Elranatamab: Механизм действий, клиническая и переводческая наука.

Clinical and Translational Card for Elranatamab

Mechanism of Action ○ BCMA‐CD3 bispecific antibody.

Indication ○ Adult patients with triple‐class‐exposed relapsed/refractory multiple myeloma.

Dosage and Administration ○ The recommended subcutaneous elranatamab dosing consists of fixed step‐up doses of 12 mg on day 1 and 32 mg on day 4 followed by the full treatment dose of 76 mg once weekly (QW) from weeks 2 to 24. In responders, 76 mg QW is reduced to every 2 weeks (Q2W) following ≥ 6 cycles and to every 4 weeks after ≥ 6 Q2W cycles.

Major metabolic pathway ○ Not applicable.

Key pharmacokinetic characteristics ○ After the first subcutaneous elranatamab dose, Cmax and AUCtau increased in a dose‐proportional manner over the evaluated dose range (≈6–76 mg). The median tmax after the first dose across all dose levels was 7 (range, 3–7) days. The t1/2 of elranatamab is 22 days following 24 weeks of dosing.

Introduction

Multiple myeloma (MM) is a currently incurable plasma cell neoplasm characterized by end‐organ damage and a range of debilitating symptoms. Patients typically experience relapse and become refractory to multiple classes of standard therapies, including proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and anti‐CD38 monoclonal antibodies (mAbs), creating an unmet need for therapies with different mechanisms of action to treat these patients.

B‐cell maturation antigen (BCMA) expression is restricted to late‐stage B cells and plasma cells and is upregulated on myeloma cells, making it an ideal therapeutic target in MM [ 1 , 2 ]. Elranatamab (ELREXFIO) is a BCMA‐CD3 bispecific antibody (BsAb) indicated for the treatment of adult patients with relapsed or refractory MM (RRMM) [ 3 , 4 , 5 ]. To date, clinical trials of elranatamab in RRMM have demonstrated deep and durable responses with a manageable safety profile [ 6 , 7 , 8 ]. In addition to its clinical benefits, elranatamab has maintained or improved measures of patient‐reported quality of life [ 3 ]. This mini‐review discusses the clinical development of elranatamab.

Drug Regulatory Approval

Elranatamab received accelerated approval for patients with triple‐class‐exposed RRMM from the US Food and Drug Administration and conditional approval from the European Medicines Agency [ 3 , 5 ]. Elranatamab is currently in development for other MM settings and for use in combination with other therapies (Table 1 ).

Mechanism of Action of Elranatamab

Elranatamab is a humanized IgG2‐alanine (hIgG2Δa) bispecific antibody that engages BCMA on myeloma cells and CD3 on T cells to induce a selective cytotoxic T‐cell response (Figure 1 ) [ 3 , 4 , 5 ]. Binding of elranatamab to BCMA and CD3 is independent of native T‐cell receptor specificity or reliance on major histocompatibility complex molecules, leading to direct T‐cell activation and the secretion of perforin, granzyme B, and cytokines, which result in myeloma cell death.

Preclinical models demonstrated that elranatamab induced dose‐dependent T‐cell activation, cytokine release, and killing of myeloma cell lines in vitro, where antitumor activity was dependent on cell‐surface expression of BCMA. Primary patient tumor cells were also effectively lysed ex vivo by elranatamab in bone marrow aspirates by autologous T cells. Elranatamab also exhibited robust in vivo activity and caused tumor regression in orthotopic myeloma xenograft models (MM.1S, OPM2, and MOLP8). In nonhuman primates, elranatamab demonstrated predictable pharmacokinetics (PK) and on‐target pharmacodynamics (PD) reflecting plasma cell and B cell depletion [ 2 ].

Key MagnetisMM Clinical Trials

Elranatamab is being developed as part of the MagnetisMM clinical program, with initial key safety, efficacy, PK, and PD data from MagnetisMM‐1, ‐2, ‐3, and ‐9 (Table 1 ). Additional study details have been published elsewhere [ 9 ]. Currently, elranatamab is being evaluated in clinical trials in combination with other agents, including IMiDs, anti‐CD38 mAbs, PIs, and CELMoDs (Table 1 ). Elranatamab is also being assessed in earlier lines of therapy, including in less heavily pretreated patients with RRMM (1–3 prior lines of therapy) and in patients with newly diagnosed MM.

Pharmacokinetics and Immunogenicity Characteristics of Elranatamab

The recommended phase 2 dose (RP2D) of elranatamab (1000 μg/kg or equivalent 76 mg fixed dose) was determined on the basis of safety, efficacy, PK, and PD data. Elranatamab has a linear PK profile and demonstrates prolonged absorption as well as generally dose‐proportional increases in exposure [ 6 , 7 ].

Elranatamab PK was adequately described using a semi‐mechanistic 2‐compartment target‐binding model with linear clearance and first‐order absorption [ 3 ]. The mean subcutaneous (SC) bioavailability of elranatamab was 56.2%. The median time to reach maximum concentration ( C max ) after the first dose across dose levels for the SC route was 7 (range, 3–7) days. Following the first SC dose of elranatamab, the C max and area under the plasma concentration‐time curve from time zero to the end of the dosing interval (AUC tau ) increased in a dose‐proportional manner over the dose range. The mean (coefficient of variation) steady state volume of distribution was 7.76 L (33%), with a clearance of 0.324 L/day (100%). The geometric mean (coefficient of variation) half‐life was 22 days (64%). No clinically relevant differences in the PK of elranatamab have been observed on the basis of age, sex, race, mild or moderate renal impairment, or mild hepatic impairment [ 3 , 4 , 5 ]. Fixed dosing has been shown to provide a consistent and manageable safety profile across a broad range of body weight (36.5–159.6 kg) with no significant impact of body weight on the PK, safety, or efficacy of elranatamab [ 10 ]. These findings support the approved fixed dosing of elranatamab in patients with RRMM.

The incidence of anti‐drug antibodies (ADA) following elranatamab is low. During treatment with elranatamab at the recommended dose, ADAs were detected in 9.5% (16/168) of study patients [ 4 ]. Population PK and exposure‐response analyses indicated no evidence of ADA impacting the safety, efficacy, PK, or PD of elranatamab.

Pharmacodynamic Characteristics

PD markers such as cytokines and serum levels of BCMA, which can be cleaved from plasma cells via γ‐secretase, resulting in the shed/soluble form (sBCMA), have been analyzed. As expected with the mechanism of action of elranatamab [ 2 , 3 , 4 , 5 ], a transient elevation in circulating cytokines, including those produced by activated T cells, has been observed after elranatamab administration [ 6 , 7 ]. The highest elevation is observed during step‐up dosing within 72 h after the first elranatamab dose (12 mg on day 1) and levels return to baseline prior to administration of the first full dose (76 mg on day 8) [ 3 , 4 , 5 ]. The transient cytokine elevations result in minimal risk of cytochrome P450 inhibition. A pooled analysis of data from the MagnetisMM‐1, ‐2, ‐3, and ‐9 studies was used to determine the optimal elranatamab priming dose regimen to mitigate cytokine release syndrome (CRS) [ 9 ].

The MagnetisMM studies previously showed that sBCMA is a potential biomarker of myeloma disease stage and burden [ 3 , 11 ]. Additionally, and regardless of prior BCMA‐directed therapy, sBCMA levels demonstrated a significant, inverse association with depth of response and objective response rate (ORR), consistent with data on other BCMA‐targeting agents [ 3 , 12 , 13 ]. Results from MagnetisMM‐3 demonstrated that among the patients who responded, 92.5% (86/93) experienced ≥ 50% reduction from their baseline free sBCMA level by cycle 2 day 1 compared with 17.9% (12/67) of non‐responding patients [ 11 ]. Lower baseline sBCMA was also associated with longer PFS and DOR and higher baseline sBCMA correlated with poor prognostic factors such as R‐ISS disease stage of 3 and penta‐drug refractory status. In addition, free elranatamab exposure was lower in patients with elevated levels of sBCMA at baseline. Therefore, the poorer outcomes in patients with high baseline sBCMA might represent the contribution of multiple factors (i.e., poor prognostic features as well as lower drug exposure) [ 14 ].

Dose Rationale for Elranatamab

The starting dose for the first‐in‐human study was determined on the basis of the minimum anticipated biological effect level. An intravenous (IV) dose of 0.1 μg/kg was projected to result in an approximate C max of 1.1 ng/mL and was selected as the starting dose for MagnetisMM‐1, administered as a 2‐h once‐weekly (QW) IV infusion. During dose escalation (IV [0.1–50 μg/kg] or SC [80–1000 μg/kg]), no dose‐limiting toxicities occurred and the MTD was not reached [ 6 ]. Despite achieving similar or higher exposure levels, SC dosing resulted in slower absorption and lower inter‐individual variability of C max after the first dose at the highest IV (50 μg/kg) and SC (1000 μg/kg) dose levels. The slower absorption rate with the SC route enabled more gradual immune priming and was associated with a lower rate of grade ≥ 2 CRS compared with IV dosing [ 3 , 9 ]. The SC route was therefore selected for subsequent studies.

The ORRs over the efficacious dose range in MagnetisMM‐1 (i.e., ≥ 215 μg/kg) were 50% (2/4) at 215 μg/kg, 75% (3/4) at 360 μg/kg, 67% (4/6) at 600 μg/kg, and 83% (5/6) at 1000 μg/kg; no responses were observed with lower SC doses (80 or 130 μg/kg) or any of the IV dose levels (all ≤ 50 μg/kg) [ 6 ]. The RP2D (1000 μg/kg or equivalent 76 mg fixed dose) achieved the highest free elranatamab exposure and resulted in a greater probability of achieving an objective response compared with lower doses. A pooled analysis of MagnetisMM‐1, ‐2, ‐3, and ‐9 showed that patients with higher elranatamab exposure were more likely to achieve an objective response, including complete responses [ 3 , 14 ]. The exposure response (ER)‐efficacy analysis for progression‐free survival (PFS) indicated an association between higher elranatamab exposure (time‐varying C avg ) and longer PFS. This observation was driven by rapid response or progression events within the first 2 or 3 cycles, further supporting initiation of elranatamab at the highest tested dose of 76 mg QW to maximize the probability of overall response and avoid early progression events. Upon achieving an objective response, reducing elranatamab dosing from QW to once every 2 weeks (Q2W) (starting in cycle 7) and further to every 4 weeks (Q4W) after ≥ 6 Q2W cycles is expected to maintain and/or further deepen the responses in later treatment cycles. This is supported by the ER‐efficacy analysis, which showed a flat relationship between elranatamab exposure and duration of response [ 14 ]. Overall, the exposure‐response efficacy analyses support the initial 76 mg QW dosing regimen for the first 24 weeks, followed by a gradual decrease in dosing frequency in later cycles.

The exposure‐safety analysis from the pooled MagnetisMM‐1, ‐2, ‐3, and ‐9 studies showed a flat relationship between elranatamab exposure and certain adverse events. The probability of experiencing grade ≥ 3 neutropenia, grade ≥ 3 anemia, grade ≥ 3 thrombocytopenia, grade ≥ 3 infections, grade ≥ 2 peripheral neuropathy, any‐grade QTcF prolongation, and adverse events leading to interruptions and discontinuations was similar, with the 76 mg QW dose compared with lower doses within the efficacious dose range (i.e., 215–1000 μg/kg, equivalent to 16–76 mg). Furthermore, the flat relationship supports the management of toxicities via dose interruptions rather than dose reductions. Given the positive ER‐efficacy described above, reducing the dose would result in a lower probability of clinical benefit, without impacting the risk of developing these AEs. Collectively, this suggests that starting with the 76‐mg dose would provide an optimal benefit/risk balance given the higher likelihood of achieving a response without worsening the safety profile [ 3 , 15 ].

Quantitative systems pharmacology (QSP) modeling provides a valuable tool for understanding the interplay between BsAbs and disease‐specific dynamics. The QSP model for elranatamab captures its mechanism of action and pertinent disease dynamics, and was calibrated to data from the MagnetisMM‐1 and ‐3 trials [ 16 ]. Virtual population simulations were used to inform dose–response relationships and evaluate the effect of baseline sBCMA levels across a range of clinically relevant regimens. Among the doses explored in the QSP model, an initial dose of 76 mg QW provided the maximal benefit in the overall patient population, including those with high baseline sBCMA (top 30th percentile which corresponds to 100 ng/mL on the basis of an ELISA‐based assay). Additionally, the simulations showed that efficacy would be maintained despite a reduction in dosing frequency (e.g., from QW to Q2W and Q2W to Q4W). The observations from the QSP model simulations supported the starting dose of 76 mg QW and guided dose selection in the ongoing MagnetisMM clinical studies in patients with RRMM. Importantly, the QSP modeling framework provides flexibility for further refinement as additional data become available.

CRS is associated with the mechanism of action of T‐cell activation and is one of the most common adverse events associated with BsAbs. Exposure‐safety analyses showed that a higher early elranatamab C max was associated with a greater probability of any grade CRS [ 3 ]. Data from MagnetisMM‐1, ‐2, ‐3, and ‐9 were analyzed to determine the optimal priming dose regimen to mitigate CRS [ 9 , 17 ]. Across trials, elranatamab priming regimens included a 1 step‐up dose priming regimen of 44 mg with (MagnetisMM‐1 part 2A, ‐2, ‐3) or without premedication (MagnetisMM‐1 part 1.1), a 2 step‐up dose priming regimen of 12 mg on day 1 and 32 mg on day 4 with premedication (MagnetisMM‐3), and a 2 step‐up dose priming regimen of 4 mg on day 1 and 20 mg on day 4 with premedication (MagnetisMM‐9) [ 9 ]. Premedication regimens (including paracetamol/acetaminophen, diphenhydramine, and corticosteroids) can reduce the immune response associated with initial BsAb dosing and further reduce the risk of CRS. Results from a two‐state Markov model that described the incidence and course of CRS over time showed that premedication with corticosteroids reduced the overall incidence and expedited the resolution of any‐grade CRS [ 17 ]. Data from the 4 clinical trials demonstrated that premedication with corticosteroids predominantly reduced the risk for grade 1 CRS events, highlighting the need for an additional strategy, such as a 2‐step‐up dose priming regimen, to reduce the risk of grade ≥ 2 CRS. Exposure‐response modeling predicted that initial doses of 12 or 4 mg would result in lower CRS rates versus 44 mg [ 9 ]. With the 12/32 priming regimen, CRS events were mainly low‐grade (43.7% grade 1, 13.7% grade 2, 0.5% grade 3) and primarily occurred with the first 3 doses (98.8%), with most occurring during the step‐up doses (90.6%). CRS recurrence (i.e., ≥ 1 CRS event) occurred in 12.6% of patients. Collectively, on the basis of these data, the recommended step‐up dosing consists of fixed SC elranatamab doses of 12 and 32 mg on days 1 and 4 followed by 76 mg on day 8 (with premedication); this resulted in a lower CRS rate, including a lower rate of grade ≥ 2 CRS compared with the 1 step‐up priming regimen and in fewer CRS events with later doses and lower CRS recurrence compared with the 4/20 regimen.

In MagnetisMM‐3, in patients who had CRS, 22.7% were treated with tocilizumab and 8.4% were treated with corticosteroids [ 8 ]. An analysis of these patients showed that tocilizumab use after the first step‐up dose (12 mg on day 1) was predictive of a decreased CRS risk after the second step‐up dose (32 mg on day 4) (Figure 2 ) [ 18 ]. When used as premedication, tocilizumab reduced the incidence of CRS without impacting short‐term efficacy in patients in the MajesTEC‐1 trial [ 19 ]. Collectively, these data support the use of tocilizumab, or potentially other IL‐6 inhibitors, as an approach for managing BsAb‐induced CRS and support the possibility of using these treatments prophylactically.

Summary of Clinical Efficacy and Safety of Elranatamab

In the phase 2 pivotal MagnetisMM‐3 trial, patients with no prior BCMA‐directed therapy (Cohort A) received the RP2D of SC elranatamab 76 mg QW on a 28‐day cycle with a 2‐step‐up priming dose regimen of 12 mg on day 1 and 32 mg on day 4 in the first week. After ≥ 6 cycles, patients who achieved partial response (PR) or better that persisted ≥ 2 months were to transition to Q2W dosing and then to Q4W after ≥ 6 cycles of Q2W dosing. Patients had received a median of 5 (range, 2–22) prior lines of therapy, and 96.7% were triple‐class refractory [ 8 ]. After a median follow‐up of 33.9 (95% CI, 33.4–34.6) months, by reverse Kaplan–Meier plot, the ORR was 61.0%, with 37.4% of patients achieving complete response (CR) or stringent complete response (sCR), 18.7% very good PR, and 4.9% PR as best response [ 20 ]. Among evaluable patients (i.e., those who achieved confirmed CR/sCR and had ≥ 1 post‐baseline MRD assessment, n = 31), the MRD negativity (10 −5 ) rate was 90.3%. Median duration of response (DOR) was not reached, and the probability of maintaining a response at 30 months was 61.0% (95% CI, 47.8–71.8). Median PFS was 17.2 (95% CI, 9.8–not evaluable [NE]) months, and median overall survival (OS) was 24.6 (95% CI, 13.4–NE) months [ 20 ]. Data from MagnetisMM‐3 have also demonstrated that elranatamab is efficacious in patients with poor prognostic features [ 3 ].

In those with prior BCMA exposure, a pooled analysis of the MagnetisMM‐1, ‐2, ‐3 (Cohort B), and ‐9 trials ( n = 87) showed that elranatamab was efficacious and well tolerated [ 21 ]. After a median follow‐up of 11.3 (range, 0.3–32.3) months, the ORR in patients with prior BCMA‐directed therapy (antibody drug conjugate [ADC] or chimeric antigen receptor [CAR]–T) was 46.0%. In responders, the median DOR was 17.1 (95% CI 9.8–NE) months. The median PFS was 5.5 (95% CI 2.2–10.0) months, and the median OS was 12.1 (95% CI 7.5–NE) months. In the prior ADC and CAR‐T subgroups, ORRs were 42.4% and 52.8%, respectively; median DOR was 13.6 (95% CI, 6.8–NE) months and not yet reached (95% CI, 9.8 months–NE), respectively. Median PFS and OS were 3.9 (95% CI, 1.9–6.6) and 12.1 (95% CI, 6.4–NE) months, respectively, in patients with prior ADC and 10.0 (95% CI, 1.9–NE) and 12.1 (95% CI, 6.5–NE) months, respectively, in patients with prior CAR‐T.

Among the 187 patients enrolled in MagnetisMM‐3, the most frequent (≥ 25%) hematologic treatment‐emergent adverse events (any grade, maximum grade 3/4) with elranatamab were anemia (53.5%, 42.2%), neutropenia (46.0%, 44.4%), thrombocytopenia (35.8%, 25.7%), and lymphopenia (29.4%, 27.3%). Other adverse events of interest included infections (overall, 71.7%; maximum grade 3/4, 38.5%; grade 5, 8.0%), CRS (overall, 58.8%, grade 3, 0.5%), and immune effector cell–associated neurotoxicity (overall, 4.3%; grade 3, 1.1% [all grade 3]) (EV, AV, ME, et al., unpublished data).

Infections are common in patients with RRMM because of underlying immunosuppression. A post hoc analysis of MagnetisMM‐3 showed a decreased infection rate, including grade ≥ 3 infections, in those with IgG levels ≥ 400 mg/dL and those receiving immunoglobulin replacement therapy; lower rates were observed across different infection types (i.e., bacterial, fungal, and viral) [ 22 ]. These data support the need to closely monitor immunoglobulin levels during treatment and highlight the benefit of immunoglobulin replacement therapy in the management of patients with RRMM treated with BCMA‐directed BsAbs.

Reduced Dosing Frequency

In MagnetisMM‐3, patients could reduce the dosing frequency to Q2W and Q4W while maintaining the same dose (i.e., leading to a decreased dose intensity within a given period). Overall, 77 patients switched from QW to Q2W dosing and 36 further reduced the dosing frequency from Q2W to Q4W. Among 67 responders with sufficient follow‐up (i.e., switched ≥ 6 months prior to the data cutoff date), who switched to Q2W and who were in response by blinded independent central review at the time of the switch, 82.1% maintained or improved their response ≥ 6 months after the switch. In all 77 patients who switched from QW to Q2W dosing, the overall incidence of grade 3/4 adverse events was 55.8% before the switch and 48.1% after the switch. Frequent (≥ 10%) grade 3/4 treatment‐emergent adverse events before and after the switch were hematologic adverse events (37.7% and 33.8%, respectively), neutropenia (31.2% and 26.0%), and infections (22.1% and 22.1%). Similar results were observed in patients who switched from Q2W to Q4W dosing. Among the 35 patients with sufficient follow‐up, 94.3% maintained response ≥ 6 months after the switch. A comparable safety profile before and after the switch was observed in the 36 patients who switched to Q4W (overall, grade 3/4: 41.7% and 47.2%, respectively; hematologic adverse events 25.0% and 30.6%; neutropenia, 19.4% and 22.2%; infections, 19.4% and 11.1%) (EV, AV, ME, et al. unpublished data). Additional results in Cohort A only have been described [ 20 ]. Reducing the dose frequency from QW to Q2W and from Q2W to Q4W provides greater patient convenience while potentially improving safety without compromising efficacy. Other regimens with overall reduced dosing frequency are being explored in earlier disease settings and/or in combination with other agents.

Other T‐Cell–Redirecting Therapies for Multiple Myeloma

The treatment landscape for MM continues to evolve beyond the established backbone therapies such as IMiDs, PIs, anti‐CD38 mAbs, and dexamethasone. Emerging classes of immune therapeutics, such as T‐cell‐engaging BsAbs and CAR T‐cell therapies, have demonstrated improved therapeutic activity, leading to evaluation in earlier treatment settings [ 23 , 24 ]. Elranatamab is one of 4 BsAbs currently approved for the treatment of MM, with teclistamab and linvoseltamab also targeting BCMA and talquetamab targeting the G‐protein‐coupled receptor, class C, group 5, member D (GPRC5D), an orphan receptor expressed in malignant plasma cells [ 25 , 26 , 27 ]. BCMA is also the target of the CAR T‐cell therapies ciltacabtagene autoleucel and idecabtagene vicleucel, currently approved as second‐line and third‐line therapies, respectively [ 28 , 29 ]. As these therapies reshape the MM treatment paradigm, the next wave of innovation will focus on enhancing efficacy by targeting dual tumor‐associated antigens or incorporating T‐cell costimulatory signals to optimize immune activation. Trispecific antibodies targeting CD3 on T cells and both BCMA and CD38 or BCMA and GPRC5D on myeloma cells are in development [ 30 , 31 ]. Dual CAR T‐cell therapies that target both BCMA and CD38, CD19 or GPRC5D are also being investigated [ 32 ]. This dual‐targeting strategy not only broadens the scope of antigen recognition but may also mitigate antigen escape, a common resistance mechanism in MM [ 32 ]. Additionally, next‐generation BsAbs and CAR‐T constructs are being engineered to include costimulatory domains such as CD28 or 4‐1BB, enhancing T‐cell persistence and cytotoxicity [ 33 , 34 ]. Collectively, further clinical development of T‐cell‐redirecting therapies may expand the range of treatment options for patients with MM and inform clinical decision‐making.

Funding

The MagnetisMM program evaluating the clinical development of elranatamab is sponsored by Pfizer.

Disclosure

Clinical and Translational Card for Elranatamab .

Mechanism of action : BCMA‐CD3 bispecific antibody.

Indication : Adult patients with triple‐class‐exposed relapsed/refractory multiple myeloma.

Dosage and administration : The recommended subcutaneous elranatamab dosing consists of fixed step‐up doses of 12 mg on day 1 and 32 mg on day 4 followed by the full treatment dose of 76 mg once weekly (QW) from weeks 2 to 24. In responders, 76 mg QW is reduced to every 2 weeks (Q2W) following ≥ 6 cycles and to every 4 weeks after ≥ 6 Q2W cycles.

Major metabolic pathway : Not applicable.

Key pharmacokinetic characteristics : After the first subcutaneous elranatamab dose, C max and AUC tau increased in a dose‐proportional manner over the evaluated dose range (≈6–76 mg). The median t max after the first dose across all dose levels was 7 (range, 3–7) days. The t 1/2 of elranatamab is 22 days following 24 weeks of dosing.

Conflicts of Interest

M.E., A.V., E.V., P.S., H.‐K.L., K.P., B.S., D.I., K.B.‐M., T.O., and J.H. are employees of Pfizer and may hold stock in Pfizer.

Acknowledgments

The authors thank the patients who participated in the MagnetisMM clinical program as well as their caregivers and families, and the medical teams at participating sites. Medical writing support was provided by Ryan Miller, PhD, of Nucleus Global and was funded by Pfizer.

References

1. Yashar D., Regidor B., Goldwater M. S., Bujarski S., Del Dosso A., and Berenson J. R., “Targeting B‐Cell Maturation Antigen for Treatment and Monitoring of Relapsed/Refractory Multiple Myeloma Patients: A Comprehensive Review,” Therapeutic Advances in Hematology 15 (2024): 20406207241275797.

2. Panowski S. H., Kuo T. C., Zhang Y., et al., “Preclinical Efficacy and Safety Comparison of CD3 Bispecific and ADC Modalities Targeting BCMA for the Treatment of Multiple Myeloma,” Molecular Cancer Therapeutics 18, no. 11 (2019): 2008–2020.

3. FDA Center for Drug Evaluation and Research , “Elranatamab (ELREXFIO) Multidisciplinary Review 2023,” accessed March 27, 2025.

4. Pfizer , “Elranatamab‐bcmm (ELREXFIO) Summary of Product Characteristics,” (2023).

5. Pfizer , “Elranatamab‐bcmm (ELREXFIO) Package Insert,” (2025).

6. Bahlis N. J., Costello C. L., Raje N. S., et al., “Elranatamab in Relapsed or Refractory Multiple Myeloma: The MagnetisMM‐1 Phase 1 Trial,” Nature Medicine 29, no. 10 (2023): 2570–2576.

7. Iida S., Ito S., Yokoyama H., et al., “Elranatamab in Japanese Patients With Relapsed/Refractory Multiple Myeloma: Results From MagnetisMM‐2 and MagnetisMM‐3,” Japanese Journal of Clinical Oncology 54, no. 9 (2024): 991–1000.

8. Lesokhin A. M., Tomasson M. H., Arnulf B., et al., “Elranatamab in Relapsed or Refractory Multiple Myeloma: Phase 2 MagnetisMM‐3 Trial Results,” Nature Medicine 29, no. 9 (2023): 2259–2267.

9. Elmeliegy M., Viqueira A., Vandendries E., et al., “Dose Optimization of Elranatamab to Mitigate the Risk of Cytokine Release Syndrome in Patients With Multiple Myeloma,” Targeted Oncology 20, no. 2 (2025): 349–359.

10. Elmeliegy M., Soltantabar P., Hibma J., Ashman O., Wang D., and Lon H. K., “Elranatamab Fixed Dosing: A Safe, Effective, and Convenient Dosing Approach,” Targeted Oncology 20, no. 5 (2025): 821–831.

11. Elmeliegy M., Lon H. K., Wang D., et al., “Soluble B‐Cell Maturation Antigen as a Disease Biomarker in Relapsed or Refractory Multiple Myeloma (RRMM): Evaluation From Elranatamab (Elra) MagnetisMM Studies,” Blood 142, no. supplement 1 (2023): 3345.

12. FDA Center for Drug Evaluation and Research , “Belantamab Mafodotin‐blmf (BLENREP) Multidisciplinary Review 2020,” accessed May 7, 2025.

13. Girgis S., Wang Lin S. X., Pillarisetti K., et al., “Effects of Teclistamab and Talquetamab on Soluble BCMA Levels in Patients With Relapsed/Refractory Multiple Myeloma,” Blood Advances 7, no. 4 (2023): 644–648.

14. Lon H. K., Hibma J., Jiang S., et al., “Population Exposure‐Response Efficacy Analysis of Elranatamab (PF‐06863135) in Patients With Multiple Myeloma,” Targeted Oncology 20, no. 5 (2025): 803–819.

15. Soltantabar P., Hibma J., Wang D., Conte U., Hickman A., and Elmeliegy M., “Elranatamab Exposure‐Safety Analysis in Relapsed or Refractory Multiple Myeloma,” Journal of Clinical Pharmacology 66, no. 1 (2026): e70130.

16. Poels K. E., Elmeliegy M., Hibma J., Wang D., Musante C. J., and Shtylla B., “Leveraging Quantitative Systems Pharmacology Modeling for Elranatamab Regimen Optimization in Relapsed or Refractory Multiple Myeloma,” NPJ Systems Biology and Applications 11, no. 1 (2025): 102.

17. Irby D., Hibma J., Elmeliegy M., et al., “A Novel Two‐Part Mixture Model for the Incidence and Time Course of Cytokine Release Syndrome After Elranatamab Dosing in Multiple Myeloma Patients,” Clinical Pharmacology and Therapeutics 117, no. 6 (2025): 1687–1695.

18. Niesvizky R., Arnulf B., Mohty M., et al., “Clinical Factors Related to Cytokine Release Syndrome and Elranatamab Dosing Recommendations After a Dose Interruption,” presented at the 49th Annual Meeting of the Japanese Society of Myeloma (JSM), Fukuoka, Japan, May 31–June 2, 2024.

19. van de Donk N. W., Garfall A. L., Benboubker L., et al., “Evaluation of Prophylactic Tocilizumab (Toci) for the Reduction of Cytokine Release Syndrome (CRS) to Inform the Management of Patients (Pts) Treated With Teclistamab in MajesTEC‐1,” Journal of Clinical Oncology 41, no. supplement 16 (2023): S8033.

20. Prince H. M., Bahlis N. J., Rodriguez‐Otero P., et al., “MagnetisMM‐3: Long‐Term Update and Efficacy and Safety of Less Frequent Dosing of Elranatamab in Patients With Relapsed or Refractory Multiple Myeloma,” presented at the 66th ASH Annual Meeting and Exposition (P4738), San Diego, California, December 7–10.

21. Nooka A., Lesokhin A., Mohty M., et al., “Efficacy and Safety of Elranatamab in Patients With Relapsed/Refractory Multiple Myeloma (RRMM) and Prior B‐Cell Maturation Antigen (BCMA)‐Directed Therapies: A Pooled Analysis From MagnetisMM Studies,” presented at the American Society of Clinical Oncology (ASCO), Chicago, Illinois, June 2–6, 2023.

22. Leleu X., Bahlis N. J., Rodriguez‐Otero P., et al., “Impact of Hypogammaglobulinemia and Immunoglobulin Replacement Therapy on Infection Rate in Patients With RRMM Treated With Elranatamab: Post‐Hoc Analysis From MagnetisMM‐3,” presented at the 20th International Myeloma Society (IMS) Meeting (P286), Athens, Greece, September 27–30, 2023.

23. Carlson S., Lin T. L., and Larson S. M., “Allogeneic Chimeric Antigen Receptors (CARs) as an “Off‐The‐Shelf” Therapy in Multiple Myeloma,” Immunotherapy 17, no. 3 (2025): 211–222.

24. Shastri T., Trabolsi A., Arumov A., and Schatz J. H., “Bispecific Antibodies in Hematologic Malignancies: Attacking the Frontline,” BioDrugs 39 (2025): 793–814.

25. Moreau P., Garfall A. L., van de Donk N., et al., “Teclistamab in Relapsed or Refractory Multiple Myeloma,” New England Journal of Medicine 387, no. 6 (2022): 495–505.

26. Chari A., Minnema M. C., Berdeja J. G., et al., “Talquetamab, a T‐Cell‐Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma,” New England Journal of Medicine 387, no. 24 (2022): 2232–2244.

27. Bumma N., Richter J., Jagannath S., et al., “Linvoseltamab for Treatment of Relapsed/Refractory Multiple Myeloma,” Journal of Clinical Oncology 42, no. 22 (2024): 2702–2712.

28. Bristol Myers Squibb , “Idecabtagene Vicleucel (ABECMA) Package Insert,” (2021).

29. Janssen Biotech , “Ciltacabtagene Autoleucel (CARVYKTI) Package Insert,” (2022).

30. Carretero‐Iglesia L., Hall O. J., Berret J., et al., “ISB 2001 Trispecific T Cell Engager Shows Strong Tumor Cytotoxicity and Overcomes Immune Escape Mechanisms of Multiple Myeloma Cells,” Nature Cancer 5, no. 10 (2024): 1494–1514, 10.1038/s43018-024-00821-1.

31. Popat R., Touzeau C., Perrot A., et al., “First‐In‐Human Study of JNJ‐79635322 (JNJ‐5322), A Novel, Next‐Generation Trispecific Antibody, in Patients With Relapsed/Refractory Multiple Myeloma: Initial Phase 1 Results,” presented at the Annual EHA Congress, Milan, Italy, June 12–15, 2025.

32. Hu Y., Xie Y., Wang X., et al., “Targeting BCMA in Multiple Myeloma: Designs, Challenges, and Future Directions,” Cancer Immunology, Immunotherapy 74, no. 3 (2025): 77.

33. Olson K., DiLillo D., Sineshchekova O., et al., “A CD38xCD28 Costimulatory Bispecific Antibody Demonstrates Potent Preclinical Combinatorial Activity With a BCMAxCD3 T Cell‐Engager,” Blood 144, no. supplement 1 (2024): 3283.

34. Sheykhhasan M., Ahmadieh‐Yazdi A., Vicidomini R., et al., “CAR T Therapies in Multiple Myeloma: Unleashing the Future,” Cancer Gene Therapy 31, no. 5 (2024): 667–686.