Elranatamab vs. teclistamab: battle of the BCMA bispecifics in relapsed/refractory multiple myeloma

KEYWORDS:

• Myeloma
• bispecific antibodies
• elranatamab
• teclistamab
• BCMA

1. Introduction

Despite recent advancements to the treatment armamentarium for patients with relapsed/refractory multiple myeloma (RRMM), myeloma remains an incurable malignancy. Prior to the development of B-cell maturation antigen (BCMA) targeting therapies, patients with triple-class refractory disease to an immunomodulatory drug (IMID), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody (mAb) had poor outcomes with a median overall survival (OS) between 6–12 months [1].

1.1. BCMA as a target

BCMA is a cell surface protein which is widely overexpressed on malignant plasma cells thus making it an ideal treatment target for patients with RRMM [2]. BCMA-directed therapies including antibody-drug conjugates, chimeric antigen receptor (CAR) T-cells, and bispecific antibodies (BsAbs) offer a new era of hope to patients with RRMM. Current commercially available BMCA-directed CAR T-cell therapies include idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) [3]. These CAR T therapies and the more recent approvals of CD3/BCMA-directed BsAbs elranatamab and teclistamab provide clinicians a plethora of BCMA-directed therapeutic options for patients with this once dismal prognosis [4–6].

1.2. BCMA-directed BsAbs

BCMA-directed BsAbs elranatamab and teclistamab bind both BCMA on plasma cells and CD3 on T-cells bringing the cells into proximity which activates T-cells and causes apoptosis of malignant plasma cells. But as each product was granted approval based on early phase data, uncertainty remains regarding the superiority of one product over the other. Here, we provide a balanced review of the similarities and differences between elranatamab and teclistamab as well as address practical considerations clinicians should consider when selecting the most clinically appropriate therapy for patients with RRMM.

1.3. Elranatamab

MagnetisMM-3 was a single-arm, multicenter, open-label, phase II trial evaluating the efficacy and safety of elranatamab in 123 patients with RRMM who were refractory to at least one IMID, PI, and anti-CD38 mAb, as well as refractory to their last line of therapy at the time of study enrollment [4,7]. Elranatamab was administered subcutaneously (SQ), and patients received step-up doses at therapy initiation consisting of 12 mg and 32 mg on cycle 1 days 1 and 4, respectively. Following step-up dosing, elranatamab was continued at a dose of 76 mg once weekly for six 28-day cycles followed by every other week dosing in patients who achieved a partial response or better; elranatamab was continued until disease progression or intolerable toxicity.

At a median follow-up of 15.9 months, the primary endpoint of overall response rate (ORR) was achieved in 61% of patients (95% CI 51.8–69.6) [7]. A complete response (CR) or better was achieved in 35.8% of patients. Both median progression free survival (PFS) and OS were not reached; 15-months PFS and OS rates were 50.2% and 56.3%, respectively. The probability of maintaining a response at 15 months was 70.8%. Common grade ≥ 3 adverse events included neutropenia (48.8%), infections (40.7%), anemia (37.4%), lymphopenia (25.2%), and thrombocytopenia (23.6%). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) of any-grade occurred in 57.7% and 3.4% of patients; there were no cases of grade ≥ 3 CRS or ICANS observed in MagnetisMM-3. Elranatamab was granted accelerated approval by the United States (US) Food and Drug Administration (FDA) in August 2023 for patients with RRMM after 4 or more prior lines of therapy [8].

1.4. Teclistamab

MajesTEC-1 was a single-arm, multicenter, open-label, phase I/II trial evaluating the dosing, safety, and efficacy of teclistamab in 165 patients with RRMM who had received at least 3 prior therapies, including an IMID, PI, and an anti-CD38 mAb [5,9]. Teclistamab was administered SQ, and patients received escalating step-up doses consisting of 0.06 mg/kg on day, followed by 0.3 mg/kg, and then 1.5 mg/kg during therapy initiation. Following the initial step-up dosing schedule, patients continued teclistamab 1.5 mg/kg once weekly until disease progression or intolerable toxicity.

At a median follow-up of 22 months, 63% of patients achieved the primary outcome of ORR (95% CI 55.2–70.4). A CR or better was achieved in 43% of patients [9]. Median duration of response, PFS, and OS were 24, 12.5, and 21.9 months, respectively. Common grade ≥ 3 adverse events included neutropenia (65%), infections (52%), anemia (38%), lymphopenia (33%), and thrombocytopenia (22%). Any-grade CRS and neurotoxicity occurred in 72.1% and 14.5% of patients, respectively, however, there were low rates of grade ≥ 3 events with these toxicities (n = 1 of each). Teclistamab was granted accelerated approval by the US FDA in October 2022 for patients with RRMM after 4 or more prior lines of therapy [10].

2. Discussion

The advent of BCMA-directed immunotherapy represents an important therapeutic breakthrough in the landscape RRMM treatment. Although BCMA-directed CAR-T cell therapy has promising efficacy, challenges including manufacturing capacity and access to care may represent barriers to care [11]. BsAbs in RRMM are an important and novel option, offering off-the-shelf access to BCMA-directed therapy. In contrast to CAR T-cell therapy, BsAbs can be immediately initiated, have lower rates of severe CRS and neurotoxicity, and are generally more accessible. Both elranatamab and teclistamab show similar degrees of efficacy, with ORR in the 60% range. At present, there are more similarities than differences between the two agents, sharing the same target antigen, route of administration, similar safety profiles, and similar efficacy. Slight differences exist in the dosing and treatment protocols for both drugs, as well as differences in baseline demographics in patients included in their registration trials. In lieu of a randomized controlled trial evaluating both agents in a direct comparison, it will be challenging to choose one product over another in terms of patient and provider preferences, integration into practice, and development of treatment pathways.

2.1. Treatment protocols

Elranatamab and teclistamab have similar constructs in both being humanized BsAb specific for BCMA and CD3. Elranatamab is an IgG2 BsAb, while teclistamab is an IgG4 BsAb; there is unlikely any substantial clinically relevant difference with this. Both therapies are administered subcutaneously, a route of administration that is often preferred by patients. SQ administration also lends itself well to pairing in combination with other non-intravenous antimyeloma therapies as combination therapies continue to be investigated.

One of the primary differences between both agents is the dosing and treatment schedule. Teclistamab utilizes a weight-based dose (1.5 mg/kg), while elranatamab is a flat dose (76 mg) [8,10]. Both therapies are continued indefinitely until disease progression or unacceptable toxicity. The current FDA approved dosing is that after 24 weeks of therapy, elranatamab can be transitioned to every other week dosing in patients with a PR or better, while teclistamab can transition to biweekly dosing in patients who achieve and maintain a CR or better for at least 6 months. Currently, this is an important treatment distinction between therapies, especially considering patient convenience and preference for less frequent visits to an infusion center.

2.2. Baseline characteristics

There are several differences in baseline characteristics between the study populations worth discussion (Table 1). Between 12–15% of patients had stage 3 disease, however the MajesTec-1 study utilized the International Staging System (ISS), whereas the MagnestisMM-3 study used the Revised ISS (R-ISS). The R-ISS incorporates lactate dehydrogenase (LDH) as well as genetic risk through fluorescence in-situ hybridization (FISH) testing. However, both studies included approximately 25% of patients with high-risk cytogenetics defined as del(17p), t(4;14), or t(14;16). There was also a higher proportion of patients in the MagnestisMM-3 study with extramedullary disease (EMD), however it is important to note the definition of EMD differed between the studies. MajesTEC-1 defined EMD as the presence of one or more extramedullary soft-tissue lesions whereas the MagnestisMM-3 definition included the presence of any plasmacytoma (extramedullary and/or paramedullary with a soft-tissue component). This is an important distinction as paramedullary EMD is associated with better outcomes than EMD arising solely from plasmacytomas [12]. Of note, there was a higher proportion of patients in the MagnestiMM-3 study who were triple and penta-class refractory which is associated with poorer outcomes. While it is important for clinicians to consider these differences, without a head-to-head study, it is difficult to make a definitive decision regarding supremacy of one BsAb over the other.

Table 1. Comparison of available anti-BCMA bispecific antibodies for multiple myeloma.

	Teclistamab (n = 165)	Elranatamab (n = 123)
Baseline characteristics, %
Median age, (range)	64 (33–84)	68 (36–89)
ECOG PS ≥ 2	Not reported	5.7
Stage III disease*	12.3	15.4
Median prior lines of therapy, (range)	5 (2–14)	5 (2–22)
High risk cytogenetics**	25.7	25.2
EMD	17	31.7
Triple class refractory	77.6	96.7
Penta class refractory	30.3	42.3
Prior stem cell transplant	81.8	70.7
Adverse events, %
CRS, all (grade ≥3)	72.1 (0.6)	57.7 (0)
ICANS, all (grade ≥3)	3 (0)	3.4 (0)
Infections, all (grade ≥3)	78 (52)	69.9 (40.7)
Neutropenia, all (grade ≥3)	72 (65)	48.8 (48.8)
Anemia, all (grade ≥3)	54 (38)	48.8 (37.4)
Thrombocytopenia, all (grade ≥3)	42 (22)	30.9 (23.6)
Efficacy, %
Best ORR	63	61
CR or better	43	35.8
MRD negativity rate, 10^−5***	26.7	60.5
Median PFS	12.5 months	Not reached
Median OS	21.9 months	Not reached
Median duration of response	24 months	Not reached

Key: CR, complete response; CRS, cytokine release syndrome; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EMD, extramedullary disease; ICANS, immune effector cell-associated neurotoxicity syndrome; MRD, minimal residual disease; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

*International Staging System (ISS) was used in MajesTEC-1 whereas MagnestiMM-3 used Revised International Staging System (R-ISS).

**Defined as del(17p), t(4;14), or t(14;16).

***MRD was only reported in patients achieving ≥CR in MagnetisMM-3.

2.3. Safety

Most patients receiving elranatamab or teclistamab in the two trials developed CRS, however, most events were grade 1–2 in severity. Due to the risk of CRS, step-up doses are recommended when initiating both therapies. Both drugs have recommendations for hospitalization for CRS monitoring during the step-up doses; differences exist here between the two [8,10]. Elranatamab step-up doses are to be administered on days 1 and 4, with 48 hours of hospitalization monitoring after day 1 dosing and 24 hours after day 4 doses. The first full treatment dose administered on day 8 has no recommendations for hospitalization. With teclistamab, step-up dosing is recommended to be administered on days 1 and 4 also; hospitalization for 48 hours is recommended after each step-up dose, as well as the first full treatment dose on day 7. Real-world studies of teclistamab have started incorporating shorter inpatient step-up dosing schedules and outpatient only administration and have shown these strategies are both are feasible and safe while also decreasing healthcare resource utilization [13–15]. While outpatient administration may also be feasible for elranatamab, to our knowledge, there is currently no real-world data investigating these administration techniques.

Another safety consideration with BCMA-directed BsAbs is serious infectious complications. A high rate of grade ≥ 3 infections were observed in both MagnetisMM-3 and MajesTEC-1. Differences in prophylaxis recommendations exist between labels of both drugs. Recommendations with teclistamab include consideration of herpes zoster prophylaxis, while with elranatamab recommendations are to consider prophylactic antimicrobials and antivirals per clinical practice guidelines as well as supplemental intravenous immune globulin (IVIg) as appropriate. In a real-world cohort of patients receiving commercial teclistamab, the incidence of all-grade infections was 28%, numerically lower than what was observed in MajesTEC-1, however most patients in this study received prophylactic IVIg [13]. As real-world data matures, prophylaxis strategies may evolve as clinicians gain a better understanding of the risk of infections with BCMA-directed BsAbs.

An additional consideration in comparing elranatamab and teclistamab with respective to infectious complications is the period of trial enrollment. Teclistamab enrolled between March 2020 and August 2021, during the peak of the COVID-19 pandemic, while elranatamab enrolled between February 2021 and January 2022. There were more COVID-19-related deaths in MajesTEC-1 (n = 12) and none in MagnetisMM-3. This difference in COVID-19-related outcomes should be interpreted with cautiously due to these differences with enrollment.

2.4. Real-world application

Real-world data will be important to provide further insights into effectiveness and safety of these therapies, as well as considerations for how they can be integrated into clinical practice. Real-world data suggests similar ORR and depth of response with teclistamab as compared to that observed in MajesTEC-1 [13]. There is currently a lack of real-world data with elranatamab, likely owing to the very recent approval and commercial availability of the drug. Operational considerations with these therapies should also be considered. Both agents have a Risk Evaluation and Mitigation Strategy (REMS) program due to the risk of CRS and neurotoxicity [8,10]. This requires certification and registration of providers and pharmacies or other dispensing health care settings. While both have similar institutional requirements, teclistamab shares a REMS program with talquetamab, the recently approved G protein-coupled receptor, family C, group 5, member D (GPRC5D) BsAb [16]. Talquetamab targets this novel antigen, offering an additional option to the treatment armamentarium for RRMM. To offer both BCMA-directed BsAbs and talquetamab, institutions may find it easier to manage one REMS program with teclistamab/talquetamab, rather than two with elranatamab/talquetamab. Challenges for health-systems exist with antimyeloma BsAbs with respect to the step-up dosing, as there is the potential need for hospitalization (Table 2). Experienced centers with proper infrastructure have been opting for outpatient teclistamab administration and monitoring [15,17].

Table 2. Details of treatment regimens per prescribing information.

	Teclistamab	Elranatamab
Mechanism of action	BCMA-directed CD3 T-cell engager	BCMA-directed CD3 T-cell engager
FDA approval	R/R MM after at least 4 LOT including a PI, IMID, and an anti-CD38 mAb	R/R MM after at least 4 LOT including a PI, IMID, and an anti-CD38 mAb
REMS requirement	Yes	Yes
Boxed warning	CRS, ICANS	CRS, ICANS
Recommended admission duration during schedule	For 48 hours after administration of all step-up doses	For 48 hours after administration of first step-up dose and 24 hours after second
Dosing schedule	Day 1: 0.06 mg/kg Day 4: 0.3 mg/kg Day 7: 1.5 mg/kg Weekly dosing starting one week after first treatment dose; may adjust to every other week dosing for patients who achieve and maintain CR or better for at least 6 months	Day 1: 12 mg Day 4: 32 mg Day 8: 76 mg Weekly dosing starting one week after first treatment dose until week 24, then every other week starting at week 25
Treatment duration	Until disease progression or unacceptable toxicity	Until disease progression or unacceptable toxicity
Required pre-medications	Prior to each step-up dose: corticosteroid, histamine receptor antagonist, antipyretic	Prior to each step-up dose: corticosteroid, histamine receptor antagonist, antipyretic
Renal dose adjustments	None; not studied in eGFR <30 mL/min	None; not studied in eGFR <30 mL/min
Hepatic dose adjustments	None expected in mild impairment; not studied in moderate to severe	None expected in mild impairment; not studied in moderate to severe
Infection prophylaxis	Consider herpes zoster; administer prophylactic antimicrobials according to guidelines	Prophylactic antimicrobial and anti-viral per protocol; consider IVIG

Key: BCMA, B-cell maturation antigen; CR, complete response; CRS, cytokine release syndrome; eGFR, estimated glomerular filtration rate; ICANS, immune effector cell-associated neurotoxicity syndrome; IMID, immunomodulatory drug; IVIG, intravenous immunoglobulin; LOT, lines of therapy; mAb, monoclonal antibody; PI, proteasome inhibitor; REMS, Risk Evaluation and Mitigation Strategy.

Cost differences between elranatamab and teclistamab are an important factor and should be considered based upon the institutional reimbursement model. For example, some US institutions may opt for teclistamab if they qualify for New Technology Add-On Payments (NTAP) and 340B pricing, while other institutions may opt for elranatamab if they are Prospective Payment System (PPS) exempt and utilize Pfizer’s no cost step-up dosing supply. At present, there are no pharmacoeconomic studies evaluating or comparing the cost effectiveness of elranatamab and teclistamab.

3. Where we stand

The advent of BCMA-directed BsAbs represents a significant breakthrough in the therapeutic landscape of RRMM treatment. Both agents have relatively high response rates as monotherapy in the setting of heavily pretreated MM. As there are no head-to-head comparative clinical trials, real-world data will be important in determining if there is any superiority in clinical efficacy or favorability in safety profiles between these BCMA-directed BsAbs. Current downsides of BsAbs include their continuous dosing until disease progression or toxicity, rather than a single-dose approach with BCMA-directed CAR T-cell therapy. While BCMA-directed BsAbs are currently approved to be administered as monotherapy, there are several ongoing clinical trials evaluating these agents in combination with other antimyeloma therapies. What remains to be seen is if combinations will improve response rates and survival, and how this will be balanced with safety.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

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