Results of an Interim Safety Analysis of a Phase 2 Study of Daratumumab (Dara) Plus Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in Previously Untreated and Relapsed Patients (Pts) with Multiple Myeloma (MM)

Background: Dara is a monoclonal anti‐CD38 antibody approved for the treatment of relapsed and refractory MM, but is associated with an infusion related reaction (IRR) rate of 46% for infusion 1 and 2% for infusion 2, and a median duration of infusions 1 and 2 of 7.0 and 4.3 hours, respectively (US Prescribing Information). CyBorD is a commonly used bortezomib based regimen for MM. This study was designed to evaluate Dara-CyBorD, as well as administration of the first Dara infusion as a divided dose over 2 days, in pts with MM who are previously untreated or have relapsed following only one line of therapy. We report results from a planned interim analysis of the first 48 pts who completed C1 of study treatment, focusing on the safety and IRR profile of Dara.

Methods: This is a multicenter, single-arm, open-label, Phase 2 study conducted at US community oncology centers. Key eligibility criteria include ≥ 18 years of age; documented MM per IMWG 2015 criteria; measurable MM; ECOG performance score of 0, 1, or 2; and no or one prior line of therapy. Approximately 100 pts will receive 4 to 8 28-day induction cycles of Dara-CyBorD, including oral cyclophosphamide 300 mg/m² on Days 1, 8, 15, and 22; subcutaneous bortezomib 1.5 mg/m² on Days 1, 8, and 15; and oral or IV dexamethasone 40 mg weekly. Dara is administered at a dose of 8 mg/kg IV on Days 1 and 2 of C1, then 16 mg/kg IV weekly from C1D8 through C2, then 16 mg/kg IV once every 2 weeks for C3-6, then 16 mg/kg IV once every 4 weeks for cycles 7-8. After completion of induction, pts may undergo an autologous stem cell transplant. All pts then receive 12 cycles of maintenance therapy with Dara 16 mg/kg IV every 4 weeks. Required pre-infusion medications are dexamethasone, acetaminophen, and diphenhydramine; montelukast is allowed at the investigator's discretion.

Results: The first 48 pts completed 1 cycle of therapy with no discontinuations during C1. Median age was 62.5 (range 41-80) years, and 65% were male. Thirty-nine pts (81%) were previously untreated, and 9 pts (19%) had received 1 prior therapy. Forty-seven pts (98%) experienced at least 1 treatment emergent adverse event (TEAE) during C1, including 35 pts (73%) who experienced TEAE(s) attributed to Dara by the investigator. No grade 5 AE was reported during C1. The most commonly reported AEs during C1 were nausea (29%), fatigue (25%), diarrhea (23%), headache (17%), and chills (15%). Serious AEs (SAEs) occurred in 10% of pts during C1; no SAE was attributed to Dara by the investigator. IRRs occurred in 44% of pts, all grade ≤ 2, including 38% at C1D1 and 4% at C1D2. The most common IRRs were chills (13%), cough (6%), and nausea (6%). Respiratory IRRs occurred in 13% of pts, including cough (6%), dyspnea (4%), bronchospasm (2%), throat irritation (2%), and oropharyngeal pain (2%). The median infusion time was 4.3 hours for C1D1 and 3.5 hours for C1D2.

Conclusion: The overall safety profile during C1 of Dara-CyBorD was consistent with that previously reported for Dara with no new safety concerns. Administration of the first Dara infusion as a split dose of 8 mg/kg/day over 2 days resulted in a similar IRR rate and a shorter median infusion time for C1D1 than the US prescribing information for single dose. No grade ≥ 3 IRRs were observed. These findings demonstrate that splitting of the first Dara infusion in the community setting is feasible, results in a similar IRR rate with no observed grade ≥ 3 IRRs, and reduces the median time for the first Dara infusion.