Targeting Nuclear Export Proteins in Multiple Myeloma Therapy

Area of Science:

• Oncology
• Hematology
• Molecular Biology

Background:

• Multiple myeloma (MM) is an incurable plasma cell cancer with frequent relapses and treatment resistance.
• Refractory MM has a poor prognosis, with median overall survival (OS) of 4-6 months despite recent treatment advances.

Purpose of the Study:

• To review the emerging role of nuclear export inhibition, specifically CRM1/XPO1 inhibition, as a novel treatment modality for refractory MM.
• To discuss the development and clinical investigation of small molecule inhibitors of nuclear export (SINEs) in MM.

Main Methods:

• Review of preclinical studies on SINEs in MM, evaluating their cytotoxicity, role in therapy resensitization, and potential impact on bone disease.
• Analysis of clinical trial data, including the STORM trial which led to the approval of selinexor for relapsed/refractory MM.
• Examination of ongoing trials investigating selinexor in combination regimens and early trials of second-generation SINEs like eltanexor.

Main Results:

• Preclinical studies demonstrate SINEs are cytotoxic to myeloma cells, can resensitize tumors to therapy, and may limit bone disease progression.
• Selinexor, the first nuclear export inhibitor, was approved in July 2019 for relapsed/refractory MM.
• Eltanexor, a second-generation SINE, shows preliminary efficacy with a potentially improved toxicity profile.

Conclusions:

• Nuclear export inhibition represents a promising novel therapeutic strategy for refractory multiple myeloma.
• Ongoing clinical trials are crucial for defining the role of SINEs, including selinexor and eltanexor, in MM treatment paradigms.