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BACKGROUND

Multiple myeloma (MM) is a neoplastic disorder affecting plasma cells. These malignant plasma cells are also antibody-producing cells. This results in a monoclonal paraprotein (M-protein) that can accumulate in the bone marrow and lead to bone marrow failure. MM is a disease of the elderly, with a median age of diagnosis of 69 years. It is anticipated that there will be over 32,000 new cases of MM in 2020, with nearly 13,000 deaths attributable to the disease.^1,2 

Patients with MM may be asymptomatic; however, many patients may experience one or more signs and/or symptoms, including bone pain, fracture, bone marrow failure, infection, hypercalcemia, and renal failure.^1,3 MM is often identified in patients who are being medically evaluated for other reasons.

MM is diagnosed when there are ≥10% clonal bone marrow plasma cells or biopsy-proven plasmacytoma (can be in bone or other extramedullary presentation) plus an MM-defining event. Patients undergo an extensive workup that includes M-protein studies and bone marrow studies to fully determine the presence of cytogenetic or molecular abnormalities. Once the work up is complete, risk assessment can be made. The majority of patients will have standard risk features (trisomies, t(11;14), t(6;14)); however, 25% will have high-risk disease (t(4;14), t(14;16), t(14;20), del(17p), gain(1q), or presence of multiple abnormalities).³ See Table 1 for detailed definitions and criteria for diagnosis of MM.^1,4,5

MM is not curable with current treatment options, including multidrug regimens or bone marrow transplantation. Still, there have been many advances over the last several years and we continue to find better ways to treat those with newly diagnosed disease. Preferred therapies are dependent on whether patients are transplant candidates or not. For induction therapy, 3-drug regimens (with 4-drug regimens in certain circumstances) are preferred over doublet therapies in both settings. The most common agents used in the treatment of MM include dexamethasone, immunomodulatory agents, proteasome inhibitors, and CD38–directed monoclonal antibodies. Minimal residual disease (MRD) status is an important prognostic indicator, with MRD-negative patients having a better prognosis.^1,3,6 Table 2 provides a summary of the response criteria for MM, based on new criteria by the International Myeloma Working Group (IMWG).^1,6

Despite best efforts, including maintenance therapy, all patients with MM will relapse at some point. Upon relapse, there are several treatment options for patients, but patients are subject to decreased response rates and shorter remission durations. Options at relapse are dependent on patient- and disease-specific factors, including response to prior therapies, duration of previous response, presence of high-risk features, and patient’s performance status or the presence of comorbidities.^3,7,8 Currently, patients will be evaluated for an autologous stem cell transplant if they have not received one in the past or if they had a prolonged response with autologous transplant. Considerations can be made for repeating initial treatment regimens for those with responses that lasted longer than 6 months.  Multidrug regimens, allogeneic stem cell transplantation, or novel targeted therapies are often necessary in patients who have relapsed on more than 1 occasion or for those who demonstrate refractory disease to 1 or more classes of drug therapy.^1,3

B-CELL MATURATION ANTIGEN

There remains an unmet need for novel therapies for RRMM, with the hope that these therapies will provide more durable responses and potentially help overcome drug resistance. One such new target is the B-cell maturation antigen (BCMA). BCMA is a member of the tumor necrosis factor receptor superfamily. It is a protein—a cell surface receptor—encoded by the TNFRSF17 gene that recognizes its ligands, B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). BCMA is involved in normal B-cell maturation and differentiation and is also necessary for the survival of bone marrow plasma cells.^9-12

Overexpression and activation of BCMA is associated with the progression of MM in preclinical studies.^9,11-13 Overexpression leads to downstream activation of nuclear factor kappa-B pathways, upregulation of antiapoptotic proteins, and expression of genes that are essential for cell growth, cell survival, adhesion, osteoclastic activation, angiogenesis, metastases, and immunosuppression. There is also evidence to suggest that BCMA overexpression correlates with chemotherapy resistance. BCMA expression may also help myeloma cells survive in the bone marrow microenvironment.^9,12

BCMA is expressed at high levels on MM plasma cells and several studies have suggested that BCMA is useful in diagnosis, prognosis, and monitoring treatment response. Soluble BCMA, or BCMA that is circulating, may serve as a biomarker.  Higher circulating BCMA values may be associated with poorer clinical outcomes or more rapid progression of disease.^11,14 Importantly, BCMA-targeted therapies have been shown to be useful in eliminating MRD or disease that is present following therapy that is not detectable using morphologic techniques. MRD negativity is associated with better clinical outcomes.^15,16 Finally, BCMA is preferentially expressed by mature B lymphocytes and it is not expressed in other organs or nonhematopoietic tissues, which makes BCMA an ideal target.⁹ This review will focus on novel therapeutics targeting BCMA.

TARGETING BCMA

Belantamab mafodotin is the first United States Food and Drug Administration (FDA)-approved drug targeting BCMA; it was approved in August 2020. However, there are several BCMA-targeting drugs in the pipeline, including other antibody-drug conjugates (ADCs), bispecific monoclonal antibodies, and chimeric antigen receptor (CAR) T-cell therapies. Some of these agents will be “off-the-shelf” therapies, and some, such as CAR T-cells, will be personalized. In this review, we examine those with the most promising clinical data to understand their role in therapy and to identify the most common adverse events associated with these agents. 

Antibody-drug conjugates

ADCs are made up of 2 components: a monoclonal antibody that is directed towards a tumor-associated antigen present on tumor cells—in this case, BCMA—and a cytotoxic moiety. The ADC will bind the antigen on the cancerous cell, be internalized by the cell, and be degraded by lysosomes to release the cytotoxic molecule to induce DNA damage and activate apoptosis.^17-19

Belantamab mafodotin. Belantamab mafodotin is a first-in-class ADC targeting BCMA. Belantamab mafodotin consists of a humanized immunoglobulin G1 monoclonal antibody attached to a microtubule inhibitor called monomethyl auristatin F (MMAF). Belantamab mafodotin works through a variety of different mechanisms, including delivery of the cytotoxic payload to BCMA-positive MM cells, enhancing antibody-dependent cellular cytotoxicity, inducing apoptosis, and inducing immunogenic cell death.^17,18

Belantamab mafodotin demonstrated single-agent activity in a heavily pretreated RRMM patient population in the DREAMM-1 trial.^17,18 Based on the favorable responses and manageable toxicities observed in DREAMM-1, the DREAMM-2 trial, a 2-arm, randomized, open-label, phase 2 study, was designed to evaluate the efficacy and safety of belantamab mafodotin in 196 RRMM patients. The following summary includes updated results from the American Society of Clinical Oncology 2020 meeting (ASCO 2020).^19,20

Patients were eligible to participate in DREAMM-2 if they were ≥18 years old, had RRMM, had good performance status, had autologous transplant or were ineligible for transplant, had ≥3 prior lines of therapy with evidence of disease progression, were refractory to an immunomodulatory agent or a proteasome inhibitor, and were refractory or intolerant to CD38-directed therapy. Patients could not have received prior BCMA-targeted therapies. Patients were randomized 1:1 to either 2.5 mg/kg or 3.4 mg/kg belantamab mafodotin intravenously (IV) every 3 weeks until disease progression. The primary endpoint of the DREAMM-2 trial was overall response rate (defined as percentage of patients with partial response [PR] or better). Secondary outcomes of interest included duration of response, time to response, progression-free survival (PFS), overall survival (OS), proportion of patients with clinical benefit, and safety. Results were updated at ASCO 2020.^19,20

Both cohorts included patients with advanced disease and high-risk cytogenetics. Overall, 31% of 97 patients in the 2.5 mg/kg group and 35% of 99 patients in the 3.4 mg/kg group achieved an objective response, with 19% and 24%, respectively, achieving a very good partial response (VGPR) or better. Median duration of response was not reached in the 2.5 mg/kg group and was 6.2 months in the 3.4 mg/kg group. Median PFS was 2.8 months in the 2.5 mg/kg group and 3.9 months in the 3.4 mg/kg group. OS at 1 year was 53%. The 2.5 mg/kg dose was chosen for future studies given its similar activity and more favorable side effect profile compared to the 3.4 mg/kg dose.^19,20

Nearly all patients in each dosing cohort had at least 1 adverse event, with more adverse events leading to dose reduction or delay in the group receiving 3.4 mg/kg. Grade 3/4 keratopathy, presenting as corneal epithelium changes found on eye examination, a known adverse event associated with MMAF-containing ADCs, occurred in 29% and 24% of patients receiving 2.5 mg/kg and 3.4 mg/kg, respectively.  Many patients with treatment delays due to keratopathy were able to reinitiate treatment. The most common symptoms experienced by patients with eye symptoms were blurred vision and dry eyes, with some patients experiencing changes in visual acuity. In an ocular substudy, topical corticosteroids did not prevent belantamab mafodotin-associated keratopathy; however, artificial tears may be helpful for patients experiencing symptoms.

Rates of grade 3/4 thrombocytopenia and anemia were higher in the group receiving 3.4 mg/kg than in the group receiving 2.5 mg/kg (32% vs. 22% and 27% vs. 21%, respectively). Most infusion-related adverse events were mild, occurring with the first infusion. Cytokine release syndrome (CRS) and neurotoxicity were not observed with belantamab mafodotin. However, there were 2 deaths attributable to the drug: 1 was a septic event in the 2.5 mg/kg cohort and the other was hemophagocytic lymphohistiocytosis in the 3.4 mg/kg cohort.^19,20 Mild to moderate renal impairment did not alter safety or efficacy of single-agent belantamab mafodotin.²¹ Preliminary data from the DREAMM-6 trial show that belantamab mafodotin may be used in combination with bortezomib and dexamethasone without additional adverse events.²²

Belantamab mafodotin-blmf (Blenrep) is indicated for RRMM patients who have received ≥4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. The drug carries several black box warnings, including changes in corneal epithelium that may result in visual changes such as severe vision loss, corneal ulcers, blurred vision, and dry eyes. Belantamab mafodotin-blmf is available through a restricted risk evaluation and mitigation strategy (REMS) program. Due to keratopathy, all patients are required to have baseline ophthalmic examinations and examinations prior to each dose.²³

Table 3 lists ongoing trials of belantamab mafodotin, as well as several other BCMA-directed ADCs.^22,24-26

Bispecific antibody constructs

Bispecific antibody constructs are designed to stimulate the immune system to target a specific antigen. They are called bispecific because they are made of 2 separate single-chain variable fragments, 1 targeting CD3 of the T-cell receptor and the other targeting BCMA on the malignant plasma cell. These 2 single-chain variable fragments are joined by a linker. Because of the bispecificity, T-cells and antigen-expressing tumor cells are brought together and result in the formation of a cytolytic synapse. Once the synapse is formed, granzymes are released from T-cells and, ultimately, the tumor cell is destroyed through the activation of apoptotic pathways. In addition, T-cells are activated and expand, resulting in increased cytokine production and increased tumor cell destruction. Lysis occurs independent of major histocompatibility complex recognition, thereby bypassing mechanisms of immune escape that would usually allow tumors to evade detection.²⁷

AMG 420. AMG 420 has been evaluated in a phase 1, dose escalation clinical trial for patients with RRMM. The primary endpoints of the study were to determine the maximum tolerated dose and dose-limiting toxicity (DLT). Additional endpoints were to characterize response, including the portion of patients with MRD negativity.¹⁶

The trial included adult patients with RRMM with progression of disease after ≥2 prior lines of therapy (including prior therapy with immunomodulatory agents and proteasome inhibitors). Escalating doses of AMG 420, from 0.2–800 mg/day, were given via continuous IV infusion for up to a maximum of 10 cycles. Each 6-week cycle consisted of 4 weeks of continuous drug delivery followed by a 2-week drug-free interval.¹⁶

A total of 42 patients were included: the median age was 65 years; one-third of patients had high-risk cytogenetics and all were heavily pretreated. The median number of prior therapies was 5 (86% prior autologous stem cell transplant, 29% prior daratumumab [21% refractory], and 10% prior elotuzumab).¹⁶

AMG 420 was studied over a variety of dosing levels and the 800 mg/day dose was associated with unacceptable toxicity (1 grade 3 CRS, 1 grade 3 peripheral polyneuropathy). DLTs were reversible and 400 mg/day was chosen as the maximum tolerated dose. In all, 16 of the 42 patients had CRS, but no occurrence was greater than grade 3. Only 1 patient received tocilizumab. Less than half (48% [n=20]) of patients experienced a serious adverse event. The most common were infection (occurring in 14 patients) and polyneuropathy (occurring in 2 patients). A single patient experienced grade 3 edema. There were no central nervous system (CNS) toxicities greater than grade 2. Patients should be monitored for abnormal liver function, which may overlap with CRS. In this study, 5 patients experienced elevated hepatic enzymes and 1 of them died.¹⁶

The overall response rate was 31%, with an objective response rate (ORR) of 70% (n=7/10) at 400 mg/day. Five of these patients experienced an MRD-negative response, 1 had a PR, and 1 had a VGPR. The median time to any response was 1 month, with many having best responses with continued administration. The median duration of response was 8.4 months (9.6 months in MRD-negative patients), with some responders having responses lasting longer than 1 year. Responses were seen across all categories, including patients with high-risk cytogenetics.¹⁶

BCMA was expressed on myeloma cells in all patients. Responders had a rapid decline in soluble BCMA levels and this may be indicative of early response.¹⁶ Given the short half-life of AMG 420, as well as considerations with administration and the resultant need for continuous infusion, AMG 701, a half-life–extended, intermittent infusion, BCMA-targeted bispecific antibody construct is in development.²⁸ See Table 4 for BCMA-targeted bispecific antibody constructs currently in development or in early-phase clinical studies for RRMM.^29-35

Chimeric antigen receptor T-cells

The final group of medications targeting BCMA are CAR T-cells: genetically modified T-cells expressing a CAR. The CAR construct consists of a single-chain variable fragment targeting a tumor-associated antigen (in this case, BCMA), the CD3 intracellular signaling domain, and 1 or more costimulatory molecules, such as 4-1BB, that allow T-cells to expand and proliferate more efficiently. CAR T-cell patients will have their own T-cells collected from the blood via leukapheresis. Using a viral vector, the T-cells are genetically modified to express the CAR and then expanded and reinfused into the patient. As this is an autologous procedure, CAR T-cells targeting BCMA will not be available as an “off-the-shelf” option. Before giving the CAR T-cell product, patients will receive chemotherapy (typically fludarabine and cyclophosphamide) to decrease the number of lymphocytes. This preconditioning chemotherapy increases the likelihood that the CAR T-cells will expand and survive for longer periods of time, ultimately increasing the ability of the T-cells to kill tumor cells.³⁶ Currently approved CAR T-cell products only target CD19 and they have demonstrated long-term efficacy in patients with relapsed/refractory hematologic diseases.

Idecabtagene vicleucel. Bb2121, also known as idecabtagene vicleucel (or ide-cel), is a CAR that is made using a lentiviral vector to transduce autologous T-cells. Each CAR has a single-chain variable fragment targeting BCMA, a 4-1BB costimulatory domain, and a CD3-zeta T-cell signaling domain. Initial results for ide-cel were evaluated in a phase 1, multicenter, dose escalation and expansion study (CRB-401) performed by Raje and colleagues. Adult patients were included if they had a diagnosis of RRMM with measurable disease (M-protein, free light chains, or bone marrow plasma cells), good performance status, and ≥3 prior lines of therapy, including disease not responsive to immunomodulatory agents or proteasome inhibitors. Patients were only considered for the dose expansion phase if they had ≥50% BCMA expression, had prior exposure to daratumumab, and were refractory to the most recent line of therapy. Patients received lymphodepletion with cyclophosphamide and fludarabine, followed by a single infusion of ide-cel. Doses for the escalation phase ranged from 50–800 x 10⁶ CAR T-cells, with 150–450 x 10⁶ CAR T-cells used in the dose expansion cohorts. The primary endpoint was safety. Additional endpoints of interest included response rates, duration of response, MRD response, PFS, OS, and several pharmacokinetic and biomarker measurements.¹⁵

A total of 33 patients received ide-cel. The median age of the cohort was 60 years. Most patients had advanced disease and had received ≥3 (median 7) lines of treatment (including autologous stem cell transplant [97%], many with prior CD38-directed therapy [82%]), and 45% of patients had high-risk cytogenetics (del(17p), t(4;14), or t14;16).¹⁵

The ORR was 85%, with 45% having a complete response (CR) or stringent complete response (sCR) (36%). Efficacy was dose dependent, with best responses (VGPR or better) occurring in patients who received ≥150 x 10⁶ CAR T-cells. Serum and tumor BCMA levels did not appear to affect response. Responses occurred early, with first PRs occurring within 1 month of therapy (including some patients with extramedullary disease). M-protein clearance occurred over longer periods of time, up to 9 months in 1 patient. All 16 responders were MRD negative: the response occurred early and preceded best response. Median PFS was 11.8 months and 40% remained progression free at 12 months.¹⁵

All patients reported at least 1 adverse effect. Many of the adverse effects, such as grade ≥3 myelosuppression (neutropenia [85%], anemia [45%], and thrombocytopenia [45%]), were associated with the lymphodepleting regimens given prior to CAR T-cell therapy. CRS occurred in 76% of patients, with most being grade 1/2 (70%). Median onset of CRS was 2 days, with a median duration of 5 days.  CRS occurred more frequently in those receiving higher doses of CAR T-cells. Seven patients received tocilizumab and 4 received glucocorticoids, which did not negatively impact T-cell expansion. Neurotoxicity was also frequent, occurring in 42% of patients, but most were grade 1/2 reactions.¹⁵

Encouraging results from the CRB-401 study resulted in the phase 2 KarMMa trial of ide-cel in RRMM, with initial results presented at ASCO 2020. Like the phase 1 trial, patients had ≥3 lines of therapy, including CD38-directed therapy. All patients were treated in the targeted dose range of 150–450 x 10⁶ cells after receiving preconditioning lymphodepleting chemotherapy; the majority received ≥300 x 10⁶ cells. Endpoints evaluated in the trial included overall response rates, duration of response, and PFS. A total of 128 patients received ide-cel. The median age was 61 years and most patients were refractory to ≥3 regimens. With a median follow-up of 11.3 months, the overall response rate was 73%, with 31% achieving CR or sCR. Median PFS was 8.6 months. All responses and reported outcomes increased with higher T-cell dose. Expansion of T-cells increased with higher doses, and CAR T-cells were detectable in 59% and 36% of patients at 6 and 12 months, respectively. Nonhematologic side effects seen in the phase 2 KarMMa trial included CRS (84% any grade) and neurotoxicity (18% any grade). The majority of both reactions were grade 1/2.³⁷ These serious adverse events with CAR T-cells are expected given our experience with current FDA-approved CAR T-cell products.

LCAR-B38M. LCAR-B38M is a dual epitope-binding CAR T-cell with a 4-1BB costimulatory domain. LEGEND-2 was a phase 1 study performed in China in a heavily pretreated RRMM population (≥3 prior therapies, 60% with prior proteasome inhibitor and immunomodulatory drug therapy). Long-term follow-up of LCAR-B38M was presented at the 2019 American Society of Hematology meeting (ASH 2019): results from the Xi’an site (n=57) were reported. Following lymphodepletion with single-agent cyclophosphamide, LCAR-B38M was infused over a range of 0.07–2.1 x 10⁶ cells in 3 split infusions. Adverse events were noted in all patients, with pyrexia occurring in 91% and CRS in 90%. CRS was mostly grade 1/2 (82%). Median time to onset of CRS was 9 days and lasted a median of 9 days. Only 1 patient experienced neurotoxicity. Overall response, defined as PR or better, occurred in 88% of patients, and 93% of responders were MRD negative. Response occurred at a median of 1.2 months and was independent of baseline BCMA expression. After a median follow-up of 25 months, PFS was 19.9 months and OS was 36.1 months (not reached among those with CR).³⁸ A phase 2 study of LCAR-B38M is currently recruiting Chinese participants with RRMM (CARTIFAN-1; NCT03758417).³⁹

JNJ-4528. JNJ-4528, an identical construct to LCAR-B38M, was evaluated for safety and efficacy in 29 RRMM patients in the United States (CARTITUDE-1). Patients included had RRMM (≥3 prior regimens, double refractory to proteasome inhibitor and immunomodulatory drugs, and received CD38-directed therapy). The median age was 60 years; 25% of patients had high-risk cytogenetics and 86% had prior autologous stem cell transplant. One-third of patients were penta-refractory. Grade ≥3 hematologic adverse events included neutropenia (93%), anemia (55%), and thrombocytopenia (69%). CRS occurred in 93% of patients, with 2 patients having grade 3 reactions. Median onset of CRS was 7 days and median duration was 4 days. Tocilizumab and corticosteroids were used in 76% and 21% of patients, respectively. Neurotoxicity occurred in 3 patients.^40,41

It is noteworthy that the ORR was 100%, with sCR occurring in 76%, VGPR in 21%, and PR in 1%. Responses occurred quickly, within a median time to CR or better of 2 months. The 6-month PFS rate was 93% and all responders evaluable at 6 months were MRD negative. Peak T-cell expansion occurred within 2 weeks of infusion and CAR T-cell persistence was not correlated with response or deepening of response.^40,41 A phase 3 trial comparing JNJ-4528 with pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd) in patients with RRMM who are lenalidomide refractory is currently recruiting patients (CARTITUDE-4; NCT04181827).⁴²  

Orvacabtagene autoleucel. Orvacabtagene autoleucel (JCARH125 or Orva-cel) is another BCMA-directed CAR T-cell with a fully human single-chain variable fragment and a 4-1BB costimulatory domain.  Orva-cel is currently being evaluated in the EVOLVE phase 1/2 clinical trial.^43,44 Updated results for higher cellular doses (300–600 x 10⁶ cells) of orva-cel were presented at ASCO 2020. All patients (N=51) received ≥3 prior lines of therapy, including a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 monoclonal antibody. Two patients had DLTs (1 grade 3 neurotoxicity at the 300 x 10⁶ cells dosing level and 1 neutropenia >28 days in the 450 x 10⁶ cells dosing cohort). The ORR was 91%, with 39% having a CR or sCR.⁴⁴ 

Table 5 compares select CAR T-cell therapies in development.^{15,37,38,40,41,44}

TOXICITIES ASSOCIATED WITH BCMA-TARGETED THERAPIES

Keratopathy (ocular toxicity)

Among the anti-BCMA agents, ocular toxicity is unique to belantamab mafodotin. Corneal events, including keratopathy (microcyst-like epithelial changes), are known complications of MMAF-containing ADCs and were documented in both the DREAMM-1 and DREAMM-2 clinical trials. Though not fully understood, it is believed that ADCs conjugated to MMAF are deposited into the basal corneal epithelial cells. In all, 27% of patients in the 2.5 mg/kg dosing cohort experienced grade ≥3 keratopathy. Keratopathy can occur with or without symptoms. When symptoms are present, they are most commonly blurred vision, decreased visual acuity, and dry eyes. Keratopathy was managed by dose modification (delays, interruptions, dose reductions, or discontinuation) and supportive care (artificial tears). Long-term effects on vision are unknown currently. Eye examinations are necessary prior to starting therapy and before administration of each dose. In an ocular sub-study of DREAMM-2, corticosteroid eye drops were not found to prevent keratopathy.^17-20 

Cytokine release syndrome

CRS is a common toxicity of cellular immunotherapy and it is triggered by the expansion of T-cells and the production of cytokines. Many different cytokines are involved in the pathophysiology of CRS, including interleukin (IL)-1, IL-2, IL-6, interferons, and other growth factors. Although there is some variability in the onset of CRS among the approved and investigational CAR T-cells, it usually occurs within the first 2 weeks following cell infusion, but it may happen anytime during the first month. Fever may be the only symptom. Patients who have advanced CRS may develop hypoxia and hypotension that requires intensive care and ventilatory/pressor support. See Table 6 for a more detailed list of potential signs/symptoms associated with CRS.^45-47

Cytokine response is dependent on a variety of factors including disease burden, patient-specific factors such as age, the type of malignancy, presence of inflammatory disease, and infection, among others. In clinical trials for BCMA-directed CAR T-cells, any-grade CRS occurred in 76%–93% of patients. Most cases of CRS were grade 1/2.^{15,37,38,40,41}

Tocilizumab, a monoclonal antibody targeting the IL-6 receptor, is an FDA-approved therapy for CRS.⁴⁹ Following tocilizumab, symptoms usually begin to resolve within hours and cytokine levels return to normal within 48 hours. The typical dose of tocilizumab is 8 mg/kg IV once, although it may be repeated up to 3 more times for a total of 4 doses. Steroids are another option in the management of progressive CRS or CRS that does not improve within a few days.^45-47 Early tocilizumab and steroid use may be associated with improved safety and does not appear to negatively impact response rates with some CAR T-cells.⁴⁸ This cannot be stated conclusively for anti-BCMA CAR T-cell therapies at this time. A better understanding of how to identify and treat CRS will result in more CAR T-cell utilization in the outpatient setting. It is important to note that, although CRS is more common with CAR T-cell therapy, it can occur with any immunotherapy that results in T-cell activation, such as AMG 420.¹⁶ Table 7 describes the grading and appropriate management of CRS.⁴⁷

Immune effector cell-associated neurotoxicity syndrome

CAR T-cell–associated neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) has a complex pathophysiology. Cytokines may passively diffuse into the CNS and higher serum levels of IL-6 and IL-15 may be associated with more significant neurotoxicity. Blood-brain barrier disruption and T-cells trafficking into the CNS may also occur. ICANS is the second most common nonhematologic toxicity associated with CAR T-cells. Neurotoxicity may be biphasic (occurring early or late) and may overlap with CRS. Delayed neurotoxicity (3–4 weeks post-CAR T-cell infusion) is usually of longer duration and more difficult to treat and not generally responsive to anti–IL-6 therapies. Low-grade ICANS may be associated with mild symptoms such as confusion, aphasia, and difficulty concentrating; however, ICANS may progress to more severe forms with seizures, increased intracranial pressure, and obtundation. The incidence of neurotoxicity in clinical trials for BCMA CAR T-cells was as high as 42%, mostly grade 1/2, and manageable with tocilizumab and corticosteroids. Neurotoxicity that is not associated with CRS is not very responsive to IL-6–directed therapy, so corticosteroids are preferred.^45-47  

CHOOSING THERAPY IN THE RRMM SETTING

Current National Comprehensive Cancer Network preferred options for RRMM are listed in Table 8.¹ Many of the BCMA-directed therapies discussed in this review will likely have similar approvals in patients who have failed multiple lines of therapy (including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD 38 antibody), including many with prior stem cell transplant. It is unlikely that there will be any randomized data among these agents for a very long time; however, some of these drugs are already being studied in combination with other drugs in the relapsed and refractory settings.

Patient selection will be important when deciding among these agents, and a variety of patient- and disease-related factors must be considered when making decisions. It will be important to factor in patient age, comorbidities, cytogenetics, and prior therapies when making decisions on which BCMA-directed therapy to use in relapsed and refractory disease.^1,3 It is also important to emphasize that the ADCs and bispecific monoclonal antibodies will be “off-the-shelf” products, meaning that they will be available as needed. CAR T-cell products have to be produced and expanded, which takes a minimum of 2 weeks. Depending on the patient situation, 2 weeks may be too long to wait.

ROLE OF THE PHARMACIST

BCMA-targeting agents are new drugs for a new target in RRMM. It is critical that pharmacists working with MM patients in any setting are aware of these drugs, understand their unique toxicities, and know how to manage these toxicities when they occur. Many of these medications, such as CAR T-cells, require preconditioning regimens that have their own toxicities that are independent of those associated with the drug therapy itself. 

Pharmacists should provide counseling to patients receiving these medications and inform them about the treatment course. Transitions of care are extremely important, as patients may pass through many levels of care after receiving these treatments, including ambulatory oncology infusion centers, the emergency room, and the intensive care unit. Pharmacists can ensure that patients understand changes to their medications and the latest treatment plan.

Pharmacists are integral members of the healthcare team and should also be involved in the education of their nursing and physician colleagues regarding the ordering and administration of these medications and appropriate supportive care. Pharmacists should be involved with order set and clinical pathway development, and pharmacists must ensure that the medications are used safely. For example, there is no single pre-conditioning regimen that is appropriate for all patients receiving CAR T-cells and it is important to appropriately consider indications, CAR T-cell products, and pre-conditioning regimens. Due to the unique toxicities seen with many of these agents, REMS programs will be required. Many of these new products may also be complex preparations requiring compounding expertise.

Finally, these medications will cost of tens of thousands, if not hundreds of thousands, of dollars for treatment. Financial clearance and formulary management will involve pharmacists practicing at many levels within health systems.

CONCLUSIONS

Although there have been many advances in the treatment of MM, it remains incurable. As such, unmet needs remain in the RRMM space. BCMA has emerged as a viable target, given its preferential expression on plasma cells. Several agents, including 1 newly approved by the FDA (belantamab mafodotin), have demonstrated efficacy with “acceptable” safety profiles.   

Currently there are 3 different classes of drugs that target BCMA: ADCs, bispecific antibody constructs, and CAR T-cells. Each of these classes of agents have unique toxicities and it is important for pharmacists to be able to identify them and communicate them to the healthcare team and their patients.

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