Measurement of ex vivo resistance to proteasome inhibitors, IMiDs, and daratumumab during multiple myeloma progression.

Autor:	Walker ZJ; Division of Hematology, Department of Medicine., VanWyngarden MJ; Division of Hematology, Department of Medicine., Stevens BM; Division of Hematology, Department of Medicine., Abbott D; Center for Innovative Design and Analysis, Department of Biostatistics and Informatics, Colorado School of Public Health., Hammes A; Center for Innovative Design and Analysis, Department of Biostatistics and Informatics, Colorado School of Public Health., Langouët-Astrie C; Division of Hematology, Department of Medicine., Smith CA; Division of Hematology, Department of Medicine.; Division of Allergy and Clinical Immunology, ClinImmune Labs, and., Palmer BE; Division of Allergy and Clinical Immunology, ClinImmune Labs, and.; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO., Forsberg PA; Division of Hematology, Department of Medicine., Mark TM; Division of Hematology, Department of Medicine., Jordan CT; Division of Hematology, Department of Medicine.; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO., Sherbenou DW; Division of Hematology, Department of Medicine.; University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2020 Apr 28; Vol. 4 (8), pp. 1628-1639.
DOI:	10.1182/bloodadvances.2019000122
Abstrakt:	The oncogenic drivers and progression factors in multiple myeloma (MM) are heterogeneous and difficult to target therapeutically. Many different MM drugs have emerged, however, that attack various phenotypic aspects of malignant plasma cells. These drugs are administered in numerous, seemingly interchangeable combinations. Although the availability of many treatment options is useful, no clinical test capable of optimizing and sequencing the treatment regimens for an individual patient is currently available. To overcome this problem, we developed a functional ex vivo approach to measure patients' inherent and acquired drug resistance. This method, which we termed myeloma drug sensitivity testing (My-DST), uses unselected bone marrow mononuclear cells with a panel of drugs in clinical use, followed by flow cytometry to measure myeloma-specific cytotoxicity. We found that using whole bone marrow cultures helped preserve primary MM cell viability. My-DST was used to profile 55 primary samples at diagnosis or at relapse. Sensitivity or resistance to each drug was determined from the change in MM viability relative to untreated control samples. My-DST identified progressive loss of sensitivity to immunomodulatory drugs, proteasome inhibitors, and daratumumab through the disease course, mirroring the clinical development of resistance. Prospectively, patients' ex vivo drug sensitivity to the drugs subsequently received was sensitive and specific for clinical response. In addition, treatment with <2 drugs identified as sensitive by My-DST led to inferior depth and duration of clinical response. In summary, ex vivo drug sensitivity is prognostically impactful and, with further validation, may facilitate more personalized and effective therapeutic regimens. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu