T cell Redirecting Bispecific Antibodies for Multiple Myeloma: Emerging Therapeutic Strategies in a Changing Treatment Landscape

Abstract

In recent years, the treatment landscape of multiple myeloma has continued to evolve with the introduction of novel immunotherapies. This progress has translated to improved overall survival for patients, but an unmet need remains in the heavily pretreated and high-risk subsets of patients. Emerging immunotherapies in the form of CAR-T cell therapies have been approved for multiple myeloma. However, CAR-T cell therapy has logistical limitations and there is a need for immunotherapies that are readily available, safe, and effective in RRMM. Currently, pending approval, there are many “off the shelf” bispecific antibodies being developed that target BCMA, GPRC5D, FcRH5 and other cell surface proteins. Preliminary efficacy data has suggested that these bispecific antibody therapies have similar response rates (~50-80%) in heavily pretreated patients. Similarly, to CAR-T cell therapy, cytokine release syndrome and immune effector cell associated neurotoxicity syndrome are adverse events of key interest and incidence range from ~40-90% and 3-20%, respectively. In this review, we highlight the various bispecific immunotherapies under development in the treatment of multiple myeloma with a focus on the data from clinical phase I and II studies.

Introduction

The treatment landscape of multiple myeloma (MM) has dramatically changed in recent years. In 2016 the approval of the first antibody-based treatment for MM, daratumumab, signaled a challenge to the traditional approach to MM therapy.[1] In this new era, drug development has shifted its focus from traditional cytotoxic therapies to finding new approaches of harnessing anti-myeloma immune responses. These efforts have resulted in novel therapies that have great promise in the treatment of MM. In 2021, the FDA approved idecabtagene vicleucel, the first chimeric antigen receptor (CAR) T-cell therapy for MM, which was more recently followed by the approval of ciltacabtagene autoleucel in March of 2022.[2,3] The emergence of bispecific antibodies (BSAbs) is closely following with multiple drugs and targets currently in development. Although, to date, no BSAb has yet been approved by the FDA for MM, we expect approvals to arrive in the near future.

Antibody-based therapies for MM, historically, started with monoclonal antibodies targeting myeloma-specific cell surface markers. In the same year, monoclonal antibodies directed against both CD38 and SLAMF7 received FDA approval, daratumumab and elotuzumab, respectively. These naked antibodies function primarily by inducing natural killer cell based antibody-dependent cell cytotoxicity (ADCC).[4] This occurs through engagement with FcγRIIIA on NK cells. Furthermore, these antibodies have the ability to induce antibody-dependent cellular phagocytosis (ADCP) by macrophages. Lastly, these antibodies may induce or activate effector cells by directly binding to them. Regardless, the primary anti-tumor activity occurs through NK cells. The second class of antibody-based molecules approved for MM was the antibody-drug conjugate (ADC), belantamab mafodotin. In this case, in contrast to naked antibodies, the ADC molecules have 3 components, the antibody that recognizes the myeloma specific target, a linker, and a payload which is typically a traditional cytotoxic chemotherapy. Belantamab mafodotin consists of an afucosylated, humanized immunoglobulin G1 monoclonal antibody against BCMA covalently linked to monomethyl auristatin F (MMAF), a microtubule inhibitor, via a protease-resistant maleimidocaproyl linker.[5] Once the drug binds MM cells, the payload is internalized and eventually causes cell death. Therefore, ADCs likely represent “targeted chemotherapy” rather than immunotherapy. This review will focus on the most recent antibody-based therapies, bispecific antibodies, which harness the immune system by physically juxtaposing myeloma cells to cytotoxic effector T cells. Figure 1 summarizes the mechanisms of action for these various antibody-based molecules.

Figure 1:

Various Therapeutic Mechanisms. A) Antibody drug conjugate (ADC) has a variable region to bind target on tumor cell. Once internalized, ADC is broken down in lysosome, releases cytotoxic payload and leads to tumor cell death. B) Bispecific Antibody (BSAb) has specificity for tumor antigen and another target (CD3 in this example which leads to release of granzymes and perforins and tumor cell death). Antibodies may be engineered to bind monovalently or bivalently to target. Also, Fc domain may be silenced or may be intact leading to ADCC. Trispecific antibodies incorporate variations of this design to target a third antigen aimed at evading resistance, improving half-life or adding a function. C) Monoclonal antibody (MAb) can recognize target on tumor cell and lead to ADCC, ADCP, CDC, and target specific modulation. D) Bispecific T-cell Engagers (BiTE) consist of a linker and two set of heavy/light variable domains target to tumor antigen and T-cell target such as CD3. When engaged, the T cell releases granzymes and perforins that lead to tumor cell death. Figure 1 Created with BioRender.com.

BSAbs take advantage of the immune system by targeting both a marker on the tumor cell, e.g. B-Cell Maturation Antigen (BCMA) and a marker on the immune cell, e.g. CD3, to direct the T cell to the myeloma cell and achieve cell death (Figure 1).[6] Through this bispecific binding, the BSAb forms an immune synapse between tumor cell and the patient’s own T cell.[7] In this synapse, perforins and granzymes are released and lead to tumor cell apoptosis and death. This effect is amplified by the BSAb ability to induce effector T cell proliferation. BSAbs vary greatly in their targets, effects and elimination half-life. Additonally, BSAbs can be categorized in various ways according to their format and composition. One major distinction between bispecific antibodies and other T cell engagers/redirectors, in general, is that the former contain an Fc region. Therapies including an Fc domain are structurally similar to IgG and will often have longer half-lives in vivo and in the case of some antibodies, trigger Fc mediated immune effector functions.[8,9] Although these effector functions can be silenced through modifications during drug development, leaving extended half-life as the major distinction. The term bi-specific T cell engagers (BiTE) encompasses a broader category of molecules that may not only include bispecific antibodies but also antibody-like molecules that lack an Fc region and consist of a single-chain variable fragment (scFv) for MM target antigen binding and another scFv for binding the a T cell, and a linker and are smaller in size.[10] This allows for deeper tissue penetration, with less non-specific immune activation but at the cost of a shorter half-life.

A significant challenge in the development of BSAbs is striking a balance between efficacy and toxicity. BSAbs that redirect T cells can result in nonspecific immune activation and associated adverse events. The common immunological adverse events observed with these agents are similar to those classically seen with chimeric antigen receptor (CAR) T-cell therapies. The two primary manifestations of immunological adverse events are cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS).[11] The pathophysiology and mechanism of CRS is not completely understood. When a T cell redirecting BSAb binds its target it leads to the activation of immune and non-immune cells.[12] This, in turn, causes an overwhelming release of cytokines including interferon-γ, IL-6 and IL-2 that can overcome homeostatic regulatory mechanisms and result in serious toxicity. CRS manifests as constitutional symptoms including fever, hypotension, hypoxia and end organ dysfunction. ICANS is a neurotoxicity commonly seen in these therapies that can occur concurrently with, following or independently of CRS. The common manifestations of ICANS include confusion, decreased attention and changes in handwriting that can progress to seizures and fatal neurotoxicity. The median time to onset and severity of CRS/ICANS varies between disease states and each agent. It is important to evaluate the immunological adverse event profile using standardized grading systems when interpreting safety of novel BSAbs. To this end, most BSAb clinical trials incorporate the American Society for Transplantation and Cellular Therapy Consensus Grading.[13]

The first BSAb approved was blinatumomab, a BiTE that targets blast cells through CD19 and engages T-cells through CD3. Blinatumomab was approved by the US FDA in 2014 for the treatment of adults with relapsed/refractory Philadelphia chromosome negative B-cell acute lymphoblastic leukemia.[14] Blinatumomab lacks a Fc domain, has a short half-life and requires administration as a continuous intravenous infusion.[15] These features are shared by early BSAbs developed for the treatment of MM. The first bispecific therapy in this space was AMG 420, also known as pacanalotamab, which targets BCMA and CD3. This therapy lacks an Fc domain, has a short half-life, and requires administration by continuous intravenous infusion.[16] These limitations led to the development of BSAbs with an Fc domain, which resulted in a larger size and extended half-life. This change has led to molecules that can be given on a once per week dosing schedule which is more convenient for patients than a continuous infusion bag. These extended half-life BSAbs have been developed for a number of targets expressed on myeloma cells. Figure 1 shows the difference between BiTEs, BSAbs, and other antibody based therapies for comparison. This paper will review BSAb therapies with a focus on targets, drugs, and clinical data in MM, summary data for efficacy can be found in Table 1 and for CRS/ICANS in Table 2.

Table 1:

Efficacy of Selected Bispecific Therapies (Abbreviations: CR, complete response; DoR, duration of response; IMiD, immunomodulatory drug; MTD, maximum tolerated dose; NA, not reported; NR, not reached; ORR, overall response rate; PI, proteosome inhibitor; Q, every; RP2D, recommended phase 2 dose; W, week)

Drug	Target	Sponsor	Phase (Total N)	Design	Dosage: MTD/RP2D (n)	Eligibility	Patient Characteristics	ORR (@RP2D)	CR	Median DoR, months	6-Month DoR
ABBV-383 (TNB-383B)[31]	BCMA	AbbVie	I (103)	Infusion Q3W; 0.025-120 mg dose range	60 mg q3W (44 ≥40mg)	Inclusion: ≥3 prior lines (PI, IMiD, anti-CD38) Exclusion: Prior BCMA therapy	Median age: 67 years High risk: NA Median # of prior lines: 5	64%	16%	NA	NA
Alnuctamab (CC-93269)[32]	BCMA	Celgene	I (19)	Step-up dosing Q1W; 0.15-10 mg dose range	≥6 mg (12)	Inclusion: ≥3 prior lines Exclusion: Prior BCMA therapy	Median age: 67 years High risk: NA Median # of prior lines: 6	83%	33%	NA	NA
Elranatamab (PF-06863135)[23]	BCMA	Pfizer	I (58)	Step-up dosing Q1W or Q2W SC; 0.08-1 mg/kg dose range	0.215-100 mg/kg (20)	Inclusion: NA Exclusion: NA	Median age: NA High risk: NA Median # of prior lines: 6	70%	30%	NR	92.3%
Linvoseltamab (REGN 5458)[29]	BCMA	Regeneron	I (68)	Infusion Q1W→Q2W; 3-400 mg dose range	96/200 mg (15)	Inclusion: prior PI, IMiD, anti-CD38) Exclusion: NA	Median age: 64 years High risk: 23.5% Median # of prior lines: 5	73.	48%	≥ 8.4	92.1% (8-month)
Pacanalotamab (AMG 420)[16]	BCMA	Amgen	I (42)	Continuous Infusion 4W on, 2W off ; 0.2 ug-700 ug/day dose range	400 mg/d (10)	Inclusion: ≥2 prior lines (PI & IMiD) Exclusion: PCL, EMD, CNS disease, allogeneic SCT	Median age: 65 years High risk: 33% Median # of prior lines: 5	70%	50%	≥ 8	NA
Pavurutamab (AMG 701)[21]	BCMA	Amgen	I (75)	Step-up Infusion Q1W; 0.14-12 mg dose range	3-12 mg (45)	Inclusion: ≥3 prior lines (PI, IMiD, anti-CD38) Exclusion: EMD, CNS, allogeneic SCT, prior BCMA	Median age: 63 years High risk: NA Median # of prior lines: 6	36%	9%	≥3.8	NA
Teclistamab (JNJ-64007957) [60]	BCMA	Janssen	II (165)	2 step-up SC doses Q1W;	1.5 mg/kg (165)	Inclusion: ≥3 prior lines (PI, IMiD, anti-CD38) Exclusion: prior BCMA	Median age: 64 years High risk: 26% Median # of 5 prior lines:	63%	39%	18.4	90%
Talquetamab (JNJ-64407564)[34]	GPRC5D	Janssen	I (95)	Step-up dosing Q1W or Q2W SC; 5-800 ug/kg dose range	405 ug/kg QW (30) 800 ug/kg Q2W (17)	Inclusion: no available therapies Exclusion: prior BCMA allowed	Median age: 62/60 years High risk: NA Median # of prior lines: NA	70% (QW) 71% (Q2W)	NR	NR	67% NR
Cevostamab (RG6160) [39]	FcRH5	Roche	I (160)	Step-up dosing Q1W or Q2W SC	90 mg QW 160 mg QW	Inclusion: no available therapies Exclusion: NA	Median age: 64 years High risk: NA Median # of prior lines: 6	37% 55%	NA	15.6	NA

Table 2:

Safety of Selected Bispecific Therapies (Abbreviations: CRS, cytokine release syndrome; ICANS, immune effector cell associated neurotoxicity syndrome; NA, not reported)

Drug	CRS		ICANS	Infections		Neutropenia	Peripheral Neuropathy
	All Grade	Grade ≥3	All Grade	All Grade	Grade ≥3	All Grade	All Grade	Grade ≥3
ABBV-383 (TNB-383B) N=103	52%	2%	NA	28%	NA	17%	NA	NA
Alnuctamab (CC-93269) N=19	90%	5%	NA	NA	26%	53% (Grade 3/4)	NA	NA
Elranatamab (PF-06863135) N=58	83%	0	NA	NA	NA	64%	NA	NA
Linvoseltamab (REGN 5458) N=68	38%	0	NA	NA	NA	16%	0	0
Pacanalotamab (AMG 420) N=42	38%	2%	NA	33%	24%	NA	5%	5%
Pavurutamab (AMG 701) N=75	61%	7%	8%	NA	17%	23%	8%	NA
Teclistamab (JNJ-64007957) N=165	72%	1%	15%	76%	45%	71%	NA	NA
Talquetamab (JNJ-64407564) N=95	73% (weekly) 78% (biweekly)	3% (weekly) 0 (biweekly)	NA	37% 13%	3% 4%	67% 44%	NA	NA
Cevostamab (RG6160) N=160	80%	1%	13%	43%	19%	18%	NA	NA

T cell redirecting bispecific antibodies in development for multiple myeloma by target

B-Cell Maturation Antigen

The protein BCMA is a member of the tumor necrosis factor subfamily and is expressed selectively on the cell surface of mature B cell lymphocytes and plasma cells.[17] Correspondingly, aberrant plasma cells have been shown to overexpress BCMA. Soluble BCMA is produced when the extracellular domain is cleaved. Moreover, BCMA overexpression and higher levels of soluble BCMA in MM has been shown to be associated with progression of disease and worse outcomes.[18] BCMA promotes myeloma cell proliferation, survival and immune microenvironment suppression through downstream signaling.[19] BCMA activation occurs through its two known ligands, B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL). APRIL is more selective for plasma cells and has a higher binding affinity for BCMA on plasma cells. BCMA and its ligands are an attractive target for drug development due to selective expression on malignant plasma cells, importance for myeloma cell survival and possible overcoming of drug resistance. As a result, several approaches have been developed targeting BCMA including antibody drug conjugates, CAR-T cells, and BSAbs.

Pacanalotamab (AMG 420) and Pavurutamab (AMG 701)

AMG420 is the first bispecific T cell engager used in the treatment of MM. This was developed as a BiTE targeting CD3 and BCMA and lacking the full structure of an antibody.[16] This scientific breakthrough was a proof of concept for T cell engaging therapies for MM and provided the framework for development of other similar therapies. The overall response rate (ORR), including all dose levels, in the phase 1 study was 31%, but at the dose level 400 mcg/kg the ORR was 70% (n=10).[20] The safety profile was also manageable with only 1 Grade 3 CRS reported. However, the administration was a continuous infusion due to the short half-life of the drug and the drug was not developed further. The pharmaceutical company refocused their efforts on AMG 701, a BSAb targeting BCMA with improved half-life allowing for weekly intravenous administration. A phase 1 trial is currently ongoing and preliminary data was presented at ASH 2020.[21] In the preliminary data, 75 patients had received AMG 701 with an ORR of 31%. Notably, Grade 3 CRS was observed in 7% (n=5).

Elranatamab (PF-06863135)

Elranatamab is a humanized BSAb that targets BCMA and engages T cells through CD3. The safety in relapsed or refractory myeloma is being evaluated in the ongoing phase 1 MagnetisMM-1 trial.[22] Patients in this trial were heavily pretreated and received a median 8 prior therapies at the time of study enrollment. In this trial, elranatamab was given subcutaneously at escalating weight based weekly doses. In the interim data reported at ASCO 2021, 30 patients had received study drug with a tolerable safety profile and no dose limiting toxicity observed. CRS and ICANS were limited to Grade 2. The most common hematological adverse events were lymphopenia, neutropenia, anemia, and thrombocytopenia. The exploratory efficacy endpoints warrant further investigation. Among patients receiving a dose of ≥ 215mcg/kg, the ORR was 75% including 30% (n=6) with a complete response (CR) or stringent complete response (sCR). An update to this was presented at ASH 2021 with a total of 58 patients receiving the drug.[23] Results were relatively consistent, as reflected in an ORR of 70% and CR/sCR of 30%. The median duration of response is not yet reported due to insufficient follow up time.

The phase 2 elranatamab monotherapy MagnetisMM-3 study is also underway with results expected to be reported in summer of 2022. Interestingly, in this trial there are two cohorts with patients who are both BCMA naive and previously exposed to BCMA targeted therapy. Patients will receive a 76 mg flat dose given weekly subcutaneously.[24] The primary endpoint is ORR and additional endpoints include duration of response and minimal residual disease (MRD) negativity. Additional studies are also underway evaluating elranatamab in combination with other anti-myeloma therapy. One such study is the MagnetisMM-5 trial evaluating it in combination with daratumumab and with daratumumab and pomalidomide. The data behind elranatamab is promising with more expected to emerge in the coming months. The subcutaneous route of administration has the potential for a more convenient schedule.

Teclistamab (JNJ-64007957)

Teclistamab is a BSAb targeted to BCMA that is currently being evaluated for the treatment of RRMM as a monotherapy and in combination with other agents. The safety and exploratory efficacy of teclistamab was reported in the phase 1/2 MajesTEC-1 trial.[25,26] The recommended phase 2 dose (RP2D) was determined to be 1500 mcg/kg given subcutaneously weekly. Recently updated data presented at ASH 2021 demonstrated an ORR of 65% in 159 patients treated at the RP2D. At the time of the update, median duration of response had not been reached. However, the 6-month duration of response was 90%. These patients had received a median of 5 prior lines of therapy. CRS was reported in 67% of patients with no Grade 3 events and all ICANS were limited to Grade 2. The most commonly observed hematological toxicities were anemia, neutropenia, and thrombocytopenia. Teclistamab is also being evaluated in combination with daratumumab with preliminary results of a phase 1b trial reported at ASH 2021.[27] At the time of presentation, 33 patients had been treated with a manageable toxicity profile. Further evaluation of this combination will be evaluated in the Phase 3 MajesTEC-3 trial which will compare teclistamab and daratumumab to daratumumab, pomalidomide, dexamethasone and daratumumab, bortezomib, dexamethasone in RRMM. The available data for teclistamab is promising in heavily pretreated patients demonstrating the possibility of durable responses. The route of administration also offers a convenient option for patients.

Linvoseltamab (REGN 5458)

Linvoseltamab is a BSAb that targets BCMA currently being evaluated in RRMM. Updated phase 1 data was recently reported at ASH 2021 and the phase two portion of the trial is currently recruiting (NCT03761108).[28,29] Similarly to other first in human BSAb trials, the patient population was heavily pretreated with a median of 5 prior lines of therapy. At the time of data reporting cutoff, 68 patients had received linvoseltamab. CRS was reported in 38.2% of patients with no Grade 3 CRS or neurotoxicity. Among patients who received a dose of at least 96 mg, the ORR was 73.3% (n=15). Thirteen patients achieved a CR/sCR. At the data cutoff median duration of response was not reached and 8-month duration of response was 92.1%. Clinical data from a related BSAb, REGN 5459, is yet to be reported.

TNB-383B

TNB-383B, a BCMA x CD3 BSAb, has modifications in its structure aimed at reducing CRS.[30] It includes an αCD3 moiety which allows lysis with minimal cytokine release and activates effector regulatory T-cells. It also has a silenced IgG4 backbone to help limit nonspecific T-cell activation. Recently updated phase 1 data was reported at ASH 2021.[31] The dosing of TNB-383B is every three weeks making it a highly practical dosing schedule. At the time of data cutoff, 103 patients had received treatment and at the RP2D, 1 patient experienced Grade 3 CRS. At doses of ≥ 40 mg every 3 weeks, the ORR was 79% (n=24).

CC-93269

CC-93269 is a BSAb with a novel design that bivalently binds BCMA and monovalently binds to CD3.[32] CC-93269 is given intravenously weekly for 3 cycles and then every 2 weeks for 3 cycles and monthly thereafter. Interim results of the phase 1 trial were reported in Blood in 2019. At the time of data cutoff, 19 patients, with a median of 6 prior therapies, had received study drug. Grade 3 or higher toxicity was reported in 78.9% of patients. The most commonly observed treatment emergent adverse effects included neutropenia, anemia, infections, and CRS. CRS was reported in 89.5% of patients with one death in the setting of CRS. Among patients who received at least 6 mg dosing, the ORR was 83.3%. The combined endpoint of CR/sCR was met in 33.3% of patients at that dose level. MRD negativity with a sensitivity of 1×10⁻⁵ was achieved in 75% of those patients. No additional safety or efficacy data has been published since that interim report.

G-Protein Coupled Receptor Family C Group 5 Member D

G-protein coupled receptor family C Group Member D (GPRC5D) is expressed on plasma cells and mature B cells as well as malignant myeloma cells but not found on normal hematopoietic cells.[33] As a result, this has the potential to serve as a target for emerging therapies and BSAbs that engage the immune system. GPRC5D is a member of the G protein-coupled receptor family but the specific physiological role is unknown.

Talquetamab is a BSAb that targets GPCRC5D and CD3 that is under investigation for the treatment of RRMM. Updated phase 1 data from the MonumenTAL-1 study was recently presented at ASH 2021 and a phase 2 trial is currently recruiting (NCT04634552).[34] The MonumenTAL-1 study lead to the identification of both a weekly and biweekly subcutaneous RP2D. At the time of data cutoff, 95 patients had been treated with talquetamab. The biweekly dosing option could provide an advantage over other BSAbs currently under investigation for RRMM. In the data presented at ASH 2021, 30 patients received the weekly RP2D (405 mcg/kg) and 23 patients had received the biweekly RP2D (800 mcg/kg). At the weekly RP2D, 73% of patients experienced CRS with one Grade 3 case. At the biweekly RP2D, CRS was reported in 78% of patients and it was all limited to Grade 2 or lower. Other commonly observed adverse effects included hematologic toxicity, skin related adverse events, infections, and dry mouth. The management of treatment emergent dermatologic and oral adverse events was described in a separate ASH abstract.[35] The etiology of these toxicities is unknown at this time but cases to date have been successfully managed with supportive care. In the 30 response evaluable patients who received the weekly RP2D, the ORR was 70%.[34] In the 17 response evaluable patients who received the biweekly RP2D, the ORR was 71%. The median duration of response was not reached at the time of data cutoff in either RP2D.

Talquetamab is being evaluated in combination with daratumumab and results from the phase 1b combination TRIMM-2 study were recently shared at ASH 2021.[36] In this trial, three dosing cohorts were used: talquetamab 400 mcg/kg weekly, 400 mcg/kg biweekly, and 800 mcg/kg biweekly; all in combination with subcutaneous daratumumab 1800 mg. At the time of data cutoff, no RP2D was determined and data was immature but the preliminary safety profile appeared consistent with the monotherapy phase 1 trial. Phase 2 studies are currently recruiting to further evaluate talquetamab monotherapy and in combination with other myeloma therapies.

Fc Receptor Homolog 5

Fc Receptor Homolog 5 (FcRH5) is a B cell lineage marker cell surface antigen of unknown function expressed exclusively on mature B-cell lineage cells including plasma cells with notable higher expression on myeloma cells.[37,38]

Cevostamab is a BSAb targeting FcRH5 and CD3. Updated phase 1 data was recently reported at ASH 2021.[39] CRS was reported in 80% of patients with 1.3% Grade 3. ICANS was also observed in 13.1% of patients. The cohort of patients receiving a double step-up dosing strategy appeared to have better safety profile than single step-up dosing. At the time of data cutoff, the ORR at the 160 mg dose level was 54% (n=44). Among responders, the median duration of response was 15.6 months. The durable responses and ORR in a heavily pretreated patient population warrants further evaluation.

CD38

CD38 is expressed universally on multiple myeloma tumor cells and is an appealing therapeutic target for the development of BSAbs in MM. It has been established as a MM target with the approval of two anti-CD38 therapeutic monoclonal antibodies, daratumumab and isatuximab. Normally, it physiologically functions as an ectoenzyme that metabolizes NAD+ and mediates nicotinamide dinucleotide (NAD+) and extracellular nucleotide homeostasis as well as intracellular calcium.[40]

GBR1342 is a BSAb targeted to CD38 and CD3 under investigation for treatment of RRMM. The phase 1 trial design and plan were presented at the 2018 ASCO meeting.[41] Safety and/or efficacy data has not yet been published. AMG 424 is a BSAb targeted to CD38 and CD3. Preclinical data was presented in 2019, however the first in human study NCT03445663 was terminated by the sponsor for non-safety reasons.[42]

Beyond Bispecific and T cell engaging antibodies

Trispecific T cell antibodies

HPN 217 is a trispecific antibody that is designed to target BCMA, CD3, and albumin. Trispecific antibodies include a third binding domain with the rationale to extend half-life, bind a costimulatory molecule, and/or evade resistance mechanisms.[43] For HPN 217, the third humanized binding domain targeting albumin allows for extension of half-life. Interim data was recently presented at ASH 2021 with an initial cohort of 21 patients with weekly dosing.[44] At the time of data cutoff the maximum tolerated dose was not reached. The median serum half-life was 74 hours. No dose limiting toxicities were observed.

CDR101 is a BCMA/CD3 BSAb with an exciting novel mechanism of action, taking advantage of PD-L1 inhibition in an attempt to evade traditional resistance mechanisms to BCMA/CD3 BSAbs.[45] Recently, at ASH 2021 preclinical data was reported for CDR101 with no clinical data yet available. In vitro, CDR101 demonstrated increased t-cell mediated target cell lysis in comparison to control BCMA/CD3 BSAbs and to independent combinations BCMA/CD3 BSAbs and a PD-L1 inhibitor. This suggests that CDR101 may selectively inhibit PD-L1 in the tumor cell microenvironment immune synapse, with the possibility of limiting classically observed systemic toxicity of immune checkpoint inhibitor therapies. First in human studies are eagerly awaited to evaluate this novel mechanism of action.

SAR 442257 is a trispecific antibody that targets CD38, CD28 and CD3.[46] The novel mechanism of SAR442257 incorporates CD28 binding on T cells, the T cell costimulatory molecule, in addition to CD3 in an attempt to further stimulate cytotoxic T cells. The first in human NCT04401020 study is currently recruiting patients.

Natural Killer Cell Engagers

Natural Killer cells (NK), along with macrophages and monocytes, play a key role in ADCC. ADCC is the process by which immune cells lyse cells that are coated with antibodies.[47] BSAbs can exploit this by selectively recognizing proteins on myeloma cells and engaging NK cells to trigger ADCC and tumor cell lysis. Drug antibodies that include an IgG Fc domain (excluding IgG4) maintain the ability to trigger ADCC. Furthermore, NK cells have various surface checkpoint receptors that can be targeted to increase NK proliferation and cytotoxicity.

R07297089 is a BSAb targeted to CD16A and BCMA. Recent phase 1 data was presented at ASH 2021.[48] In the trial R07297089 was given as weekly intravenous infusion at escalating doses. At the time of data cutoff, 21 patients had received study drug with a median of 8 lines of previous therapies. No dose-limiting toxicities (DLT) were reported in this interim analysis. However, toxicities Grade 3 or above included transaminitis and decreased lymphocyte count. Infusion related reactions occurred in 48% of patients but were limited to Grade 2. Protocol amendments were made including slower infusion, additional premedication and splitting first dose over 2 days to prevent future infusion-related reactions. Currently, only limited efficacy data is available for the dose escalation cohorts. Of the 18 response eligible patients, 10 patients had stable disease and 1 had a partial response. No DLTs have been reported and the RP2D has not been identified. We are eagerly awaiting mature data at the RP2D for this novel mechanism of action.

Similarly, AFM26 is a tetravalent BSAb targeted bivalently to BCMA and bivalently to CD16A to engage natural killer cells.[49] Natural killer cells mediate ADCC and CD16A is a key part of the process. CD16 is found on the surface of NK cells. It exerts its function by binding to the Fc domain of antibodies, triggering ADCC. Mechanistically the binding of CD16A occurs at a site that is not impacted by serum IgG.[50] In theory this is important because it prevents high levels of m-protein from blocking AFM26 engagement of CD16A. To date, only preclinical data has been published in Blood in 2018.[51] The invitro data is promising and supports the further development of this novel mechanism of action.

The Future of Bispecific Immunotherapies in the treatment of Multiple Myeloma

In this review, we have highlighted the various development programs for bispecific immunotherapies in the treatment of multiple myeloma with a focus on the data for the further developed CD3 x BCMA BSAbs. As of this writing and with the publication of MajesTEC-1 study results, it appears that teclistamab may be the first to gain FDA approval and be readily available in the clinic. In summary, teclistamab, in a highly pretreated patient population (median of 6 prior lines of therapy) was associated with an ORR of 65% and a CR rate of 40%. These initial results including the relative tolerability is very encouraging and highly favorable compared with previously approved multiple myeloma drugs for this line of therapy.[52] Moreover, even more encouraging and as discussed above, the other CD3XBCMA BSAbs have preliminarily demonstrated similar efficacy and safety (Table 1 and 2), albeit, cross trial comparison should be interpreted with much caution. In the near future, two other major issues which are intertwined will have to be studied, first, the timing or sequence of BSAbs in the overall management of MM relative to other modalities and second, the sequence of BSAbs in terms of their respective targets. This is even more important in the context of two new MM CAR T approvals. Within this framework, the key questions are should BSAbs be given in earlier lines of therapy as triplets or quadruplets?, can BSAbs be used as a means of “consolidation” and replace high dose melphalan with stem cell support (HDM-ASCT)?, or can BSAbs be used in the maintenance phase with or without lenalidomide, especially in an adaptive way to convert patients from MRD positive to negative? More importantly, the role of CAR T vs. BSAbs will have to be better defined given their very similar mechanisms of action in terms of activating anti-MM T cell responses. Thus far, albeit long term follow-up data is not mature, CAR T and BSAbs appear to have similar efficacy results while higher Grade CRS and neurotoxicity have been associated more closely with CAR T, potentially limiting its use in more frail patients. There is no doubt that CAR T immunotherapy has revolutionized the treatment paradigm for MM, however, now that products are commercially available, one of the major challenges has been production.[53] Currently, long waiting lists have been created for patients urgently in need of these therapies.[54] Other limitations for CAR T compared to BSAbs is the time needed to produce the patient-specific product, while these times are quickening, many patient still require bridging therapies until CAR T infusion, whereas BSAbs can be given off the shelf. On the other hand, CAR T’s single infusion is more practical than the repeated dosing needed for BSAbs. Both modalities suffer from the same limitation of requiring close observation, usually hospitalization during the initial doses for CRS.

BSAbs in the treatment of MM opens the second chapter for novel immunotherapies. As more immunotherapies are developed and shown to be safe and effective, a paradigm shift from standard cytotoxic chemotherapies is heralded. In fact, antibody-based immunotherapies have already entered in treatment algorithms for first line treatment of newly diagnosed MM and have been associated with significant improvement in efficacy endpoints. For example, the MAIA study for non-HDM-ASCT candidates, demonstrated a 47% improvement in PFS by combining daratumumab to the lenalidomide and dexamethasone backbone.[55] Excitingly, recent data from both the quadruplet MANHATTAN and MASTER trials have shown the additive benefit of adding daratumumab to the carfilzomib, lenalidomide, and dexamethasone arm in NDMM.[56,57] Notably, the MANHATTAN study did not incorporate early HDM-ASCT intent and demonstrated an MRD negative CR rate of 71% (10⁻⁵ sensitivity). Given the depth and quality of these responses, the old paradigm of early HDM-ASCT for all patients comes into question. This is even more an important question in the current state of the global public health crisis of the COVID-19 pan/endemic. HDM-ASCT leads to both immediate and sustained immunosuppression that significantly increases the risk of viral and other infections.[58] Moreover, the prolonged hospitalization with HDM-ASCT may place the patient at considerable risk of not only hospital associated COVID-19 infections but also other serious bacterial infections. Therefore, paradigm shifts toward more novel and less toxic immunotherapies in the upfront setting for the treatment of MM is very welcome.

In terms of the individual BSAbs, each antibody has slight variations in design but it is yet to be determined whether these slight changes lead to clinically meaningful differences. Along these lines, multiple MM targets are being deployed (i.e. BCMA, GPCRC5D, FcRH5, CD38) and we are yet to see whether the targets chosen also play a role in efficacy and more importantly on target off tumor adverse reactions. But it is attractive to hypothesize, although speculative, that targets can be sequentially used at the time of progression as a means to overcome resistance. This is especially true for the BCMA target as we currently have one antibody drug conjugate and two CAR T therapies all using this target that are FDA approved. However, in reality, the practical aspects in drug administration for the particular antibodies will be one of the most important aspects in decision making. For example, subcutaneous administration over intravenous and the time saved is likely to play an important role as it has in the administration of daratumumab. Along these lines, BSAbs that are administered on less frequent schedules (e.g. every 3 weeks instead of one) are likely to be highly favored. As discussed above, trispecific antibodies in an attempt to increase efficacy are being developed and we will have to see shortly whether this will be feasible or whether the safety profile will be significantly detrimental. In fact, given the high rates of infection and neutropenia, better mitigation strategies will have to be developed to prevent fatal outcomes from these toxicities. Moreover, recent data suggest that patients with multiple myeloma treated with BSAb especially, not only have a diminished antibody response but also fail to mount a T cell response to COVID-19 vaccination.[59] Therefore, in the real-world, at any given time, clinicians will have to gauge the benefit to risk of using BSAb, as with other therapies such as autologous transplant, in the setting of viral pandemics and infection spikes as we have observed with the COVID-19 pandemic. As all these drugs are developed, the underlying knowledge of immune system biology and the microenvironment will also be expanded and we are likely to see potential biomarkers of response/resistance which may lead to drug prediction models as more and more studies read out. For example, preliminary work has shown that expression of target antigen along with the ratio of Treg cells and other inhibitory cells in the microenvironment play a key role in both response and resistance.

Lastly, as discussed above, CRS and neurotoxicity has become a very important practical and clinical constraint for both CAR T and BSAbs. Although, most CRS for BSAbs are low grade, for the near future, the practical aspect of hospitalization for observation is not ideal. Moreover, albeit rare, life threatening CRS does occur. Therefore, as the entire class of novel immunotherapies from advanced CAR T constructs to trispecific antibodies, further CRS mitigation strategies will have to be developed. These approaches may include fine tuning antibody or vector construct designs to advancing concomitant medication approaches.

In conclusion, novel immunotherapies and in particular BSAbs are here to stay and are taking the place of more traditional cytotoxic chemotherapies. Early data for BSAbs have already demonstrated considerably favorable efficacy and tolerability and we eagerly await more mature data to assess durability of responses and comparative randomized trials in various lines of therapy.