Selinexor for the Treatment of Patients with Intermediate and High-Risk Smoldering Multiple Myeloma

Plasma cell disorders are a spectrum of diseases ranging from monoclonal gammopathy of undetermined significance (MGUS), to smoldering multiple myeloma (SMM), to multiple myeloma (MM). Multiple myeloma is preceded by an asymptomatic precursor state in the majority of cases. While the vast majority of these patients do not progress to have symptomatic disease, there is an intermediate to high-risk subset of patients with SMM that do go on to meet criteria for MM, including hypercalcemia, anemia, renal insufficiency, and lytic bone lesions.

There are numerous risk stratification systems that have been devised to predict which patients have the highest risk of progression. The Mayo Clinic group identified 3 factors as predictors for early progression. these factors include a bone marrow plasma cell burden of greater than 20%, a monoclonal protein (M-spike) of 2g/dL or greater, and a ratio of involved to uninvolved serum free light chains of 20% or greater. Patients with one more of these risk factors have an increased risk of progression to MM in the first five years after diagnosis.

The current standard of care for the treatment of patients with SMM is observation because numerous early studies failed to demonstrate a survival advantage with pharmacologic intervention. More recent studies have aimed to select out the high-risk patients where intervention is more likely to be beneficial in preventing or delaying progression. The approaches have ranged in intensity and aim, with some approaches aimed at preventing or delaying progression, and others aimed at treating aggressively with curative intent. While the preliminary results of these studies have been promising, there is no consensus on the optimal approach in patients with intermediate to high-risk smoldering multiple myeloma.

Selinexor is a small-molecule selective inhibitor of nuclear export (SINE), which inhibits exportin-1 (XPO1) in a slowly reversible, covalent manner. XPO1 is a transport protein that is responsible for transport of over 200 proteins from the nucleus to the cytoplasm. Inhibition of XPO1 leads to accumulation of tumor suppressor proteins, cell-cycle regulators, and oncoprotein mRNAs in the nucleus and eventually leads to apoptosis of malignant cells. XPO1 inhibition has been shown to induce apoptosis in malignant MM cells and impede osteoclastogenesis without toxicity to surrounding bone marrow stromal cells (BMSCs).

Selinexor has been FDA approved for the treatment of relapsed and refractory multiple myeloma and is currently being studied in the frontline and relapsed settings with different therapeutic combinations in the STOMP trial. Selinexor has not been studied in the precursor disease population. While the exact mechanisms of progression from SMM to MM are incompletely understood, it has been shown that XPO1 expression is increased during progression of disease, which makes this a promising target in this population of patients. The investigators aim to limit the side effect profile while maintaining efficacy of treatment for SMM, with the goal of delaying or preventing progression to MM. The investigators hypothesize that at a low tumor-burden disease, a lower dose of selinexor may be efficacious and lead to an improved toxicity profile than standard dosing.