A Randomized Phase 2 Trial for High-Risk Multiple Myeloma That is Refractory or in First Relapse with Daratumumab, Teclistamab (DT) Versus Daratumumab, Pomalidomide, Dexamethasone (DPd) or Daratumumab, Carfilzomib, Dexamethasone (DKd)

Survival in multiple myeloma has improved significantly over the past two decades and now exceeds 10 years for many newly diagnosed, fit patients. However, the disease is usually not curable. Furthermore, these survival gains have primarily benefited patients with standard-risk disease. High-risk multiple myeloma refers to a subset of the disease with genetic and clinical features that make it more likely to return sooner and more difficult to treat.

Although patients with high-risk disease have been included in phase 3 randomized controlled trials, they typically have represented less than 15% of participants and were often evaluated only in ad hoc subgroup analyses. As a result, these patients historically have received the same treatment as those with standard-risk disease, despite having poorer outcomes. New treatment strategies supported by clinical evidence are needed for patients with high-risk disease.

The typical treatment approach for newly diagnosed multiple myeloma—both standard- and high-risk—includes three phases: 1) induction treatment with a combination of three or four drugs (targeted therapies, immunotherapies, and steroids), 2) autologous stem cell transplant, when appropriate, and 3) maintenance treatment for 2-3 years or longer. The goal is to achieve a deep and lasting treatment response.

EAA232 is the first randomized controlled trial specifically for patients with high-risk multiple myeloma. It includes patients who experience a first relapse (after a period of remission following initial treatment described above). It also includes those with refractory myeloma (that does not respond or has stopped responding to treatment). The study aims to identify the treatment approach that delivers the longest-lasting disease control and best outcomes.

This trial is evaluating an experimental approach with dual immunotherapy that includes daratumumab-hyaluronidase plus teclistamab (DT), versus one of two commonly used regimens: daratumumab-hyaluronidase, pomalidomide, and dexamethasone (DPd) or daratumumab-hyaluronidase, carfilzomib, and dexamethasone (DKd). Teclistamab is a bispecific antibody, a newer type of immunotherapy.

This phase 2 study will enroll 80 patients who will be randomized 1:1 to receive either DT or one of the two standard regimens (DPd or DKd). For patients randomized to the standard care arm, the treating physician will guide them as to which option is best for them.

Researchers will assess which approach is more effective by using a bone marrow test taken after 6 cycles of treatment. The test will look for microscopic traces of cancer cells that may remain after treatment. Researchers will compare the number of patients in each group who achieve minimal residual disease (MRD)-negative status, meaning that no remaining cancer cells can be detected using highly sensitive tests. Treatment will continue until disease progression or unacceptable toxicity. All patients will be followed for up to 10 years.

Patients are eligible for this study if they have high-risk multiple myeloma that has relapsed or become refractory after one prior line of therapy (the three-phase treatment approach described above counts as one line of therapy). Patients are not eligible if they have previously received daratumumab-hyaluronidase (or isatuximab) or are sensitive to it. All participants must have cancer cell DNA testing at the start of the trial using the clonoSEQ® assay. This highly sensitive test will be used throughout the study to detect very small amounts of remaining disease (MRD).

The study chair for this trial is Muhamed Baljevic, MD (Vanderbilt University/Vanderbilt-Ingram Cancer Center), and the co-chair is Shaji Kumar, MD (Mayo Clinic). The community co-chair is Natasha Edwin, MD (Providence Saint Vincent Medical Center).