The Role of Bispecific Antibodies in Relapsed Refractory Multiple Myeloma: A Systematic Review

Multiple myeloma is a heterogeneous clonal malignant plasma cell disorder, which remains incurable despite the therapeutic armamentarium’s evolution. Bispecific antibodies (BsAbs) can bind simultaneously to the CD3 T-cell receptor and tumor antigen of myeloma cells, causing cell lysis. This systematic review of phase I/II/III clinical trials aimed to analyze the efficacy and safety of BsAbs in relapsed refractory multiple myeloma (RRMM). A thorough literature search was performed using PubMed, Cochrane Library, EMBASE, and major conference abstracts. A total of 18 phase I/II/III studies, including 1283 patients, met the inclusion criteria. Among the B-cell maturation antigen (BCMA)-targeting agents across 13 studies, the overall response rate (ORR) ranged between 25% and 100%, with complete response/stringent complete response (CR/sCR) between 7 and 38%, very good partial response (VGPR) between 5 and 92%, and partial response (PR) between 5 and 14%. Among the non-BCMA-targeting agents across five studies, the ORR ranged between 60 and 100%, with CR/sCR seen in 19–63%, and VGPR in 21–65%. The common adverse events were cytokine release syndrome (17–82%), anemia (5–52%), neutropenia (12–75%), and thrombocytopenia (14–42%). BsAbs have shown promising efficacy against RRMM cohorts with a good safety profile. Upcoming phase II/III trials are much awaited, along with the study of other agents in concert with BsAbs to gauge response.


Introduction
Multiple myeloma (MM) is a heterogeneous clonal malignant plasma cell disorder accounting for approximately 15% of all annually reported hematologic malignancies in the Western world [1]. With the expanding arsenal of therapies, the 5-year relative survival of MM has improved to 57.9%, per Surveillance, Epidemiology, and End Results (SEER) Program 2012-2018 data [2].
Currently, different classes of myeloma therapies exist, including steroids, alkylators, proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), selective inhibitors of nuclear export, monoclonal antibodies, and B-cell maturation antigen (BCMA)-targeted therapies; these agents are often used in combination for myeloma management [3]. However, myeloma cells may become resistant to the therapies owing to the tremendous pressure of the immunosuppressive bone marrow microenvironment (BMM) and genetic alteration within tumor cells, resulting in "relapsed and refractory" multiple myeloma (RRMM) [4].
Per the International Myeloma Working Group (IMWG), RRMM is defined as the progression of MM within 60 days of last therapy in patients who have achieved ≥ minimal response (MR) or those who are unresponsive to primary/salvage therapy [5,6]. MM patients undergo a variety of regimens, resulting in a heavily pretreated yet refractory and relapsed cohort "triple-refractory disease" defined as disease refractory to prior treatment with at least one anti-CD38 antibody, a PI, and an IMiD, and "penta-refractory disease" having prior exposure to two PIs, two IMiDs, and one anti-CD38 monoclonal antibody; the latter having overall survival of fewer than six months [7]. Chimeric antigen receptor T cells (CAR-T) are a newer addition to the treatment regimen of RRMM. These are fusion proteins that could be autologous or allogeneic depending on the source of origin [8]. The United States Food and Drug administration (FDA) has recently approved two genetically modified autologous CAR-T cells, namely idecabtagene vicleucel (March 2021) and ciltacabtagene autoleucel (February 2022) for use in RRMM after ≥4 prior lines of therapy including an IMiDs, a PI, and an anti-CD38 monoclonal antibody [9,10]. However, the incurable nature of the disease underscores the urgency of developing newer agents to treat this RRMM cohort effectively.
Bispecific antibodies (BsAbs) are artificially engineered antibodies that bind to two different antigens, whereas monoclonal antibodies bind to only one [11]. To facilitate an anti-tumor cytotoxic mechanism, one arm of BsAbs binds to CD3 molecules on tumorspecific T cells, and the other binds to an antigen on MM cells [12]. Some of the potential targets on MM cells are BCMA, G-protein-coupled receptor family C group 5 member D (GPRC5D), Fc receptor-homolog 5 (FcRH5), CD19, and CD38 [13]. BsAbs are also being developed against SLAMF7-and CD138 but are in therapeutic exploration phase [14]. This immunological synapse causes T-cell activation and degranulation, which perforate the MM cell membrane, thereby causing apoptosis by expressing perforin and granzyme B [15]. Interestingly, BsAbs activate T cells in a major histocompatibility complex 1 (MHC-1)-independent manner and do not require co-stimulation [16]. This reduces the risk of anergy in the absence of antigen-presenting cells (APCs) and cytokine signaling [17]. Moreover, it can evade tumor evasion by initiating tumor lysis even in low antigen expression levels [18].

Methods
We performed a literature search using three databases (PubMed, Cochrane Library, and EMBASE) following the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) guidelines. The MeSH terms and keywords used were 'Multiple Myeloma', 'B Cell Maturation Antigen', and 'Bispecific Antibodies' from inception to 31 October 2022. We also manually searched 64th American Society of Hematology (ASH) abstracts to look for updated results or new studies published on 15 November 2022. The search revealed 1182 articles imported to Endnote X9.3.3 citation management tool.
We used the National Institute of Health (NIH) quality assessment of systematic views and meta-analysis tool for our review and rated it as good [37]. Given the hete geneity of the included studies, we were not able to perform any statistical analysis, b rather conducted narrative synthesis.

Results
Twelve studies were phase I, one study was phase II, four studies were phase I and one was phase III. A total of 1283 patients were assessed, and the median age rang from 62 to 68 (Table 1). The BsAbs that target BCMA are teclistamab, elranatamab, p canalotamab, ABBV-383, REGN5458, pavuratamab, RO729089, and WVT078. On the oth hand, the non-BCMA BsAbs that target tumor-associated antigens (TAAs) a talquetamab, RG6234, cevostamab, and ISB-1342. The efficacy and safety of 12 differe bispecific agents are discussed in detail in Tables 2-5. Two authors (PP and ZR) independently extracted data on patient demographics, treatment response, and treatment-related adverse events (TRAE). The treatment responses were expressed in the form of the overall response rate (ORR), complete response (CR), stringent complete response (sCR), very good partial response (VGPR), partial response (PR), stable disease (SD), and progression of disease (PD). The TRAE reported were cytopenia (anemia, neutropenia, thrombocytopenia, lymphopenia), cytokine release syndrome (CRS), neurotoxicity/immune cytokine-associated neurotoxicity syndrome (ICANS), overall infection, infusion related reaction (IRR), fever, fatigue, diarrhea, and transaminitis.
We used the National Institute of Health (NIH) quality assessment of systematic reviews and meta-analysis tool for our review and rated it as good [37]. Given the heterogeneity of the included studies, we were not able to perform any statistical analysis, but rather conducted narrative synthesis.

Results
Twelve studies were phase I, one study was phase II, four studies were phase I/II, and one was phase III. A total of 1283 patients were assessed, and the median age ranged from 62 to 68 (Table 1). The BsAbs that target BCMA are teclistamab, elranatamab, pacanalotamab, ABBV-383, REGN5458, pavuratamab, RO729089, and WVT078. On the other hand, the non-BCMA BsAbs that target tumor-associated antigens (TAAs) are talquetamab, RG6234, cevostamab, and ISB-1342. The efficacy and safety of 12 different bispecific agents are discussed in detail in Tables 2-5.     Teclistamab, the first BsAb got approval of U.S. Food and Drug Administration (FDA) for use in adult RRMM patients who received at least four prior lines of therapy based on the data from the MajesTec-1 trial (NCT04557098). It targets BCMA and CD3 receptors. Touzeau et al. conducted a phase I/II trial (NCT04557098) evaluating safety and efficacy of teclistamab. A total of 38 patients were administered teclistamab subcutaneously at 1.5 mg/kg in weekly intervals. The ORR was observed in 40% (10/25) patients, with 20% (5/25) achieving >/= CR. Median time to first response was 1.2 months, and median time to best response was 2.1 months. [19]. In another phase I/II study (NCT03145181) conducted by Martinez-Lopez et al., 165 patients were administered teclistamab weekly subcutaneously at 1.5 mg/kg. The overall response rate (ORR) was 64% (105/165), with 30% (50/165) achieving CR or better [20]. A phase Ib trial (NCT04108195) assessed teclistamab in combination with daratumumab, an anti-CD38 antibody. A total of 46 patients were administered daratumumab subcutaneously at 1800 mg along with a 1.5-3 mg/kg subcutaneous injection of teclistamab either weekly or biweekly. The ORR was 78% (29/37), with 24% (9/37) achieving CR and 73% (27/37) VGPR. The median time to first response was 1 month [21]. Another phase 1b (NCT04722146) study investigated the combination of teclistamab along with daratumumab (1800 mg) and lenalidomide (25 mg), where teclistamab was given weekly at 0.72 or 1.5 mg/kg step-up dosing. The ORR was recorded in 81% (13/16) of patients at a 1.5 mg/kg dose. The median follow-up time was 4.17 months and median time to first response was 1 month [22]. In all four studies, neutropenia was the most common hematologic adverse event and CRS was the most common non-hematologic adverse event [19][20][21][22].
Elranatamab (PF-06863135) is a BCMA-CD3 BsAb. A phase I trial conducted by Rahe et al. evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of elranatamab (NCT03269136). A total of 55 patients were administered the antibody subcutaneously at doses ranging from 80 to 1000 µg/kg on a weekly or biweekly basis. The ORR was 64% (35/55), with 38% (21/55) experiencing CR, and 56% (31/55) experiencing VGPR. The probability of being event-free for the responders was 59% [23]. A phase II trial (NCT04649359) conducted by Bahlis et al. recruited 123 RRMM patients. Patients were administered 76 mg elranatamab subcutaneously for a week. The ORR was 61% (75/123). Median time to response was 1.2 months [24]. A phase III (NCT05020236) study assessed the safety of elranatamab in combination with daratumumab, where elranatamab was given as a priming regimen for the first week followed by full weekly dose from cycle 1 to 6, and then biweekly dose from cycle 7. After a median treatment duration of 6.8 months, 50% of patients experienced CRS; median time to onset was 2 days. The study did not comment on the efficacy of the agent [25].
Pavuratamab (AMG 701) is a BCMA-CD3 half-life extended BsAb, which was evaluated in a phase I trial (NCT03287908) by Harrison et al. A total of 75 patients received weekly intravenous (IV) infusions of 0.8 mg step up dose prior to the target doses ≥1.2 mg to prevent severe CRS. At the 3-12 mg dosage, there was a 36% (16/45) overall response rate. At 12 mg, there was a 29% (2/7) response rate, with 14% achieving VGPR (1/7) and PR (1/7). The median time to response was 1 month, and time to best response was 2.8 months. CRS (61%) and anemia (43%) were the most common complications encountered [26].
REGN5458, a BCMA-CD3 bispecific antibody, being assessed in a phase I/II trial (NCT03761108) conducted by Bumma et al. A total of 167 patients followed a doseescalation system. A step-up approach was utilized to minimize occurrence of CRS. The ORR was 52% (38/73) with CR achieved in 38% (27/73); greater response rate (75%) was noticed for those treated at ≥200 mg than for those treated with less than 200 mg (40.8%) [30].
ISB 1342, a non-BCMA CD3xCD38 BsAb, studied in a phase I trial to evaluate its safety (NCT03309111). Patients received ISB 1342 in 6 dose escalation groups from a 0.2/0.3 mg/kg to a 1.0/4.0 mg/kg dose intravenously, on a weekly basis. A total of 21% patients experienced anemia, and 42% experienced infusion-related reactions. No efficacies were recorded [36].

Discussion
In MM, the bone marrow microenvironment (BMM) is altered at a very early stage [38]. Furthermore, expression of surface marker BCMAis upregulated in MM, promoting tumor growth, immune evasion, and inhibiting apoptosis [39]. T-cell redirection has the propensity of eliminating MM cells, making BsAbs a next-generation therapy for this vulnerable population.
ISB 1442 is a fully human bispecific antibody with anti-CD38 and anti-CD47 arms, designed to overcome the resistance of daratumumab in RRMM patients. In vitro, it exhibited a higher killing potency in comparison to daratumumab and magrolimab [41]. Currently, a phase I/II clinical trial is underway investigating the efficacy of ISB1442 in RRMM (NCT05427812) [42]. In contrast, trispecific antibodies have garnered attention as novel immunotherapies capable of binding to three antigens simultaneously: two tumor cell antigens and one T-cell antigen, or one tumor antigen and two T-cell antigens, resulting in enhanced T-cell redirection and signal transduction, respectively [43]. Examples of trispecific antibodies include SAR442257 (CD38/CD3XCD28), HPN217 (BCMAXCD3), and CDR101 (BCMAXCD3XPD-L1). There are two phase I clinical trials studying the efficacy and safety of SAR442257 (NCT04401020) and HPN217 (NCT04184050) in RRMM, whereas data on CDR101 are still in the preclinical stage [44][45][46].
Our review has many limitations. Given the heterogeneity of the included studies, data could not be pooled to conduct a meta-analysis. Moreover, we could not compare outcomes between agents as patients received different prior lines of therapies, were either at fixed-duration-dose or dose-escalation cohorts, received monotherapy or combination therapy, had no control group, and had a variable follow-up period. Furthermore, cross comparisons of these trials should be given minimal weight, as these are mostly early phase (I/II) trials with different study population and drug escalation schemes. Herein, our review focused mainly on the relative efficacy of these agents for summary purposes and quick reference.

Conclusions
We conclude that BsAb has an excellent potential to emerge as an effective treatment for advanced RRMM; however, given aging T cells and changing repertoire throughout the disease course of myeloma, earlier introduction of BsAb during treatment before reaching the refractory stage might be of benefit. Given the selective nature of BsAb, adverse effects are also limited. The combined efficacy might result in a deeper hematological response, with early MRD negativity and less toxicity. The combination of different BsAbs together or with other drugs, such as daratumumab as an immunomodulator, are underway in ongoing trials and might be the future of treatment.