A functional assay for ex vivo determination of drug susceptibility for multiple myeloma patients

Multiple myeloma is the second most common hematological malignancy and remains incurablewithof patients surviving less thanyearsPatient relapse is inevitable despite an increase in therapeutic optionshighlighting the significant need for predictive biomarkers that can rapidly and accurately determine tumor drug susceptibility to direct utilization of optimal therapiesWe 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 myelomaMMthe second most common blood cancerNew classes of drugsincluding proteasome inhibitorsimmunomodulatory drugsIMiDsand antibody based therapeutics have improved MM patient survivalbut the vast majority of patients eventually die following treatment refractory relapseOne difficulty is that all current MM therapies lack geneticmolecularor other predictive biomarkers to guide their useso treatment decisions are made empiricallyTo further improve patient survivalit is essential to identify predictive biomarkers to guide therapeutic decision makingPreviouslywe developed an ex vivo functional assay for drug susceptibility leveraging the measurement of single cell mass accumulation rateMARwith a novel platform known as a serial suspended microchannel resonatorsSMRBy measuring the MAR of livepurifiedsingle tumor cells in the presence of therapeutics applied ex vivowe can assess a tumor s sensitivity within hoursIn a preliminary MM studythe 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 marrowBMbiopsiesImportantlythe biomarker demonstrated compatibility across a range of standard of careSOCtherapies each with unique mechanisms of actionThese results are promisingdemonstrating the assay s ability to define cell intrinsic drug sensitivity for an individual patient s tumor cellsHoweverto have broad clinical impacta functional assay for MM must also address the significant influence on drug response of cell extrinsic tumor microenvironmentalTMEfactorsIn this proposalwe aim to further develop and validate the clinical value of this assay by altering the context of therapeutic testing to include TME factorsIn shortwith patient BM biopsies and consultation provided by the Munshi Lab at the Dana Farber Cancer Institutewe will refine our protocol by drugging tumor cells prior to purification and while still in the presence of the BM milieui estromal cellsosteoblastsT cellsan approach shown to capture the majority of the TMEEach BM biopsy will be subjected to both this new protocol and the original protocol where drugs are applied following purificationin order to contrast the influence of the TME on drug responseWe expect the presence of the TME to alter MAR response to drugsparticularly for IMiDswhich have greater dependence on cell extrinsic factorsIt will also allow us to test antibody basedT cell dependent therapeutics like daratumumabOnce the new approach is validatedwe will use it to run a prospective pilot study ofrelapsed patientsThis blinded comparison of assay results matched to clinical outcome will be an important step towards the goal of generating an all inclusivemechanism agnostic biomarker for MM