CAR T-Cell Therapies: Idecabtagene Vicleucel and Ciltacabtagene Autoleucel

CAR T-Cell Therapies in Relapsed or Refractory Multiple Myeloma

Multiple myeloma remains largely incurable despite remarkable treatment advances that have led to improved overall patient outcomes, including survival.^1,2 With each new disease relapse and line of treatment, remissions become progressively shorter, and many patients eventually become triple-class–refractory—to proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. Until recently, these patients faced poor outcomes, with survival measured in months.^2-4 The U.S. Food and Drug Administration (FDA) approval of chimeric antigen receptor (CAR) T-cell therapies that target B cell maturation antigen (BCMA)—idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti)—has ushered in a new era for this challenging patient population.^5-8

These FDA approvals were based on the safety and unprecedented efficacy data in patients who received a median of five or six previous lines of therapy in the KarMMa and CARTITUDE-1 trials, repectively.^9,10 Idecabtagene vicleucel and ciltacabtagene autoleucel also demonstrated exceptional outcomes on their own in real-world clinical practice, even in patients who would be ineligible to enroll in KarMMa and CARTITUDE-1 trials,^11,12 and when indirectly compared with conventional care in patients with triple-class–exposed multiple myeloma.^13,14 As a result of these successes in patients with heavily pretreated relapsed or refractory multiple myeloma, these two agents are now being evaluated in a number of clinical trials in earlier disease settings (eg, KarMMa-3, CARTITUDE-4), and emerging data are promising.^15,16

Perspectives on Clinical Trials and Real-World Practice Experience

Noopur Raje, MD, Director of the Center for Multiple Myeloma at the Mass General Hospital Cancer Center, Boston, shared these initial comments with JNCCN 360: “We currently use ide-cel and cilta-cel pretty much equally, and that is partly driven by the limited number of available slots.^17,18 However, as we are dealing with two very different products, my sense is that once they become more accessible and available, providers will tend to prefer cilta-cel over ide-cel.¹⁹ For now, we have a lot of experience with and are very comfortable using ide-cel, which has more extensive long-term data compared to cilta-cel. In my practice, familiarity with ide-cel is especially relevant for older patients. I use ide-cel in patients in their late 70s or 80s based on the more substantial data (vs. with cilta-cel) in that patient population from KarMMa vs CARTITUDE trials.”²⁰

“Additionally, I use ide-cel as a standard of care in patients with rapidly progressing disease,” Dr. Raje continued. “I know I can get the product back in 4 weeks. With cilta-cel, on the other hand, we sometimes have to wait 8 weeks to get the product back.”

With regard to bridging therapy, Dr. Raje noted: “It is a challenge because patients have been practically exposed to all currently used classes of therapy and therefore are less likely to respond to other agents from those classes. So, typically, we try to use cyclophosphamide-based or selinexor-based therapy. After cell collection, we often used belantamab mafodotin, until it was withdrawn from the U.S. market. Patients should be referred earlier, after the second relapse, instead of waiting until the fourth relapse, as is the current practice.”²¹

Patients should be referred earlier, after the second relapse, instead of waiting until the fourth relapse, as is the current practice.

One of the most critical questions today is, when is the right time to collect cells from the cell fitness perspective? Is it in a newly diagnosed patient with full-blown disease, or is it during the first remission? Dr. Raje explained: “We still need to figure that out. Because collecting cells and storing them for later use presents a logistical nightmare, I think the solution is moving CAR T-cell therapy earlier in the course of treatment.” As already noted, Dr. Raje said, there are also other reasons for moving CAR T-cell therapy into earlier settings, and research is moving in that direction (KarMMa and CARTITUDE trials). 

Overview of Adverse Events

Cytokine-release syndrome (CRS), neurotoxicity (such as immune effector cell–associated neurotoxicity syndrome [ICANS]), infections, and hematologic toxicities (cytopenias) can be serious and potentially life-threatening adverse events with idecabtagene vicleucel and ciltacabtagene autoleucel. They require close monitoring and proactive management.^22-27

Cytokine-Release Syndrome

Symptoms of CRS include fever, chills, fatigue, and anorexia, which may persist for several days. Typically, CRS occurs a few days after CAR T-cell infusion and is reversible if recognized and treated promptly. Hospitalization for monitoring and management is recommended. Management is based on the severity of symptoms. For treatment of most low-grade events, analgesics, antipyretics, intravenous fluids, and early administration of tocilizumab may be of benefit. For treatment of severe cases or those refractory to tocilizumab, a low-dose and short-duration glucocorticoid regimen is an option.^22-24

Neurotoxicity

Neurotoxicity such as ICANS typically occurs after CRS, but they may coincide. The risk of ICANS development may also be affected by preexisting neurologic comorbidities, high tumor burden, and the severity of CRS.²⁵ Early-onset neurotoxicity/ICANS may be relatively mild.

Mild neurotoxicity/ICANS symptoms include confusion, transient aphasia, bradyphrenia, agitation, hallucination, delirium, tremor, dizziness, and vertigo. Severe and rare neurotoxicity/ICANS symptoms include cerebral edema, obtundation, and seizures. ^22-24 Late neurotoxicity (non-ICANS) may manifest as movement and neurocognitive disorders, cranial nerve palsies, and (rarely) Guillain-Barré syndrome; they may develop after the recovery period from CRS and/or ICANS and typically have a longer and usually irreversible nature.²⁶

To potentially prevent ICANS, effective management of CRS is critical. Once present, ICANS is typically managed with glucocorticoids. If there is no or insufficient response to glucocorticoids, use of additional immunosuppressive agents such as anakinra and cyclophosphamide can be attempted. ICANS grade ≥ 3 and more severe cases may require continuous monitoring in an intensive care setting and/or mechanical ventilation for airway protection.^22-25

Infections

By virtue of their targeting BCMA on myeloma as well as healthy plasma cells, idecabtagene vicleucel and ciltacabtagene autoleucel may cause severe hypogammaglobulinemia, leading to increased risk of serious infections. Bacterial infections, especially pneumonia, are among the most common.

For patients with neutropenia, prophylaxis with levofloxacin, amoxicillin/clavulanic acid, cefdinir and, for more severe cases, granulocyte colony-stimulating factor (G-CSF) may be used; the latter, however, should not be given within 2 weeks of CAR T-cell infusion. For patients with confirmed bacterial infection, empiric treatment with broad spectrum antibiotics should be started.^22,23

All patients should be screened for viral infections (eg, cytomegalovirus; hepatitis A, B, and C; HIV, and COVID-19) prior to CAR T-cell infusion. With regard to antifungal prophylaxis, azoles can be used for patients with prolonged and severe neutropenia per local guidelines.

Hematologic Toxicities

Cytopenias are common with the two CAR T-cell therapies. Transfusion support to mitigate thrombocytopenia and anemia, with prophylactic antibiotics during neutropenia, is commonly used.

For severe hematologic adverse events, urgent management of serious bleeding may be needed, as severe thrombocytopenia and hypofibrinogenemia can occur. For prolonged thrombocytopenia, cytokine support with romiplostim or eltrombopag may be used. For severe neutropenia, G-CSF may be used. In patients experiencing late cytopenias (> 30 days), stored CD34-positive stem cells can be given to hasten recovery. For patients with severe hypogammaglobulinemia, intravenous immunoglobulin is recommended to mitigate the risk of infections.^22,23

Clinical Experience in Managing Comorbidities and Toxicities

As for patients with renal insufficiency or renal failure and those who are older or frail, according to Dr. Raje, fludarabine is typically dose adjusted or omitted altogether, and cyclophosphamide is used alone for lymphodepleting chemotherapy.

“With regard to managing CRS and ICANS,” Dr. Raje commented, “I am pretty aggressive about it. We have enough data showing that aggressively managing those adverse events does not negatively impact response to CAR T-cell therapy.”

We have enough data showing that aggressively managing CRS and ICANS does not negative impact response to CAR T-cell therapy.

One major difference between the T-cell therapies is the timing of the onset of CRS. “With ide-cel, the onset of CRS is typically within 24 to 48 hours after the infusion,” stated Thomas G. Martin, MD, Clinical Research Director of Hematologic Malignancies at the University of California San Francisco (USCF) Helen Diller Family Comprehensive Cancer Center. “Most patients are admitted to the hospital just before the CAR T-cell infusion. In contrast, because CRS onset with cilta-cel is typically between days 5 and 8, the patient can receive lymphodepleting chemotherapy (starting day –5) and the CAR T-cell infusion (day 0) as an outpatient, with admission to the hospital preplanned at day 4 after infusion. “Overall, we prefer to have patients in the hospital to coincide with the potential onset of CRS,” he told JNCCN 360.

“We have learned much about the toxicities of CAR T cells, and CRS tends to be one of the most common, needing prompt therapy,” Dr. Martin said. Overall, for CRS management, he continued, “we tend to treat aggressively on initial onset, using tocilizumab at the first signs of fever, even if the CRS is grade 1. We try to mitigate the symptoms right away.” And Dr. Martin agreed with Dr. Raje that data have shown tocilizumab does not adversely affect the efficacy of CAR T-cell therapy. “Once the CRS has resolved, it typically won’t recur,” according to Dr. Martin. He also believes this approach may reduce the risk of neurotoxicity, which can occur in the first few weeks, often concurrent with CRS. “We always have to be vigilant about monitoring for infection and promptly initiating treatment if a serious infection occurs,” Dr. Martin added.

When patients relapse after receiving CAR T-cell therapy, subsequent treatment decisions depend partly on the duration of disease remission. Those with a relatively long remission after receiving CAR T-cell therapy tend to do reasonably well, Dr. Raje reported. “In those patients, I use therapies I would never have used before in that late setting,” she told JNCCN 360. “For example, I use elotuzumab with pomalidomide or lenalidomide and dexamethasone, because elotuzumab seems to work well in relapsed disease after CAR T-cell therapy. Patients who don’t derive much benefit from CAR T-cell therapy, such as those with a relatively short remission duration, are a particularly tough population. We typically use bispecific antibody in those patients, with some success, but they are definitely a challenge.”

CAR T-Cell Therapy: Not for Everyone

Dr. Martin told JNCCN 360 that access to CAR T-cell therapy remains problematic for patients with relapsed or refractory multiple myeloma.

“There are still more patients who would benefit from CAR T-cell therapy than there are available CAR T-cell manufacturing slots,” he observed. However, Dr. Martin believes that both companies with commercially available CAR T-cell products are working diligently to improve access. In addition, partly because of the late-line setting in which CAR T cells are used in patients with multiple myeloma, about 10% to 20% of these individuals do not produce a product with FDA specifications.

There are still more patients who would benefit from CAR T-cell therapy than there are available CAR T-cell manufacturing slots.

“These so-called out-of-spec [OOS] T-cell products can often still be given,” Dr. Martin explained, but they must be administered as part of an expanded access protocol. A T-cell product may be deemed OOS, he said, if the T-cell viability is less than 80% or the product has a low-cell dose.

Exposure to High-Dose Steroids or Alkylators and Low ALC

Possible causes for this phenomenon were explored. It was observed that it more commonly occurs in patients who were exposed to a high-dose steroid and/or intensive alkylator therapy close to the time of apheresis. “In general, we try to avoid these drugs in the period before the apheresis procedure,” said Dr. Martin. “Another predictor of OOS T cells is low peripheral blood absolute lymphocyte count (ALC; < 0.3 × 10⁹ cells/L).”

Bulky Disease and Rapidly Progressing Disease

“Clinical characteristics that predict for worse outcomes after CAR T-cell therapy include having bulky disease, high M-protein or plasma cell percentage in marrow, evidence of extramedullary plasmacytomas, presence of high-risk cytogenetics, and high stage,” Dr. Martin noted. Patients with rapidly progressing disease “are also a difficult group to take to CAR T-cell therapy due to the limited slot availability, prolonged manufacturing times (which can exceed 6–9 weeks), and the need for aggressive bridging therapy to keep patients stable while awaiting arrival of the product.”^17,18

Currently, in patients with aggressive and/or bulky disease who undergo apheresis, “we give hyperfractionated cyclophosphamide-based chemotherapy to keep their disease under control or, better yet, to try to debulk the disease prior to lymphodepletion therapy. It is well known that CRS and ICANS occur more frequently in patients with bulky or high-burden disease going into lymphodepletion therapy,” Dr. Martin told JNCCN 360. More effective bridging strategies are needed, he continued, and, as CAR T-cell therapy moves to earlier lines of treatment, “it should be possible to achieve a minimal burden of disease state, pre-CAR T-cell use, in the majority of patients.”

Severe Neurologic Issues, Pulmonary Compromise, Renal Insufficiency

There are patient-related factors, including comorbidities, that help select appropriate candidates, Dr. Martin noted. “We typically would not use CAR T-cell therapy in patients with preexisting severe neurologic issues, recent stroke, active central nervous system myeloma, or seizures.” He also noted that in patients with prior cardiac disease (eg, ejection fraction < 30%) or in those who have a baseline pulmonary compromise and may need supplemental oxygen, CAR T-cell therapy is likely not to be possible. Eligible patients need to be able to survive an episode of severe bacteremia and sepsis. As for patients with moderate to severe renal insufficiency, including those who are on dialysis, “several reports have been published showing these individuals can successfully receive CAR T-cell therapy, provided fludarabine is appropriately dose reduced.²⁸ However, my preference is to use bispecific therapy, especially in patients on dialysis, as the toxicity is generally less severe with the latter vs CAR T cells.”

Outpatient CAR T-Cell Therapy

Jennifer Smith, APRN, CNP, MSN, of the Mayo Clinic in Rochester, Minnesota, shared her experience with CAR T-cell therapy with JNCCN 360: “I feel really lucky to be working at the Mayo Clinic because we have been a key center for CAR T-cell therapy since its very inception. I have been working with it and watching it evolve, since our very first patient—first as a bedside nurse and now as a nurse practitioner—and it’s been a truly fascinating experience.”

Ms. Smith explained that the Mayo Clinic uses “an exceptional hospital-based outpatient management program; after an initial set up, we manage patients in an outpatient setting from the day of lymphodepleting chemotherapy all the way to day 30 post CAR T-cell infusion, unless they experience CRS and/or ICANS.”²⁹ According to Ms. Smith, patients and their caregivers have access to the team around the clock during that period; remote patient monitoring tools (typically vital signs and neurologic assessments every 4 hours) are used, allowing early intervention if necessary. “We have really good outcomes with the least aggressive management approach, preventing the development or escalation of serious adverse events,” she observed. “Patients feel comfortable knowing the same team is involved with both inpatient and hospital-based outpatient management programs.” She stated this unique approach “sets us apart from most other institutions.”

With regard to CRS and ICANS management, the Mayo Clinic follows the grading system and protocols provided by the manufacturers of these CAR T-cell therapies and by the American Society for Transplantation and Cellular Therapy.³⁰ “Because we typically cannot predict who will and who will not experience those adverse events, we have to be vigilant at all times,” Ms. Smith stressed. “That is true even in patients whose disease was successfully debulked with a bridging therapy.”

Nevertheless, Ms. Smith pointed out, patients who receive CAR T-cell therapy have already been exposed to multiple lines of therapy and may present some challenges, even in the absence of early CRS and/or ICANS. For example, during CAR T-cell expansion, “it is not unusual for patients to experience an inflammatory response with debilitating pain at the site of their disease,” Ms. Smith added. “A rapid rise in C-reactive protein in those patients can help predict who may experience CRS and likely neurotoxicity, and earlier use of tocilizumab in those patients may improve their outcomes.”

Concluding Remarks

With regard to post-CAR T-cell therapy, Dr. Raje observed that “what is becoming apparent, and something we still do not yet fully understand, is that CAR T-cell therapy changes the patient’s overall immune landscape, including regulatory T cells, myeloid-derived suppressor cells, and plasmacytoid dendritic cells. That altered immune landscape may be a determining factor regarding the response to therapy after the patient relapses on CAR T-cell therapy.”

Despite the accumulated chronic debilities associated with long-standing myeloma, Dr. Martin stated: “In my practice, patients who receive CAR T-cell therapy experience significantly improved quality of life, especially for those who achieve remission for a year or longer.” 

One of the particular challenges associated with using CAR T-cell therapy, Ms. Smith commented, is in older patients. “Although these older adults may fulfil all the eligibility criteria for CAR T-cell therapy, especially in terms of overall fitness, their abilities to recover from potentially debilitating adverse events are highly variable and unpredictable.” She noted that similar challenges are encountered in younger patients with comorbidities. Finally, Ms. Smith emphasized the importance of a good psychosocial support system for both patients and caregivers in the overall care of patients receiving CAR T-cell therapy. “This aspect of care, unfortunately, is often overlooked,” she observed.

Disclosures

Noopur Raje, MD, has served as a consultant to Janssen and BMS. 

Thomas G. Martin, MD, has received research funding from BMS, Janssen, and Sanofi and has served as a consultant to Pfizer and GSK.

Jennifer Smith, APRN, CNP, MSN, reported no conflicts of interest.

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