Results of an Early Access Treatment Protocol (EAP) of Daratumumab in United States Patients with Relapsed or Refractory Multiple Myeloma

Background: Daratumumab (dara) is 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. Accelerated approval was granted in the United States (US) in November 2015, based largely on the results of MMY2002, a pivotal phase 2 study in this pt population.

Methods: The objectives of this multicenter, open-label early access treatment protocol (EAP) were to provide early access to dara treatment and collect safety and patient-reported outcome (PRO) data in this pt population. Eligibility criteria were similar to those of pivotal study MMY2002 and included 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. Serious adverse events (SAEs), grade 3-4 AEs, infusion related reactions (IRRs), and PRO data were collected.

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. Three-fourths of pts were symptomatic with an ECOG score of 1 (58%) or 2 (16%). Pts received a median of 8 (range 1-17) doses, and median treatment exposure was 1.9 (range 0.03-6.0) months. Median durations of infusion were 7.4, 4.4, and 3.5 hours for the first, second, and all subsequent infusions, respectively. Half of pts (52%) transitioned to commercial drug after marketing authorization, whereas 37% discontinued due to progressive disease. Treatment emergent grade >3 AEs were reported in 51% of pts. The most common grade ≥3 AEs were thrombocytopenia (15%) and anemia (14%). SAEs occurred in 35% of pts, including 12% of pts with SAEs which were reported by investigators as drug-related. The most common SAEs were infections, which occurred in 11% of pts. Nine percent of pts discontinued therapy due to AEs, including 3% for drug-related AEs. Thirteen (4%) pts had an AE with a fatal outcome, including 2 (0.6%) pts with drug-related AEs (pyrexia, thrombocytopenia/ subdural hematoma). 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 were respiratory or thoracic symptoms (cough, dyspnea, throat irritation, nasal congestion), which occurred in 31% of pts. The median change from baseline in all the domains of the EQ-5D-5L and EORTC QLQ-C30 scales after 1 and 2 cycles as well as at pts' last assessment was 0, with the exception of EQ-5D-5L VAS, which showed a median increase of 1 and 2 units after 1 and 2 cycles, respectively.

Conclusions: EAP results in US pts confirmed the safety profile of dara in MM pts with >3 prior therapies including a PI and IMID or who were refractory to both PI and IMID. SAEs occurred in one-third of pts, but only 12% of pts experienced a drug-related SAE. More than half of pts experienced IRRs, which primarily occurred during the first infusion and were grade 1-2 in severity. Pts maintained their health-related quality of life during a median duration of 2 months of therapy.