AQUILA, COBRA, TecLILLE, and MajesTEC-3 Trials Signal Shifts in Myeloma Management

Ben Derman, MD University of Chicago | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• Daratumumab significantly delayed progression to active multiple myeloma (MM) in high-risk smoldering multiple myeloma (SMM) and demonstrated an overall survival (OS) benefit in the AQUILA trial.

• In the COBRA study, KRd (carfilzomib, lenalidomide, dexamethasone) led to higher rates of minimal residual disease (MRD) negativity and improved progression-free survival (PFS) benefit over VRd (bortezomib, lenalidomide, dexamethasone), regardless of standard- or high-risk newly diagnosed myeloma.

• The TecLILLE trial showed that teclistamab plus daratumumab in transplant-ineligible frontline patients produced striking MRD negativity rates, signaling a potential shift toward bispecific-based doublets or triplets.

• Impressive PFS and OS in first relapse was demonstrated in MajesTEC-3, especially among daratumumab-naïve patients.

Four major studies presented at the 2025 ASH Annual Meeting showcased data that are redefining treatment strategies across the myeloma continuum, from high-risk smoldering disease to first relapse.

In a discussion with the Oncology Brothers, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park, Ben Derman, MD, of University of Chicago, provided expert insight on the AQUILA, COBRA, TecLILLE, AND MajesTEC-3 trials.

 AQUILA Trial: Who Receives the Most Benefit?

Daratumumab significantly prolonged time to progression to symptomatic MM compared with observation in the AQUILA study, and demonstrated an OS benefit, even though OS was not the primary end point.

However, Dr. Derman explained that a central challenge in interpreting AQUILA is the definition of high-risk SMM at the time of study design. Enrollment required at least 10% bone marrow plasma cells, plus additional risk features such as an M-protein 3 or greater g/dL, immunoglobulin A subtype, or immunoparesis. Since then, the Mayo 20/20/20 criteria have become the more widely adopted risk model, defining high-risk disease as meeting two or more of the following: M-protein 2 or greater g/dL, free light chain ratio greater than 20, and bone marrow plasma cells greater than 20%.

While you see benefits across the board with daratumumab, Dr. Derman said it is most profound among patients with two or more high-risk features.

Despite these compelling data, incorporating daratumumab into routine SMM practice remains controversial, he said. In his practice, he has historically avoided treating smoldering disease outside of clinical trials and believes that older adults may derive greater benefit from this therapy than younger patients.

KRd vs VRd Debate

In the COBRA study, which compared KRd versus VRd in standard-risk patients with newly diagnosed MM, KRd demonstrated a PFS advantage over VRd, as well as higher rates of MRD negativity.

“I think despite some design quirks, KRd feels like one of these regimens that I wish we had some FDA approval for,” Dr. Derman said.

The optimal proteasome inhibitor choice remains an area of active discussion, Dr. Derman said. Carfilzomib avoids peripheral neuropathy that is commonly associated with bortezomib and may offer deeper or more durable responses in certain populations, such as high-risk patients. In the era of daratumumab-based quadruplet therapy, Dr. Derman favors daratumumab plus VRd because the evidence remains stronger. However, in high-risk disease, he will treat with carfilzomib. 

Bispecifics: The Near Future

The phase 2 TecLILLE trial results offered a glimpse of what future regimens may look like, Dr. Derman said. Teclistamab plus daratumumab in frontline, transplant-ineligible patients, demonstrated that 100% of evaluable patients with available samples achieved MRD negativity.

The regimen also offered a convenient dosing schedule, which reduces clinic visit burden, he said. However, safety remains a concern.

“If this can be replicated in larger cohorts, which are currently being studied, it may be that we are looking at doublets or triplets with a bispecific in the near future,” Dr. Derman said.

MajesTEC-3 Trial Toxicities

Finally, MajesTEC-3 evaluated teclistamab plus daratumumab in first relapse, with many enrolled patients who were daratumumab-naïve. It showed significant improvements in PFS and OS outcomes, surprising many clinicians, Dr. Derman said. The compelling data may lead to an FDA approval.

Dr. Derman pointed out that infection risk remains a major consideration with bispecific therapy. Prophylactic intravenous immunoglobulin (IVIG) has emerged as an essential supportive care. He said that infection rates dropped significantly when IVIG was incorporated proactively. While teclistamab-based regimens are reshaping relapse treatment, Dr. Derman still leans toward chimeric antigen receptor T-cell therapy for high-risk patients.