CAR T-Cell Therapies Extend Treatment-Free Intervals in Multiple Myeloma With Regular Toxicity Monitoring

Douglas W. Sborov, MD, MS

The introduction of CAR T-cell therapies to the multiple myeloma treatment paradigm has expanded therapeutic options for patients with relapsed/refractory disease, although these products are far from a one-size-fits-all approach, according to Douglas W. Sborov, MD, MS, who added that careful baseline characteristic consideration and post-infusion toxicity monitoring is necessary to ensure optimal patient outcomes. 

“The decision [to] recommend these different products is based on their FDA approvals, but [treatment selection] is more about expected response rates, toxicity profiles, and patient preferences,” Sborov said in an interview with OncLive^®.

In the interview, Sborov discussed where idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti) each fit into the myeloma treatment paradigm; characteristics that make patients good candidates for one product over the other, and the importance of considering the toxicity profiles of CAR T-cell therapies when making treatment decisions.

Sborov is an associate professor in the Department of Internal Medicine—Division of Hematology and Hematologic Malignancies, as well as the director of the Hematology Disease Center and Plasma Cell Dyscrasias Program at the University of Utah Huntsman Cancer Institute in Salt Lake City.

OncLive: In April 2024, ide-cel and cilta-cel were FDA approved for the treatment of select patients with relapsed/refractory multiple myeloma who had received at least 2¹ and 1 or more² prior lines of therapy, respectively. How have these approvals altered the myeloma treatment paradigm?

Sborov: The myeloma field is quickly moving [forward]. As soon as we get an approval and work out treatment algorithms, we have new approvals just around the corner. Until April 2024, we had FDA approvals for both ide-cel and cilta-cel, along with BCMA- and GPRC5D-directed bispecific antibodies, for patients previously treated with 4 or more prior lines of therapy. Until [April 2024], when we made treatment recommendations, we were generally recommending 3-drug combinations with novel drugs, based on prior treatment refractoriness. 

Then, cilta-cel became available for patients who are lenalidomide [Revlimid] refractory after 1 prior line of treatment, and ide-cel was approved for patients previously treated with 2 prior therapy lines. That’s when the revolution began. Most patients are on indefinite treatment, so the opportunity to provide them with this prolonged treatment-free interval is incredible.

Additionally, when we consider engaging the immune system with new immunotherapeutics, we believe a less beat-up immune system would be more active in killing myeloma [cells]. In my clinic, we discuss early CAR T-cell therapy with all patients who are eligible to receive it. These drugs are that good. Ultimately, if we’re using early CAR T-cell therapy, then our prior treatment algorithms all change. Understanding the sequencing of drugs in the relapsed or refractory setting is a huge issue that we’re all trying to work through, both with clinical trials and with investigation of real-world data.

What patient characteristics do you consider when determining whether a patient with myeloma is a candidate for CAR T-cell therapy?

Beyond eligibility based on prior drug exposure—such as, in the case of cilta-cel, lenalidomide refractoriness—it is essential for me as an oncologist to be on the same page with the patient. We discuss the workup, the time needed for leukapheresis, the waiting time associated with manufacturing, the exposure to lymphodepleting chemotherapy, and the CAR T-cell infusion itself. We discuss requirements to stay [at the Huntsman Cancer Institute] for 30 days [post-infusion], the need for long-term monitoring [following] treatment, and the unique toxicities and risks associated with the treatment. Just like we do with patients receiving autologous stem cell transplant, we consider age, fitness level, the kinetics of disease progression, overall status of the disease, and then whether the CAR T-cell therapy fits into the patient’s life plans. Ultimately, because we have the BCMA- and GPRC5D-directed bispecific antibodies available in the later-line setting, a lot of treatment decisions come down to patient preference.

Findings from the phase 3 CARTITUDE-4 (NCT04181827) and KarMMa-3 (NCT03651128) trials supported the FDA approvals of cilta-cel and ide-cel, respectively, in earlier lines of therapy. How did the patient populations differ between these studies?

KarMMa-3 included patients previously treated with 2 to 4 lines of therapy who were refractory to their last line of treatment.³ In CARTITUDE-4, key eligibility criteria included patients previously treated with 1 to 3 lines of therapy who were refractory to lenalidomide.⁴ When considering the patient populations treated in each of the trials, the median numbers of prior lines of therapy were 3 in KarMMa-3³ and 2 in CARTITUDE-4. [Additionally,] 42%³ and 59.4%⁴ [of patients] had high-risk cytogenetics in [the CAR T-cell therapy arms of] KarMMa-3 and CARTITUDE-4, respectively. Between 39% and 51% of patients [in the CAR T-cell therapy arms] of both trials [harbored] 1q abnormalities.^3,4

The biggest difference between the 2 populations is that in CARTITUDE-4, 14.4% of patients were considered triple-class refractory,⁴ meaning refractory to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, vs 66% of patients in KarMMa-3.³ For this reason, we saw a more heavily pretreated population in KarMMa-3 than in CARTITUDE-4. This is reflected in the current FDA approvals.

How do the data from these 2 studies influence the selection between CAR T-cell therapies in clinical practice?

For patients being considered for CAR T-cell therapy who are lenalidomide refractory and [have been] previously treated with 1 prior line of therapy, based on CARTITUDE-4, cilta-cel is the only approved agent. For patients under consideration for CAR T-cell therapy after 2 or more prior lines of therapy, both [cilta-cel and ide-cel] are available, and the recommendations we make to patients are more nuanced. When we look at the overall body of data for ide-cel vs cilta-cel, whether it be [from] single-arm or randomized trials like KarMMa-3 or CARTITUDE-4, or even real-world data, cilta-cel is a more powerful drug. That said, we have to remember that ide-cel is a good drug; when it came to the clinic, it was a significant game changer for the field and patients.

There are certainly differences between the expected toxicity profiles of the 2 drugs. Both have rare but significant risks for the development of hemophagocytic lymphohistiocytosis, higher-grade cytokine release syndrome, and immune effector cell–associated neurotoxicity syndrome. Clinically, cilta-cel has a greater tendency to be associated with these rare but potentially life-altering toxicities, including Parkinsonism and gut-related issues. My patients have had outstanding results with both drugs, so patient selection remains key.

How should community oncologists counsel patients who are candidates for CAR T-cell therapy?

I’ve had a lot of conversations with colleagues who are not using CAR T-cell therapy themselves. What remains clear is that, based on experience, most of those oncologists prefer that the CAR T-cell therapy conversation occurs with a group [that is] able to perform the procedure. That said, some basic points should be highlighted.

First, CAR T-cell therapy is a relatively new type of drug that’s associated with impressive response rates in patients with early and late disease progression. [Second,] CAR T-cell therapy requires work and significant time spent with an oncologist and the team that’s providing the CAR [T-cell product], and if successful, treatment with CAR T-cell therapy can lead to a prolonged treatment-free interval. In general, the earliest possible use of these drugs provides more benefit than waiting until later. Lastly, an oncologist should recommend that the patient have at least an early discussion about CAR T-cell therapy with a CAR T-cell center so [the patient is] aware of their current and future treatment options.

Do treatment follow-up and long-term disease management differ for patients who receive CAR T-cell therapy vs those who receive other myeloma therapies?

As much as we discuss the treatment-free interval following CAR T-cell infusion, there can be issues post-day 30 after infusion. There are a few helpful points to highlight. One, even though we’re not expecting disease progression early after CAR T-cell therapy, it’s important that we continue to monitor the patient’s disease to make sure we’re not seeing progression. Two, primarily due to the lymphodepleting chemotherapy, patients can have prolonged cytopenias. Although we can consider other interventions like granulocyte colony–stimulating factor or darbepoetin alfa (Aranesp), we need to be mindful that patients with prolonged cytopenias may need to be considered for a stem cell boost.

Three, like with all other novel immunotherapeutics, we need to monitor for infections and be sure to revaccinate patients. In general, patients will continue to receive antiviral prophylaxis or pneumocystic jirovecii pneumonia prophylaxis until their CD4 counts are above the threshold. Early intervention in the case of bacterial infections [is also important]. We monitor immunoglobulin-G levels closely and provide support with intravenous immunoglobulin as indicated, especially in patients with infections. Lastly, we need to be mindful of late neurological and gut toxicities. We monitor for changes that may be associated with facial nerve palsies, neuropathy, Parkinsonism, and significant changes in the gut.

The FDA has mandated that black box warnings for second primary malignancies be added to the 2024 indications for ide-cel and cilta-cel in myeloma.^1,2 How has this influenced your consultation with patients who are candidates for these treatments?

The issue with second primary malignancies associated with CAR T-cell therapy is important. Like other rare toxicities, such as rare gut issues or late-onset neurotoxicities, patients need to be aware that [these second primary malignancies] can happen and ultimately, [this risk is] on the important list of toxicities we talk to patients about. Does this affect my use of the drugs? It does not at this point.

What is your main message for colleagues regarding the emergence and evolution of CAR T-cell therapies in myeloma management?

[According to] the historical data [for myeloma] before bispecific antibodies and CAR T-cell therapies, patients’ median overall survival was 1 year or shorter. When CAR T-cell therapies emerged, they changed the entire treatment paradigm for patients. It’s been remarkable. Patients are living longer, living better lives, and having treatment-free intervals. Even patients who have been receiving treatment for 10 years suddenly have a couple of years of a break from treatment. It’s been a big deal.

We’ve been using bispecific antibodies and CAR T-cell therapies in the later-line setting. We’ve now moved up CAR T-cell therapy and we’ll be moving bispecific antibodies into earlier lines. The hope is that we can harness a healthier immune system and [achieve] longer-term, positive outcomes for patients.

References

1. US FDA approves Bristol Myers Squibb and 2seventy bio’s Abecma for triple-class exposed relapsed or refractory multiple myeloma after two prior lines of therapy. News release. Bristol Myers Squibb and 2seventy bio, Inc. April 4, 2024. Accessed October 28, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-FDA-Approves-Bristol-Myers-Squibb-and-2seventy-bios-Abecma-for-Triple-Class-Exposed-Relapsed-or-Refractory-Multiple-Myeloma-After-Two-Prior-Lines-of-Therapy/default.aspx
2. Carvykti is the first and only BCMA-targeted treatment approved by the US FDA for patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy. News release. Johnson & Johnson. April 5, 2024. Accessed October 28, 2024. https://www.jnj.com/media-center/press-releases/carvykti-is-the-first-and-only-bcma-targeted-treatment-approved-by-the-u-s-fda-for-patients-with-relapsed-or-refractory-multiple-myeloma-who-have-received-at-least-one-prior-line-of-therapy
3. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614
4. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379