TABLE 2:

BCMA CAR T-Cell Toxicities, Risk Factors, and Mitigation Strategies

Toxicity	Risk Factors	Mitigation/Treatment Strategies
CRS	High tumor burden Rapidly progressive disease (inadequate bridging therapy)	Effective pre-CAR T cytoreduction/bridging to minimize tumor burden If rapidly progressing, EMD, >50% marrow, R-ISS III May use combo of novel agents either with unused drug or in new combo if available [55] For penta-refractory consider Selinexor combo or infusional chemo (KD-PACE, DCEP) [53, 54] Prior non-CAR T BCMA therapy may decrease PFS, but unclear if BCMA or GPRC5D TCE BsAb may be used safely as bridging [4] Alkylator bridging may be assoc. with lower PFS/OS [58] Avoid bendamustine prior to apheresis due to risk of manufacturing failure [57] Low grade CRS: Ide-cel: Supportive care, tocilizumab if persistent grade 1 CRS or early onset with high tumor burden Cilta-cel: Early tocilizumab +/− corticosteroids Higher grade CRS (2+):[109] Early tocilizumab +/− corticosteroids Prophylactic dex 10 mg days 0, 1, & 2 effective in preventing in CD19 CAR but not studied in BCMA [18]
ICANS	High grade CRS High tumor burden Poorly understood	Early Corticosteroids Anakinra if refractory to steroids [21, 109] Neuro consult, EEG, MRI, seizure prophylaxis if severe [110] Mitigation strategies: Prophylactic steroids used in CD19 CAR with high tumor burden but not studied in BCMA [18] Prophylactic anakinra appears effective in CD19 CAR but not studied in BCMA [19]
Non-ICANS Neurotoxicity	Cilta-cel (rare with ide-cel) Previous high grade CRS Previous ICANS High tumor burden	Effective pre-CAR T cytoreduction/bridging to minimize tumor burden [14] Baseline Neuro Imaging/consult for those at risk Early/aggressive treatment of CRS/ICANS, especially cilta-cel Avoid cilta-cel in pre-existing neurologic disorder (severe neuropathy, baseline Parkinson’s symptoms, etc)
MAS/HLH (IEC-HS)	High tumor burden Severe CRS Baseline inflammation Poorly understood	Early Recognition & timely intervention [38] Anakinra if HLH suspected, rapidly rising ferritin, or if severe CRS not responding rapidly to steroids/IL-6 therapy [111] Ruxolitinib if refractory to anakinra/steroids [112] Etoposide or Cytoxan if refractory to above
Severe, refractory, or prolonged cytopenias (ICAHT)	Pre-existing cytopenias High tumor burden High grade CRS/ICANS	Growth factor and transfusion support [27] filgrastim (long acting if persistent or refractory) thrombopoietin receptor agonists Antibimicrobial prophylaxis Marrow biopsy to rule out relapse or MDS Stem cell boost if persistent (if frozen PBSC available) [32, 33]

MAS, macrophage activation syndrome; HLH, hemophagocytic lymphohistiocytosis; IEC-HS, immune effector cell associated HLH-like syndrome; ICAHT, immune effector cell associated hematotoxicity; IL-6, interleukin-6; PBSC, peripheral blood stem cells; MDS, myelodysplastic syndrome