Novel Combination Therapy for the Treatment of Multiple Myeloma

ABSTRACT There has recently been tremendous progress in the treatment of multiple myelomaMMCurrently effective therapeutics include proteasome inhibitorsPIssuch as bortezomib and carfilzomib and immunomodulatory drugsIMiDssuch as lenalidomideand pomalidomideIt has been found that combination therapy with doublet or triplet combinations of drugs with different mechanisms of actions is superior to monotherapyEven with these advancesmultiple myeloma remains mostly incurablegiving rise to a continuous search for new agents with different mechanisms of action and in different combinationsthat could prove more effective against drug resistant diseaseWe now propose to develop and characterize a therapeuticanti CDIFNwith a novel mechanism of action to add to the therapeutic options for combination therapyAnti CDIFNconsists of an antibody recognizing CDan antigen expressed on virtually all myeloma cells fused to IFNIFNs have direct cytotoxic effects and are potent regulators of cell growth and the immune responsewith proven therapeutic efficacy against many tumors including MMWe have shown that by fusing IFN to an antibody that recognizes an antigen expressed by a tumorwe are able to achieve therapeutically effective doses in the absence of toxicityWe now hypothesize that the anti CDIFNfusion protein will provide a novel class of therapeutics thus augmenting the currently available treatments and will improve anti tumor activity when it is included in combination therapiesThe goal of the current proposal will be to evaluate the potential of this new therapy to combine with existing therapies for treatmentinitially evaluating double treatmentbut with the option of moving forward to include multiple agents for treatmentSpecifically we willEvaluate the therapeutic efficacy of anti CDIFNin combination with the PIs bortezomib and carfilzomibandEvaluate the therapeutic efficacy of anti CDIFNin combination with the IMiDs lenalidomide and pomalidomideFor each combination the in vitro anti tumor activity against a panel of MM cells representing different types of myeloma will initially be evaluatedFor selected combinationsthe in vivo protection in xenografts will be determinedCombination or synergistic anti tumor activity in vitro and in vivo will support the fact that anti CDIFNhas the possibility of providing an effective new therapy for the treatment of MM PROJECT NARRATIVE Although current therapeutics for multiple myelomasuch as lenalidomideand pomalidomideand proteasome inhibitors are effectivemultiple myeloma remains mostly incurablegiving rise to a search for new agents with different mechanisms of actionthat could prove more effective against drug resistant diseaseWe now propose to characterize a therapeuticanti CDIFNwith a novel mechanism of action and test its efficacy against a panel of cell lines in vitro and in vivo when used in combination with existing therapies