While treatments targeting B-cell maturation antigen (BCMA) have demonstrated promising efficacy in recent clinical trials, they are associated with characteristic toxicities that are nevertheless manageable, according to Dr. Shah. Among the immunotherapy options being investigated, chimeric antigen receptor (CAR) T-cell therapies have the most safety data to draw upon, particularly with regard to cytokine release syndrome (CRS) and neurotoxicity. Meanwhile, clinical trials of BCMA-directed antibody-drug conjugates (ADCs) and bispecific T-cell engager (BiTEs) antibody constructs have yielded data that have helped to establish the safety profiles of these emerging approaches.
Cytokine Release Syndrome and CAR T-Cell Therapy
Cytokine release syndrome (CRS) is a systemic inflammatory response commonly occurring after CAR T-cells activate and expand, Dr. Shah said in her presentation. It is associated with high levels of cytokines and inflammatory markers including C-reactive protein, ferritin, IL-6, and IL-10. CRS typically occurs 1 to 14 days after infusion, a time period during which patients should therefore be carefully monitored. While CRS is often characterized by mild, flu-like symptoms with fever, it can progress to life-threatening hypotension, hypoxia, and death. More severe CRS has been associated with high disease burden, though in clinical practice, this is not always the case, according to Dr. Shah.
Fever is typically the first sign of CRS, though constitutional symptoms such as headaches, malaise, and myalgia are often seen. The toxicities of CRS can impact the majority of organ systems (cardiovascular, neurologic, pulmonary, hepatic, renal, hematologic, gastrointestinal, and musculoskeletal).1 Thus, according to Dr. Shah, clinicians need to be alert for a wide variety of symptoms, ask many questions of patients, carefully review laboratory measurements, and intervene quickly when CRS is identified.
The grading of CRS severity has varied substantially between clinical trials and centers, making it challenging to assess the relative safety of different CAR T-cell therapies and devise strategies to adequately manage this toxicity. Recently, experts who convened in a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT) developed consensus grading recommendations not only for CRS, but also for the neurologic toxicity associated with immune effector cells (as discussed later). Key CRS parameters included in the consensus grading system included fever, which is required for a diagnosis of CRS; hypotension; and hypoxia.2 According to Dr. Shah, these objective criteria are easy to apply and may help all providers in the myeloma community assess and accurately categorize CRS severity as CAR T-cell therapies.
The incidence of CRS has varied widely across clinical trials of CAR T-cell therapies targeting BCMA in the treatment of multiple myeloma, though the aforementioned variations in CRS severity grading make it challenging to compare across studies. Results from the phase 1 study of bb2121 published in the New England Journal of Medicine, indicate that 25 of 33 patients (76%) experienced this toxicity, which was grade 1-2 in 23 patients (70%) and grade 3 in two patients (6%).3 In other clinical trials of anti-BCMA CAR T-cell therapies, overall rates of CRS have ranged from 10% to 100%;. In her presentation, Dr. Shah said that the take-home point from these varied studies is that CRS can happen in clinical practice, and that healthcare providers should be prepared to manage it in patients with myeloma.
Fortunately, CRS has proven to be manageable with supportive care, the interleukin (IL)-6 receptor blocker tocilizumab, and steroids, according to Dr. Shah. First-line treatment of CRS will depend in part on severity, eg, slow onset grade 1 CRS can be treated symptomatically, while rapid onset (within 72 hours) may warrant consideration of tocilizumab with or without dexamethasone. In general, patients with CRS that does not resolve with supportive care should be promptly treated with tocilizumab, which binds soluble and membrane‐bound IL‐6 receptors, thereby inhibiting IL-6-mediated signaling.4 However, some patients will not respond to tocilizumab, in which case dexamethasone is given, and if CRS persists, high-dose methylprednisolone may be tried. There was initially some concern that high-dose steroids would attenuate antitumor response due to inhibition of T-cell function, though multiple studies have now demonstrated responses to CAR T-cell therapy despite use of this approach.5
Neurotoxicity Related to CAR T-Cell Therapy
Neurologic toxicity, now sometimes referred to as immune effector cell associated neurotoxicity syndrome (ICANS), is also commonly seen in patients who have received CAR T-cell therapy. While the pathophysiology is unclear, typical manifestations include delirium, encephalopathy, aphasia, difficulty in concentrating, and agitation, among others.2 Notably, headaches are also common in these patients, but they may or may not be related to neurotoxicity. Aphasia may be one of the first symptoms to manifest, making it important for the healthcare provider to watch carefully for difficulty with expression or understanding of speech, and to talk to caregivers, who according to Dr. Shah are often the first to notice these issues.
Similar to evaluation of CRS, evaluation of neurotoxicity has recently evolved. Notably, the ASTCT has developed not only consensus grading for ICANS in adults, but also an updated encephalopathy assessment tool that takes into account a patient’s ability to name objects, follow commands, write, count backwards, and orient themselves to time and location.2
In clinical trials of anti-BCMA CAR T-cell therapies, the incidence of neurotoxicity and its reporting has varied according to the agent, dosing, and trial. In the phase 1 trial of bb2121, neurologic toxic effects were observed in 14 of 33 patients (42%); 13 of these were grade 1 or 2, while one reversible grade 4 neurologic toxic effect was reported.3 In a phase 1/2 multicenter study of JCARH125, neurological events were reported in 11 of 44 patients (25%); more specifically, grade 1 or 2 neurological events were seen in 18% of patients, while grade 3 or greater events occurred in 7% of patients.6 Some anti-BCMA CAR T- cell studies have reported relatively lower incidences of neurotoxicity; the variability may be explained by differences in diagnosis, interpretation, and experience of the investigators giving these therapies, Dr. Shah said.
Management of neurotoxicity related to CAR T-cell infusions includes seizure prophylaxis, which may be started as early as when the patient is undergoing lymphodepleting therapy, Dr. Shah said. However, the hallmark of management is use of dexamethasone, which usually leads to improvements within 1 to 2 days. If not, an increased dose of steroid may be warranted.
Toxicity of Anti-BCMA Bispecific Agents
Neuropathy, CRS, and infections are some of the notable adverse effects associated with AMG 420, an anti-BCMA bispecific T-cell engager (BiTE). In a first-in-human phase 1 dose escalation study of AMG 420 including 42 patients with relapsed/refractory multiple myeloma, dose-limiting toxicities included one case of grade 3 CRS and two cases of peripheral polyneuropathy.7
Both cases of peripheral polyneuropathy improved with intravenous immunoglobulin (IVIg) and corticosteroids; in one case, this adverse effect completely resolved within a month, and in the other, it returned to baseline (grade 1) in two months. According to Dr. Shah, providers should be aware of this neurotoxicity associated with AMG 420, which she said is more akin to the polyneuropathy associated with Guillain-Barré syndrome, rather than a bortezomib-like peripheral neuropathy .
Similar to what is observed with anti-BCMA CAR T-cell therapies, CRS is an adverse event associated with AMG 420. In the phase 1 study, CRS of any grade was observed in 16 patients (38%), including 13 grade 1, two grade 2, and one grade 3. AMG 420 treatment was also associated with infections, including treatment-related grade 2 or 3 infections in 13 patients (31%).7 Generally speaking, management of toxicities related to anti-BCMA BiTE therapy may consist of steroids pre- or post-treatment, tocilizumab, and close observation for infections.
Toxicity of Anti-BCMA ADCs
Antibody-drug conjugates consist of an antibody linked to toxins that are released following internalization into antibody binding cells.8 GSK2857916, now known as belantamab mafodotin, is an ADC that was recently granted Food and Drug Administration (FDA) priority review for relapsed or refractory multiple myeloma; this agent consists of an anti-BCMA antibody conjugated to monomethyl auristatin-F (MMAF), a microtubule-disrupting agent.9
Thrombocytopenia and corneal events were commonly reported in DREAMM-1, a dose expansion phase 1 study of belantamab mafodotin. Specifically, grade 3 thrombocytopenia was observed in 26% of patients, while corneal events, an adverse event known to be associated with MMAF, were seen in 69% of patients and included blurred vision, dry eye, and photophobia.10
While thrombocytopenia may be more familiar to healthcare providers in the myeloma community, the less-familiar corneal events can be clinically significant and uncomfortable for patients, according to Dr. Shah. In the DREAMM-1 study, all patients used steroid eye drops for 4 days around the time of each infusion in an effort to mitigate corneal events; in future studies, other approaches such as cooling eye masks and extending the duration of eye drop use from 4 to 7 days will be evaluated.
- Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: Recognition and management. Blood. 2016;127(26):3321-3330. doi:10.1182/blood-2016-04-703751
- Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood
- Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. New Engl J Med. 2019;380(18):1726-1737. doi:10.1056/NEJMoa1817226
- Le RQ, Li L, Yuan W, et al. FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell‐Induced Severe or Life‐Threatening Cytokine Release Syndrome. Oncologist. 2018;23(8):943-947. doi:10.1634/theoncologist.2018-0028
- Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk Manag. 2019;15:323-335. doi:10.2147/TCRM.S150524
- Mailankody S, Htut M, Lee KP, et al. JCARH125, Anti-BCMA CAR T-cell Therapy for Relapsed/Refractory Multiple Myeloma: Initial Proof of Concept Results from a Phase 1/2 Multicenter Study (EVOLVE). Blood. 2018;132(Supplement 1):957-957. doi:10.1182/blood-2018-99-113548
- Topp MS, Duell J, Zugmaier G, et al. Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: Updated results of a first-in-human (FIH) phase I dose escalation study. J Clin Oncol. 2019;37(15_suppl):8007-8007. doi:10.1200/JCO.2019.37.15_suppl.8007
- Kamada H, Tsunoda S-I. Generating functional mutant proteins to create highly bioactive anticancer biopharmaceuticals. In: Park K, ed. Biomaterials for Cancer Therapeutics. Woodhead Publishing; 2013:95-112. doi:10.1533/9780857096760.2.95
- January 21, 2020. FDA grants priority review to belantamab mafodotin for relapsed, refractory multiple myeloma. https://www.healio.com/hematology-oncology/myeloma/news/online/%7B85493cd7-5b42-486d-8b2d-d52ab83a4f86%7D/fda-grants-priority-review-to-belantamab-mafodotin-for-relapsed-refractory-multiple-myeloma. Accessed January 24, 2020.
- Trudel S, Lendvai N, Popat R, et al. Antibody–drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study. Blood Cancer J. 2019;9(4):37. doi:10.1038/s41408-019-0196-6