For Multiple Myeloma, Triplet Therapy Is Standard. Now Research Is Pointing To a Quadruplet Approach.

Darzalex (daratumumab) is an anti-CD38 humanized monoclonal antibody that is used to treat multiple myeloma. The drug has been administered intravenously, but the infusions take a long time and some people have infusion-related reactions, such as hives and fever or, more seriously, difficulty breathing and large drops in blood pressure. Results of studies of subcutaneous administration of the drug have shown that it is safe and well tolerated.

Another positive result for subcutaneous Darzalex was reported at the American Society of Hematology meeting in December 2023 and simultaneously published in the New England Journal of Medicine. Multiple myeloma is now commonly treated with “triplet” therapy: a trio of agents that includes Velcade (bortezomib), Revlimid (lenalidomide), and dexamethasone and then Revlimid by itself as maintenance therapy.

Pieter Sonneveld, M.D., Ph.D.

The lead author of this recent study, Pieter Sonneveld, M.D., Ph.D., of Erasmus MC Cancer Institute in Rotterdam, Netherlands, said in an email to Managed Healthcare Executive that he expects the favorable results, which include a marked improvement in progression-free survival, as well as favorable results from other studies, to change the standard of care so it includes the addition of Darzalex. If that happens, the triplet therapy for multiple myeloma will be giving way to a quadruplet regimen.

Darzalex may, though, have the drawback of making adverse events more common. In this trial, serious cases of neutropenia, thrombocytopenia, diarrhea and pneumonia occurred more often among the patients treated with Darzalex than among those in the control group.

The open-label trial, which was sponsored by Janssen, the maker of Darzalex, involved 709 people newly diagnosed multiple myeloma who were eligible for bone marrow transplants. Typically, candidates for bone marrow transplants are younger and healthier those who are candidates.

The trial, named PERSEUS, compared patients treated with the standard regimen Velcade-Revlimid dexamethasone and then Revlimid maintenance therapy to patients treated with those agents plus Darzalex, which was added both in the initial “induction” phase of treatment, the “consolidation” phase after the bone marrow transplant, and during the subsequent maintenance phase when patients are treated with just Revlimid.

After a median follow-up period of 48 months, 84% of the patients treated with the Darzalex quadruplet regimen experienced progression-free survival compared with 68% in the triplet group. The patients in the Darzalex group also fared better when it came to measurements of complete response and minimal residual disease.

Serious adverse events (grade 3 or 4) were, however, consistently more common in the Darzalex group, including neutropenia (62% in the Darzalex group vs. 51% in the standard treatment group), thrombocytopenia (29% vs. 17%) and diarrhea (10.5% vs. 6.1%). Sonneveld and his colleagues noted, though, that the discontinuation rate was lower in the group that received Darzalex. There were also fewer deaths in the Darzalex group (34 vs. 44).

In addition to testing the subcutaneous formulation of Darzalex, the PERSEUS trial stands out because it tested adding the drug in all three phases — induction, consolidation and maintenance — of multiple myeloma treatment.

Sonneveld and his colleagues emphasized n the conclusion of their New England Journal of Medicine write-up of the research that the positive results from the PERSEUS trial were in line with other studies ofcalled GRIFFIN and CASSIOPEIA. All three trials, they note, “show a benefit with respect to the depth of response and progression-free survival after the use of daratumumab-based quadruplet therapy followed by daratumumab-containing maintenance therapy in transplantation-eligible patients with newly diagnosed multiple myeloma.”