MajesTEC-3 Trial Outcomes May Change Course of Myeloma Treatment

The exceptional results of the MajesTEC-3 study of teclistamab and daratumumab has created much buzz in the hematology community. The study of 587 patients with relapsed/refractory disease showed 36-month progression-free survival rates of 83.5%, compared to 29.7% in the standard-of-care arms.

ConsultQD recently talked with hematologist/oncologist Sandra Mazzoni, DO, about the implications of these findings.

Q: What was the purpose of the MajesTEC-3 study?

Everything was in flux as far as where cell therapy was going to land in the treatment sequence. Initially, it was approved after four lines of therapy. Most recently, CAR T-cell therapy was approved after first relapse. Now we have bispecific antibodies and need to determine where they play a role.

The MajesTEC-3 study was designed to move those options further up and use them at first relapse. Researchers studied the BCMA-targeted bispecific antibody teclistamab used in combination with the immunotherapy daratumumab.

The study findings also bring into play considerations for patients who aren’t the best candidates for CAR T-cell therapy but would be excellent candidates to safely receive bispecific antibodies.

Q: Were you surprised by the study findings?

I think people were surprised by how comparable the efficacy and safety rates were to CAR T-cell therapy.

Beforehand, patients at first relapse would have the option to go to CAR T-cell therapy, have a triplet of standard options or participate in a clinical trial. Now with the high-level evidence from MajesTEC-3 and supporting NCCN guidelines, there is the option to use teclistamab and daratumumab at first relapse.

Q: What are the most important takeaways from the MajesTEC-3 trial?

The study was done during the COVID era, and infection rates were initially high (54.1% with grade 3 or 4 infections) among patients receiving teclistamab and daratumumab.

Infection rates dropped off since then because there’s more use of prevention strategies like immunoglobulins and prophylactic antibiotics like sulfamethoxazole-trimethoprim to protect against Pneumocystis jirovecii pneumonia (PJP). At our center, we mandate IVIG monthly as well as sulfamethoxazole-trimethoprim, or an alternative if the patient has sulfa allergies.

The infection rates also drop dramatically once the frequency of therapy was spaced out from weekly to biweekly and then to monthly.

In terms of takeaways from the study, long-term I think there’s going to be even more debate about how to sequence drugs that target BCMA. Traditionally, the thought was that if you’re going to expose someone to BCMA, use CAR T-cell therapy first because it doesn’t do much in terms of alteration to the BCMA target, whereas chronic exposure with a bispecific has a higher risk of altering the BCMA target itself.

Q: I understand this study has people talking about the potential of a functional cure in myeloma. What are your thoughts about that?

I think it's a bit premature to say that, but everyone is very excited by the survival curves. The survival benefit is one of the highest we've seen in a study in a long time.

Q: Is the expectation that patients would stay on this therapy indefinitely as long as it’s working?

In this study, yes, that was the case. However, in real practice, I think there's going to be a big question mark about this. There's likely going to be two strategies: One is using the combination therapy for a fixed duration until the patient achieves minimal residual disease (MRD)-negative status, then close observation, and the other is taking an immune boostering approach where patients are re-dosed every four to six months.

Q: Can you explain how teclistamab and daratumumab work together?

The thought is that there are synergies between the two medications. Teclistamab targets CD3 on T-cells, and daratumumab alters the T-cell subsets and is thought to help with the fitness of the helper T-cells and increase the number of CD8 cytotoxic T-cells.

Keep in mind that only about 5% of the patients in this study were previously exposed to daratumumab, whereas in the real world, most patients at first relapse have been exposed to daratumumab and many are daratumumab refractory. There’s going to be a discussion point about whether you really need daratumumab in those cases.

I think it’s possible that teclistimab is the real workhorse in this scenario, and that many of us will provide it as a single agent to patients at first relapse.

Q: I understand that patients on the trial weren’t prescribed steroids after the first treatment cycle. Can you talk about what it means to patients with myeloma to have the option of treatment free of steroids?

There’s definitely a role for steroids in myeloma, especially for newly diagnosed patients or those with a high disease burden. Steroids also help to palliative bone pain. That said, I’m excited to see us pulling away from using steroids over and over though, as I see more side effects with steroids than I do with any other therapies.

Q: What’s next in terms of the study of teclistamab and daratumumab?

Cleveland Clinic is participating in the MajesTEC-7 study, which is now open. This trial is studying combinations of teclistamab, daratumumab and lenalidomide versus talquetamab, daratumumab and lenalidomide versus standard of care with daratumumab, lenalidomide and dexamethasone in the frontline setting for patients who are ineligible for autologous stem cell transplant or who choose to defer transplant. These results may have the community rethinking the role of transplant in the future.

Q: What needs to happen to make cell therapies like this more accessible in the community setting?

There’s a lot of fear in community sites around how to safely manage patients, especially in the initial step-up dosing, based on the initial study data about rates of cytokine release syndrome (CRS) and concern around management of the rare high-grade CRS. Many community sites may not have the ability to directly admit patients to the hospital or their local hospital lacks an ICU.

One of the answers is to have partnerships between academic sites and community practices where we take patients through the acute toxicity window and then they return to their community practice for ongoing care.

We also have better strategies in place now to manage CRS and other toxicities preventatively. Giving tocilizumab up front, for example, reduced CRS rates from 50-60% down to single digits. With these preventative measures, the majority of CRS cases are grade 1 and treatable with Tylenol and steroids.

Q: When should community oncologists consider referring a patient to an academic medical center?

Especially with all the new cell therapies now available at first relapse, it’s important to make referrals early. Don’t necessarily wait until the patient meets the strict definition of disease progression.

In our clinic, if we see early evidence of disease progression, we start talking about CAR T-cell therapy. The time to do this is when the disease is very manageable. Outcomes, particularly with CAR T-cell therapy, are better with a lower disease burden.