Heavily pretreated patients with relapsed or refractory multiple myeloma (RRMM) treated with CD38-directed daratumumab through an early-access treatment protocol (EAP) had safety results consistent with those reported in clinical trials, according to a study published in Cancer.1 Additionally, treatment with daratumumab had no negative impact on patient-reported outcomes, according to the study authors.

“This EAP study confirms the safety profile of daratumumab monotherapy in a large cohort of patients with relapsed and refractory multiple myeloma that was similar to the initial population indicated for daratumumab in the US,” wrote Ajai Chari, MD, Icahn School of Medicine at Mount Sinai, New York, New York, and colleagues. “The large safety sample size is of value, and EAPs offer an ethical, compliant means of addressing unmet needs in patients with limited treatment options, or who have exhausted all available options, by making a drug accessible to those who are not eligible for ongoing trials and before the drug is commercially available.”

Patients in the study gained access to daratumumab prior to its commercial availability, but the drug was subsequently approved by the US Food and Drug Administration (FDA) in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone in patients with myeloma and 1 or more prior lines of therapy.

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This approval was supported by data from 2 phase 3 studies: CASTOR and POLLUX.2,3 In the CASTOR study, patients were treated with bortezomib plus dexamethasone with or without daratumumab. Daratumumab reduced the risk for death or progression in patients by 61% and had an overall response rate of 83%. In POLLUX, where daratumumab was studied with lenalidomide instead of bortezomib, there was a 63% reduction in risk for progression or death and an overall response rate of 93%.

This study included 348 patients enrolled at 39 sites in the United States between June 2015 and December 2015. Patients were included if they had 3 or more prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent, or if they were refractory to both of these types of agents.

Patients were treated with 16 mg/kg daratumumab for 8 weeks, every other week for 16 weeks, and monthly until they progressed, had unacceptable toxicity, or 60 days after the drug gained FDA approval.

The median time on therapy was 1.9 months. More than half of patients (52%) transitioned to commercially available daratumumab after the FDA approval, and more than one-third (37%) discontinued treatment due to disease progression.

Grade 3 adverse events occurred in half of the patients, including 15% with thrombocytopenia and 14% with anemia. More than one-third of patients had serious adverse events, including 12% that were determined to be drug-related.

Premedication Protocol

At first infusion, 56% of patients had site reactions; however, this decreased to only 2% of patients on the second and all subsequent infusions — a finding consistent with prior studies, the researchers noted. Among 50 patients across 2 study sites who received montelukast as a premedication prior to first infusion, 38% had infusion-site reactions at first infusion compared with 59% of patients who did not receive montelukast as a premedication before primary infusion.

“There are published case reports using montelukast (a leukotriene receptor antagonist used to treat asthma and allergies) in resensitization protocols for patients who have hypersensitivity reactions to monoclonal antibodies,” the researchers wrote.

“Patients who received montelukast had fewer respiratory and gastrointestinal symptoms than those who did not receive montelukast, whereas systemic symptoms, such as chills, were similar in both groups,” they continued. “This positive effect may have been caused by generalized histamine secretion and local inflammation inhibition by montelukast, as leukotriene receptors are present in both the lung and the gut.”

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The trial was not powered to look at efficacy; however, 23% of patients had an objective response: 18% with a partial response, 5% with very good partial response, and stringent complete response in 0.6% of patients. A previous phase 2 trial of daratumumab reported a similar overall response rate of 29%.4 However, the researchers noted that the utility of the overall response data from the current trial is limited.


  1. Chari A, Lonial S, Mark TM, et al. Results of an early access treatment protocol of daratumumab in United States patients with relapsed or refractory multiple myeloma [published online November 5, 2018]. Cancer. doi:10.1002/cncr.31706
  2. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.
  3. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.
  4. Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387:1551-1560.