Elranatamab: Роман B-клеточного созревания T-клеточного агента.

Introduction

Plasma cells are immune cells involved in humoral immunity. 1 They are the product of terminal differentiation of B cells. B cells originate in the bone marrow through a process of maturation from pro-B-cells to pre-B-cells and ultimately naïve B cells that circulate through secondary hematopoietic organs. Upon encounter with their specific antigen, naïve B cells undergo maturation, eventually becoming antibody-producing plasma cells or memory B cells. Plasma cells can be short-lived, undergoing apoptosis after a few days of antibody secretion, or rather long-lived, homing to the bone marrow for low‑titer, long‑term immunity. 2 , 3 Dysfunction of plasma cells can lead to autoimmune (auto-antibody production) or malignant disorders (clonal expansion and secretion of toxic immunoglobulins, such as in light chain deposition disease, AL amyloidosis, and multiple myeloma). 4

Multiple myeloma is a hematologic malignancy characterized by expansion of clonal plasma cells leading to end organ damage (hypercalcemia, renal dysfunction, anemia, and bone disease). 5 It is the second most common hematologic malignancy, representing 10–15% of all cases and afflicting primarily patients aged 65 to 75 y old. A newly diagnosed multiple myeloma patient faces a clinical course characterized by induction and maintenance therapy followed by subsequent relapses with acquisition of resistance to chemotherapy. As the disease progresses, durations of response typically shorten, and myeloma cells acquire more biologically aggressive features, such as the capability of proliferating outside the bone marrow (extramedullary disease). While multiple myeloma is incurable, the development of highly effective therapies with enhanced supportive care has resulted in a steady increase in 5 y survival rate (currently ~60%) with a functional cure achievable for older patients with more indolent disease.

New regimens such as CD38 antibodies daratumumab or isatuximab, in combination with immunomodulatory drugs (IMiD), lenalidomide, and proteasome inhibitor bortezomib or carfilzomib, and dexamethasone have changed the landscape of newly diagnosed patients. Upon relapse, patients have a variety of options, including second-generation IMiDs, SLAMF7-targeting elotuzumab, and XPO1 inhibitor selinexor that can be deployed in combination. Ultimately, most patients will become refractory to these agents, and B-cell maturation antigen (BCMA) has emerged as a novel therapeutic target for cellular and immunotherapy approaches.

BCMA (CD269, or TNFRSF17) is a type III transmembrane glycoprotein that is a member of the tumor necrosis factor receptor superfamily. 6 BCMA has limited expression in hematopoietic stem cells, pre-B cells, memory cells, and naïve B cells. However, it is highly expressed in normal and clonal plasma cells and plasmablasts. 7 BCMA natural ligands, B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), trigger a downstream cascade of pro-survival and pro-proliferative effects. 6 BCMA is overexpressed in myeloma cells, facilitating survival, cell adhesion, and migration.

Transmembrane BCMA can be cleaved by gamma-secretase at a cysteine‑rich extracellular domain, resulting in the production of a soluble fragment (sBCMA) that is released in the bloodstream. Soluble BCMA can be used as a marker to assess plasma cell burden but can have detrimental effects on anti-BCMA therapies. Increases in sBCMA suggests lower concentrations of targets on malignant plasma cells and can act as a sink preventing anti-cancer effects. This can affect monoclonal antibodies such as BsAbs and antibody–drug conjugates, as well as chimeric antigen receptor (CAR) T‑cell therapies. 8–10 Despite this limitation, BCMA remains an enticing target for novel therapies for plasma cell disorders ( Table 1 ).

Belantamab mafodotin is a BCMA-binding IgG1 monoclonal antibody conjugated with monomethyl auristatin F (MMAF). 11 , 12 BCMA-belantamab mafodotin complex is internalized by plasma cells, releasing MMAF, a cytotoxic payload. MMAF is a microtubule‑targeting agent, causing direct cytotoxicity to cells. Belantamab mafodotin is effective through several mechanisms of action: antibody-dependent cellular toxicity, antibody-dependent cellular phagocytosis, block of BCMA prosurvival signaling, and finally, MMAF-direct toxicity. The phase II clinical trial DREAMM-2 assessed the safety and efficacy of belantamab mafodotin in relapsed/refractory myeloma patients. After a median follow‑up of 12.5 (range, 0.1–40.4) months, the overall response rate (ORR) was 32%. The median progression‑free survival (PFS) was 2.8 months with an OS of 15.3 months. Additional studies have shown benefit for belantamab mafodotin when used in combination with either pomalidomide or bortezomib. 13 , 14 These studies have allowed for the return of belantamab after a voluntary withdrawal. European Medicines Agency has approved belantamab in combination with bortezomib and dexamethasone, as well as in combination pomalidomide and dexamethasone. The United States has only approved belantamab in combination with bortezomib and dexamethasone.

There are currently two CAR T therapies commercially available. Idecabtagene vicleucel (Ide-cel, Abecma) was generated by incorporating an anti-BCMA single-chain variable fragment, a CD137 costimulatory motif, and a CD3-ζ signaling domain. 15 , 16 In the phase two KarMMa study, relapsed/refractory myeloma patients who had undergone succesful ide-cel manufacturing underwent lymphodepletion with fludarabine and cyclophosphamide prior to CAR T infusion. After a median follow‑up of 24.8 months, ORR was 73% with 33% achieving ≥CR. The median PFS was 8.6 months, and the median OS was 24.8 months. Ide-cel was also studied against standard of care regimens in triple-class exposed myeloma patients who have progressed on 2–4 lines of therapies, showing superiority in response and progression‑free survival. 17

Ciltacabtagene autoleucel (Cilt-cel, Carvykti) contains two BCMA-targeting single-domain antibodies, a CD137 costimulatory domain, and a CD3-ζ signaling domain. 18–20 CARTITUDE-1 is a phase 1b/2 of cilta-cel following fludarabine/cyclophosphamide lymphodepletion in 97 relapsed/refractory myeloma patients. ORR was 98% with a median OS of 60.7 months after a follow-up of 61.3 months. 18 In a phase 3 study, lenalidomide‑refractory patients were randomized to either cilta-cel or physician’s choice (DPd or DVd). Patients who received cilta-cel had a greater ORR of 84.6% as compared to standard of care (67.3%). The PSF at 12 months in the cilta-cel group was longer at 75.9% as compared to the standard of care group at 48.6% with a longer PFS. 21 Additional BCMA CAR Ts are being explored. Examples include anitocabtagene autoleucel which has a novel synthetic BCMA binding domain and AZD0120, a dual‑targeting BCMA/CD19 CAR T. 22 , 23 CAR T technology is also expanding out to additional targets including G protein couples receptor class C group 5 member D (GPRC5D), signaling lymphocyte activation molecule family member 7 (SLAMF7), CD138, and others. 24–26

The newest class of BCMA‑targeting agents includes bispecific antibodies. There are currently three FDA‑approved drugs in this class: teclistamab, elranatamab, and linvoseltamab. A fourth BsAb, etentamig, remains in pre-approval status. There are no head-to-head studies comparing these agents. In clinical trials, all three approved agents were evaluated in patients who had received a median of 5 prior lines of therapy. Compared to CAR T products, the risk of CRS and ICANS is lower with BsAb. Cilta-cel had a CRS incidence of 95% with grade 3 or higher occurring in 5%. ICANS or neurotoxicity had occurred in 21% with grade 3 or higher occurring in 9%. 19 Similarly, ide-cel reported a CRS incidence of 84% with 5% having grade 3 or higher events. Neurotoxic events were reported in 18% of patients with 3% having grade 3 or higher effects. 16 In comparison, teclistamab reports an CRS incidence of 72.1% with 0.6% having a grade 3 or higher event. 27 Elranatamab had an incidence of 57.7% with no grade 3 or higher events. 28 Lastly, linvoseltamab reports an incidence of 46.2% with 0.9% having grade 3 or higher CRS. ICANS and other neurotoxicity occurred in low rates. 29 Teclistamab had an incidence of 14.5%, with 0.6% representing grade 3 or higher. 27 Elranatamab had ICANS occurred in 3.4% of patients, but there were no grade 3 or higher events. 28 Linvoseltamab reports an incidence of 7.7% with grade 3 or higher occurring in 2.6% of patients. 29 Teclistamab has an ORR of 63%, and elranatamab has an ORR of 61%. 27 , 28 , 30–32 Linvoseltamab currently has the highest ORR at 70.9% with a median OS of 31.4 months. 29 Linvoseltamab was approved in 2025, thus less data are available about real‑world use of this agent.

Nirogacestat is a γ-secretase inhibitor that inhibits the cleavage of the extracellular domain of BCMA. 33 Thus, it reduces sBCMA levels in favor of increased BCMA density of expression on the cell membrane. This prevents binding of therapeutic agents to sBCMA that is not bound to malignant plasma cells, thus inhibiting the sink effect and resulting in increased efficacy of BCMA-targeting agents. 10 , 34 While nirogacestat is currently only approved for desmoid tumors, clinical trials evaluating its use in plasma cell disorders are ongoing.

Elranatamab – an overview

Elranatamab, formerly known as PF-0683135 or PF-3135, is a 148.5 kDa, humanized, IgG2ΔA Kappa bispecific antibody with binding epitopes to BCMA on malignant plasma cells and CD3 on T cells. 35 This bridge between antigen and CD3 bypasses normal MHC and TCR complexes and can lead to T cell redirection and activation, resulting in lysis of target cells through perforins and granzyme release.

Bispecific antibodies were initially generated by screening for BCMA‑targeting antibodies that were cross‑reactive to both humans and cynomolgus monkeys. 35 The ones that were highly specific were then further evaluated. CD3 antibodies were generated in mice and then humanized. Each monoclonal antibody provided one heavy chain and one light chain. The heavy chains were then combined using IgG2 Fc mutations that allow for heavy‑chain heterodimer formations via 5 interchain disulfide bond. The Fc mutation (G2ΔA) also reduces Fcγ binding. By doing so, nonspecific T-cell activation can be reduced. The BCMA‑binding epitope was then further mutated to have low, medium, or high affinity for BCMA. Preclinical cytotoxic activity suggested that the high‑affinity BCMA antibody was most potent.

Cyanomolgus monkeys were administered either 0.1 or 0.3 mg/kg of elranatamab intravenously (IV) on Days 1 and 8. 35 This resulted in elimination of peripheral and bone marrow plasma cells by Day 10. After the first dose of elranatamab, serum interferon gamma (IFNγ), interleukin (IL‑6) 6, IL‑10, and IL‑2 transiently increased. These cytokines returned to baseline and did not rise with Day 8 dose. Treatment also led to decreased spleen- and lymph node-resident B lymphocytes. However, it should be noted that cynomolgus monkeys have high levels of BCMA expression on CD20+ cells. The bone marrow also had decreased cellularity.

Elranatamab was approved by the Food and Drug Administration on 14 August 2023 and European Medicines Agency on 7 December 2023. 36 It is currently indicated for the treatment of relapsed/refractory myeloma patients who have progressed after 4 prior lines of therapy, including an immunomodulatory agent, proteasome inhibitor, and an anti-CD38 monoclonal antibody. Due to the risk of cytokine release syndrome (CRS) and immune cell–associated neurotoxicity (ICANS), a Risk Evaluation and Mitigation Strategy program that limits use to certified sites and providers. It is currently supplied in two available vial sizes: 76 mg/1.9 mL and 44 mg/1.1 mL solutions.

Elranatamab is contraindicated in pregnant and lactating women as maternal IgG antibodies may cross the placenta after the first trimester and are present in breast milk with potential for serious adverse events on the fetus or newborn. 36 Furthermore, pregnant women may be at increased risk for adverse outcomes if they were to develop CRS, and continue dosing of BsAb may lead to chronic lymphopenia. It is advised that fertile women use contraception and avoid breastfeeding during therapy and for 4 months after the last dose.

Pharmacokinetics

In the MagnesitMM-1 phase I study, elranatamab showed linear pharmacokinetics with exposure increasing with higher doses. 37–39 The bioavailability of SQ elranatamab is 56.2%. 36 The median T max is 7 d (range 3–7). 37 , 39 Absorption (k a ) is 0.287/Day (68% Coefficient of Variation [CV]). Following the first full dose, the C avg is 31 mcg/mL (94% Confidence Interval [CI]) with a C max of 3.8 mcg/mL and C trough 31.2 mcg/mL. This increases after weekly doses to a C avg 32.7 mcg/mL (49% CV) with a C max 33.6 mcg/mL and C trough of 31.2 (50% CV).

The volume of distribution (V D ) of elranatamab is 7.76 L. The central compartment V D is 4.78 L, and the peripheral compartment is 2.83 L.

Elranatamab is a monoclonal antibody and is metabolized into small peptides by catabolism. The average clearance is 0.324 L/d (100% CV), with the elranatamab: sBCMA complex being 0.164 L/d (79% CV). The time to 50% elranatamab exposure reduction was approximately 25 d. The approximate half-life of elranatamab is 22 d (64% CV) after 24 weekly treatment doses. There is also minimal immunogenicity with only 8.6% of patients developing anti-drug antibodies – none of which occurred in the R2PD 1000mcg/kg or 76 mg QW.

Currently, there are no clinically significant differences in pharmacokinetics based on age, body weight, sex, or race. Patients with moderate to severe hepatic impairment (total bilirubin >1.5 ULN and any AST) were not studied in registrational trials as such dose modifications are not available.

Patients with mild to moderate renal dysfunction (eGFR 30–89 ml/min) are not expected to require any change in dosing. However, those with severe renal dysfunction (15–20 ml/min) or end-stage renal disease (<15 ml/min) were not studied. Based on the pharmacokinetics and elimination pathways of these treatments, it is not expected to significantly affect elranatamab. A case report by Van de Wyngaert et al. described a dialysis‑dependent 79-y-old woman with IgA Lambda multiple myeloma who had relapsed on 4 prior lines of therapy presenting with new lytic lesions and an M-spike of 3.7 g/L. 40 She started on elranatamab (after dialysis) and experienced Grade 1 CRS treated with tocilizumab with no ICANS. This patient achieved a complete response after 1 month of treatment.

Step-up dosing and premedications

CRS is a hyperinflammatory syndrome resulting from the overactivation of immune cells and the attendant release of proinflammatory cytokines. CRS inevitably presents with fever and signs/symptoms of hypoperfusion such as hypotension, hypoxia, and organ failure can occur. In advanced grade CRS, patients may need intensive care unit level of care for respiratory of pressure support. In the phase II MagnetisMM-3 study, CRS occurred in 44.5% of patients after the first step-up dose (Grade 1 = 33.6%, Grade 2 = 10.9%) and 20.2% of patients after the second step-up dose (Grade 1 = 17.6%, Grade 2 = 2.5%). 28 , 31 , 32 The first full dose resulted in a low occurrence of CRS (Grade 1 = 4.2%, Grade 2 = 1.7%). While there were 15.1% recurrences, there were no Grade ≥3 CRS events. The median time to resolution CRS resolution was 2 d (range 1–19). ICANS similarly stems from increased permeability of the blood–brain barrier in the setting of T‑cell activation. 41 Patients with ICANS experience headaches, confusion, delirium, tremors, and potentially seizures. Treatment of CRS and ICANS entails supportive care along the use of IL-6-targeting antibody tocilizumab and dexamethasone as per guidelines. 42 , 43 In this study, steroids and tocilizumab were used in 1.7% of events each, with 0.8% of patients receiving levetiracetam for seizure prophylaxis. The incidence of CRS and ICANS is relatively similar in both clinical trials and real‑world studies. The French Compassionate Use Program noted similar rates of CRS at 45% with no grade ≥3 and ICANS at 3% (all grade 1–2). 44 During the step-up dosing, institutions may draw IL-6, LDH, ferritin, CRP, as well as vital monitoring and ICE scores.

The risk of CRS and ICANS has been partially mitigated with the use of the subcutaneous route over intravenous, the use of two step‑up doses, and premedications. 37 , 45 In early clinical trials, with patients receiving IV, full‑dose elranatamab without premedications or step‑up/priming, CRS and ICANS incidence and severity were significantly higher than what was reported with subcutaneous (SC), step‑up dosing administration. 45 CRS incidence for patients who received 30–50 mcg/kg of IV elranatmab was 80–100%. Moreover, the 50 mcg/kg cohort of patients had a rate of grade 2 CRS of 83.3%. Subcutaneous administration of elranatamab had a similar relationship between dose and CRS incidence. The severity of CRS was reduced with subcutaneous administration. For example, in the highest dose cohort (1000mcg/kg), the severity of CRS was limited (Grade 2 = 33.3% with no grade ≥3). The addition of a single 44 mg SQ step-up dose with premedications (dexamethasone 20 mg, acetaminophen 650 mg, and diphenhydramine 25 mg) led to a 21.7% decrease in CRS incidence. All events occurred after the first step-up dose. This strategy was further refined into administering two distinct step-up doses with pre-medications to help mitigate the risk. The first step‑up dose is 12 mg SQ, and the second step‑up dose is 32 mg SQ. The incidence of any grade CRS was 57.9% with grade ≥2 being 14.2%. Most events occurred after the first dose (43.2%) or second dose (19.4%). A 4 mg and 20 mg step-up dosing strategy was also evaluated, but it appeared that the initial dose of 4 mg did not adequately engage T cells, leading to the majority of CRS events occurring after the 20 mg dose. 46

The two step-up doses with pre-medication approach were also effective in reducing the risk of neurotoxicity. 45 Patients who received the single 44 mg step-up dose followed by 76 mg full dose without pre-medications had an overall ICANS incidence of 17.4% as compared to 3.3% for those who received the two12mg/32 mg step-up doses with pre-medications.

In addition to the implementation of step-up doses and premedications, patients are also recommended to be hospitalized for 48 h after the first step‑up dose and 24 h after the second step-up dose to guarantee prompt recognition and treatment of CRS and ICANS. Due to resource and logistical limitations, outpatient step‑up dosing programs, including the use of prophylactic tocilizumab, are emerging.

Tocilizumab is an interleukin-6 receptor inhibitor used for the management of CRS. Due to the lack of detrimental effects on plasma cell-directed therapy efficacy, it has been explored as a possible prophylactic medication for bispecific antibodies. In a prospective study by Kowalski et al., tocilizumab was administered as a single 8 mg/kg (maximum of 800 mg) prior to the first step-up dose and after pre-medications. 47 A total of 119 patients (elranatamab = 40 patients) were included in this study. The incidence of any grade CRS was low at 10.1% for all patients with CRS incidence of 12.5%, mostly grade 1 (Grade 2 = 2.5%, Grade ≥3 = 0%), in patients receiving elranatamab. There was no recurrence of CRS after tocilizumab dosing, and no additional doses of tocilizumab or dexamethasone were used. The incidence of ICANS was also low at 5.9% across the entire cohort, being 0% for patients receiving elranatamab. Several other studies have explored tocilizumab prophylaxis prior to bispecific therapies with similar conclusions. 48 , 49 As such, this has been adopted by NCCN guidelines as a recommendation. 50

Clinical efficacy

The phase 2 registrational MagnetisMM-3 study assessed the efficacy and safety of elranatamab in patients with relapsed/refractory multiple myeloma. 28 This was a multi-center, open-label, single arm study for myeloma patients who had received at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 monoclonal antibody. Patients were divided into two cohort: BCMA-naïve patients (Cohort A) and BCMA‑exposed patients (Cohort B). In Cohort A, 123 patients received treatment. The median age of patients enrolled in this cohort was 68 y old (range: 36–89) and heavily pre-treated, having received a median of 5 (2–22) prior lines of therapy with 42.3% being penta-drug refractory. High‑risk cytogenetics as defined by the presence of t(4;14), t(14;16), or del17p were found in 25.2% of patients, and EMD was present in 31.7%.

After a median follow‑up of 33.9 months ((95% CI): 33.4–34.6), the ORR was 61% in Cohort A. 31 The complete response rate or better (≥CR) was 37.4% with very good partial response achieved in 18.7% and partial response in 4.9%. Median duration of response was not reached (95% CI: 29.4–NE), median progression‑free survival was 17.2 months (95% CI: 9.8–NE), and median overall survival was 24.6 months (95% CI: 13.4–NE). 32

BCMA‑exposed patients were included in several studies including MagnetisMM-1, MagnetisMM-3, and MagenistisMM-9. 51 A pooled analysis included 86 patients with a median age of 66 (range 40–84) y old. Patients received a median of 7 prior lines of therapy (range 3–19), including BCMA-directed antibody–drug conjugate (67.4%), CAR T Cells (41.9%), or both (9.3%). The median follow‑up was 10.3 months (0.3–32.3) with a median duration of treatment of 3.3 months (0.03–30.4). The overall response rate was 45.3% for the pooled analysis, 41.4% for previous antibody–drug conjugate exposure, and 52.8% for previous CAR T exposure. The median progression‑free survival was 4.8 months (95% CI 1.9–7.7 months), but the median duration of survival and overall survival were not reached. This data indicated that BCMA-exposed patients may still respond to elranatamab, though not as robustly as BCMA‑naïve patients.

There are currently no head-to-head studies comparing elranatamab with teclistamab. Mol et al. conducted an unanchored matching indirect comparison (MAIC) study using the patients enrolled in the MagnetisMM-3 study and the teclistamab registrational MajesTEC-1 study. 52 , 53 Patients treated with elranatamab were reweighted to match the selected baseline characteristics of teclistamab patients using propensity score-type logistical regression. Variables of interest included age, median time since diagnosis, ISS disease stage, high-risk cytogenetics, extramedullary disease, prior lines of therapy, ECOG performance status, penta-drug exposed, and refractory status. Patients were compared after a median follow‑up of 28.4 months in MagnetisMM-3 and 30.4 months in MajesTEC-1. 52 The median progression‑free survival was longer with elranatamab (17.2 months vs 11.4 months). This was also true for overall survival (24.6 months vs 22.2 months) and DoR (24.8 months vs 24 months). While elranatamab did not show a statistically significant difference in PFS, OS, or DoR in the original comparison, all these outcomes favored elranatamab in the weighted cases. The PFS HR was 0.55 (0.37–0.81), OS HR was 0.6 (0.4–0.91), and DoR HR was 0.56 (0.21–0.99).

There is also limited evidence comparing elranatamab to other anti-plasma cell directed therapies. Costa et al. used two EHR databases (COTA and Flatiron Health) to conduct retrospective real-world comparison of patients with triple‑class exposed multiple myeloma cohorts. Patients were matched via filtering based on the inclusion and exclusion criteria of MagnetisMM-3 leading to a total of 239 patients in COTA and 152 patients in Flatiron Health. Elranatamab patients were noted to have a higher ORR in both unadjusted (61%) as compared to COTA (30.5%) and Flatiron Health (30.3%). This difference was preserved in the adjusted analysis for COTA (71.7 vs. 31.8%) and Flatiron Health (57.4 vs. 30.5%). The median OS was significantly longer with elranatamab as compared to COTA (unadjusted HR = 0.65 and adjusted HR = 0.46). Flatiron Health also performed worse at 24 months, with elranatamab patients surviving an additional 3.37 months (unadjusted) and 2.34 months (adjusted).

Another similar study compared the results of MagnetisMM-3 to a prospective non-interventional study that evaluated physician’s choice of treatment for patients with triple‑class exposed or refractory myeloma patients (LocoMMotion). The LocoMMotion study had index lines of therapy that included 91 different therapies. The most common regimens included carfilzomib/dexamethasone (14.1%), cyclophosphamide/pomalidomide/dexamethasone (14.1%), and pomalidomide/dexamethasone (11.7%). 54 , 55 The MAIC method was used to compare the relative effectiveness of therapies. This showed a statistically significantly improved PFS of 12.6 months (naïve HR = 0.42, weighted HR = 0.32) and median OS of 10.8 months (naïve HR = 0.66, weighted HR = 0.50) for elranatamab when compared to physician’s choice. The median PFS with elranatamab was 17.2 months (95% CI: 9.8–NE) as compared to 4.6 months (3.9–5.6). The median OS for elranatamab was 24.6 months (95% CI: 13.4–NE), as compared to 13.8 months (10.8–17.0) in physician’s choice.

Due to the recent approval, there are limited real‑world evidence studies assessing the safety and efficacy of elranatamab. One of note is the French compassionate use program which retrospectively compiled 101 patients from 22 centers across the country. 44 Patients were treated per the package insert. 36 The median age of this population was 68 y old (range = 39–87). The median time to diagnosis was 75 (range = 16–239) months with 80% having a R-ISS II or III disease. Thirty-five percent of patients had extramedullary disease and 29% had del17p. The median prior lines of therapy was 5 (range 1–17), and 17% had prior BCMA therapy. After a median of 15.5 months (range = 3.5–18.8), the overall response rate was 51.5%, with ≥VGPR being 42%. The 1-y PFS was 34% (95% CI = 31.7–52.1) with the 1-y OS being 42% (CI: 31.1–64). While the response rates are lower than what was reported in MagnetisMM-3, this can be attributed to prior BCMA exposure and a higher number of patients with ECOG ≥2.

Central nervous system (CNS) involvement is a rare complication of relapsed myeloma that has limited treatment options and no standard of care treatment. While intrathecal options are possible, efficacy is modest, and additional treatment options are needed for this critical unmet need. Mutlu et al. reported a case of a 37-y-old man with IgG lambda, R-ISS II myeloma who had relapsed after several regimens inclusive of proteasome inhibitors, immunomodulatory agents, 2 autologous stem cell transplants, VD-PACE, and anti-CD38 monoclonal antibodies. 56 At this point, the patient was diagnosed with CNS myeloma with cerebrospinal fluid showing clonal CD138‑positive plasma cells. After two cycles of elranatamab and daratumumab, there was significant improvement in CNS disease and improvement in neurological symptoms, alongside resolution of plasmacytomas. The patient is currently deemed in a complete response after approximately 6 months follow-up.

Elranatamab has also been evaluated in combination with other agents. Magnetismm-5 assessed elranatamab in combination with daratumumab in 28 patients with relapsed/refractory multiple myeloma. 57 , 58 The median number of prior therapies was 5 with 18% having triple‑class refractory disease. This study is now moving into part 2, where patients will be enrolled into elranatamab monotherapy, elranatamab with daratumumab, or daratumumab with pomalidomide and dexamethasone.

MagnetisMM-20 combined elranatamab with carfilzomib in the treatment of 12 patients with relapsed/refractory multiple myeloma. 59 These patients had a median of 2 prior lines of therapy (1–3) with 66.7% having a previous stem cell transplant. The overall response rate was noted to be 100% with 75% achieving ≥CR. After a median follow‑up of 8.9 months, no new DLTs were observed.

In patients with newly diagnosed, transplant‑ineligible multiple myeloma, elranatamab in combination with daratumumab, lenalidomide, and dexamethasone was compared to daratumumab/lenalidomide/dexamethasone. 60 Prior to the phase 3 comparison, the recommended phase 3 dose would need to be determined. Patients were first enrolled into a dose‑finding study, Part 1. Thirty-four patients received elranatamab/daratumumab/lenalidomide/dexamethasone in dose level G. The median age of enrolled patients was 75 y old (range 67–83) with 24.3% being identified as frail using the simplified IMWG frailty score. After a median follow‑up of 4.6 months (range 1.2–6.2), the overall response rate was 91.9% with 81.1% achieving a ≥VGPR.

Outside of multiple myeloma, elranatamab has shown efficacy in AL amyloidosis. In a retrospective case series by Vianna et al., reporting on real‑world use in 9 patients with relapsed AL amyloidosis after daratumumab therapy, a hematologic response occurred in 100% of patients, including MRD‑negative responses, and both cardiac and renal responses were noted. 61 Grade 2 CRS occurred in two patients and was managed with fluids, tocilizumab, and dexamethasone. There was one case of grade 2 ICANS. Despite patients in the study being frail and with advanced cardiac involvement, there were no cases of acute heart failure decompensation or intensive care unit admissions in this cohort. The positive experience with elranatamab in relapsed AL amyloidosis has also prompted a phase II clinical trial evaluating its use in the second‑line setting.

Safety

Pre-clinical studies suggested that elranatamab may have bone marrow-associated adverse effects. 35 Patients were noted to have cytopenia that included neutropenia (all grade 28.6%, grade ≥3 = 25%), lymphopenia (all grade = 7.1%, grade ≥3 = 7.1%), anemia (all grade 10.7%, grade ≥3 = 0%), and thrombocytopenia (all grade 31.7%, grade ≥3 = 23.6%). As a consequence of the leukopenia as well as drug-induced hypogammaglobulinemia and normal plasma cell depletion, 70.7% (Grade 3 or 4 = 41.5%, Grade 5 = 7.3%) of patients suffered infections (bacterial, viral, and fungal). 28 , 31 , 32 Opportunistic infections such as aspergillosis, pneumocystis JirovecI pneumonia, and cytomegalovirus reactivation were reported in patients who had received elranatamab. Hypogammaglobulinemia occurred in 75.5% of patients treated, and 43.1% were treated with immunoglobulin replacement therapy. This is reflected in the French Compassionate Use study, showing an infections incidence rate of 45% with grade ≥3 infections being reported at 24%. 44

At this stage, International Myeloma Working Group (IMWG) and National Comprehensive Cancer Network (NCCN) guidelines recommend supporting patients with antiviral prophylaxis and PJP prophylaxis throughout treatment. 42 , 50 , 62 Antibacterial prophylaxis can be implemented during episodes of neutropenia with the addition of antifungals during prolonged periods of neutropenia. Intravenous immunoglobulins for those who have hypogammaglobulinemia are recommended. Hepatitis B virus should be treated if detected, and treatment for CMV reactivation may be considered based on local guidelines. Institutions may complete respiratory panels and hepatitis screening for patients prior to step‑up dosing. Additionally, as changes in elranatamab schedules with less frequent dosing are being implemented, we expect the risk of infections to decrease. For example, for patients who transitioned from weekly to monthly dosing, Grade ≥3 infections decreased by 7.2%. The incidence of grade 3 or 4 infections in the weekly treatments was 17.9% as compared to 10.7% in the monthly treatments. Per the package insert, patients who achieve a ≥VGPR after 24 weeks of therapy may transition to every 2-week dosing. 36 There is also evidence suggesting that every 4-week dosing may be an option as patients maintain response with improved safety. 32 The MagnetisMM-3 study allowed for patients to transition to every 4-week dosing after ≥ 6 cycles of every 2-week dosing. The median follow‑up was 33.9 months. Twenty-eight patients were able to switch to every 4‑week dosing. Of these patients, 92.6% were able to maintain their response, inclusive of those with complete responses or better.

Other notable side effects include motor (17.1%) and sensory (13.8%) neuropathy. 28 , 31 , 32 Constitutional side effects such as diarrhea (42.3%), fatigue (36.6%), decreased appetite (33.3%), and nausea (26.8%) were common but generally mild. Injection site reactions occurred in 26.8% of patients with no Grade ≥3 reported.

Quality of life (QoL) and patient‑reported outcomes (PROs) were an exploratory endpoint in the MagnetisMM-3 study. 63 Patients were assessed via the validated cancer-specific questionnaire, European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ-C30), the myeloma-specific questionnaire (EORTC QLQ-MY20), patient global impression change (PGIC), and other tools. Taken together, these scales assessed functional and global health status, symptom status, disease-specific symptoms, and side effects of treatment. Patients were given electronic surveys on Day 1 and Day 15 of the first 3 cycles, followed by day 1 of each cycle from 4 to 12. Patients had their quality of life assessed in regular intervals and compared to themselves at earlier timepoints. Patients initially experienced a decrease in health scores compared to baseline, but this returned to their baseline by cycle 3. BCMA-naïve patients noticed improvements in pain, disease symptoms, and future perspectives. This was similar for BCMA‑exposed patients, except their pain levels returned to baseline after cycle 5. Overall, this study suggests that elranatamab did not significantly harm QoL and rather kept patients at baseline or resulted in overall improvements in the medium and long term.

Conclusion

Elranatamab is a BCMA-targeting bispecific antibody that has significantly improved quality of life and outcome in relapsed and refractory multiple myeloma with emerging data of activity and safety in AL amyloidosis and overall manageable safety profile.

Biographies

Shahrier Hossain is a clinical pharmacy specialist specializing in multiple myeloma and AL-amyloidosis at Dana-Farber Cancer Institute. He earned his Doctor of Pharmacy degree at the University of Buffalo, NY, followed by a first-year training program at Albany Medical Center, Albany, NY, followed by a second-year training program at Dana-Farber Cancer Institute, Boston, MA. Dr. Hossain cares for patients with multiple myeloma, AL-amyloidosis, and other related plasma cell disorders. His research is primarily focused on supportive care strategies and real-world evidence in this setting.

Giada Bianchi is a physician-scientist and Co-Director of the Amyloidosis Program at Brigham and Women’s Hospital/Dana-Farber Cancer Institute and Assistant Professor at Harvard Medical School, Boston, MA. She is also a principal investigator with the Division of Hematology at the Brigham and Women’s Hospital where her lab focuses on protein homeostasis in plasma cell disorders. Dr. Bianchi earned her MD degree summa cum laude from Vita-Salute San Raffaele University in Milan, Italy. She trained in Internal Medicine at the Mayo Clinic, Rochester, MN, and in Hematology-Oncology at Dana Farber/Partners Cancer Care program in Boston, MA. Dr. Bianchi attends to the care of patients with AL amyloidosis, multiple myeloma, MGUS, MGRS and smoldering myeloma. Her clinical and research expertise is in plasma cell disorders and plasma cell biology. Dr. Bianchi is the recipient of numerous awards, including the Damon Runyon Physician Scientist Training Award, 2016; the Doris Duke Charitable Research Foundation Clinical Scientist Development Award, 2019; the American Society for Clinical Investigation (ASCI) Young Physician-Scientist Award, 2021; the American Society of Hematology Scholar Award, 2022; and the 2025 V Foundation Scholar Award.

Funding Statement

The author(s) reported that there is no funding associated with the work featured in this article.

Disclosure statement

SH: Advisory boards/speaker fees from Johnson and Johnson, Pfizer, and Sanofi.

GB: Consultancy/speaker fees from Prothena, Alexion, Protego, Pfizer, and Janssen; Clinical Research Support: Pfizer, Alexion, and Prothena.

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