Improving immune modulation for smoldering myeloma

Summary All cases of multiple myeloma (MM) are preceded by precursor state termed as monoclonal gammopathy of undetermined significance (MGUS). Therefore targeting precursor states may be an effective approach to prevent this malignancy. In a recent randomized trial, we have shown that lenalidomide led to reduced risk of progression of smoldering myeloma (SMM) to clinical myeloma. In prior studies, we have shown that the immune system is capable of recognizing myeloma precursor lesions. In recent studies, we have also shown that immune dysfunction is an early feature of myeloma suggesting that earlier application of immune modulation may be needed to mediate immune prevention. In particular, evolution of clinical myeloma is associated with attrition of stem-like memory T cells and the accumulation of terminally differentiated effector T cells. In this proposal, we will test the hypothesis that immune control of myeloma precursor states is determined in part by the cell states and spatial architecture of immune cells in these conditions. We further posit that immune modulation to alter these properties could prevent evolution of clinical myeloma. This will be evaluated with the following specific aims. In Aim 1, we will evaluate whether properties of immune cells at baseline in SMM correlate with the risk of progression to clinical myeloma. Aim 2 will evaluate changes in circulating and bone marrow immune cells in patients undergoing therapy with iberdomide or iberdomide and dexamethasone under a randomized phase II clinical trial. Studies in aim 3 will evaluate the effect of immune modulation on spatial heterogeneity of immune cells in preclinical model systems. Together, these studies will not only provide new insights into improving immune modulation as a strategy to prevent clinical myeloma but may also help develop novel immune based combinations to treat myeloma.