Management of Adverse Reactions for BCMA-Directed Therapy in Relapsed Multiple Myeloma: A Focused Review

Anti-B-cell maturation antigen therapies consisting of bispecific antibodies, antibody–drug conjugates, and chimeric antigen receptor T cells have shown promising results in relapsed refractory multiple myeloma (RRMM). However, the severe side effects include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, cytopenia(s), infections, hemophagocytic lymphohistiocytosis, and organ toxicity, which could sometimes be life-threatening. This review focuses on these most common complications post-BCMA therapy. We discussed the risk factors, pathogenesis, clinical features associated with these complications, and how to prevent and treat them. We included four original studies for this focused review. All four agents (idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, belantamab mafodotin) have received FDA approval for adult RRMM patients. We went through the FDA access data packages of the approved agents to outline stepwise management of the complications for better patient outcomes.


Introduction
Multiple myeloma (MM) remains incurable despite the advances made with the discovery of many novel drugs and three-to four-drug combination regimen therapy consisting of alkylators, proteasome inhibitors (PI), immunomodulatory agents (IMiD), corticosteroids, histone deacetylase inhibitors (HDAC inhibitors), and monoclonal antibodies [1]. Treatment failure is seen mainly secondary to resistance to these therapeutic agents, with a death rate of 3.1 per 100,000 population per year, as seen in SEERS 2016-2020 [1,2].
B-cell maturation antigen (BCMA) is a member of the tumor necrosis factor (TNF) receptor superfamily, usually found on the surface of normal B-lymphocytes; however, it is overexpressed in pathogenic plasma cells [3]. BCMA has two ligands, a proliferationinducing ligand (APRIL) and a B-cell activating factor (BAFF), where APRIL has a greater affinity to bind to its receptor when compared to BAFF [4]. These ligands activate the downstream signals, such as nuclear factor kappa-B, rat sarcoma/mitogen-activated protein kinase, and phosphoinositide-3-kinase-protein kinase B/Akt, activating anti-apoptotic protein resulting in cell survival and proliferation [5][6][7]. BCMA can be targeted in three different ways: chimeric antigen receptor T (CAR-T) cell therapy, bispecific antibodies (BsAbs), and antibody-drug conjugates (ADCs).
In 2017, the efficacy of anti-BCMA CAR-T therapy was first published on relapsed/refractory multiple myeloma (RRMM) patients [8,9]. CAR-Ts, including idecabtagene vicleucel (ABECMA, March 2021) and ciltacabtagene autoleucel (Carvykti, February 2022), are genetically modified autologous T-cells received approval from Food and Drug Administration (FDA) for use in RRMM after four or more prior lines of therapy, including an ImiD, a PI, and an anti-CD38 monoclonal antibody [10,11]. Belantamab mafodotin is the first BCMA/ADC that received accelerated approval by the FDA to be used in adult RRMM; however, it was later withdrawn from the US market in November 2022 as the DREAMM-3 phase 3 trial did not meet its primary endpoint [12]. It is currently used in some circumstances as an expanded access program. On the other hand, teclistamab is the first bispecific antibody to attain accelerated approval by the FDA for adult RRMM who have received at least four prior lines of therapy including a PI, an IMiD, and an anti-CD38 monoclonal antibody [13].
To date, the BCMA-targeting agent has shown 70-100% overall responses in heavily treated RRMM [14]. However, patients can encounter life-threatening complications such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenia(s), infections, hemophagocytic lymphohistocytosis, and other systemic toxicities. In this review, we have discussed common toxicities associated with anti-BCMA therapy and management of these toxicities.

Method
We have mainly focused on four studies based on three predetermined criteria: original completed phase I/II clinical trials, BCMA agents that received FDA approval, relapsed refractory multiple myeloma, and age > 18 years [15][16][17][18]. All four agents (idecabtagene vicleucel, ciltacabtagene autoleucel, teclistamab, belantamab mafodotin) have already been approved by the FDA for use in adult RRMM. We have also reviewed these agents' FDA access data packages and highlighted their recommendations made for treating the complications [19][20][21][22].

Types of BCMA Agents
As mentioned earlier, BCMA can be targeted in three different ways:
Antibody-drug conjugates (ADCs) Chimeric antigen receptor-T cells (CAR-T) are genetically modified T cells that express chimeric antigen receptors (CAR) that could beautologous vs. allogeneic, consisting of three domains: an extracellular (usually from a single-chain variable fragment of an antibody), an intracellular, and a co-stimulatory domain [14]. These cells bind to tumor antigens in a major histocompatibility complex (MHC)-independent manner, resulting in cytotoxic T-cell mediated tumor lysis [23]. To date, the FDA has approved two autologous CAR-T cells for adult RRMM patients who received four or more prior lines of therapy, including an IMiD, a PI, and an anti-CD38 monoclonal antibody [10,11]. The approval of idecabtagene vicleucel (ide-cel) was granted after a single-arm study (KarMMa, NCT03361748) on patients with RRMM; the multicenter multicohort phase II of this study (KarMMa-2) is ongoing (n = 31), which showed an overall response rate (ORR) of 87.1% with complete response/stringent complete response (CR/sCR) in 74.2%, very good partial response (VGPR) in 3%, and partial response (PR) in 1% patients after a median follow up (mFU) of 27.5 months [15]. An open-label phase III study (KarMMa-3, NCT03651128) assessed the difference in response in RRMM patients to ide-cel versus standard therapy. These patients previously received two to four regimens, including an IMiD, PI, and daratumumab. The ORR was recorded at 71% (CR in 39%) in ide-cel cohort, and 42% (CR in 5%) in the standard therapy cohort after a mFU of 18.6 months. The median progression-free survival (mPFS) was 13.3 and 4.4 months in the ide-cel and standard-therapy group, respectively [24]. The approval of the second CAR-T therapy ciltacabtagene autoleucel (cilta-cel) for RRMM came after the CARTITUDE-1 trial (NCT03548207), a phase Ib/II study (n = 97), in which eligible patients received ≥ 3 prior line of therapy (LOT) or were double refractory to a PI and IMiD. ≥CR was achieved in 78.3% of the cases after an mFU of 33.4 months. The median duration of response (mDOR) was 33.9 months, and the mPFS was 34.9 months [16]. In CARTITUDE-2 (NCT4133636), a phase II study, which is being conducted on three different cohorts, cohort A (n = 20) has patients with progressive MM after 1-3 prior LOT (including a PI and IMiD) with no previous exposure to BCMA, cohort B (n = 19) has patients with early progressive MM with one prior LOT without any exposure to BCMA, and cohort C (n = 20) has patients with progressive MM after exposure to BCMA-targeting agent. The ORR was recorded at 95% (≥CR in 85% and ≥VGPR in 95%), 100% (≥CR in 90% and ≥VGPR in 100%), and 60% (≥CR in 30% and ≥VGPR in 55%) in cohort A, B, and C, respectively [25][26][27]. Recently, a phase 1 clinical trial (NCT03287804) got published, in which dual targeting CAR was constructed to target two myeloma antigens and BCMA. In this study (n = 11), patients received a median of 5 prior LOT, with 81.8% being double-refractory and 18.2% penta-refractory. A total of 45.5% responded, with 9% showing VGPR, 27.3% PR, and 9% a minimal response. The mPFS was five months, and the median overall survival (mOS) was 375 days [28].
Bispecific antibodies (BsAbs) are molecules that bind simultaneously to the tumor binding domain (such as BCMA) of MM cells and CD3-positive T cells, resulting in perforin and granzymes-mediated MM cell lysis [29]. Even though multiple bispecific antibodies are being investigated in different clinical trials, only teclistamab got FDA approval for use in adult RRMM patients, who have received at least four lines of therapy, including a PI, IMiD, and anti-CD38 monocloncal antibody [13]. The approval came after the MajesTEC-1 trial (NCT03145181 and NCT04557098), which evaluated 165 RRMM patients with a median age of 64. Patients had a median of five prior LOT, with 78% of the included population being triple refractory. A total of 43% of the patients achieved ≥ CR after an mFU of 22 months. The mDOR, mPFS, and mOS were 24, 12.5, and 21.9 months, respectively [17]. Moreover, another BsAb named elranatamab received FDA breakthrough therapy designation based on the result of a multicentered phase II MagnetisMM-3 study (NCT04649359) [30]. In this study, 123 patients were enrolled; 96.7% were triple-refractory and 42.3% were pentarefractory. The ORR was recorded at 61%, with CR/sCR seen in 31.7%, VGPR in 23.6%, and PR in 5.7% of patients after an mFU of 12.8 months [31].

Complications Post-BCMA Therapy and Treatment
Even though BCMA-directed therapies have shown excellent efficacy in RRMM, the side effect profile is unique and requires management expertise. In this review, we will focus on the most common side effects of BCMA therapy and discuss their treatment in detail (Table 1).

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For the symptomatic or severe cases of cytopenia(s), supportive management with blood product transfusion (packed red blood cell transfusion for Hgb < 7 and platelet transfusion if count < 10 K) is the mainstay. Usually, leuko-reduced and irradiated blood products are used for patients receiving CAR-T therapy.

•
For thrombocytopenia refractory to transfusion, romiplostim or eltrombopag could be used.

•
The use of granulocyte colony-stimulating factor (G-CSF) during periods of neutropenia is controversial. Some studies support using it to shorten periods of neutropenia decreasing the risk of infection; in contrast, others recommend against it as it increases the risk of CRS. • It is recommended to perform a bone marrow biopsy in refractory or prolonged cytopenia(s) to rule out MDS, primary malignancy, AML, or persistence of myeloma. • Autologous stem cell infusion has promising effects in refractory or prolonged cytopenic cases.

Infection
Cytopenia and infection are common complications post-BCMA therapy and are strongly co-related; however, infection can still happen without cytopenia. As per the population-based study conducted on 9253 MM patients over a period from 1988 to 2004, it was found that there was a seven-fold increased risk of any infections in MM patients compared to the general population [51]. In patients receiving BCMA therapy, the risk of infection further increases, and the factors responsible are the same as cytopenia [52]. The pathogenesis involved are immune exhaustion, decreased bone marrow reserve before receiving anti-BCMA therapy, and delay in immune recovery and neutropenia posttherapy [53]. The incidence of overall infection was recorded at 78%, with respiratory infections at 56%, COVID-19 in 27%, other viral in 10%, fungal in 5%, pneumocystis in 4%, and hepatitis B in 0.6% of patients [17]. From real-world experience, infection was seen in 31%, 28.6%, 35%, and 1.9% of patients following ide-cel, cilta-cel, teclistamab, and blenrep administration, respectively [40][41][42][43].
Prophylaxis against infection [53][54][55][56][57]: • Antiviral prophylaxis with acyclovir 400 mg or valacyclovir 500 mg two times a day started on day 0 of CAR-T/BsAb and continued until absolute CD4 > 200 cells/µL. • Anti-bacterial prophylaxis with ciprofloxacin 500 mg orally twice a day (or equivalent for quinolone-intolerant patients) initiated on day 0 of CAR-T and continued until ANC > 1000/µL. Regarding BsAbs, it is recommended to start prophylaxis at the onset of therapy, continue for the first month, and anytime ANC < 500/µL. In some centers, tixagevimab/cilgavimab is being given as a pre-exposure prophylaxis for SARS-CoV-2 to prevent symptomatic infections.

Cytokine Release Syndrome (CRS)
CRS is a supraphysiologic inflammatory response of the immune system. Although little is known about the pathophysiology of CRS in the case of bispecific antibody or CAR-T, it is considered to be due to the binding of these agents to their target resulting in the secretion of interferon-gamma (IFN-γ), tumor-necrosis-factor-alpha (TNF-α), granulocyte-monocyte colony-stimulating factor (GM-CSF), catecholamines, which activates both immune (macrophage) and non-immune (endothelial) cells [58,59]. Activated macrophages and endothelial cells produce many cytokines, such as IL-6, IL-1, nitric oxide (NO), and TNF-α, but IL-6 is pivotal in CRS [58][59][60][61]. The degree of elevation of IL-6 correlates with the severity of CRS [60]. These cytokines further activate endothelial cells, leading to capillary leakage and resistant hypotension, activate complement pathways and coagulation cascade, and inhibit myocardial function leading to cardiomyopathy [58,[62][63][64].
The risk factors associated with severe cases are high disease burden, lymphodepletion with fludarabine and cyclophosphamide conditioning regimen, high CAR-T cell doses, thrombocytopenia before treatment initiation, and bulk CD8+ T cell selection without central memory [65]. The incidence of CRS was found to be 58.1% following ide-cel, 94.8% following cilta-cel, and 72% following teclistamab administration [15][16][17]. No incidence of CRS was recorded after blenrep administration [18]. From real-life experience, CRS was seen in 94% and 53% of patients following ide-cel and teclistamab administration, respectively [40,42].
Laboratory monitoring with CBC, basic metabolic panel, renal and hepatic function tests, coagulation profile, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferritin, and cytokine levels.

Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS)
ICANS can range from mild headache, confusion, and somnolence to life-threatening situations, including seizures, cerebral edema, and comatose condition [66]. The risk factors associated with ICANS are young age, increased disease burden, severe CRS, high dose of CAR-T cells, and pre-existing neurologic disorder [75]. Similarly to CRS, the pathogenesis of ICANS involves cytokines such as IL-1, IL-2, IL-3, IL-5, IL-6, IL-10, GM-CSF, and IFN-γ; the higher peak concentration of these cytokines is associated with severity of neurotoxicity [76]. Moreover, a xenograft mouse model showed the resolution of ICANS following IL-1 blockage by anakinra but not through IL-6 blockage, demonstrating monocyte activation through both IL-1 and IL-6, causing systematic inflammation [77]. Another mechanism involved in ICANS is the disruption of the blood-brain barrier (BBB), evident by high levels of protein and leukocyte count in cerebrospinal fluid (CSF) [75]. Moreover, there were increased levels of cytokines such as IL-6, IFN-γ, TNF-α, and GM-CSF in the cerebrospinal fluid, indicating either the disruption of the BBB or increased production in CSF [75]. These cytokines are responsible for astrocyte injury, increasing astrocyte markers such as glial fibrillary acidic protein (GFAP) and calcium-binding protein B (S100B) in the CSF following CAR-T [75]. Finally, endothelial activation evident by an increase in angiotensin 2: angiotensin 1 ratio in response to inflammatory cytokines also contributes to ICANS by causing further disruption of BBB, vascular dysfunction, increased capillary permeability, and coagulation cascade activation [75]. The incidence of ICANS is recorded as 6.5% following ide-cel, 21.6% following cilta-cel, and 3% following teclistamab administration [15,17,36]. No incidence of ICANS was recorded after blenrep administration [18]. From real-world experience, ICANS was seen in 6%, 19.8%, and 6% of patients following ide-cel, cilta-cel, and teclistamab administration, respectively [40][41][42].
The onset of ICANS is typically within five days of CAR-T and 2-8 days of teclistamab administration [44,67]. CTCAE v5.0 and CRES are the scales commonly used to grade ICANS (Table 4) [44,71]. • The management of ICANS post-BCMA therapy is mentioned in Table 5.

Hemophagocytic lymphohistiocytosis/Macrophage activation Syndrome (HLH/MAS)
HLH/MAS is a life-threatening immunological disorder that could happen due to primary (familial) or secondary (malignancy, infection, autoimmune disorder) etiologies [78]. These triggers result in the hyperactivation of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, causing them to over-activate and hyper-proliferate the antigen-presenting cells such as macrophages [78]. Macrophages secrete cytokines such as IFN-γ, IL-1, IL-2, IL-6, TNF-α, which send further positive feedback to CTLs and NK cells [78,79]. This hypersecretion of cytokines is termed as a cytokine storm, which could contribute to tissue damage and systemic organ failure, leading to the development of clinical and laboratory features of HLH [80]. HLH/MAS represents a complication of CAR-T therapy among anti-BCMA therapy (carHLH), the exact pathophysiology of which is yet to be found in the literature. However, Lichtenstein et al. found pathologic T cell expansion, high IFN-γ, IL-1, IL-6, IL-8, IL-10, IL-18 levels in peripheral blood (PB) and bone marrow (BM) of 59 patients with carHLH [81]. It is imperative to differentiate HLH/MAS from sepsis, ICANS, or CRS, given the overlapping signs and symptoms [44]. To diagnose carHLH/MAS (which is different from primary or secondary HLH/MAS), patients must have ferritin > 10,000 ng/mL, with any two of the following organ toxicities: grade ≥ 3 increase in liver enzymes or serum bilirubin, grade ≥ 3 increase in serum creatinine, grade ≥ 3 pulmonary edema, presence of hemophagocytosis in the bone marrow or other organs [44]. The incidence of carHLH/MAS was found to be 1% following CAR-T administration [44].

•
Assess improvement by checking lactate dehydrogenase (LDH) levels, blood ferritin level, fibrinogen, liver enzymes, and kidney function. If there is no improvement of the above parameters in 48 h, one can either add etoposide 75-100 mg/m 2 (can be repeated every 4-7 days depending on the clinical response) or intrathecal cytarabine along with hydrocortisone for carHLH-related neurotoxicity. • Anakinra, a recombinant IL-1 receptor antagonist, is also recommended, given its short half-life and favorable side effects profile. • Ruxolitinib, a Janus kinase 1/2 inhibitor, is also being used in some small studies, as blockage of the pathway can suppress the inflammatory cytokines.

Keratopathy
Keratopathy is described as changes in the corneal epithelium with or without visual changes. It is hypothesized that blenrep initially enters the cornea through the vessels in the limbus or the tear film and then enters corneal epithelial cells through micropinocytosis [85,86]. This eventually results in apoptosis and the extrusion of corneal epithelial cells [85,86]. In the DREAMM-2 trial, keratopathy was the most common complication, occurring in 71% of the cases [18]. In this study, a change in visual acuity was seen in 21%, blurred vision in 23%, and dry eye in 15% of the cases [18]. From real-world experience, keratopathy was seen in 68.4% of patients (40% G ≥ 3) and blurred vision in 36.8% (6.3% G ≥ 3) following blenrep administration [43].
Prophylaxis/monitoring against keratopathy [22,86]: • All patients should have a baseline eye exam, which includes a visual acuity assessment and slit lamp examination. The findings are combined and graded based on keratopathy and visual acuity scale (KVA). The exam should be repeated before every use and with any changes in vision while taking blenrep.
Management of keratopathy [22,86] • To continue blenrep for grade 1 or mild superficial keratopathy (mild loss in visual acuity, one-line reduction in Snellen chart from baseline).

•
For grade 2 or moderate superficial keratopathy (2-3-line reduction from baseline not worse than 20/200), one should withhold blenrep until the patient reaches grade ≤ 1 and then resume at a similar dose. • For grade 3 or severe superficial keratopathy (>3 lines reduction from baseline not worse than 20/200), one should withhold blenrep until grade ≤ 1 and then resume at a lower dose. • For grade 4 keratopathy (corneal erosion/ulceration, visual acuity < 20/200), one can either follow the recommendation for grade 3 keratopathy or discontinue medication indefinitely.

Conclusions
MM is the second most common hematologic malignancy, which remains incurable despite advances in its treatment secondary to drug resistance and the presence of minimal residual disease. Recently, BCMA agents have shown favorable outcomes in heavily pretreated RRMM cohorts, as evidenced by multiple published clinical trials. Despite being targeted immunotherapies, these are not free from adverse effects. With the increasing age, multiple prior lines of therapy, and baseline ECOG performance status, some patients might be more susceptible to the adverse effects than others. Constant monitoring, early identifi-cation of worsening symptoms, and prompt response might mitigate the complication with favorable outcomes. However, further phase III clinical trials with longer follow-up periods are needed to establish the safety of such novel agents in this vulnerable population.