Multiple myeloma is the second most common hematological malignancy and remains incurable, with 50% of patients surviving less than 5 years. Patient relapse is inevitable despite an increase in therapeutic options, highlighting the significant need for predictive biomarkers that can rapidly and accurately determine tumor drug susceptibility to direct utilization of optimal therapies. We will apply Travera?s mechanism-agnostic functional biomarker to determine the drug susceptibility of individual patient?s tumors to available therapies and towards the goal of being the first predictive biomarker for standard-of-care treatment of multiple myeloma.
Significant progress has been made in the treatment of multiple myeloma (MM), the second most common blood cancer. New classes of drugs, including proteasome inhibitors, immunomodulatory drugs (IMiDs), and antibody-based therapeutics have improved MM patient survival, but the vast majority of patients eventually die following treatment refractory relapse. One difficulty is that all current MM therapies lack genetic, molecular, or other predictive biomarkers to guide their use, so treatment decisions are made empirically. To further improve patient survival, it is essential to identify predictive biomarkers to guide therapeutic decision making. Previously, we developed an ex vivo functional assay for drug susceptibility leveraging the measurement of single-cell mass accumulation rate (MAR) with a novel platform known as a serial suspended microchannel resonator (sSMR). By measuring the MAR of live, purified, single tumor cells in the presence of therapeutics applied ex vivo, we can assess a tumor?s sensitivity within hours. In a preliminary MM study, the MAR biomarker accurately identified drug sensitivity in nine patients and was uniquely suited to working with the limited number of tumor cells available after purification from patient bone marrow (BM) biopsies. Importantly, the biomarker demonstrated compatibility across a range of standard of care (SOC) therapies each with unique mechanisms of action. These results are promising, demonstrating the assay?s ability to define cell-intrinsic drug sensitivity for an individual patient?s tumor cells. However, to have broad clinical impact, a functional assay for MM must also address the significant influence on drug response of cell-extrinsic tumor microenvironmental (TME) factors. In this proposal, we aim to further develop and validate the clinical value of this assay by altering the context of therapeutic testing to include TME factors. In short, with patient BM biopsies and consultation provided by the Munshi Lab at the Dana-Farber Cancer Institute, we will refine our protocol by drugging tumor cells prior to purification and while still in the presence of the BM milieu (i.e. stromal cells, osteoblasts, T-cells), an approach shown to capture the majority of the TME. Each BM biopsy will be subjected to both this new protocol and the original protocol where drugs are applied following purification, in order to contrast the influence of the TME on drug response. We expect the presence of the TME to alter MAR response to drugs, particularly for IMiDs, which have greater dependence on cell-extrinsic factors. It will also allow us to test antibody-based, T-cell dependent therapeutics like daratumumab. Once the new approach is validated, we will use it to run a prospective pilot study of 10 relapsed patients. This blinded comparison of assay results matched to clinical outcome will be an important step towards the goal of generating an all-inclusive, mechanism-agnostic biomarker for MM.
