From Pages to Practice

By Ahmad Zaheen, MD, MSc

Published October 9, 2019


In 1850, the Scottish physician William MacIntyre described one of the earliest documented cases of multiple myeloma (MM) in the report “Case of mollities and fragilitas ossium, accompanied with urine strongly charged with animal matter.” The patient, Thomas Alexander McBean, was a 45-year-old tradesman who, after “vaulting out of an underground cavern…felt as if something had snapped or given way within the chest.” Before succumbing to his disease one year later, Mr. McBean was treated with an array of interventions that included bloodletting, topically applied leeches, and steel and quinine. It would take another 50 years before the plasma cell was identified and another 50 years after that before the first randomized controlled trial of urethane for the treatment of MM.

Interestingly, Mr. McBean apparently had a clinical response to steel and quinine and was “bounding over the hills…as nimbly as any of his companions,” before a disease recurrence eventually led to his death. Today, MM patients encounter a similar course of remission and recurrence as they progress through the now extensive treatment options available. MM remains incurable for all but a few patients who successfully complete allogeneic stem-cell transplant. The three modern classes of treatment include targeted antibodies (daratumumab, elotuzumab), proteasome inhibitors (e.g., bortezomib, carfilzomib, and ixasomib), and immunomodulatory medications (e.g., thalidomide and lenalidomide).

The STORM trial, published in NEJM, was designed to evaluate the efficacy of the novel drug selinexor in patients with MM that is refractory to all three therapeutic classes, and for whom limited options exist. The results showed that 26% of participants met the primary outcome of a ≥50% drop in paraprotein level in response to selinexor plus dexamethasone. Selinexor, now FDA-approved, is the newest treatment option in the hematologist’s arsenal for highly refractory MM.

The following NEJM Journal Watch summary explains the study and results in more detail:


A New Option for Treatment-Refractory Multiple Myeloma

Michael E. Williams, MD, ScM reviewing Chari A et al. N Engl J Med 2019 Aug 22

Multiple myeloma patients who are refractory to the three major classes of targeted therapies — proteasome inhibitors, immunomodulatory agents, and the anti-CD38 monoclonal antibody daratumumab — have limited treatment options and poor survival.

Now, investigators have conducted an industry-sponsored, multicenter, open-label, phase IIb trial of the exportin 1 inhibitor selinexor in 123 multiple myeloma patients with prior exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent (median number of prior regimens, 7). Of these patients, 102 had undergone prior stem-cell transplantation, 2 had received prior CAR-T cell therapy, and 118 were refractory to carfilzomib, pomalidomide, and daratumumab. Patients received selinexor (80 mg) plus dexamethasone (20 mg) orally on days 1 and 3 each week in 4-week cycles; treatment continued until disease progression, discontinuation, or death.

The overall response rate (≥50% decrease in myeloma paraprotein level; the primary endpoint) was 26%, with 2 patients achieving complete remission; an additional 13% achieved minimal response. Median progression-free survival was 3.7 months. Overall survival was 15.6 months in patients achieving minimal response or better, 5.9 months in those with stable disease, and 1.7 months in those with progressive or non-evaluable disease. Grade 3 or 4 adverse events included thrombocytopenia, anemia, hyponatremia, and neutropenia.

Comment: This trial identifies selinexor as a novel agent with unique mechanisms of action that, when combined with dexamethasone, has relevant clinical activity in heavily pretreated myeloma patients, including those with poor-risk biomarkers. Based on these results, selinexor was recently approved by the FDA for multiagent-refractory myeloma.

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Ahmad is a 2019-2020 editorial fellow at the New England Journal of Medicine. He is from Toronto, Canada where he is completing his training in pulmonary medicine at the University of Toronto.