Optimizing Cilta-Cel Sequencing and Community Coordination in Multiple Myeloma

In this CancerNetwork® Around the Practice program, Surbhi Sidana, MD, moderated a discussion with Doris Hansen, MD, and Prerna Mewawalla, MD, on optimizing the use of ciltacabtagene autoleucel (cilta-cel; Carvykti) in multiple myeloma across lines of therapy. The panel examined where cilta-cel fits relative to bispecific antibodies and other immunotherapy options at first relapse, the evidence supporting a CAR T-first sequencing approach, and the long-term remission signals from the phase 1b/2 CARTITUDE-1 trial (NCT03548207) that have introduced the concept of functional cure in multiple myeloma.^1,2 The conversation also covered effective bridging strategies, community referral pathways, the transition to a shared-care model after day 28, and the recognition and management of delayed toxicities including movement neurocognitive toxicities and immune effector cell–associated enterocolitis (IEC-E).

Sidana is associate professor at Stanford University, where she leads the Myeloma CAR T program. Hansen is associate professor at Moffitt Cancer Center and the University of South Florida Morsani College of Medicine, with a focus on multiple myeloma and cellular therapies. Mewawalla is director of the stem cell transplant and cellular therapy program at Allegheny Health Network and associate professor at Drexel University College of Medicine.

Where Cilta-Cel Fits: CAR T-First in the Immunotherapy Era

Sidana: We have a plethora of options for early relapse, including standard therapies, bispecific antibodies, and now CELMoDs. Where does CAR T, specifically cilta-cel, belong among those therapies? For late relapse, we now have very long follow-up data showing that some patients might be functionally cured. Let’s start with the very big picture. Cilta-cel was first approved for 4 prior lines of therapy—late relapse. It has now moved to first relapse, as second-line therapy. In your practice, where does cilta-cel belong today?

Hansen: I do believe that we are living in a revolution in multiple myeloma. In late line, we are seeing a third of patients alive and progression-free at 5 years, which is something we haven’t seen before from a one-and-done type of treatment. In the late-line setting, I believe we should sequence CAR T before any other type of immunotherapy, this has been established, and the International Myeloma Working Group guidelines agree with this. In the early-line setting, there is less guidance, especially with newer data from [the phase 3 MajesTEC-3 trial (NCT05083169), the phase 3 MajesTEC-9 trial (NCT05572515), and the phase 3 MonumenTAL-3 trial (NCT05455320).] Nonetheless, I still believe we should utilize CAR T first in my practice. The reason is that we want healthier and fitter T cells. Data from our German colleagues show that if you can manufacture cilta-cel earlier in the disease course, you generally have more product in specification. This is probably one of the most consequential decisions we will make in this field; not only what is best in second-line, but what is best in the long term.

Mewawalla: I completely agree, and I want to reaffirm that when CARTITUDE-1 data came out—especially the 1-in-3 patients being progression-free and alive at 5 years in a population that was so heavily pretreated, with no prior treatment anywhere close to that—that is what made us start using the word “cure” or defining cure in myeloma. For me, when it comes to how I approach a patient, it is very individualized. We talk about bispecifics, we talk about CAR T, we talk about pros and cons of each. I try to use CAR T earlier over BCMA bispecifics, because we know from retrospective consortium data that CAR T efficacy is significantly lower when used after BCMA bispecifics. Wherever possible, if I need to do CAR T and there is a BCMA bispecific in the picture, we do CAR T first.

Defining Candidates: When CAR T Is and Is Not the Right Next Step

Hansen: This is an individualized decision. Patient considerations include comorbidities, whether a patient is on dialysis, age—though age is not necessarily a determinant—and frailty status. Disease-specific considerations include how rapidly the patient is relapsing, whether they can await manufacturing, what bridging options are available, and whether they have high-risk disease such as extramedullary involvement or functional high-risk features. Very importantly, contextual factors: are patients able to travel to a treatment center? Can they take off work? Do they have a caregiver for a prolonged period?

We also have to think about toxicities. With certain BCMA-directed CAR T products, there may be delayed movement and neurocognitive toxicities, and with bispecifics, we are seeing high rates of severe infection. If a patient is older, has significant comorbidities, and cannot get to a treatment center, a bispecific or an antibody-drug conjugate may be the right option. If someone is rapidly relapsing and you want to reduce disease burden before infusion, I might consider a bispecific as a bridge.

Mewawalla: It is very individualized. Younger patients who are high-risk are ones where I am like, yes, maybe we need to do CAR T earlier. For a patient who is older, frail, or who does not have access to a CAR T center, but can get bispecifics, which we have been able to roll out even in the community—that is a different conversation. Access is sometimes a deterring factor as well.

Communicating the Prospect of Functional Cure

Sidana: Two-thirds of patients may not reach the 5-year milestone. How do you talk about this with patients without overpromising?

Mewawalla: I separate what we know about the study population from what I can predict for the patient in front of me. I cover all the available data and then put it in perspective. Patients often come in saying, “We’ve heard multiple myeloma cannot be cured,” and I reframe it: we use the term “remission” in multiple myeloma, and now we are defining functional cure in some patients who live [disease-free] for years. The idea of remaining treatment-free after receiving CAR T resonates profoundly. My patients have liked being chemotherapy-free after being on lenalidomide for years: that itself is freeing.

Hansen: Patients who come back, even when disease relapses, want a second CAR T because they very much enjoy their time off therapy. We’ve tried to enroll patients on clinical trials because they truly do enjoy forgetting that they have cancer and moving toward a functional cure. We are seeing significant improvement in health-related quality of life for these patients, and when disease relapses, they want that experience again.

Building the Referral Partnership: What Community Oncologists Need to Know

Mewawalla: Being a community oncologist is a tough job. They see 20 [or more] patients a day across breast, lung, and myeloma. Making the referral process simple, fast, and seamless is essential. I believe every patient [with multiple myeloma] should receive a referral at the time of diagnosis…because even in the frontline setting, clinical trials or alternative approaches may be available. With telehealth, this is now possible without requiring a 3-hour drive to the academic site. Our goal is still for patients to receive as much care in the community as possible. If we have an established relationship with both the patient and the community physician at diagnosis, when the time comes for CAR T or bispecifics, that relationship is already in place. Large health networks should enable one-click secure chat referral. Smaller networks should have a dedicated text or call number that gets answered immediately.

Hansen: Ideally referral should happen at first relapse, but earlier if a clinical trial is a possibility. Multiple myeloma labs, including immunoglobulin, light chains, and relevant imaging, are important to have in hand, but the key message is this: if a patient can wait, do not start holding therapy. Have the conversation first about whether they are eligible for a clinical trial. If there is no trial or the patient cannot wait, holding therapy can be started, with the dual principles that you should not use lymphotoxic drugs or T-cell engagers before apheresis. That close communication with the community team about what is available determines whether holding therapy is necessary at all.

Shared Care After Day 28: Discharge Planning and Ongoing Monitoring

Mewawalla: Discharging at or after day 28 is not the end of CAR T care: it is a transition from center-led care to truly shared care. Before the patient leaves, I communicate directly with the community team with a concise, one-page bulleted treatment summary: what CAR T product was used, the infusion date, what cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) occurred, and the going-forward plan for antimicrobial prophylaxis, intravenous immunoglobulin (IVIG) thresholds, and vaccination. That summary should be easy to read, not a 20-page discharge note. Telehealth has made a huge difference; once a month, I can still see patients from Erie, PA or DuBois, PA via video to check for delayed neurotoxicity, prolonged cytopenias, and other late effects. Patients get a dedicated site-specific phone number to call if any [adverse] effects occur after going home.

Hansen: We have recommended a lower limit of roughly 3 weeks before discharge, depending on patient status. If patients have severe infection, profound cytopenia, or lymphocytosis that might predict delayed toxicities, we keep them longer. After month 1, we do at minimum weekly labs, then monthly follow-up through month 3, when restaging occurs: PET scan, bone marrow biopsy, and myeloma labs. At month 3 we start the vaccination series. Thereafter, roughly quarterly visits for 1 to 2 years. Acyclovir prophylaxis continues for at least 1 year. Pneumocystis prophylaxis begins at month 1 and continues for at least 6 months based on CD4 count recovery. Monthly IVIG is coordinated with the community provider and given there; it continues for six months to one year based on immunoglobulin levels.

Recognizing and Managing Delayed Toxicities

Hansen: Two delayed toxicities require particular vigilance. The first is movement neurocognitive toxicities, which can include Parkinsonism. This occurs in less than 1% of patients in the early-line setting, but clinicians should watch for flat facies, a shuffling gait, or a change in affect or responsiveness starting 2 to 3 weeks post-infusion. A high absolute lymphocyte count, 3000 cells/μL or greater, may predict this risk; we give prophylactic dexamethasone in those patients until the count comes down. High-dose chemotherapy is currently used for established cases, and early recognition and intervention are critical.

The second is IEC-E, an increasingly recognized non-bloody diarrhea that typically presents around 3 months post-infusion, though it can occur earlier or later. Diagnosis requires both upper and lower endoscopy, as it most commonly involves the duodenum; and the endoscopic appearance may look benign while pathology shows GVHD-like changes. Treatment has shifted from anti-TNF alpha agents such as infliximab (Remicade) toward JAK inhibitors and T cell-directed therapies such as cyclophosphamide and cyclosporin, with earlier intervention yielding better outcomes. There is a 40% to 50% overlap between patients who develop Parkinsonism and those who develop IEC-E, so clinicians seeing one should have a high index of suspicion for the other.

Mewawalla: For suspected delayed neurotoxicity, we have these patients transferred to our primary site for management. For fever at 6 or 7 weeks post-infusion, this most commonly reflects infection rather than late CRS, and we manage these collaboratively keeping some patients in the community depending on resources and severity, while transferring those with complex presentations.

Closing Takeaways

Sidana: For the majority of patients, CAR T first makes sense. Real-world data shows that older adults, even those above 75 years, and some patients with renal impairment can safely receive CAR T. If someone is truly frail or lacks access to a treatment center, a bispecific antibody may be more appropriate, and it is reassuring that we have those options for that minority of patients. As CAR T moves earlier, our success rate of moving from apheresis to infusion is approaching 100%, in part because we go in earlier with lower disease burden, and effective bridging options are better than ever. This communication channel between the community and the CAR T center must remain open. Some things can be treated locally, others require urgent transfer—and that shared care model, with clear discharge summaries, telehealth follow-up, and a direct contact number at the academic site, is what makes this work for our patients.

References

1. Martin T, Usmani S, Berdeja JG, et al. Ciltacabtagene autoleucel in patients with heavily pretreated relapsed/refractory multiple myeloma: 5-year follow-up from CARTITUDE-1. Blood. 2024;144(suppl 1):3334. doi:10.1182/blood-2024-198143
2. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389:335-347. doi:10.1056/NEJMoa2303379