Multiple myeloma (MM) remains an incurable plasma cell cancer despite great advancements in chemo- and immunotherapies. All MM patients have preceding asymptomatic stages which primarily consist of monoclonal gammopathy of undetermined significance (MGUS), which is often followed by development of a more severe condition called smoldering MM (SMM). Patients with MGUS, and especially SMM, convert to overt MM and no therapeutic methods are available to prevent their progression to MM. Therefore, this is an unmet need to develop chemo- and/or immunoprevention strategies for MGUS and SMM. Dickkopf-1 (DKK1) may be an excellent target for this purpose. DKK1 is absent from normal tissues including normal bone marrow (BM) plasma cells but is highly expressed in BM plasma cells from MGUS and SMM patients, and their expression is further elevated in MM cells. Our studies showed that DKK1 was an excellent tumor-associated antigen (TAA), and DKK1 vaccine was therapeutic against established MM in vivo. The objective of this project is to, for the first time, determine the potential of targeting DKK1 by a vaccine for immunoprevention of MM development. This work will support the clinical development of novel immune-based, less toxic (than chemotherapy) treatments for patients with MGUS or SMM to prevent progression to overt MM. Completing these studies are highly significantly and clinically impactful, as DKK1-specific humanized mAbs are already available and have been tested in human cancers.

Despite improvement in chemotherapy treatments and recent advances in immunotherapies for MM, resistance remains the major problem in its management. Most MM patients experience relapse after treatment and eventually die from the disease. Prior to developing MM, all patients undergo a clonal expansion of BM plasma cells called MGUS, which is considered benign and carries a 1% annual risk of converting to MM. MGUS is followed by a further expansion of BM plasma cells called SMM that is considered malignant and carries a 10% annual risk of converting to MM. Both MGUS and SMM are asymptomatic but can be clinically recognized by detection of elevated levels of serum M-protein. There is an urgent and unmet need to develop novel strategies to prevent the evolution of MGUS and SMM patients to overt MM. The goal of this project is to develop a vaccine to DKK1 and to determine whether it can provide an effective method to prevent MGUS or SMM conversion to MM. Successful completion of this project would support the clinical development of a DKK1 vaccine for MM prevention/interception.