Choosing the Best Treatment Path in the Relapsed/Refractory Multiple Myeloma Setting

Written by Dr. Kaique Filardi

There are many treatment regimens for first-line therapy in multiple myeloma, often combining drugs from different classes, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, chimeric antigen receptor (CAR) T cells, and bispecific antibodies.

Fortunately, the arsenal of therapy for patients diagnosed with relapsed or refractory disease is also diverse. In this scenario, the choice of the agent at each relapse is based on prior therapies used, response to these treatments, comorbidities, and disease aggressiveness.

There is no single standard therapy for relapsed or refractory multiple myeloma, and practice varies widely. Therefore, it is essential to share the decision with patients and, when possible, encourage eligible patients to participate in clinical trials.

For instance, among the currently available therapies are Daratumumab (Darzalex), Chimeric Antigen Receptor T (CAR T), and Teclistamab (Tecvayli). They have distinct mechanisms of action and also different clinical indications.

Daratumumab (Darzalex)

Daratumumab (Darzalex) has gained broad indications in the past few years. Not only is it prescribed as part of the first-line therapy, but it’s also been indicated as monotherapy in frail patients and a combined therapy for patients who have received at least three prior lines of treatment, including a proteasome inhibitor and an immunomodulatory drug or who are double-refractory to a proteasome inhibitor and an immunomodulatory drug.

When offering this medication, it is highly recommended to use a fixed dose, subcutaneously, in combination with hyaluronidase. Prior studies have shown lower rates of infusion-related reactions, similar costs, and similar overall response rates compared to intravenous administration.

“What this [subcutaneous Daratumumab administration] allows is for the time that the Daratumumab or Darzalex is being given to be much shortened. And you don’t need an IV place at the chemotherapy suite. So you can imagine where usually you’d spend several hours getting therapy, now you may spend only 30 minutes,” Dr. Nina Shah, a hematologist at UCSF Health, told SurvivorNet in a previous chat about the benefits of giving the drug in shot form.

Following the first infusion of Daratumumab, most patients are expected not to need on-site monitoring.

Patients and their caregivers should be advised to use acetaminophen and/or diphenhydramine if they develop mild signs or symptoms of an infusion reaction at home.

Chimeric Antigen Receptor T (CAR T)

Another important option is using Chimeric Antigen Receptor T (CAR T) cell therapy. This approach is highly individualized due to significant toxicity and complex and expansive manufacturing process. Typically, CAR T-cell therapy should be offered to patients in the second or later relapse setting, as the benefits in this setting seem to outweigh the risks.

In the United States, there are two options for CAR T prescription: Ide-cel and Cita-cel. The Ide-cell therapy is approved for relapsed or refractory multiple myeloma following at least one line of systemic treatment, including an immunomodulatory agent and a proteasome inhibitor that is refractory to lenalidomide. The CAR T with Cilta-cel is approved in relapsed or refractory multiple myeloma after two or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

This therapy is associated with serious complications. The KarMMa-3 and CARTITUDE 4 trials reported common side effects, with Cytokine Release Syndrome (CRS) being life-threatening and frequent. When diagnosed, CRS should be treated with aggressive supportive care, including tocilizumab and corticosteroids.

Teclistamab (Tecvayli)

As an alternative approach, bispecific antibodies such as Teclistamab (Tecvayli) play a crucial role in the treatment of relapsed or refractory multiple myeloma. While CAR T-cell therapy is offered in the context of relapsed disease after one or two prior therapies, Teclistamab is indicated for patients who have received at least four prior lines of treatment.

As an “off-the-shelf” treatment option, it may be useful for rapidly progressing diseases that are unlikely to be controlled during the wait for CAR T-cell manufacturing.

Additionally, recent data from a phase 3 MajesTEC-7 trial suggests that the combination of teclistamab + daratumumab + lenalidomide is efficient and safe in patients newly diagnosed with multiple myeloma who were ineligible for transplant.

This medication is administered subcutaneously in gradually increasing doses over the first week, followed by weekly dosing. Patients are closely monitored for at least 48 hours after each dose escalation.

In addition to CRS as common toxicity, the use of Teclistamab is associated with hepatotoxicity, infections, neutropenia, hypersensitivity and other administration reactions, and embryo-fetal toxicity.

Overall, the management of relapsed or refractory multiple myeloma is highly complex and requires a personalized approach. The choice of therapy should be tailored to the individual patient’s previous treatment history, comorbidities, and overall health status.