Use of Montelukast to Reduce Infusion Reactions in an Early Access Treatment Protocol of Daratumumab in United States Patients with Relapsed or Refractory Multiple Myeloma

Background: Daratumumab (dara), a human CD38-directed monoclonal antibody indicated for the treatment of patients (pts) with multiple myeloma (MM) who have received ≥3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMID) or who are double-refractory to a PI and an IMID, was granted accelerated approval in the United States (US) in November 2015. CD38 is expressed on airway smooth muscle cells, and infusion related reactions (IRRs) in registration studies were marked by symptoms (cough, wheezing, rhinorrhea) similar to those of allergic rhinitis. Anecdotal reports indicated that premedication with montelukast, a leukotriene receptor antagonist, may reduce the IRR rate associated with dara therapy.

Methods: A multicenter, open-label early access treatment protocol (EAP) was conducted to provide early access to dara treatment and collect safety data including IRRs. Eligibility criteria were similar to those of pivotal study MMY2002 in pts with double-refractory MM or >3 prior therapies including a PI and an IMID, age ≥18 years, documented MM, progression by IMWG criteria following the most recent therapy, ≥3 prior lines of therapy including a PI and an IMID or disease double-refractory to a PI and an IMID, ECOG performance status score 0-2, no known chronic obstructive pulmonary disease or persistent asthma, no ongoing MM therapy, and no prior exposure to anti-CD38 antibody therapy. Pts received dara 16 mg/kg IV weekly for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks until disease progression, unacceptable toxicity, or 60 days after US approval. Pre- and post-infusion medications were administered as in study MMY2002 and included pre- and post-infusion systemic corticosteroids for all pts as well as post-infusion inhaled corticosteroids and bronchodilators for pts with obstructive lung disorders. Montelukast was not recommended but was allowed at the investigator's discretion.

Results: In total, 400 pts were screened and 348 pts were enrolled and dosed at 39 US sites from July to November 2015. Median age was 65 (range 27-94) years; 72% were white, and 17% were African American. Most (74%) pts were symptomatic with an ECOG score of 1 or 2. Pts received a median of 8 (range 1-17) doses, and median treatment exposure was 1.9 (range 0.03-6.01) months. Median durations of infusion were 7.4, 4.4, and 3.5 hours for the first, second, and all subsequent infusions, respectively. IRRs occurred in 56% of pts, including 8% with grade ≥3 IRRs. IRRs occurred in 56%, 2%, and 2% of first, second, and all subsequent infusions, respectively. The most common IRRs at the first infusion were respiratory or thoracic symptoms, which occurred in 31% of pts and included cough (14%), dyspnea (8%), throat irritation (6%), and nasal congestion (5%). Fifty pts received montelukast 10 mg given >30 minutes prior to the first infusion, and 298 pts did not. The IRR rate at first infusion was 38.0% and 58.5% (respiratory symptoms 20% and 32%), respectively, in pts who did or did not receive montelukast. Gastrointestinal symptoms were observed in 4% and 11% of pts who did or did not receive montelukast, respectively, while chills were observed in 14% of pts in both groups. Median time for first infusion was 6.7 and 7.6 hours for pts who did or did not receive montelukast, respectively, while times for the second and all subsequent infusions were similar in both groups.

Conclusions: The findings of the EAP study in US pts with MM who had received >3 prior therapies including a PI and IMID or were double-refractory observed that the IRR rate during the first dara infusion was one-third lower in pts who received 10 mg of montelukast >30 min prior to the first dara infusion. Respiratory and gastrointestinal symptoms were lower in pts who received montelukast, whereas chills were observed at a similar rate in both groups. The median time for the first infusion was 0.9 hours shorter in pts who received montelukast. Additional studies of montelukast to mitigate the IRRs associated with the first infusion of dara are indicated.