Multiple myeloma (MM) is a plasma cell malignancy defined by complex genetics and extensive patient heterogeneity. Despite a growing arsenal of approved therapies, MM remains incurable and in need of guidelines to identify effective personalized treatments. Here, we survey the ex vivo drug and immunotherapy sensitivities across 101 bone marrow samples from 70 patients with MM using multiplexed immunofluorescence, automated microscopy and deep-learning-based single-cell phenotyping. Combined with sample-matched genetics, proteotyping and cytokine profiling, we map the molecular regulatory network of drug sensitivity, implicating the DNA repair pathway and EYA3 expression in proteasome inhibitor sensitivity and major histocompatibility complex class II expression in the response to elotuzumab. Globally, ex vivo drug sensitivity associated with bone marrow microenvironmental signatures reflecting treatment stage, clonality and inflammation. Furthermore, ex vivo drug sensitivity significantly stratified clinical treatment responses, including to immunotherapy. Taken together, our study provides molecular and actionable insights into diverse treatment strategies for patients with MM.

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Elderly or unfit patients with relapsed acute myeloid leukemia (AML) face a poor prognosis and are likely to rapidly exhaust all registered treatment options. Pharmacoscopy, an image-based ex vivo drug screening platform, has previously been suggested as a tool for treatment selection in AML. We used pharmacoscopy to generate personalized treatment recommendations for 30 relapse settings of 24 AML patients which exhausted all standard therapeutic options. We evaluated whether pharmacoscopy can be employed within the narrow timeframe available under an AML relapse setting, how often recommended regimens could be started and whether they provided durable clinical benefits. 17 of 30 screens (56.7%) resulted in patients receiving a recommended therapy, leading to promising trends in clinical response and survival. A drug regimen's integrated pharmacoscopy score proved to be an excellent predictor of clinical response: Patients receiving a regimen with above-median scores showed significantly higher rates of complete remission (OR 3.01, p < 0.0005) and significantly longer overall survival (ratio 3.39, p < 0.006). We conclude that pharmacoscopy is an efficient and valuable tool for therapy selection in AML at relapse and propose concrete measures to further improve clinical implementation.

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