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. 2019 May;33(5):1291-1296.
doi: 10.1038/s41375-018-0374-8. Epub 2019 Jan 24.

Functional profiling of venetoclax sensitivity can predict clinical response in multiple myeloma

Shannon M Matulis  1 , Vikas A Gupta  1 , Paola Neri  2 , Nizar J Bahlis  2 , Paulo Maciag  3 , Joel D Leverson  3 , Leonard T Heffner Jr  1 , Sagar Lonial  1 , Ajay K Nooka  1 , Jonathan L Kaufman  1 , Lawrence H Boise  4
Affiliations

Functional profiling of venetoclax sensitivity can predict clinical response in multiple myeloma

Shannon M Matulis et al. Leukemia. 2019 May.
No abstract available

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Conflict of interest statement

Conflict of Interest

NJB funding and honorarium from Celgene and Janssen

PM and JDL employment, Abbvie

LTH, research funding, Abbvie

SL consultancy Takeda, Celgene, Novartis, Abbvie, Amgen, Janssen, Bristol-Myers Squibb

AKN advisory board or consultancy, Amgen, Adaptive Technologies, Janssen, Celgene, Spectrum Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Takeda

JLK Consultancy, Abbvie, Janssen, Bristol-Myers Squibb, Takeda, Data Monitoring Committee, Karyopharm, Pharmacyclics

LHB, consultancy, Abbvie, honorarium, AstraZeneca.

Figures

Figure 1.
Figure 1.. Ex Vivo Response of Patient-Derived Plasma Cells to Venetoclax.
Buffy coat cells were treated with Venetoclax for 24 h and apoptosis of the plasma cells was determined as described in the Supplemental Methods section. Dose curves using concentrations of 0, 10, 100 and 1000 nM venetoclax were used to calculate the IC50 for each patient sample. A. The samples were clustered based on the presence (N=31) or absence (N=36) of the t(11;14) translocation and graphed according to IC50. Whiskers extend from 10–90%, P=0.0176. Post-venetoclax treatment samples were removed from this analysis due to the effects of acquired resistance. B. Samples separated into 3 categories according to venetoclax sensitivity; Green – highly sensitive, IC50 up to 100 nM, Yellow – intermediate sensitivity, IC50 170 nM – 450 nM, Red – resistant, IC50 ≥ 900 nM. Asterisks denote samples from t(11;14)-positive patients C. Clinical response of 16 patients graphed versus IC50. Progressive disease (PD) N = 4, Single agent venetoclax; stable disease (SD) N = 2, single agent venetoclax. Partial response (PR) N = 4, venetoclax monotherapy; very good partial response (VGPR) N = 2, 1 single agent venetoclax, 1 venetoclax plus daratumamab and dexamethasone; stringent complete response sCR N = 4, 2 venetoclax monotherapy, 2 venetoclax plus dexamethasone. Dotted line represents the cutoff for the most sensitive cohort (100 nM), solid lines represent the median IC50 for each response. Symbol colors represent sensitivity as shown in Figure 1B. D. (Left) Ven IC50 for MM91, MM100, and MM93 before treatment and upon progression. (Right) Post-Ven IC50 for MM77 and MM99. Pre-treatment samples were not obtained.
Figure 2.
Figure 2.. Combining Dexamethasone with Venetoclax Decreases IC50 and Shifts Sample Classification.
Buffy coat cells were isolated and treated with Ven as before, +/− 0.5 μM Dex. A. IC50 changes in samples sensitive to Ven alone. B. Shifts in IC50 of samples displaying intermediate sensitivity to Ven C. IC50 shifts in samples resistant to Ven alone. Symbol colors represent sensitivity as shown in Figure 1B.
See this image and copyright information in PMC

References

    1. Kumar S, Kaufman JL, Gasparetto C, Mikhael J, Vij R, Pegourie B, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130(22):2401–9. - PubMed
    1. Ni Chonghaile T, Sarosiek KA, Vo TT, Ryan JA, Tammareddi A, Moore Vdel G, et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science. 2011;334(6059):1129–33. - PMC - PubMed
    1. Touzeau C, Dousset C, Le Gouill S, Sampath D, Leverson JD, Souers AJ, et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2014;28(1):210–2. - PMC - PubMed
    1. Matulis SM, Gupta VA, Nooka AK, Hollen HV, Kaufman JL, Lonial S, et al. Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax. Leukemia. 2016;30(5):1086–93. - PMC - PubMed
    1. Kaufman JL, Gasparetto CJ, Mikhael J, Moreau P, Touzeau C, Vij R, et al. Phase 1 Study of Venetoclax in Combination with Dexamethasone As Targeted Therapy for t(11;14) Relapsed/Refractory Multiple Myeloma. Blood. 2017;130(Suppl 1):3131-.

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