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Multiple myeloma gammopathies

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

Leukemia volume 33, pages 1291–1296 (2019)Cite this article

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In a phase I clinical trial of venetoclax in patients with t(11;14) relapsed/refractory multiple myeloma (MM), 40% of the patients treated achieved an objective response [1]. While this response rate with a single agent in MM is impressive, it demonstrates that t(11;14) is not an optimal biomarker for response to venetoclax. Functional profiling of BCL2 family members has been shown to predict responses to therapy in myeloma and other diseases [2]. Therefore, we set out to determine how ex vivo sensitivity to venetoclax corresponds to clinical response and resistance.

The samples appeared to cluster into three groups based on sensitivity. Thirty of the 76 total samples (39.5%) had an IC50 of 100 nM or less (Fig. 1b, green bars), consisting primarily from t(11;14)-positive samples (73.3%). A second cohort of 20 samples (26.3%) had an IC50 from 170 to 450 nM (Fig. 1b, yellow bars). In the remaining 26 samples (34.2%), the IC50 was 900 nM or greater (range 900−18,400 nM, Fig. 1b, red bars). The presence of t(11;14) was the only significant difference between the sensitive group and the others (Supplemental Table 2). Twenty patients received venetoclax as a single agent (n = 10) or in combination with dexamethasone (n = 9) or daratumamab/dexamethasone (n = 1) and 18 had ex vivo sensitivity tested immediately prior to venetoclax treatment (Supplemental Tables 1 and 3). A patient with nonsecretory disease and another that withdrew consent prior to completing one cycle were not included in this analysis. Ten of the 16 remaining patients had a clinical response (partial response (PR) or better), nine of which were in the most sensitive cohort. Only one of the six nonresponding patients was in the most sensitive group (Fig. 1c). Thus, the sensitivity of the assay is 0.9 while the specificity is 0.83 (Fisher’s exact test, P = 0.0076). Examples of ex vivo concentration−response curves and clinical responses are provided in Supplemental Figure 1. Together these data suggest that ex vivo pretreatment sensitivity can predict patient responses to venetoclax.

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Acknowledgements

The authors thank the patients for providing the samples used in this study. They also acknowledge the hard work and dedication of the Winship Myeloma Research Team for consenting patients and collecting samples. Funding was provided by R01 CA192844, P30 CA138292 and the Emory Myeloma Working Group.

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Authors and Affiliations

  1. Department of Hematology and Medical Oncology, Emory University School of Medicine and the Winship Cancer Institute of Emory University, Atlanta, GA, USA

    Shannon M. Matulis, Vikas A. Gupta, Leonard T. Heffner Jr., Sagar Lonial, Ajay K. Nooka, Jonathan L. Kaufman & Lawrence H. Boise

  2. Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada

    Paola Neri & Nizar J. Bahlis

  3. Oncology Development, Abbvie, North Chicago, IL, USA

    Paulo Maciag & Joel D. Leverson

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  1. Shannon M. Matulis
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Correspondence to Lawrence H. Boise.

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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. The other authors declare that they have no conflict of interest.

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Matulis, S.M., Gupta, V.A., Neri, P. et al. Functional profiling of venetoclax sensitivity can predict clinical response in multiple myeloma. Leukemia 33, 1291–1296 (2019). https://doi.org/10.1038/s41375-018-0374-8

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