractory (R/R) MM.MethodsThis ongoing study (NCT01794520) has 2 distinct phases. Phase 1 (P1) consisted of separate dose escalation, safety expansion, and Ven+d combination cohorts. The phase 2 (P2) portion is an expansion cohort of Ven+d to further evaluate its efficacy. The safety and efficacy of the Ven+d cohorts from P1 and P2 are reported here.Eligible patients (pts) were adults with t(11;14) R/R MM ≥18 years of age. Key eligibility criteria for the Ven+d cohort in P1 included prior treatment with a proteasome inhibitor (PI) and an immunomodulatory drug (IMID), and an ECOG score ≤1. In P2, eligibility included an ECOG score ≤2, disease progression on or within 60 days from the last dose on previous treatment and having received at least two lines of therapy with a PI, IMID, daratumumab, and glucocorticoids. Additional inclusion criteria for both phases included measurable disease and adequate bone marrow function in all pts, and the presence of t(11;14) determined by fluorescence in-situ hybridization.In both phases, pts received oral Ven 800 mg/day + oral d 40 mg (20 mg for pts ≥75 years of age) on days 1, 8, and 15 of each 21-day cycle. In P1, preliminary efficacy was assessed as the overall response rate (ORR), time to progression (TTP), progression free survival (PFS), and duration of response (DOR) of Ven+d based on the 2011 International Uniform Response Criteria for MM. Efficacy in P2 further evaluated ORR, very good partial response (VGPR) or better, PFS, DOR, TTP, and overall survival (OS) using 2016 IMWG response criteria.ResultsIn P1, as of 15thApril, 2019, 20 pts were enrolled (17 [85%] male; median age, 63 years [range, 46-77]). The median number of prior therapies received was 2.5 (range: 1-7). Nineteen pts (95%) discontinued the study (18 due to progressive disease and 1 underwent transplant). The treatment-emergent adverse events (TEAEs) are summarized in the Table. Most frequent TEAEs were insomnia (45%), hypophosphatemia (40%), hyperglycemia (35%), diarrhea (35%), and thrombocytopenia (30%). Predominant Grade 3 or 4 TEAEs included neutropenia (21%), lymphopenia (29%), and hypophosphatemia (20%). The most common serious TEAE was tumor lysis syndrome (TLS) (10%). No deaths were reported in the treatment-emergent period. ORR was achieved by 13 (65%) and ≥VGPR was achieved by 6 (30%) pts respectively. Partial response (PR) was observed in 7 (35%) pts and stable disease (SD) in 4 (20%) pts. Median time to first response was 1.4 mos (95% CI: 0.7, 2.8). The DOR was 13.1 mos (95% CI: 10.9, 21.9). Median PFS and TTP were both 12.4 mos (95% CI 3.6, 20.9).In P2, as of March 18, 2019, 31 pts were enrolled (18 [58%] male; median age, 65 years [range, 48-80]). The median number of prior therapies received were 5 (range: 1-9). Eight (26%) pts discontinued the study (6 deaths, 1 withdrew consent, 1 due to physician's decision). The most frequent TEAEs reported were diarrhea (32%), nausea (26%) and lymphopenia (32%). The most frequent Grade 3 or 4 TEAEs were lymphopenia (32%), thrombocytopenia (11%), and hypertension (10%). Most common serious TEAE was sepsis (10%). Six (19%) deaths were reported (5 due to progressive disease and 1 due to adverse event). In the intention to treat population, the median TTR was 0.7 mos (range: 0.6-1.5). ORR was achieved by 14 (45%) and >VGPR was observed in 8 (26%) pts. PR was observed in 6 (13%) pts and SD in 8 (26%) pts. Median PFS, DOR, and OS were not reached at the time of data analysis. The 9-mo estimates for PFS, DOR, and OS were 57% (95% CI: 19% 82%), 66% (95% CI: 16%, 91%), and 71% (95% CI: 44%, 87%) respectively.ConclusionIn both phases of this study, Ven+d was efficacious and demonstrated tolerable safety in pts with t(11;14) R/R MM. These results support further investigation of Ven combinations in this pt population. This combination is also being investigated in the ongoing Phase 3 trial M13-494 (CANOVA) in t(11;14) positive R/R MM.

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Published In

Blood

DOI

EISSN

1528-0020

ISSN

0006-4971

Publication Date

November 13, 2019

Volume

134

Issue

Supplement_1

Start / End Page

926 / 926

Publisher

American Society of Hematology

Related Subject Headings

  • Immunology
  • 3213 Paediatrics
  • 3201 Cardiovascular medicine and haematology
  • 3101 Biochemistry and cell biology
  • 1114 Paediatrics and Reproductive Medicine
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology
 

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Kaufman, J. L., Gasparetto, C., Schjesvold, F. H., Moreau, P., Touzeau, C., Facon, T., … Kumar, S. K. (2019). Phase I/II Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Dexamethasone As Targeted Therapy for Patients with t(11;14) Relapsed/Refractory Multiple Myeloma. In Blood (Vol. 134, pp. 926–926). American Society of Hematology. https://doi.org/10.1182/blood-2019-125871
Kaufman, Jonathan L., Cristina Gasparetto, Fredrik H. Schjesvold, Philippe Moreau, Cyrille Touzeau, Thierry Facon, Lawrence H. Boise, et al. “Phase I/II Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Dexamethasone As Targeted Therapy for Patients with t(11;14) Relapsed/Refractory Multiple Myeloma.” In Blood, 134:926–926. American Society of Hematology, 2019. https://doi.org/10.1182/blood-2019-125871.
Kaufman JL, Gasparetto C, Schjesvold FH, Moreau P, Touzeau C, Facon T, et al. Phase I/II Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Dexamethasone As Targeted Therapy for Patients with t(11;14) Relapsed/Refractory Multiple Myeloma. In: Blood. American Society of Hematology; 2019. p. 926–926.
Kaufman, Jonathan L., et al. “Phase I/II Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Dexamethasone As Targeted Therapy for Patients with t(11;14) Relapsed/Refractory Multiple Myeloma.” Blood, vol. 134, no. Supplement_1, American Society of Hematology, 2019, pp. 926–926. Crossref, doi:10.1182/blood-2019-125871.
Kaufman JL, Gasparetto C, Schjesvold FH, Moreau P, Touzeau C, Facon T, Boise LH, Alzate S, Macartney T, Pesko J, Salem AH, Ross JA, Hong W-J, Maciag PC, Pauff JM, Kumar SK. Phase I/II Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Dexamethasone As Targeted Therapy for Patients with t(11;14) Relapsed/Refractory Multiple Myeloma. Blood. American Society of Hematology; 2019. p. 926–926.

Published In

Blood

DOI

EISSN

1528-0020

ISSN

0006-4971

Publication Date

November 13, 2019

Volume

134

Issue

Supplement_1

Start / End Page

926 / 926

Publisher

American Society of Hematology

Related Subject Headings

  • Immunology
  • 3213 Paediatrics
  • 3201 Cardiovascular medicine and haematology
  • 3101 Biochemistry and cell biology
  • 1114 Paediatrics and Reproductive Medicine
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology