Approval Sought for Subcutaneous Formulation of Daratumumab in Multiple Myeloma


A Biologics License Application was submitted to the FDA seeking approval for a new subcutaneous formulation of daratumumab in select patients with multiple myeloma.

A Biologics License Application (BLA) was submitted to the FDA seeking approval for a new subcutaneous (SC) formulation of daratumumab (Darxalez) in select patients with multiple myeloma.1

An intravenous (IV) formulation of daratumumab is currently approved for several indications in multiple myeloma.

The BLA is supported by data from thephase III COLUMBA trial, which was presented at the 2019 ASCO Annual Meeting.2The trial was a noninferiority comparison between the IV administration of daratumumab and the SC formulation in patients with relapsed or refractory multiple myeloma. Additional data from the phase II PLEIADES trial were also included in the BLA submission.1

The SC formulation of the anti-CD38 monoclonal antibody is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20) using the Halozyme Enhanze drug delivery technology.

"This submission represents our commitment to develop innovative treatment options for people living with multiple myeloma," Craig Tendler, MD, vice president, Clinical Development and Global Medical Affairs, Oncology, Janssen Research & Development, LLC, said in a statement. "The Darzalex subcutaneous formulation showed non-inferiority to the existing IV formulation, both as a monotherapy and in combination with common background therapies, while administered with a considerably shorter infusion time. We look forward to working closely with the FDA in their review of the data supporting this regulatory application."

In the randomized, open-label, multicenter phase III COLUMBA (MMY3012) trial, 522 patients with relapsed or refractory multiple myeloma were randomized to receive IV (n = 259) or SC (n = 263) daratumumab. Patients had received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or had disease that was refractory to both PI and an IMiD.

In the SC group, daratumumab was administered at a flat dose of 1800 mg over 3 to 5 minutes, and the IV group was given daratumumab at 16 mg/kg. Treatment in both arms was given weekly in the first 2 cycles followed by every 2 weeks for cycles 3 to 6 and every 4 weeks from cycle 7 until disease progression. Each cycle was 28 days, and patients were treated until disease progression or unacceptable toxicity.

Co-primary endpoints of the trial were overall response rate (ORR) and maximum Ctroughconcentration.

The median duration of infusion in the IV arm was 7.0 hours for the first infusion, 4.3 hours for the second infusion, and 3.4 hours for subsequent infusions. The median duration of treatment was about 5 months, with a median of 6 completed cycles.

In the SC arm, the ORR was 41.1% compared with 37.1% in the IV arm, meeting the criteria for noninferiority (relative risk [RR], 1.11; 95% CI, 0.89-1.37;P<.0001). With the SC formulation, the ORR consisted of a complete remission (CR) or better rate of 1.9% and a rate of very good partial response (VGPR) or better of 19.0%. In the IV-formulation group, the rate of CR or better was 2.7% and the rate of VGPR or better was 17.0%.

For Ctrough, the ratio of geometric means for the SC to IV formulation was 107.93% (90% CI, 95.74%-121.67%), which also met the requirements for noninferiority.

Investigators also looked to body median as a determinant of outcome with the 2 formulations, with a flat dose used in the SC group compared with a body weight—based dose used in the IV group. The median body weight was 73.0 kg in the IV arm versus 72.4 kg in the SC arm.

Body weight did not appear to affect the efficacy findings, with the relative risk favoring noninferiority between the 2 doses for those with a weight &ge;85 kg (RR, 1.34; 95% CI, 0.86-2.12) and for those with a weight &le;65 kg (RR, 1.34; 95% CI, 0.86-2.12).

After a median follow-up of 7.46 months, the median progression-free survival was 6.1 months with the IV formulation compared with 5.6 months with the SC formulation (HR, 0.99; 95% CI, 0.78-1.26;P= .9258).

At 6 months, the rate of overall survival was 83.0% with IV daratumumab versus 87.5% with SC daratumumab (HR, 0.90; 95% CI, 0.59-1.35;P= .6032).

Importantly, there were infusion-related reactions (IRR) events observed in only 12.7% of patients in the SC group compared with 34.5% seen in the IV group (odds ratio, 0.28; 95% CI, 0.18-0.44;P<.0001). The median time to onset of IRR was 1.5 hours in the IV group compared with 3.6 hours for the SC arm.

The safety profile was otherwise similar between the 2 arms. The rate of grade 3/4 neutropenia was higher in the SC group, at 13% compared with 8%. The rates of any-grade chills (11% vs 5%) and dyspnea (12% vs 6%) were lower in the SC group versus the IV group, which could have been due to a reduction in the IRRs, the investigators hypothesized.

Treatment satisfaction questionnaires noted that patients were generally more satisfied with the SC formulation of daratumumab compared with the IV version. A median difference of 5.9 points was observed between the 2 groups, with a score near 90 for the SC arm during cycle 10 compared with a score just below 80 in the IV arm.

The BLA comes close on the heels of arecent approval for daratumumabwhen used in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of patients with multiple myeloma who are ineligible for autologous stem cell transplantation, based on the results of the phase III MAIA trial.


  1. Janssen Submits Application to U.S. FDA Seeking Approval of New DARZALEX&reg; (daratumumab) Subcutaneous Formulation [press release]. Raritan, NJ: Janssen Pharmaceutical Companies of Johnson & Johnson; July 12, 2019. Accessed July 15, 2019.
  2. Mateos M-V, Nahi H, Leggier W, et al. Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients (pts) with relapsed or refractory multiple myeloma (RRMM): COLUMBA.J Clin Oncol.2019;37(suppl; abstr 8005). doi: 10.1200/JCO.2019.37.15_suppl.8005.
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