Acute management of ICANS following bispecific antibody therapy

Dexamethasone treatment of ICANS

• Dexamethasone is first line therapy for treatment of acute ICANS all grades.
• Dosing: Grades 1-2, doses ranging from Dexamethasone 10-20mg Q12 hours until resolution are the mainstay of treatment. Higher grades of ICANS are rare with bispecific therapy and other etiologies need to be considered. Higher doses of corticosteroids should be considered for Grades 3-4 ICANS as per IMWG Bispecific guidelines
• In all settings (outpatient/ER/hematology/oncology service), a complete evaluation should be performed in patients who experience ICANS and consideration for use of anti-seizure prophylaxis in those experiencing ICANS.
• Patients should be monitored closely whether treated inpatient or outpatient with serial ICE evaluations and neurologic exams per institutional guidelines

Acute management of ICANS following CAR T-cell therapy

Dexamethasone treatment of ICANS in CART therapy

• Dexamethasone should be used for the management of acute ICANS all grades.
• Dosing: Grades 1-2, doses ranging from Dexamethasone 10-20mg Q12 hours. Higher grades of ICANS can be treated with higher doses of corticosteroids per IMWG CART guidelines
• In all cases, a complete evaluation should be performed in patients who experience ICANS and consideration of anti-seizure prophylaxis for those not already receiving prophylactic medications.
• Patients should be monitored closely during their inpatient time and throughout outpatient follow-up with serial ICE evaluations and neurologic exams per IMWG and/or institutional guidelines

Late-Neurologic toxicity:

IEC-Parkinsonism (IEC-PKS) – Generally limited to CAR T-cell Therapy

Diagnosis: Must be vigilant in identifying new-onset symptoms, these most commonly occur 3 weeks to 3 months post CAR-T infusion

• Symptoms include; isolated changes in movement (bradykinesia, rigidity), altered cognition (confusion, slowed responses), personality change (paucity of speech, flat affect) and/or micrographia
• Only 1 neurologic symptom should prompt full evaluation; Neurology consultation with comprehensive movement disorder evaluation, MRI brain, lumbar puncture to assess for infection, and handwriting assessments for micrographia
• Any symptoms/concern for IEC-PKS identified by the community practice should elicit – discussion with the original CAR-T center. Both teams should coordinate the evaluation and management
• Patients experiencing lymphocytosis within 3 weeks post-CAR infusion are at higher risk of neurotoxicity

Treatment Strategies: experiences are limited to retrospective reports and case series

• Prompt evaluation and initiation of therapy is imperative. Recommended 1^st line treatment includes; steroids (Dex 10 mg BID) and IVIG (2-4 gm/kg) with or without dopamine agonist (dopamine agonists can be used in concert with neurology although the general experience is that dopamine aganist are ineffective in improving symptoms).
• Morbidity and mortality is high in severe cases, therefore escalation/additional treatment options should be considered when no improvement is seen in 1-2 weeks or if lymphocytosis persists
• Systemic chemotherapy (cyclophosphamide IV 1–2 g/m²) and/or intrathecal chemotherapy have utilized with some success. A high rate of infection has been seen especially with systemic cyclophosphamide thus vigilant infection surveillance and antimicrobial prophylaxis should be administered

Mitigating strategies

• Myeloma disease burden reduction, prior to CAR-T therapy has been associated with decreased incidence
• Patients with absolute lymphocyte count rise to above normal threshold (3×10^9/L) in the first 3 weeks after CART therapy (peak CAR-T expansion ~Day 12-14) are at increased risk for IEC-PKS. Whether intervention at this time can reduce risk of IEC-PKS is currently being studied. Patients should have close follow-up for assessment of IEC-NT and IEC-EC symptoms.

References: A Kumar et al, ASH 2024, abstract # 655; Sidana et al Blood 2025: 145(1):85-97. Graham C. E. Et al Blood 2023. Karschnia P et al Blood 2023. Kelly K et al Blood Adv 2025. Lim K et al. ASCO 2025.

 IEC-Guillaine Barre Syndrome (IEC-GBS)

• This is a rare toxicity occurring in <2% of BCMA targeted CART patients. Consider this in patients with sudden onset of severe back pain and/or progressive neuropathy after CAR T-cell therapy. Symptoms include worsening sensory neuropathy with progression to motor neuropathy or severe back pain without other cause. Early signs may be confounded by history of myeloma bone disease and prior neuropathy.
• Prompt evaluation with Neurology consultation is warranted in patients experiencing these symptoms
• Treatment experiences are limited. First-line treatment with steroids, IVIG and plasmapheresis have most commonly been attempted with reported success. Treatment should be coordinated in consultation with Neurology.
• Community clinicians should contact the CAR-T treatment center to discuss coordination of care, planned evaluation and management

IEC-Cranial Nerve Palsy (IEC-CP)

• Consider IEC-CP in patients presenting with new-onset cranial neuropathies
  • Symptoms typically present between 3 weeks and 3 months after CAR
  • Facial nerve (CN VII, Bell’s palsy) is most commonly involved, with cranial nerve III, V involvement less common, and can be unilateral or bilateral. More than 1 cranial nerve abnormality may also occur
  • Symptoms of drooling, increased tearing/eye watering, double vision should warrant further evaluation
• Prompt evaluation including Neurology consultation, contrast enhanced MRI brain, infectious disease testing of blood and CSF (HHV6, HHV7, HSV, VZV, CMV, EBV) and lumbar puncture to assess for lymphocytosis (and presence of CAR T-cells if possible). PET, EEG and other exams as deemed necessary.
• Community clinicians should contact the CAR-T treatment center to discuss coordination of care, planned evaluation and management
• Treatment experience from case reports and real world data, suggest good response with steroids (Dex) and high-dose IVIG (2-4 g/kg)
• Median time to partial resolution has been reported to be 11 days, with full resolution typically achieved by 2 months.

 References: Kumar et al, ASH 2024, abstract # 655; Sidana et al Blood 2025: 145(1):85-97

Other Non-ICANS Neurotoxicities: Bulbar and Cerebellar Toxicity associated with GPRC5d-targeted agents (CAR and bispecific therapy)

Diagnosis

• Consider in patients with unexplained ataxia, gait instability, dysmetria, bulbar aphasia or other bulbar or cerebellar symptoms occurred after the start of GPRC5D-targeting T-cell engager or CAR-T therapy.
• Time to onset is around 1^st month but can be identified at later timepoints, and with variable severity of the symptoms.
• Prompt evaluation including Neurology consultation, contrast enhanced MRI brain, infectious disease testing of blood and CSF (HHV6, HHV7, HSV, VZV, CMV, EBV) and lumbar puncture to assess for lymphocytosis (and presence of CAR T-cells if possible). PET, EEG and other exams as deemed necessary.
• Community clinicians should contact the CAR-T treatment center to discuss coordination of care, planned evaluation and management

Management

• Pathogenesis is poorly understood and there are no known effective treatments
• Recommended management includes:
• Permanent interruption of the GPRC5d-targeting T-cell engager if grade 2 or higher. Grade 1 symptoms should elicit dose hold with reinitiation of therapy upon resolution and with a dose reduction. Recurrent or persistent symptoms would elicit treatment discontinuation
• Consider early implementation of corticosteroids or IVIG, although no formal treatment has shown efficacy for symptom resolution

Acute management of Cytopenias during bispecific antibody therapy

Management of Cytopenias

• Treatment with bispecific antibodies often elicit an inflammatory response together with CRS that frequently results in cytopenias. Neutropenia is the most common and can occur intermittently throughout the duration of treatment. Thrombocytopenia and anemia are less common but also occur and more commonly in the first few cycles of treatment and in patients with bulky disease.
• These cytopenias generally respond to treatment with cytokines. Short and long-acting WBC growth factors (G-CSF, PEG-G-CSF), erythropoietic agents, and thrombopoietic mimetics should be initiated per institutional guidelines. These agents can be used throughout the treatment duration, even concomitant with bispecific dosing.
• In patients experiencing significant cytopenias despite Growth Factor, consideration of other cause with further evaluation including bone marrow sampling may be necessary.

Acute management of Cytopenias following CAR T-cell therapy

Dexamethasone treatment of ICANS in CART therapy

• Cytopenias are the most common toxicity after CAR T-cell therapy, due to the lymphodepletion chemotherapy and the inflammatory milieu including CRS.
• Neutropenia is most common (Gr3/4 in >50%) and is most severe in the first 2-4 weeks after CART therapy with ~20% experiencing persistent neutropenia after the first month. Thrombocytopenia and anemia are also common and occur most commonly in the first few weeks following CART therapy.
• Management of acute cytopenias generally includes cytokines and transfusion therapy. Cytokines can be safely initiated following the risk period for CRS. Short and long-acting growth factors (G-CSF, PEG-G-CSF), erythropoietic agents, and thrombopoietic mimetics should be initiated per institutional guidelines.
• In patients experiencing persistant cytopenias despite cytokine therapy, consideration of other cause with further evaluation including bone marrow sampling should be considered.
• Stem cell support, in those that have stored CD34 stem cell aliquots (³2 million CD34/kg recipient weight), can be utilized with resolution of cytopenias generally within 2-3 weeks of stem cell infusion.
• Secondary malignancies including myeloid malignancies (MDS and AML) have been reported in upwards of 10% of patients receiving BCMA CART therapy and must be evaluated in those experiencing late cytopenias (after 1-3 months).

IEC-Enterocolitis

Diagnosis

• Consider in patients with unexplained, non-bloody diarrhea with negative infectious work-up occurring 1-3 months post-CAR-T. This may also be seen post T-cell engagers.
• Evaluation to include GI and ID specialists:
  • Perform endoscopic evaluation with biopsies that are specifically reviewed by a hematopathologist, as inflammation often resembles patterns seen in GVHD following allogeneic transplantation
  • Infections are common preceding or concurrent, should be evaluated and treated if identified
  • Perform T-cell receptor clonal rearrangement on GI biopsy as part of evaluation to identify T-cell lymphoproliferative disorder
• Collaborate with product manufacturers to test for CAR-T presence on enteral biopsies

Management

• Treatment experience are limited to retrospective reports & case series. Morbidity and mortality is high with severe cases. Consider TPN support early in severe cases.
• IVIG and steroid, +/- budesonide can be trialed first. If lack of improvement in 1-2 weeks, consider stopping systemic steroid, and try infliximab or vedolizumab.
• Consider T-cell modulating or lymphotoxic drug such as high dose cyclophosphamide in refractory cases or in cases of T-cell lymphoproliferative disorder
• Remain vigilant of antimicrobial prophylaxis and infection surveillance during treatment

References: Fortuna et al, Blood Cancer Journal; 14:180 (2024) Bar et al, IMS 2024 P-008. Ozdermilni et al NEJM 2024. Harrison SJ et al NEJM 2025. Lim, K et al EHA 2025. 

GPRC5D mediated side effects

Background

Talquetamab is a bispecific antibody (BsAb) targeting CD3 on T cells and GPRC5D on multiple myeloma (MM) cells. However, GPRC5D expression in epithelial tissues also leads to unique oral and dermatologic side effects. The GPRC5D mediated side effects have a higher incidence and severity in patients receiving Talquetamab, but can also be seen in patients receiving a BCMA/GPRC5D Trispecific and in CAR T that targets GPRC5D. Dermatologic toxicities include rashes, palmar/plantar peeling, dry skin, pruritus and nail changes. Oral toxicities include dysgeusia, dry mouth, dysphagia and weight loss. It is imperative to educate patients and care partners about these side effects and management prior to starting therapy.

Dermatologic side effects:

Monitoring/Prevention

• Assess for skin-related toxicities (rash, dryness, palmar/plantar peeling, pruritus) and nail disorders (discoloration, dystrophy, onycholysis, onychoclasis) throughout treatment.
• Educate patients on interventions for skin and nail changes prior to starting treatment
• Educate patients to report any rashes, injection site reactions or signs of a fungal infection of the nails (thickened or discolored nails)

Interventions: Dermatologic Side Effects

Skin care tips:

• Take a short, lukewarm shower as hot water will dry the skin.
• Apply emollients (Cera-Ve, Eucerin, Cetaphil) within minutes of getting out of the shower
• For pruritus, can try an antihistamine such as loratadine (Claritin) 10mg tablet or diphenhydramine (Benadryl) 25mg tablet.
• Consider topical steroids for G1-G2 rashes; may need oral steroids for > G3 rashes
• Consider topical steroids+ ammonium lactate 12% for palmar/plantar peeling +/- Aquaphor. Wearing cotton gloves after applying these products can help to increase absorption and effectiveness
• Adjust or delay dosing based on severity of adverse events, especially during step- dosing phases.
• Consider Dermatology consult as needed

Nail Care tips:

• Keep nails short and clean
• Apply a heavy moisturizer like Vaseline/Aquaphor to hands and Vitamin E oil to cuticles.
• A nail hardener, like Mavala, may help with thinning.
• Avoid putting pressure on nails (e.g. avoid tight shoes or sports that would affect nails)
• Can consider a low dose topical steroid for peeling around the nails
• Avoid acrylics or gels as they may increase the risk of fungal infections

Interventions: Oral Side Effects

Monitoring/Prevention:

• Establish baseline oral assessment.
• Consider zinc serum level (deficiency may contribute to dysgeusia/anosmia).
• Dietician consult can be considered in select patients to establish nutritional baseline, deficits and interventions.
• Monitor for onset of taste alterations, loss of smell, dry mouth (xerostomia), dysphagia.
• Review good oral hygiene measures: Tooth brushing twice daily with a soft toothbrush, flossing daily, dental assessment and visit twice per year
• Medication review. Identify and, if possible, discontinue or modify medications contributing to anticholinergic symptoms.
• Assess for oropharyngeal candidiasis.

Xerostomia (Dry mouth) tips:

• OTC rinses (Biotene Dry Mouth Gentle, CVS Brand Alcohol Free Dry Mouth Mouthwash, ACT Dry Mouth Rinse) as directed
• Dry mouth lozenges (Xylimelts, Biotene, Therabreath, CVS Health Dry Mouth Discs)
• Sugar free hard candies/lozenges (Halls Defense SF Citrus Lozenges, Jolly Rancher Sugar Free Hard Candy, Werther’s Sugar Free Hard Caramel)
• Reduce/eliminate caffeine, tea, alcohol, soda/flavored water, tobacco/cigars/THC-CBD (smoking)
• Replace chewing gum and candies/lozenges with sugar-free or xylitol-based alternatives
• Encourage use of a humidifier at home in fall/winter – can be helpful especially at night
• Increase oral fluid intake (sips throughout the day)

Dysgeusia tips:

• Dietician recommendations for taste changes – can target interventions based on taste changes (salty, sweet, bitter, hypogeusia/ageusia)
• Mild salt water & baking soda solution (½ tsp salt + ½ tsp baking soda in 1g water), rinse and gargle 3x/day before and after meals
• Can consider a dose reduction in Talquetamab when appropriate

Dysphagia tips:

• Sit upright with meals; sip liquids with solids
• Cut foods into small, bite-sized pieces
• Add oil, sauces, gravies, etc to food to make easier to swallow – also adds calories
• Soft/pureed diet with gravy or sauces; avoid foods that may increase choking risk.
• Soft foods or foods that can be cooked until tender (mashed potatoes, squash, ground beef/turkey, soups, smoothies).
• Consider topical steroids for dysphagia/odynophagia:
• Budesonide PO slurry 1–2g daily (divided doses), swish and swallow
• Fluticasone spray with MDI (without spacer): 220mcg, 2 sprays PO BID (total 4 sprays daily), to oral cavity and swallow. Document response 1–2 days after initiation.

Weight loss tips:

• Consume small, frequent meals/snacks to get enough calories
• Consume nutritious liquids (smoothies, supplement drinks, milk, 100% juice)
• Consume protein (plant/animal) with each meal/snack
• Choose nutrient dense food/liquids; calorie boosting food with each meal (olive oil, avocado, nut butter, hummus)
• Consider starting an appetite stimulant

Stomatitis/Glossitis:

• Assess for infection
• Viscous lidocaine 2% swish and spit or Magic Mouthwash (Maalox/Lidocaine/Benadryl)
• Oral pain medication prn
• Dexamethasone mouth rinses (with antifungal like Nystatin or Clotrimazole)

Oropharyngeal candidiasis

Grade 1:

• If positive: Nystatin 400,000–600,000 units swish and swallow 4x/day
• Clotrimazole Troche 10mg, dissolve in mouth 5x/day
• Miconazole mucoadhesive tablets 50mg once daily (preferred for adherence)

Grade 2 (moderate dietary modifications, most common)

• If positive: Nystatin 400,000–600,000 units swish and swallow 4x/day
• Clotrimazole Troche 10mg, dissolve in mouth 5x/day
• Miconazole mucoadhesive tablets 50mg once daily
• Fluconazole 100–200mg PO daily for 7–14 days (depends on severity)

>Grade 3:

• Grade 2 interventions + Artificial Saliva Gel
• Short term pain management
• Oral Budesonide – Slurry 1-2gm PO Daily (2 divided doses). Patients can swish and swallow – reaches entire esophagus

Published Guidelines: Infection

Please refer to the current guidelines: Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group

Fatigue

Overview

Fatigue is defined as a subjective feeling of exhaustion, burnout, or overwhelming tiredness. Fatigue is rarely an isolated symptom and most commonly occurs with other symptoms and signs, such as pain, emotional distress, anxiety, depression, anemia, and sleep disturbances, and changes in cognitive function in symptom clusters; yet, it is a commonly reported symptom among patients receiving CAR T-cell therapy (NCCN, 2026). and is often accepted by patients as a side effect of their cancer and treatment and often under-reported (Dekker et al,, 2025).

Causes of fatigue in myeloma patients undergoing CAR T-cell therapies are often multifactorial, as fatigue arises not only from the underlying cancer and preconditioning regimens but also from common side effects such as immune activation, cytokine release, cytopenias, and treatment-related stress  (Dai et al., 2022). Fatigue ranges in incidence and severity, yet even mild fatigue can be devastating to the individual, with rates as high as 90% across studies. Although specific CAR T-related fatigue data are still emerging, quality-of-life assessments indicate that many patients report persistent fatigue up to 6 months post-treatment, reflecting the ongoing impact of both therapy and disease-associated processes. Yet, trends toward improvement in symptoms over time have been observed (Mina et al., 2025).

Effective management requires a comprehensive understanding and intervention of these contributing factors such as disease activity, type of treatment, sleep disturbances, nutritional status, lack of physical exercise, or psychological stress (Catamero et al., 2017).

Preventative

Preventative strategies for fatigue focus on patient optimization and on minimizing modifiable risk factors during treatment. This includes:

• Pre-treatment assessment optimization: Includes correction of anemia, addressing nutritional deficiencies, and diagnosis and management of sleep disorders — all recognized contributors to fatigue in myeloma patients.
• Patient education and expectation management: It is critical to recognize the important role of the patient and caregiver in addressing fatigue, addressing treatment toxicities, and helping patients adopt energy-conserving behaviors.
• Encourage patients to engage in light physical activity as tolerated and safe, which can help prevent deconditioning.
• Prophylactic measures such as antibiotics, antivirals, and IVIg aim to reduce the incidence or severity of infections that may worsen fatigue.
• Enhanced psychosocial support and structured counseling are recommended to address and reduce levels of psychological stress and uncertainty before and after CAR T-cell infusion.

Monitoring & Diagnosis

Routine and systematic monitoring is essential to distinguish CAR T-related fatigue from other causes. This involves:

• Patient-reported outcome tools are available to quantify fatigue severity and its impact on one’s health over time.
• Baseline and longitudinal laboratory assessments —Regular monitoring of complete blood counts to evaluate anemia and cytopenias, complete metabolic panels to check for electrolyte abnormalities, and endocrine evaluations (such as TSH and testosterone levels) as appropriate.
• Active surveillance for acute CAR T-associated toxicities, such as cytokine release syndrome (CRS) and ICANS, is recommended, which can indirectly contribute to fatigue through systemic effects.
• Recognizing that persistent or worsening fatigue beyond the expected recovery period warrants evaluation for late effects, disease progression, secondary complications, or psychosocial factors.
• underscores the importance of routine symptom assessment and documentation as part of comprehensive myeloma care, including for fatigue and related quality-of-life concerns.

Management

Management of fatigue in this MM patients receiving immunotherapies is multifactorial and individualized. Strategies include:

• Address underlying and reversible causes such as anemia (e.g., with transfusion support or erythropoiesis-stimulating agents when appropriate), metabolic abnormalities, and endocrine dysfunction.
• Non-pharmacologic interventions: structured energy conservation, sleep hygiene, gentle exercise or rehabilitation programs, nutritional support, and psychosocial counseling.
• Symptom management frameworks are advocated by the IMF’s Nurse Leadership Board and emphasize proactive recognition and holistic care planning that accounts for both physical and emotional contributors to fatigue.
• Pharmacologic options (e.g., stimulants or ginseng) may be considered selectively after addressing modifiable physiological causes, and only when clinically appropriate.

Importantly, patient education and shared decision-making are central to effective fatigue management — empowering patients to report symptoms, understand triggers, and actively participate in mitigation strategies.

References:
Catamero, D., Noonan, K., Richards, T., Faiman, B., Manchulenko, C., Devine, H., Bertolotti, P., & Gleason, C. (2017). Distress, Fatigue, and Sexuality: Understanding and Treating Concerns and Symptoms in Patients With Multiple Myeloma 
. Clinical journal of oncology nursing, 21(5 Suppl), 7–18. https://doi.org/10.1188/17.CJON.S5.7-18

Dai H, Xu S, Wang Z, et al. Quality of life and symptom burden among hematologic malignancy patients undergoing CAR-T therapy: a cross-sectional study. Sci Rep. 2025;15(1):17763. Published 2025 May 22. doi:10.1038/s41598-025-02720-6).

Dekker, J., Welling, C., & Labots, M. (2025). Acceptance in Patients With Cancer: A Scoping Review. Cancer reports (Hoboken, N.J.), 8(11), e70324. https://doi.org/10.1002/cnr2.70324

Mina R, Mylin AK, Yokoyama H, et al. Patient-reported outcomes following ciltacabtagene autoleucel or standard of care in patients with lenalidomide-refractory multiple myeloma (CARTITUDE-4): results from a randomized, open-label, phase 3 trial. Lancet Haematol. 2025;12(1):e45-e56. doi:10.1016/S2352-3026(24)00320-X)

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue. Version 2.2026. Available at: NCCN Guidelines for Cancer-Related Fatigue.