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While triplet regimens were once standard for newly diagnosed multiple myeloma, more recent studies have shown a clinical benefit of quadruplet therapy that adds an anti-CD38 monoclonal antibody for transplant-eligible patients.

These trials include the phase III , which added the anti-CD38 antibody daratumumab (Darzalex) to bortezomib (Velcade), thalidomide, and dexamethasone, as well as the phase II which added daratumumab to bortezomib, lenalidomide (Revlimid), and dexamethasone (VRd).

"Without a doubt, CASSIOPEIA showed that adding daratumumab was associated with improved overall response, depth of response in terms of minimal residual disease, or MRD, and duration of response -- with a trend toward overall survival, too," Jacob P. Laubach, MD, of Dana-Farber Cancer Institute in Boston, and a co-investigator on the GRIFFIN trial, told 番茄社区app.

"Informative data from these trials have really moved the clinical needle," Laubach continued. "A decade ago, many places were using two-drug regimens and then moved relatively quickly to three-drug therapy. Since 2015, strong data have moved the needle in favor of four-drug regimens."

While quadruplet therapy is evolving to become standard of care, Prashant Kapoor, MD, of the Mayo Clinic in Rochester, Minnesota, noted that the very term "standard" seems too ephemeral in multiple myeloma.

"The treatment paradigm is changing at an unprecedented pace, thanks not only to the rapid development of effective therapies for patients with relapsed or refractory disease, but also to the swift integration of these newer regimens into earlier treatment settings," he said. "But with this incorporation comes uncharted territory where the data are obviously sparse, particularly when these newer agents are exhausted within the first few lines of treatment."

The phase III PERSEUS study of VRd, with or without daratumumab, found that adding the anti-CD38 agent to induction and maintenance therapy significantly improved progression-free survival (PFS) and increased depth of response (complete response or better and MRD negativity), with a consistent PFS benefit across all clinically relevant subgroups.

At a median follow-up of 47.5 months, the 4-year PFS rate was 84.3% for those who received daratumumab plus VRd and 67.7% in the VRd-alone group. The percentage of patients with a complete response or better was also higher in the quadruplet group (87.9% vs 70.1%). Greater, too, was the proportion with MRD-negative status (75.2% vs 47.5%).

According to the PERSEUS investigators, these data, together with those from GRIFFIN, showed a consistent benefit with a quadruplet regimen over standard induction and maintenance therapy and support adding daratumumab as "a new standard of care for transplant-eligible" newly diagnosed multiple myeloma.

"This combination is being widely adopted by oncologists as a standard induction," said Kapoor. "However, the effect of daratumumab as part of the induction or in combination with lenalidomide as part of post-transplant consolidation and maintenance could not be isolated in PERSEUS."

Laubach noted that follow-up hasn't been long enough for "definitive insights on overall survival. However, it is quite possible that quadruplet therapy will change the way we treat patients if the higher rate of MRD negativity correlates to longer duration of response."

Might these positive results significantly reduce the need for stem cell transplant? "If a patient is MRD-negative, a decision might be made to collect stem cells but not go forward immediately with transplant," Laubach said. "This scenario might play out more frequently if we have more patients achieving an MRD-negative state."

He added that both daratumumab and isatuximab (Sarclisa), another anti-CD38 agent, are reasonably well tolerated in quadruplet therapy, with acceptable hematologic toxicities, such as low platelet and neutrophil counts due to bone marrow suppression. "While there's a mild increased risk of infection, there's not a lot of major GI toxicity or organ damage such as lung and heart. We can readily manage safety issues," he said.

In other quadruplet studies, France's is focusing on an MRD-adapted strategy for risk-stratified patients (standard vs high-risk) with transplant-eligible newly diagnosed multiple myeloma. The study is adding isatuximab to carfilzomib (Kyprolis), lenalidomide, and dexamethasone induction (KRd) in all patients.

While MRD is a good surrogate endpoint, the timepoint at which it needs to be achieved is unclear, and loss or resurgence is also a marker of poorer outcomes, Kapoor noted. "So sustained negativity is what clinicians strive for. Whether the addition of another agent to the quadruplet backbone will be of benefit if MRD is not achieved is unknown, but clearly the toxicity will be incrementally greater with each new agent added to a regimen."

Still, second- and third-line regimens for multiple myeloma may soon include other novel agents, such as the monoclonal antibody elotuzumab (Empliciti), for transplant-ineligible or transplant-deferred patients with high-risk multiple myeloma.

Quintuplet Therapy?

A quintuplet regimen is currently being investigated in the , which is adding cyclophosphamide to the daratumumab-VRd backbone for patients with ultra-high-risk myeloma and plasma cell leukemia.

"These patients typically relapse early and are hard to rescue with salvage therapies," noted Kapoor. As of 2022, this study reported a 30-month PFS rate in excess of 75% after a median follow-up of more than 40 months.

"As more data have emerged showing the efficacy of adding a monoclonal anti-CD38 antibody to VRd or KRd regimens with decent tolerability, clinicians are becoming more comfortable with using these quadruplets in the frontline setting," Kapoor said. Furthermore, insurers are showing more willingness to cover these regimens.

For Laubach, accelerating the already fast pace of therapeutic progress will require an ongoing joint commitment from patients, oncologists, and referring community physicians, as well as from partners in government and the pharmaceutical industry. "This is the constellation that will move things forward."

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