Clinical Review of Cellular Therapies for Multiple Myeloma Part II: Toxicities of CAR-T for the Community and Rural Oncologist

Introduction

Since the U.S. Food and Drug Administration (FDA) approvals of idecabtagene vicleucel (ide-cel; brand name Abecma) in March 2021 and ciltacabtagene autoleucel (cilta-cel; brand name Carvykti) in February 2022, anti-BCMA (B-cell maturation antigen) chimeric antigen receptor T-cell (CAR-T) therapy has rapidly transitioned from a niche investigational modality to an established pillar of multiple myeloma therapeutics [1, 2]. In our previous article, we provided an overview of these products for the community and rural oncologist as patients treated with CAR-T spread further into non-tertiary care settings.

Toxicities of CAR-T therapies

While ide-cel and cilta-cel are generally considered safe and have remarkable therapeutic impact for relapsed/refractory myeloma, both agents carry a broad and clinically significant toxicity burden that practitioners must recognize and actively surveil. These adverse effects include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity (ICANS), other neurotoxicities, cytopenias, infections, and rarer, ill understood issues such as hemophagocytic lymphohistiocytosis-like syndromes [3]. Some of these effects such as CRS and ICANS are universally seen in CD3+ T cell redirecting (TCR) therapies across myeloma, lymphoma, and solid tumor products, while some toxicities seem to be more unique to cilta cel especially [4].

Cytokine Release Syndrome

CRS is the most common acute toxicity of anti-BCMA CAR T therapy, resulting from the massive cytokine cascade, principally interleukin-6 (IL-6), interferon-γ, and tumor necrosis factor-α. Grading is standardized per the 2019 American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria, in which fever (≥38°C) is an obligate defining feature. CRS grade is then determined by the degree of hypotension and hypoxia. In CARTITUDE-1, any-grade CRS occurred in 95% of patients, while grade ≥3 CRS was observed in approximately 4%; comparatively, in KarMMa-1, any-grade CRS was in 84% and grade ≥3 occurred in approximately 5%.

Management is graded: Grade 1 CRS (fever alone) warrants supportive care with antipyretics, hydration, and empiric broad-spectrum antibiotics if febrile neutropenia cannot be excluded. Grade 2 CRS (fever with hypotension responsive to fluids or hypoxia requiring supplemental oxygen) mandates tocilizumab 8 mg/kg IV (not to exceed 800 mg per dose), an FDA-approved IL-6 receptor antagonist. Grade 3-4 CRS requires immediate corticosteroids, typically dexamethasone 10 mg IV every 6 hours, in combination with tocilizumab, aggressive hemodynamic support. Siltuximab, a direct anti-IL-6 antibody, may be employed in tocilizumab-refractory cases and numerous other treatments have been used to mitigate CRS when severe such as ruxolitinib and anakinra. It should be noted that CRS onset is almost universally within the first 10 days of CAR T-cell infusion, so fevers observed in patients treated with ide-cel or cilta-cel in later weeks is rarely from this and far more likely to be of infectious origin.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

ICANS reflects the neuroinflammatory consequence of cytokine-mediated blood-brain barrier disruption and direct neuronal engagement by immune effector cells. The ASTCT grading schema for ICANS incorporates the 10-point Immune Effector Cell-Associated Encephalopathy (ICE) score alongside assessment of consciousness level, seizure activity, motor findings, and signs of elevated intracranial pressure. Grade 1 ICANS (ICE score 7–9) is managed with observation and close neurologic monitoring. Grade 2 (ICE 3–6) warrants initiation of corticosteroids, such as dexamethasone 10 mg IV every 6 hours, with neuroimaging and neurology consultation. Grade 3-4 ICANS, characterized by severe confusion, seizures, or cerebral edema, requires high-dose steroids and emergent neurology involvement in an intensive care setting. Critically, tocilizumab is not generally indicated as monotherapy for ICANS and may worsen neurologic outcomes unless concomitant CRS is seen. Similar to CRS onset, ICANS in ide-cel and cilta-cel is rarely observed beyond two week of CAR T-cell infusion. Real world data [5] suggests that “late-onset CRS and ICANS” beyond 2 weeks following cell infusion are essentially 0% and 1.6%, respectively.

Delayed Neurotoxicities

A toxicity phenotype distinct from ICANS and particular to cilta-cel that has emerged as a major clinical concern is delayed neurotoxicity (DNT). These are fortunately rare [6] but as treatment spreads, including to community and rural oncologists, more will be seen. DNTs include cranial nerve palsies but most notably immune effector cell-associated parkinsonism (IEC-PKS), characterized by bradykinesia, tremor, masked facies, micrographia, shuffling gait, rigidity, and in severe cases, akinetic mutism. Neuropathological studies have confirmed the presence of BCMA expression in basal ganglia neurons and astrocytes. In CARTITUDE-1, 5% of patients developed this syndrome, with median onset approximately 43 days post-infusion (range 15-108 days), and median duration in excess of 234 days. Unlike conventional Parkinson's disease, this syndrome is largely unresponsive to carbidopa/levodopa. 

Emerging data, however, suggest that early intervention with high-dose cyclophosphamide (1.5–2 g/m²) at the time of symptom onset may induce rapid clinical improvement; in a 2025 Mayo Clinic standard-of-care cohort, all four IEC-PKS patients who received cyclophosphamide within 13 days of symptom onset demonstrated observable improvement within 1–2 days, with ongoing recovery at last follow-up [7]. Ruxolitinib, a JAK1/2 inhibitor, has also been reported as a potentially effective intervention in refractory cases. Given that symptom onset commonly occurs after patients have returned to their local oncologist, awareness of these emerging treatment options and prompt communication with the originating cellular therapy center upon first signs of parkinsonism is essential. The reason is not clear but may be due to dopaminergic pathway disruption secondary to neuroinflammation rather than Lewy body pathology seen in conventional Parkison’s disease.

Published real-world analyses confirm cilta-cel's substantially higher risk of delayed neurotoxicity relative to ide-cel [4]. Prophylactic corticosteroids, while empirically employed in some centers for patients with high post-infusion absolute lymphocyte counts (a correlate of robust CAR expansion), failed to demonstrate significant reduction in IEC-PKS incidence in a 2026 retrospective analysis. Community and rural practitioners must therefore maintain heightened vigilance for emerging parkinsonian features throughout the first six months post-infusion. More broadly, any unusual neurologic syndrome seen post one year of cilta-cel would be reasonable to refer promptly to neurology and the treating CAR-T center.

Infectious Complications and Prophylactic Strategies

The infectious vulnerability of CAR-T recipients arises from multiple compounding immunologic deficits: pre-existing myeloma-associated immune suppression, lymphodepletion conditioning, post-infusion neutropenia (grade 4 in up to 73% of patients in CARTITUDE-4), B-cell interference with resultant hypogammaglobulinemia, and the iatrogenic immunosuppression imposed by tocilizumab and corticosteroids administered for CRS and ICANS management. However, in general, anti-BCMA therapies appear to cause a clinically meaningful rise in infections. Indeed, infections represent the leading cause of non-relapse mortality following CAR-T therapy. For instance, in CARTITUDE-4, four of six treatment-related deaths in the cilta-cel arm were attributable to infection.

The infectious risk is temporally heterogeneous [8]. The early period (days 0–30) is dominated by bacterial infections such as gram-negative bacteremias, pneumonias, and catheter-related bloodstream infections which may be largely driven by neutropenia. Between days 31 and 100, bacterial infections persist while viral reactivations become increasingly prevalent. Even common viral ailments such as rhinovirus can be significant infections post-CAR T. Beyond day 100, viral infections (CMV, EBV, respiratory viruses) and opportunistic organisms predominate in the context of ongoing lymphopenia and dysfunctional humoral immunity. The question of when the infection risk after ide cel or cilta-cel subsides is an ongoing study, however general acceptable that the first year is an appropriate timeframe to consider these patients at high risk.

Intravenous Immunoglobulin (IVIG)

Hypogammaglobulinemia is virtually universal following anti-BCMA CAR T therapy, a consequence of on-target B-cell aplasia and plasma cell depletion. IVIG (or subcutaneous immunoglobulin ScIg) replacement is recommended by guidelines for all anti-BCMA CAR-T patients with a typical dose of 0.4 g/kg every 3–4 weeks. The question of how long to do this is not yet established but IVIG replacement should generally be continued for a minimum of 6–12 months (or until evidence of B-cell reconstitution), regardless of a patient’s total IgG levels. Beyond this timeframe, the usual guidance of favoring IVIG when functional total IgG levels fall below 400 mg/dL, particularly in patients with recurrent sinopulmonary infections, is advised [9]. As IVIG infusion is generally an accessible intervention for community and rural oncologists, supporting replacement is a favorable measure.

Antimicrobial Prophylaxis

Antibacterial prophylaxis with fluoroquinolones (typically levofloxacin) or cephalosporins (typically cefpodoxime) during the neutropenic nadir mirrors post-autologous stem cell transplant guidelines and is broadly recommended for at least the first month post-infusion [10]. Antifungal prophylaxis with fluconazole or even posaconazole is indicated during periods of neutropenia. Posaconazole is preferred in patients with prolonged neutropenia (>3 weeks) or requiring sustained corticosteroid exposure. Antiviral prophylaxis with acyclovir or valacyclovir is recommended for a minimum of 12 months post-infusion (potentially indefinitely) to prevent HSV and VZV reactivation, with extension guided by CD4+ T-cell reconstitution. Most authorities recommend continuation until CD4+ counts reliably exceed 200/μL. 

Pneumocystis jirovecii pneumonia (PJP) prophylaxis with inhaled pentamidine, trimethoprim-sulfamethoxazole tablets, or oral solution atovaquone is recommended for 6–12 months post-infusion, with cessation also guided by CD4+ recovery. In the rural oncology practice, trimethoprim-sulfamethoxazole is the most pragmatic option with atovaquone reserved for sulfonamide-intolerant patients.  Although confirmed PJP and fungal cases following BCMA-directed CAR-T therapy are not as common as bacterial or viral infection, the widespread availability of these preventive measure make them prudent for community and rural oncologists. The totality of available evidence supports continuation of antifungal, antiviral, and PJP prophylaxis through at least 6 months post-infusion, with extension to 12 months or longer in patients with ongoing cytopenias, recurrent infections, persistent hypogammaglobulinemia, or delayed immune reconstitution. 

Warning Signs and Criteria for Tertiary Referral

For the rural oncologist managing patients in follow-up after a patient has had CAR-T infusion at an academic center, a systematic and structured approach to surveillance is essential. Warning signs mandating urgent communication with or transfer to the treating CAR-T center include: any fever in the first 30 days post-infusion (mandatory evaluation for infection and theoretically late CRS); new neurologic symptoms at any point within 6-12 months (encephalopathy, tremor, gait instability, aphasia, facial palsy, handwriting deterioration); persistent infectious complication (despite IVIG and antimicrobial prophylaxis). 

Moreover, other toxicities from CAR T therapy can occur such as persistent cytopenias, immune effector cell-associated enterocolitis (IEC-EC), immune effector cell-associated hemophagocytic lymphohistiocytosis (HLH)-like syndrome, and others ([9]. As these therapies are still relatively new, more is revealed of their medium-term and long-term toxicities warranting any new, significant, unexpected symptoms to be worth referring to tertiary care. Community and rural oncology practitioners should establish explicit referral pathways and direct communication channels with the originating CAR T center prior to patient discharge, as real-time management decisions for these toxicities require institutional expertise that is difficult to reliably be replicated at a non-specialist facility.

Conclusion

Anti-BCMA CAR-T therapy has delivered remarkable outcomes for relapsed/refractory multiple myeloma. The increasing use of CAR T therefore collectively require that community and rural oncologists develop increasing fluency in the management of these therapies’ complex toxicity profiles. As patients proliferate inevitably towards community and rural oncology practices rather than the tertiary care, academic centers basic management with IVIG, antimicrobials, and index of suspicion will continue to serve myeloma patients well.

Patient Perspective / Plain-Language Summary (100–150 words):

Two newer treatments for multiple myeloma, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), can produce remarkable and long-lasting remissions but can also cause serious side effects that community and rural oncologists outside of major cancer centers need to recognize and manage. Shortly after treatment, patients may develop a flu-like inflammatory reaction called cytokine release syndrome, or a form of brain inflammation called ICANS, both of which require prompt medical attention. An important but rare concern with Carvykti is a delayed Parkinson's-like movement disorder that can appear weeks to months after treatment and requires specialized care. Because these treatments weaken the immune system for an extended period, patients also face a high risk of infections for at least a year following therapy, requiring preventive antibiotics, antiviral medications, antifungal agents, and regular immunoglobulin infusions to replace depleted antibodies. As more myeloma patients receive these therapies and return to their local cancer doctors for ongoing care, community and rural oncologists must be familiar with these side effects so that patients receive timely, safe, and coordinated care closer to home.

Key Takeaways

- Prophylactic IVIG recommend for 6-12 months for all patients who have had ide-cel or cilta-cel

- Prophylactic antimicrobials such a levofloxacin or cefpodoxime, fluconazole or posaconazole, and PJP prophylaxis recommended for 6-12 months

-Prophylactic acyclovir or valacyclovir should be continued for 12 months or indefinitely

- Recognition and prompt management of CRS, ICANS, and delayed neurotoxicities (DNT) is essential for safe community follow-up

-Unexpected, significant new ailments are worth referring to a treating tertiary care cellular therapy center

References:

1. Munshi, N.C., et al., Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med, 2021. 384(8): p. 705-716.

2. Berdeja, J.G., et al., Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet, 2021. 398(10297): p. 314-324.

3. Afrough, A., et al., Toxicity of CAR T-Cell Therapy for Multiple Myeloma. Acta Haematol, 2025. 148(3): p. 300-314.

4. Hansen, D.K., et al., Comparison of Standard-of-Care Idecabtagene Vicleucel and Ciltacabtagene Autoleucel in Relapsed/Refractory Multiple Myeloma. J Clin Oncol, 2025. 43(13): p. 1597-1609.

5. Wesson, W., et al., Timing of Toxicities and Non-Relapse Mortality Following CAR T Therapy in Myeloma. Transplant Cell Ther, 2024. 30(9): p. 876-884.

6. Hansen, D.K., et al., Safety and efficacy of ciltacabtagene autoleucel for relapsed/refractory multiple myeloma: a CIBMTR study. Blood Cancer J, 2026. 16(1).

7. Lim, K.J.C., et al., Clinical course, risk factors and mitigating strategies for Immune effector cell-associated late onset neurotoxicities after ciltacabtagene autoleucel CAR-T in multiple myeloma. Blood Cancer J, 2025. 16(1): p. 18.

8. Dima, D., et al., Cytopenias and infections following ciltacabtagene autoleucel in heavily pretreated relapsed or refractory multiple myeloma. Haematologica, 2026. 111(1): p. 184-195.

9. Wonnaparhown, A., et al., IgG replacement in multiple myeloma. Blood Cancer J, 2024. 14(1): p. 124.

10. Shahid, Z., et al., Best Practice Considerations by The American Society of Transplant and Cellular Therapy: Infection Prevention and Management After Chimeric Antigen Receptor T Cell Therapy for Hematological Malignancies. Transplant Cell Ther, 2024. 30(10): p. 955-969.

Corresponding author: 

Adeel M. Khan, M.D., M.P.H., M.S.
Assistant Professor of Medicine & Public Health 
Harold C. Simmons Comprehensive Cancer Center & Peter O’Donnell Jr School of Public Health
University of Texas Southwestern Medical Center
5323 Harry Hines Boulevard, Dallas, TX, USA 75390
Tel: (405) 623 3337   E-mail: [email protected] / [email protected]

ORCiD: 

Adeel Khan: 0000-0002-9462-6316

Aimaz Afrough: 0000-0003-2645-8557

Samer Al Hadidi: 0000-0003-4297-8042 

Sean Taasan: 0000-0001-6937-0120

Larry Anderson: 0000-0002-6531-9595

Relevant Disclosures/Conflict of Interest:

AMK: Johnson & Johnson, Legend, Sanofi, Pfizer, AbbVie

AA: AbbVie, Adaptive Biotech, K36 Therapeutics, Johnson & Johnson, Regeneron, Bristol Myers Squibb, Karyopharm Therapeutics, Sanofi, and Pfizer

SAH: Johnson & Johnson, Legend, Sanofi, Pfizer

ST: none

LDA: Johnson & Johnson, Celgene, Bristol Myers Squibb, Amgen, GSK, AbbVie, BeiGene, Karyopharm, Pfizer, Cellectar, Sanofi, Prothena, and Arcellx