Investigation of CAR T-cell Therapy in Earlier Treatment Lines Could Continue to Alter Treatment Sequencing in Myeloma

Luciano Costa, MD, PhD

Ongoing investigations with the BCMA-directed CAR T-cell therapies idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti) could help shift CAR T-cell therapy into earlier settings, potentially offering patients a better chance of durable remissions, according to faculty from an OncLive® Institutional Perspectives in Cancer webinar on multiple myeloma.

The event, chaired by Luciano Costa, MD, PhD, a professor of medicine in the Department of Hematology, Medical Oncology, at the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham in Alabama, highlighted the current treatment approach for patients with relapsed/refractory multiple myeloma, the management of patients with newly diagnosed multiple myeloma, and the potential for CAR T-cell therapy to continue to alter the treatment paradigm.

Costa was joined by his colleagues:

• Gayathri Ravi, MD, an assistant professor in the Department of Hematology at the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham.
• Susan Bal, MD, an assistant professor in the Department of Hematology, Medical Oncology, at the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham.
• Kelly Godby, MD, an assistant professor in the Department of Hematology, Medical Oncology, at the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham.
• Meera Mohan, MD, MS, FACP, an assistant professor of hematology in the Department of Medical Oncology, at the Froedtert & The Medical College of Wisconsin in Wauwatosa.

Below, Costa, Ravi, Bal, Godby, and Mohan summarize the main messages from their presentations.

The Standard Approach for Patients With Relapsed/Refractory Multiple Myeloma

Costa: Combination [treatment] is always better than single-agent [treatment]. Triplets are better than doublets. Always rely on your pillars—immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies—as much as you can. Introduce a monoclonal antibody [to a patient] at the earliest opportunity. For patients with relapsed disease who have not yet received [a monoclonal antibody] in earlier lines [of treatment], that should be your first ingredient. We are always better off by introducing a new class of agent, [rather] than recycling within the same class.

Pay attention for t(11;14) [multiple myeloma]. [This] will give you an extra avenue to pursue therapy that is not present for most other patients. [Additionally], stay tuned, because CAR T-cell [therapies] and bispecific [antibodies] are about to transform how we treat even early relapses.

The Management of Newly Diagnosed Multiple Myeloma

Godby: Quadruplet induction should be standard of care in all transplant-eligible patients. Autologous stem cell transplant [ASCT] continues to deepen response and improve progression-free survival, which is very important. I am a big believer in the [mantra that] first cut is the deepest. Therefore, if you can incorporate ASCT, especially for those who have high-risk disease, it is a very effective tool that can deepen responses and help maintain responses in our patients.

Triplet induction is preferred even for transplant-ineligible patients, as long as they remain relatively fit. Also in this patient population, incorporating [CD38-directed] monoclonal antibodies is very important.

T-cell Engagers Represent Potential Options for Triple-Class Exposed Multiple Myeloma

Ravi: Patients with triple-class refractory multiple myeloma continue to do poorly overall. However, the main encouraging [factor] is that there are more emerging treatments with newer agents, especially with T-cell engagers.

However, this leads to an interesting challenge of sequencing therapy, [regarding] how we choose one [option over] the other. Again, [investigations] of the combinations of T-cell engagers with other chemotherapy agents are ongoing. Additionally, [studies of] T-cell engagers [with different] targets are also ongoing. It will be interesting to see if there is deepening of response with these agents.

Ongoing Investigations Aim to Move CAR T-cell Therapy to Earlier Lines of Treatment

Bal: CAR T-cell [therapies] targeting BCMA have shown remarkable efficacy and are available now. [They] are very effective in the treatment of [patients with] relapsed/refractory multiple myeloma [who have received at least 4 prior lines of therapy]. Several ongoing studies are now looking to move [CAR T-cell therapy] into earlier lines of therapy, including the frontline setting [such as with ide-cel in the phase 1 KarMMa-4 trial (NCT04196491)], with the hope that we can use healthier T cells from these patients early on in the course of the disease to manufacture more fit, more effective, and more persistent CAR T cells.

Several alternate targets [for CAR T-cell therapy] are being explored with impressive efficacy, including [in] patients who are responding after relapse [on a BCMA-targeted agent]. Several different approaches are currently under study to improve the structure and function of these CAR T cells.

Management of Cytokine Release Syndrome (CRS) and Neurotoxicity Associated With CAR T-cell Therapy

Mohan: CAR T-cell therapy is associated with distinct toxicities. However, these [toxicities] are typically manageable and reversible. Tocilizumab [Actemra] and steroid therapy are used for the management of CRS. Steroids are the mainstay of treatment for neurotoxicity management. Cytopenias are common, and [they] can be severe and persistent. Infection risk is real, and optimization of infection monitoring and prophylaxis is needed.