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

Abstract

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.

Emerging Therapeutic Strategies to Overcome Drug Resistance in Multiple Myeloma

“…This would involve identifying reliable predictive biomarkers of response and profiling individual patients for what agents are likely to elicit a successful therapeutic response, which would inform effective treatment regimens. Approaches to accomplishing this could include predicting patient drug response based on their genetic profile or to profile patient’s sensitivity to anti-myeloma agents ex vivo over their disease course [ 54 , 125 , 126 ]. Several of these approaches are currently being assessed in clinical trials for MM.…”

“…In the cases where IMiD resistance results from CRL4 CRBN component or Ikaros mutations, these agents may be ineffective and thus studying the relationship between mutational status and clinical response will be helpful in the development of CELMoDs. The direct ex vivo measurement of IMiD response may be a valuable way to determine when CELMoDs are likely to benefit an IMiD-refractory patient [ 54 ].…”

High-Throughput Drug Screening and Multi-Omic Analysis to Guide Individualized Treatment for Multiple Myeloma

“…A potential solution to address this limitation would be to use 3D tissueengineered bone marrow cultures and a flow cytometric readout, which has been demonstrated by others in preclinical studies. 14,15 Although this study aimed to evaluate in vitro cytotoxicity of single agents, we are conducting ongoing studies to evaluate the synergy of multiple agents. 16 It is well known that by exploiting multiple mechanisms of action, combination chemotherapy decreases the likelihood of tumor resistance.…”

An ex vivo platform to guide drug combination treatment in relapsed/refractory lymphoma

“…As a corollary to biomarker-driven approaches in precision medicine that identify a “subgroup” of patients who are likely to respond to a drug, phenotypic assays such as ex vivo drug sensitivity testing offer the possibility of truly personalized, patient-specific information ( 7 ). Advances in cell-handling robotics, microfluidics, and high-throughput assays have reinvigorated the field of ex vivo drug sensitivity prediction in hematologic cancers, as exemplified by the extended analysis for leukemia and lymphoma treatment (EXALT) trial ( 8 ) and other recent studies ( 9 – 11 ). Most current approaches, however, use single-drug sensitivity assays ( 12 , 13 ) and do not address patient-specific synergistic or antagonistic drug combination interactions.…”