Five-Minute SC Injection of Daratumumab in R/R Multiple Myeloma

Alexander M. Castellino, PhD

December 08, 2020

Data from the Apollo study provide proof for the subcutaneous administration (sc) of daratumumab (Darzalex Faspro) in combination with pomalidomide (Pomalyst) and dexamethasone (Pd) for patients with relapsed or refractory multiple myeloma (RRMM).

The sc formulation of daratumumab (with hyaluronidase) was approved in the US in May, and is administered by injection into the abdomen over 3-5 minutes. Previously the drug was available only as an intravenous infusion.

"The appeal of subcutaneous daratumumab is the 5 minutes it needs for administering, cutting down considerable on 'chair/clinic' time. Intravenous daratumumab is given over several hours," said Joseph Mikhael, MD, MEd, chief medical officer of the International Myeloma Foundation, who was approached for comment. He also highlighted the low rates of infusion reactions seen with the subcutaneous daratumumab triplet.

"In the COVID era the subcutaneous route may be the way to go," he told Medscape Medical News.

"This is an effective combination with a predictable safety profile that allows for the use of sc daratumumab along with oral pomalidomide and dexamethasone for patients who have received at least one prior line of therapy that included lenalidomide [Revlimid] and a proteasome inhibitor," commented lead author Meletios A. Dimopoulos, MD, of National and Kapodistrian University of Athens, Athens, Greece.

The triplet combination was associated with a 37% reduced risk for progression or death compared with the two-drug combination of pomalidomide and dexamethasone.

He presented the results from the Apollo trial at the at the American Society of Hematology (ASH) 2020 virtual meeting.

Treatment Landscape of RRMM

Mikhael, who is also professor in the Applied Cancer Research and Drug Discovery Division at the Translational Genomics Research Institute, Phoenix, Arizona, provided Medscape Medical News with his insights into Apollo as well as how this triplet fits into the treatment landscape of RRMM.

Daratumumab is approved for use in both RRMM and newly diagnosed MM, either alone or in combination with standard-of-care regimens. The drug already has eight specific indications for the intravenous formulation, and five indications for the sc formulation of daratumumab, Mikhael noted. The Apollo study "will likely provide the subcutaneous approval for the daratumumab triplet in MM," he said.

According to Mikhael, the triplet of daratumumab with pomalidomide and dexamethasone is the most commonly used combination at first relapse, and this phase 3 study provides confirmatory evidence for its initial approval. The initial approval for intravenous daratumumab and Pd was based on a phase 1b study, he noted.  

"The Apollo study is the first randomized trial comparing the triplet of D-Pd to Pd," Noopur Raje, MD, of the Massachusetts General Hospital, Boston, told Medscape Medical News. She explained that the majority of patients included in Apollo were refractory to lenalidomide, which is the patient population typically seen at the time of first relapse. "This regimen will be adopted at either first or second relapse in the majority of patients," Raje said.

"In keeping with strategy in MM, we use the best triplet first and do not save the best for last," Mikhael said. The triplet of the proteasome inhibitor bortezomib (Velcade), lenalidomide, and dexamethasone is used in first-line MM. "Most patients meet the criteria for using D-Pd at first relapse," he added, noting that all patients in the study have received a proteasome inhibitor and lenalidomide as first-line therapy and had relapsed with or were refractory to these agents. 

"The short administration time and significantly low rates of infusion-site reactions are two important considerations for using this triplet with the subcutaneous formulation of daratumumab [at first relapse]," he said.

In the treatment landscape of MM, the triplet of isatuximab (Sarclisa), pomalidomide, and dexamethasone has recently been approved for RRMM based on data from the ICARIA study. Isatuximab and daratumumab are both CD38-directed antibodies. Mikhael pointed out that the the datasets from ICARIA and Apollo with respect to progression-free survival (PFS) and hazard ratios overlapped and were remarkably similar. However, daratumumab now has an advantage in being available as an sc formulation. 

The landscape of MM treatment has been changing rapidly in recent years, and more changes may be afoot. Mikhael suggested that the quartet of daratumumab, bortezomib, lenalidomide, and dexamethasone is likely to move into the first-line setting for MM based on data from the GRIFFIN study (trial update in Abstract 3243), and then the choice of drugs to use in first relapse would also change.

Apollo Study Details

Apollo was an open-label, phase 3 study that randomly assigned patients with RRMM to receive sc daratumumab in combination with pomalidomide and low-dose dexamethasone (D-Pd; n = 151) or the two-drug combination of Pd
(n = 153).

Approximately 80% of the patients were refractory to lenalidomide and half were refractory to a proteasome inhibitor.

Median duration of sc daratumumab administration was 5 minutes. Median duration of study treatment was longer for patients on D-Pd (11.5 months vs 6.6 months for Pd).

For the primary endpoint, at a median follow up of 16.9 months, median PFS was 12.4 months for patients receiving D-Pd and 6.9 months for those receiving Pd. One-year PFS was 52% for patients receiving the triplet combination and 35% for those receiving Pd. Treatment effect was generally consistent across subgroups examined, Dimopoulos reported.

Depth of response was significantly higher for patients on D-Pd. Stringent complete remission (CR) or CR was seen in 25% of patients on D-Pd vs 4% on Pd. Overall response rate was 69% for patients on D-Pd and 45% for patients on Pd alone (P < .0001). Minimal residual disease negativity was more than four times higher with D-Pd (9% vs 2% for Pd; P = .0102).

The safety profile of D-Pd was consistent with the known safety profile of sc daratumumab and Pd. Infusion-site reactions were of grade 1 or 2 and occurred in 5% of patients; in addition, only grade 1 injection-site reactions were seen and occurred in 2% of patients. The most serious treatment-emergent adverse events in patients on D-Pd were pneumonia (15% vs 8% for Pd) and lower respiratory tract infection (12% vs 9% for Pd). Incidence of secondary primary malignancy was 2% for each group.

Apollo Results Were "No Surprise"

"These results are of no surprise and further support the current practice of using a three-drug combination in the relapsed setting," Henry Fung, MD, chair of the Department of Bone Marrow Transplant and Cellular Therapies at Fox Chase Cancer Center, Philadelphia, Pennsylvania, told Medscape Medical News.

Although Fung agreed that the triplet of a proteasome inhibitor, an IMiD (immunomodulating drug) such as lenalidomide, and the steroid dexamethasone is becoming the standard of care for newly diagnosed MM, D-Pd should be considered an excellent option for patients who have limited choices in the relapsed/refractory setting.

However, he said that the median PFS of 12.4 months for patients receiving D-Pd after a median of two prior regimens is not satisfactory.

"The impact on the natural history of the disease will be limited and the duration of responses decline with each treatment regimen, and the true impact on the disease will be an effective front-line strategy." Fung said. "This will not be a practice-changing trial. We need to find out which three-drug regimen works best and what biomarkers can predict the response to individual regimen."

Dimopoulos reports receiving honoraria from Beigene, Bristol-Myers Squibb, Amgen, Takeda, Celgene, and Janssen. Mikhael reports receiving honoraria from Amgen, GSK, Janssen, Karyopharm, Sanofi, Takeda; consults with Celgene; and receives research funding from Celgene and Sanofi. Fung is on the speakers' bureau of Apollo and receives honoraria from Jansen Oncology and Celgene/BMS. Raje is a consultant for BMS and Janssen.  

American Society of Hematology (ASH) 2020 Annual Meeting: Abstract 412. Presented December 6, 2020.

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