Subcutaneous Daratumumab/Pomalidomide Triplet Improves PFS in Relapsed/Refractory Myeloma

Jan van de Winkel, PhD

Subcutaneous daratumumab (Darzalex) in combination with pomalidomide (Pomalyst) and dexamethasone showed an improvement in progression-free survival (PFS) versus pomalidomide and dexamethasone (Pd) alone in patients with relapsed/refractory multiple myeloma who received prior treatment with lenalidomide (Revlimid) and a proteasome inhibitor (PI), meeting the primary end point of the phase 3 APOLLO (MMY3013; NCT03180736) trial.¹

“We are pleased with these positive results for daratumumab, administered as a subcutaneous formulation, in combination with Pd,” Jan van de Winkel, PhD, chief executive officer of Genmab, stated in a press release. “The corresponding intravenous (IV) regimen was previously approved by the US FDA based on the phase 1 single-arm EQUULEUS study.”

Moreover, Janssen Biotech, Inc, which obtained worldwide license to develop, manufacture, and commercialize daratumumab from Genmab in 2012, plans to discuss the APOLLO findings with health authorities to prepare for regulatory submissions. The data are projected to be presented at an upcoming medical meeting, according to Genmab.

In the multicenter, randomized, open-label, phase 3 trial, investigators set out to compare daratumumab plus Pd with Pd alone in patients with relapsed/refractory disease who received and progressed on at least 1 previous treatment regimen with both lenalidomide and a PI.²

To be eligible for enrollment, patients had to be at least 18 years of age, had to have an ECOG performance status of 0 to 2, and had creatinine clearance of 30 mL/min or more.³ Patients who received only 1 prior treatment must have shown disease progression at 60 days or less after treatment with the lenalidomide-based regimen. Patients were not able to have received previous treatment with anti-CD38 therapy or pomalidomide.

In the trial, participants were randomized 1:1 to receive either the triplet or the doublet. In the experimental arm, patients received a 16 mg/kg dose of IV daratumumab or an 1800-mg subcutaneous dose of the agent at weekly intervals for 8 weeks, then every 2 weeks, for an additional 16 weeks, then every 4 weeks thereafter. Oral pomalidomide was given at 4 mg on days 1 to 21 of each 28-day treatment cycle, while oral dexamethasone was given at 40 mg once daily on days 1, 8, 15, and 22, of each 28-day cycle. In the control arm, pomalidomide and dexamethasone were administered on the same schedule as the experimental arm.

The primary end point of the trial was comparison of PFS between the arms, while key secondary end points included overall response rate (ORR), very good partial response (VGPR) or better rate, a complete response (CR) or better rate, minimal residual disease negativity rate, time to response, duration of response (DOR), time to next therapy, overall survival, and safety, among others.

APOLLO was designed to the confirm the results reported in the phase 1b EQUULEUS trial, results of which led to the June 2017 FDA approval of daratumumab for use in combination with Pd in patients with multiple myeloma who had received at least 2 previous therapies, including a proteasome inhibitor and lenalidomide. Results from the trial showed that the triplet elicited an ORR of 59% (95% CI, 49.1%-68.8%) in patients with relapsed/refractory disease.⁴

A total of 103 patients with multiple myeloma who had received previous treatment with a PI and an immunomodulatory agent were enrolled on the Pd arm of the trial. The median patient age was 64 years and 8% of participants were 75 years of age or older. The median number of prior lines of treatment received was 4; notably, three-fourths of patients received prior autologous stem cell transplant. Eighty-nine percent of patients were refractory to lenalidomide, 71% were refractory or bortezomib, and 64% were refractory to both drugs.

The VGPR rate with the triplet was 28%, while the CR rate was 6% and the stringent CR rate was 8%. The median time to response was 1 month and the median DOR was 13.6 months.

With regard to safety, the most frequently reported adverse effects included infusion reactions (50%), diarrhea (38%), nausea (30%), vomiting (21%), fatigue (50%), pyrexia (25%), upper respiratory tract infection (50%), muscle spasms (26%), cough (43%), and dyspnea (33%). Furthermore, the most commonly reported treatment-emergent hematology laboratory abnormalities included lymphopenia (94%), neutropenia (95%), thrombocytopenia (75%), and anemia (57%).

In February 2019, the FDA approved a split-dosing regimen of daratumumab for patients with multiple myeloma, providing the option to split the first infusion of the CD38-directed monoclonal antibody over 2 consecutive days or complete in a single session based on data from EQUULEUS which showed that the pharmacokinetic concentrations of daratumumab at 16 mg/kg were comparable at the end of weekly dosing, regardless of whether it was a split-dose or a single infusion.⁵

References

1. Genmab announces European Myeloma Network and Janssen achieve positive topline results from phase 3 APOLLO study of daratumumab in combination with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma. News release. Genmab. July 31, 2020. Accessed August 3, 2020. https://bit.ly/31ddLBd.
2. Comparison of pomalidomide and dexamethasone with or without daratumumab in subjects with relapsed or refractory multiple myeloma previously treated with lenalidomide and a proteasome inhibitor daratumumab/pomalidomide/dexamethasone vs pomalidomide/dexamethasone (EMN14). ClinicalTrials.gov. Updated July 22, 2020. Accessed August 3, 2020. https://clinicaltrials.gov/ct2/show/NCT03180736
3. Sonneveld P, Terpos E, Dimopoulos MA, et al. Pomalidomide and dexamethasone (pom-dex) with or without daratumumab (dara) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): a multicenter, randomized, phase 3 study (APOLLO). J Clin Oncol. 2018;36(suppl 15):TPS8059. doi:10.1200/JCO.2018.36.15_suppl.TPS8059
4. Daratumumab. Prescribing Information. Genmab/Janssen; 2017. Accessed August 3, 2020. https://bit.ly/33nvGI8.
5. US FDA approves Darzalex (daratumumab) split-dosing regimen. New release. Janssen. February 12, 2019. Accessed August 3, 2020. https://prn.to/2tkVelH.