Talquetamab in Multiple Myeloma: Efficacy, Safety, and Future Directions

ABSTRACT

Relapsed and refractory multiple myeloma (RRMM) remains a challenging condition despite advances in immunotherapies. Novel bispecific antibodies (BsAbs), including talquetamab, have shown promising efficacy in heavily pretreated patients, even those with triple‐ and penta‐refractory disease. Talquetamab, recently approved by the FDA and EMA, is indicated for patients who have progressed after at least three or four prior lines of therapy (LOTs). Administered following a step‐up dosing phase to manage cytokine release syndrome (CRS), talquetamab demonstrated a high overall response rate (ORR) of approximately 70%, including in patients previously treated with T‐cell redirecting therapies. Its safety profile is consistent with other BsAbs, with hematologic adverse events such as anemia and neutropenia commonly reported, alongside unique on‐target off‐tumor toxicities like dysgeusia and skin‐related events. Infections were less frequent compared to other BsAbs. The optimal sequencing of talquetamab and other therapies, including CAR‐T cell treatments, remains an area of active research, as resistance to anti‐BCMA therapies presents ongoing clinical challenges. Current trials are exploring the use of talquetamab in combination therapies, as well as therapeutic strategies post‐treating progression. The real‐world data further support talquetamab's efficacy, making it a valuable addition to the RRMM treatment landscape.

1. Introduction

Multiple myeloma (MM) is a heterogeneous hematologic malignancy characterized by the clonal proliferation of plasma cells within the bone marrow, accounting for approximately 15% of hematological cancers in Western countries. Despite recent advances leading to improved survival rates globally, MM remains a significant cause of mortality with an estimated 12 000 MM‐related deaths in USA in 2023, according to the latest cancer statistics [1].

The current frontline standard of care for MM patients involves a combination of agents from different therapeutic classes, which have markedly improved outcomes of therapy‐naïve MM patients over the past two decades. The introduction of proteasome inhibitors (PIs) such as bortezomib, carfilzomib, and ixazomib, alongside immunomodulatory drugs (IMiDs) including thalidomide, lenalidomide and pomalidomide, anti‐CD38 monoclonal antibodies (mAbs) and autologous stem cell transplant, has significantly enhanced progression‐free survival (PFS) of MM patients [2, 3, 4, 5].

Nevertheless, despite these advancements, most patients eventually experience or develop resistance to these agents. This leads to progressively shorter times between relapses and a decline in median overall survival (mOS), with heavily pre‐treated patients, that is, those with penta‐refractory or penta‐exposed disease, showing a mOS of approximately 5 months [6].

Relapsed and refractory multiple myeloma (RRMM) is defined by the International Myeloma Working Group (IMWG), as progression within 60 days of the last therapy in patients who had achieved at least a minimal response (MR) or as disease refractory to primary or salvage therapy [7].

Patients with RRMM who have been heavily pretreated are further classified based on their exposure to previous therapies, with “triple‐refractory disease” referring to cases resistant to prior treatment with at least one anti‐CD38 antibody, a PI, and an IMiD, and “penta‐refractory disease” defined by prior exposure to two PIs, two IMiDs, and one anti‐CD38 monoclonal antibody [8].

Currently, there is no standardized treatment strategy for patients with triple‐class‐exposed (TCE) MM (defined as having received at least a PI, IMiD, and anti‐CD38 mAb), and new therapeutic options or strategies must be explored to improve outcomes of this population [9]. Recently, novel drugs, such as selinexor and iberdomide, have shown efficacy in this heavily pretreated group of patients [10, 11, 12].

Over the past few years, advances in understanding the mechanism of immunomodulation within the bone marrow microenvironment (BMM) and the genetic alterations in MM cells have driven the development of novel agents targeting B cell maturation antigen (BCMA), a member of the tumor necrosis factor (TNF) receptor superfamily. BCMA is overexpressed on plasma cells, including malignant MM cells, and may play a role in improving the outcomes of RRMM [13, 14, 15]. Ongoing clinical trials and newly approved therapies targeting BCMA include various approaches such as chimeric antigen receptor T cell (CAR‐T), bispecific antibodies (BsAbs), and antibody‐drug conjugates (ADCs) [16, 17, 18, 19, 20].

Between 2021 and 2022, two CAR‐T therapies were approved by the United States Food and Drug Administration (FDA) for the treatment of RRMM, based on data from the phase II trial and subsequent data from the phase III trial [21, 22].

While CAR‐T therapy holds promise as a therapeutic option for RRMM patients after ≥ 4 prior lines of therapy, including an IMiD, a PI, and an anti‐CD38 monoclonal antibody, its widespread use is limited by factors such as the long manufacturing time to the individual, high costs, and availability at only a few specialized cancer centers.

Bispecific antibodies (BsAbs) are engineered antibodies that bind two distinct antigens: one arm binds to CD3 molecules on tumor‐specific T cells, while the other arm binds to an antigen on MM cells. Teclistamab was the first BCMA‐directed BsAb to receive approval (in October 2022), following the positive outcomes of the seminal MajesTEC‐1 trial, which involved a similar RRMM population as those receiving CAR‐T therapy [23, 24].

Elranatamb, the second BCMA‐directed BsAb to be approved, demonstrated efficacy in the MagnetisMM‐3 trial [25]. However, despite the initial promising results from these BCMA‐specific T‐cell‐redirecting therapies many patients eventually become refractory, and survival curves fail to show a plateau.

Starting from this data, novel agents for T‐cell‐redirecting therapy are currently being investigated in both pre‐clinical and clinical settings.

Talquetamab, the first‐in‐class humanized antibody that binds to G‐protein‐coupled receptor class 5 member D (GPRC5D) represents a promising new approach. In August 2023, the FDA granted accelerated approval to talquetamab, based on the impressive efficacy and safety results of the MonumenTAL‐1 trial (NCT03399799, NCT4634552) [26, 27]. Numerous ongoing clinical trials are evaluating its efficacy in a broader patient population, including in combination with other agents, to overcome resistance mechanisms—a critical unmet clinical need in the treatment of RRMM.

2. Mechanism of Action

Talquetamab, a first‐in‐class BsAb targeting GPRC5D, represents an innovative immunotherapy for MM and is positioned as a treatment option following anti‐BCMA therapies. This off‐the‐shelf, full‐sized, humanized BsAb redirects to MM cells by simultaneously binding CD3 on T‐cells and GPRC5D on plasma cells, thereby forming an immune synapse [28, 29, 30, 31]. GPRC5D is an uncharacterized 7‐pass transmembrane receptor, coupled with a G‐protein, resembling members of the fifth group of family C (associated with metabotropic glutamate receptor‐like) of the superfamily of mammalian G‐protein coupled receptors (GPCRs). Unlike other family C members, which typically possess long amino‐terminal domains (ATD) of 500–600 amino acids, GPRC5D has a short ATD of 30–50 amino acids [32]. Its gene is located on chromosome 12 (12p13) but its ligand and biological function remain largely unknown [33].

Due to its short extracellular domains, the epitopes of GPRC5D available for binding by T‐cell‐redirecting agents are positioned close to the plasma membrane, facilitating the formation of a highly efficient immune synapse between T‐cells and MM cells, which enhances T‐cell‐mediated cytotoxicity. Upon activation, T‐cells release granules containing granzymes and perforins, leading to malignant cell death [29, 30, 34, 35]. The mechanism of action of talquetamab is exemplified in Figure 1.

FIGURE 1.

Talquetamab, an off‐the‐shelf, full‐sized, humanized BsAb redirects to MM cells by simultaneously binding CD3 on T‐cells and GPRC5D on plasma cells, thereby forming a highly efficient immune synapse between T‐cells and MM cells, which enhances T‐cell‐mediated cytotoxicity. Upon activation, T‐cells release granules containing granzymes and perforins, leading to malignant cell death.

GPRC5D expression has been characterized using sensitive analytic techniques in both normal and pathologic tissues. It is highly in epithelial structures such as the tongue and skin (including the base of tongue papillae, hair follicles, and eccrine glands) and in certain immune compartments [28, 36, 37, 38, 39]. Low levels of GPRC5D m‐RNA have been detected in the motor neurons of the inferior olivary nucleus of the brainstem, although the corresponding protein is not expressed. Importantly, plasma cells exhibit the highest GPRC5D expression within the immune cell compartment, while it is minimally or not detected in normal B cells, T cells, natural killer cells, monocytes, granulocytes, and bone marrow progenitors. In addition, GPRC5D expression is absent in peripheral blood, distinguishing it from other targeted antigens in MM therapies [28, 36, 40].

GPRC5D is highly expressed in the bone marrow of patients with MM and smoldering MM, where its increased expression is correlated to worse clinical outcomes. Elevated GPRC5D mRNA levels in MM cells are associated with a higher frequency of genetic aberrations and high‐risk disease, and GPRC5D expression is linked to the International Staging System (ISS) and β2‐macroglobulin levels [28, 40, 41].

These observations suggested the use of GPRC5D as a clinical therapeutic target, particularly in patients who have relapsed after anti‐BCMA therapies. Although GPRC5D and BCMA are both expressed on CD138+ cells, their expression patterns are independent, and loss of the BCMA does not affect the GPRC5D expression [36].

Mechanisms of resistance have been described in the literature, including biallelic genetic inactivation or long‐range epigenetic silencing of GPRC5D promoter and enhancer regions [42].

3. Pre‐Clinical Trials

Encouraging pre‐clinical results on the mechanism of action, efficacy, and safety of GPRC5D‐targeting T‐cell‐redirecting antibodies (TRABs) tested in vitro and in vivo in mouse models provided the basis for advancing talquetamab into clinical research.

Kodama et al. first demonstrated that GPRC5D protein expression is predominantly limited to MM plasma cells and B cells, while CD34‐positive human bone marrow cells and other hematopoietic cells lack GPRC5D expression. Consistent with earlier findings, this study confirmed that GPRC5D expression was significantly elevated in skin tissue involved in keratin synthesis, such as hair follicles. This tissue‐restricted expression offered an advantage in terms of cytotoxicity, which appeared limited to a few non‐essential tissues [39].

A critical focus of pre‐clinical studies has been the relationship between genetic alterations and prognosis. One of the most investigated genetic alterations associated with poor prognosis in MM is the t (4;14) translocation. It was found that GPRC5D mRNA expression correlated with this translocation, further linking mRNA GPRC5D expression to worse prognosis. However, in GPRC5D‐positive tumor models (e.g., NCI‐H929 with t (4, 14) translocation), GPRC5D‐targeting TRABs therapy exhibited enhanced efficacy, suggesting that GPRC5D‐directed therapies may still be effective in high‐risk patients [39, 40].

Further integrating these results, Verkleij et al. used gene expression profiling and flow cytometry to confirm the high expression of GPRC5D mRNA and protein in MM cells, both in treatment‐naïve and in heavily pretreated patients. They demonstrated that talquetamab mediates its antitumor activity through T‐cell activation, pro‐inflammatory cytokine release, T‐cell degranulation, and the release of cytotoxic molecules such as granzyme B, involving both CD4+ and CD8+ T‐cells.

However, the ex vivo efficacy of talquetamab varied across different patient samples largely due to the variability in GPRC5D expression levels and differences in the immune microenvironment. Samples with higher GPRC5D expression generally showed greater talquetamab‐mediated efficacy [24].

The immune microenvironment was found to play a significant role in determining the response to talquetamab. T‐cell‐rich microenvironments, paradoxically, exhibited lower proportions of activated and degranulated T cells, while high levels of regulatory T‐cells (Treg) were associated with diminished talquetamab activity. Moreover, microenvironments enriched with T‐cells expressing PD‐1 or HLA‐DR at baseline were linked to poorer responses to talquetamab. Finally, elderly patient samples showed reduced talquetamab activity, likely due to an exhausted immune microenvironment, adversely affecting therapy response [26].

The combination of talquetamab with pomalidomide, an immunostimulatory agent, increased T‐cell activation and granzyme B secretion in co‐culture models while reducing Treg frequency. Additionally, the CD38‐targeting antibody daratumumab increased nicotinamide adenine dinucleotide levels in T cells, which enhanced T‐cell antitumor responses in mouse models, further amplifying talquetamab's efficacy [28]. These preclinical findings highlight the potential of combining talquetamab with other MM therapies to improve therapeutic outcomes.

4. Pivotal Clinical Study

Talquetamab (JNJ‐64407564) received accelerated FDA approval in August 2023 for adults with RRMM who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti‐CD38 monoclonal antibody [34]. The European Medicines Agency (EMA) also approved talquetamab in monotherapy for RRMM who received at least three previous treatments for their cancer, including an immunomodulatory agent, a proteasome inhibitor, and an anti‐CD38 antibody, and whose cancer has worsened since receiving the last treatment [35].

The approval was based on the phase 1/2 MonumenTAL‐1 trial (NCT03399799, NCT4634552), a multicenter, open‐label Phase 1/2 trial assessing talquetamab in RRMM patients. The trial included two phases: a dose‐escalation phase (Part 1) and a dose‐expansion phase (Part 2) (Table 1).

TABLE 1.

Summary of efficacy and safety data from the monumenTAL‐1 trial for talquetamab treatment across various dosage regimens.

Trial ID	References	Phase	Treatment	mFU months	ORR	≥ VGPR	mDOR	AEs any grade
MonumenTAL‐1 trial (NCT03399799, NCT4634552)	Chari A. et al. [27]	I	Talquetamab i.v.	4.0	72%	61%	27.8	CRS 49% Skin‐related AEs 24% Dysgeusia 37%
			Talquetamab s.c. 0.4 mg/kg QW	11.7	70%	57%	10.2	CRS 77% Skin‐related AEs 67% Dysgeusia 63%
			Talquetamab s.c. 0.8 mg/kg Q2W	4.2	64%	52%	7.8	CRS 80% Skin‐related AEs 70% Dysgeusia 57%
	Schinke CD et al. [43]	II	Talquetamab s.c. 0.4 mg/kg QW	14.9	74%	59%	9.5	CRS 79% Skin‐related AEs 56% Dysgeusia 57%
			Talquetamab s.c. 0.8 mg/kg Q2W	8.6	73%	57%	NR	CRS 75% Skin‐related AEs 71% Dysgeusia 48%
			Prior T‐cell redirection therapies (0.4 mg/kg QW or 0.8 mg/kg Q2W)	11.8	63%	53%	/	CRS 77% Skin‐related AEs 69% Dysgeusia 61%

Abbreviations: ≥ VGPR, very good partial response or better; AEs, adverse events; CRS, cytokine release syndrome; i.v., intravenous; LOTs, Lines of therapies; mDOR, median duration of response; mFU, median follow‐up; ORR, objective response rate; Q2W, every other week; QW, weekly; s.c., subcutaneous.

In the dose‐escalation phase, 232 patients received treatment intravenously or subcutaneously. Enrolled patients had a median of 6 previous lines of therapy (LOTs) (range 2–20), with 79% and 30% of cases presenting triple‐ and penta‐drug‐refractory disease, respectively. In addition, 87% showed refractoriness to the last line of therapy. The primary endpoints of the first part were to assess dose‐limiting toxic effects, adverse events, and laboratory abnormalities to define the recommended phase 2 (RP2D) for the subsequent dose‐expansion phase.

Talquetamab was administered intravenously in 102 patients, with or without step‐up doses (ranging from 0.5 to 3.38 μg/kg weekly or biweekly, or 5 to 180 μg/kg weekly), and subcutaneously to 130 patients, with step‐up doses ranging from 5 to 405 μg/kg weekly, 800 μg/kg weekly or every other week, 1200 μg/kg every other week, or 1600 μg/kg monthly. During part 1 of the study, two subcutaneous dosing regimens were selected for further evaluation in part 2: 405 μg/kg weekly with step‐up doses of 10 and 60 μg/kg in 30 patients, and 800 μg/kg every other week with step‐up doses of 10, 60 and 300 μg/kg in 44 patients.

In the dose‐expansion phase, patients received the RP2D of 0.4 mg/kg weekly (QW) or 0.8 mg/kg every 2 weeks (Q2W) with step‐up doses. The efficacy data showed were overlapping for both dose levels.

Efficacy outcomes, assessed according to International Myeloma Working Group (IMWG) criteria, are summarized as follows. At the 0.4 mg/kg weekly (QW) dose level, with a median follow‐up of 18.8 months, the overall response rate (ORR) was 74.1% and a very good partial response rate (VGPR) or better in 59.4% of patients, with a complete response (CR) of 9.8% and a stringent complete response (sCR) in 23.8%. The median duration of response was 10.2 months. At the 0.8 mg/kg (Q2W) dose level, with a median follow‐up of 12.7 months, the ORR was 71.7%, with a VGPR or better of 60.7%, a CR of 9%, and an sCR in 29.7% of patients. The median duration of responses was 7.8 months.

The updated Phase II results corroborated the findings from the previous phase of the study. Schinke CD. et al. reported outcomes for patients previously treated with and without T‐cell redirection therapies. Of the total patient cohort, 51 individuals had received prior T‐cell redirection therapy and were subsequently treated with either 0.4 mg/kg QW or 0.8 mg/kg Q2W. Among these patients, 89% were triple‐class refractory, 41% penta‐drug were refractory, and 12% received belantamab as part of their prior therapy. Regarding prior TRABs therapies, 71% received CAR‐T therapy, 35% BsAbs, and 6% received both modalities. At a median follow‐up of 11.8 months this cohort achieved an ORR of 63%, including a VGPR or better rate of 53%. The median PFS was 5.1 months.

The updated efficacy data from the pivotal cohort is consistent. These results confirmed that the ORR was sustained across all subgroups, regardless of baseline ISS stage, cytogenetic risk, number of prior LOTs, and previous belantamab exposure. In patients with baseline plasmacytomas, the ORR was 49% in both cohorts. Notably, responders exhibited higher T‐cell counts and lower levels of exhausted T cells and CD38+ Tregs [43].

The last updated results, presented at the ASH 2023 conference, confirmed the previously reported efficacy data. Specifically, in the population previously exposed to TRABs (anti‐BCMA), the ORR was 73%, with a median duration of response (mDOR) exceeding 1 year following CAR‐T therapy [44].

5. Adverse Events

The adverse events (AEs) observed in the MonumenTAL‐1 trial for talquetamab treatment (s.c.) at RP2Ds were carefully documented, especially due to their unique management requirements. At the date cut‐off of January 17, 2023, talquetamab was evaluated in 288 patients, with 143 receiving 0.4 mg/kg QW and 145 receiving 0.8 mg/kg Q2W, including 51 patients who had previously undergone T‐cell redirection therapy [43].

In phase 1 of the trial at the selected doses, the common AEs observed were CRS in 77% and 80% of patients, skin‐related events in 67% and 70%, and dysgeusia in 63% and 57% of patients, respectively. CRS events were primarily of grade 1 (G1) or G2 severity. One patient receiving the 800 μg/Kg dose experienced dose‐limiting toxicity, presenting as a G3 rash [27].

In phase 2, last updated safety data were consistent with previous findings, with most AEs classified as G1 and G2 and manageable. The most common AEs included CRS in 77% of patients, skin‐related AEs in 69%, nail‐related AEs in 61%, dysgeusia in 61%, and infections in 71% (of which 26% were G3–G4). Dose reductions due to AEs occurred in 10% of patients, while treatment discontinuation was noted in 6% of patients. Immune effector cell‐associated neurotoxicity syndrome (ICANS), a potentially severe complication observed in patients receiving immune‐based therapies and assessed using the American Society for Transplantation and Cellular Therapy (ASTCT) criteria, which incorporates Cell‐Associated Encephalopathy (ICE) score [45, 46], was observed in 3% of patients, with no treatment‐related deaths reported [43].

These AEs are consistent with those observed in other GPRC5D‐targeting therapies, but differ from those seen with other BsAbs approved for RRMM treatment [22, 48, 49, 50, 51, 52, 53]. Data indicated that these AEs are manageable, with a low incidence of treatment discontinuations. Importantly, no talquetamab treatment‐related deaths have been reported [43].

Recently, Chari et al. published an analysis of updated safety data from the MonumenTAL‐1 trial, providing insights into clinical measures for RRMM patients treated with talquetamab, thereby facilitating improved management strategies for this patient population [47].

AEs observed in the study included CRS, ICANS, infections, neutropenia, oral events, dermatologic toxicity, and other rare adverse events. Treatment discontinuation occurred in 4.9% of patients receiving the 0.4 mg/kg QW dose level, 8.3% of patients with the 0.8 mg/kg Q2W dose, and 9.8% of patients previously treated with T‐cell redirection therapy. Serious AEs were reported in 51.6% of the total patient population. G5 AEs were observed in 3.2% of patients, including two cases of COVID‐19 and general health deterioration, and one case involving fungal sepsis, infection, septic shock, respiratory failure, acute respiratory failure, pulmonary embolism, and basilar artery occlusion.

The incidence of CRS was consistent with rates observed in trials involving other BsAbs and CAR‐T cell therapy [43, 48]. Among a total of 399 patients treated across three cohorts, CRS was reported in 79% (113/143) of patients in the 0.4 mg/kg QW cohort, 74.5% (108/145) in the 0.8 mg/kg Q2W cohort, and 76.5% (39/51) in the cohort of patients previously treated with T‐cell redirection cohort. The median time to CRS onset was 25.9 h in the 0.4 mg/kg QW cohort, 28.0 h in the 0.8 mg/kg Q2W cohort, and 26.3 h in the T‐cell redirection therapy cohort. The median duration of CRS ranged from 14.5 to 20.4 h across the three cohorts.

The majority of AEs related to CRS was of G1–G2 severity and primarily occurred during the step‐up dosing and the first full dose. From the second treatment cycle onward, CRS was reported in only five patients in the 0.4 mg/kg QW cohort, in five patients in the 0.8 mg/kg Q2W cohort, and in two patients in the T‐cell redirection cohort. Dose modifications due to CRS were required for 18, 21, and 3 patients, across the three cohorts, respectively. Only one patient discontinued treatment to due CRS‐related AEs [43].

In the MonumenTAL‐1 trial phase 2 trial, ICANS were observed in 13 patients (10.7%) in the 0.4 mg/kg QW cohort, in 12 patients (11%) in the 0.8 mg/kg Q2W cohort, and in 1 patient (2.9%) in the prior T‐cell redirection cohort, as per the ASTCT criteria. The median time to onset of ICANS was 23.6, 31.9, and 115.5 h for the respective cohorts, with a median time to recovery ranging from 7.8 to 48.5 h. The majority of ICANS cases were classified as G1–G2, predominantly occurring during the step‐up or initial full‐dose phases; serious ICANS were reported in 4.1%, 3.7%, and 2.9% of patients in each cohort. Dose modifications were necessitated in four patients, while three patients discontinued treatment due to ICANS. Notably, ICANS primarily manifested following or concurrent with CRS [29, 43, 44, 45, 46, 47].

In the MonumenTAL‐1 trial, infections were reported in 84 patients (58.7%) from the 0.4 mg/kg cohort, in 96 patients (66.2%) from the 0.8 mg/kg cohort, and in 37 patients (72.5%) from the T‐cell redirection cohort. According to the Common Terminology Criteria for Adverse Events (CTCAE), G3–G4 AEs were reported in 19.6%, 14.5%, and 27.5% of patients across the respective cohorts.

The most frequently reported infections included COVID‐19, upper respiratory tract infections, urinary tract infections, nasopharyngitis, bronchitis, and pneumonia [43, 47, 48, 49, 50]. Notably, over 87% of infections resolved, while opportunistic infections were detected in five patients (3.5%) in the 0.4 mg/kg QW cohort, in eight patients (5.5%) in the 0.8 mg/kg Q2W cohort, and in three patients (5.9%) in the T‐cell redirection therapy cohort. Infections occurred in association with G3‐G4 neutropenia in 13.1%, 3.1%, and 24.3% of patients in each cohort, respectively. Dose modification due to infection‐related AEs was recorded in 32, 29, and 10 patients across the cohorts. Discontinuation of treatment was noted in two patients from the 0.4 mg/kg QW cohort and in one patient from the T‐cell redirection cohort. Additionally, five patients died because of infections, specifically two from COVID‐19 pneumonia, and one each from septic shock, fungal sepsis, and another unspecified infection. Importantly, no cases of pneumocystis pneumonia were reported.

Hypogammaglobulinemia was reported across all cohorts and managed with intravenous immunoglobulins; however, statistical analysis indicated that this AE was less frequent compared to BCMA‐targeting BsAbs. During the step‐up dose phase and initial full dose cycles, it is critical to differentiate between CRS and infections to ensure appropriate management strategies are employed [43, 47, 48, 49].

Oral events recorded in the MonumenTAL‐1 trial included dysgeusia, dry mouth, and dysphagia. The underlying mechanisms responsible for these oral AE remain unclear. GPRC5D expression is limited to filiform papillae and plasma cells, yet taste receptors are not located in these areas, which does not fully explain the occurrence of dysgeusia. Further investigation is required to better understand the pathophysiology behind these oral AEs and to improve management strategies for affected patients.

Dysgeusia was observed in 103 patients (72%) in the 0.4 mg/kg QW cohort, 103 patients (71%) in the 0.8 mg/kg Q2W cohort, and 39 patients (76.5%) in the T‐cell redirection cohort. The majority of these cases were of G1 severity. Investigators proved that dose reductions or delays could improve patient compliance without compromising treatment efficacy [43, 47, 51, 52].

G1‐G2 dry mouth events were reported in 38 patients (26.6%) in the 0.4 mg/kg QW cohort, 58 patients (40%) in the 0.8 mg/kg Q2W cohort, and 26 patients (51%) in the T‐cell redirection cohort. Dose modifications were necessary for nine patients; however, no treatment discontinuations were attributed to dry mouth [53, 54].

Dysphagia was reported in 34 patients (23.8%) in the 0.4 mg/kg QW cohort, 36 patients (24.8%) in the 0.8 mg/kg Q2W cohort, and 12 patients (23.5%) in the T‐cell redirection cohort. G3 dysphagia occurred in only three patients, all from the 0.8 mg/kg Q2W cohort. Dose modification was necessary for fewer than 6% of patients across all cohorts, and no treatment discontinuations were attributed to dysphagia [55, 56].

Dermatologic toxicity included both skin and nail toxicity, likely related to the high expression of GPRC5D in hair follicles, eccrine glands, and the keratogenous zone of nails. Nail toxicity, as suggested by pre‐clinical studies, seems to be an on‐target, off‐tumor effect, driven by GPRC5D expression in these non‐tumor tissues.

Skin toxicities were categorized into rash and non‐rash skin toxicities. Rash‐related toxicity included rash, maculopapular rash, erythematous rash, and erythema. Non‐rash skin toxicities comprised skin exfoliation, dry skin, pruritus, and palmar‐plantar erythrodysesthesia syndrome.

Rash toxicities were reported in 57 patients (39.9%) in the 0.4 mg/kg QW cohort, 43 patients (29.7%) in the 0.8 mg/kg Q2W cohort, and 18 patients (35.3%) in the T‐cell redirection cohort. Non‐rash skin toxicities were observed in 80 patients (55.9%) in the 0.4 mg/kg QW cohort, 106 patients (73.1%) in the 0.8 mg/kg Q2W cohort, and 35 patients (68.6%) of the T‐cell redirection cohort. Data showed that the majority of skin toxicities were G1 or G2, with only 12 cases of G3 rash skin toxicity and 1 case of G3 non‐rash skin toxicity. Dose modifications were necessary for only a few events, and 3 patients discontinued treatment because of non‐rash skin toxicities.

Nail toxicity that included nail discoloration, nail disorder, onychomadesis, onycholysis, nail dystrophy, and nail ridging occurred in 78 patients from 0.4 mg/kg QW cohort (54.5%), in 78 patients from the 0.8 mg/kg Q2W cohort (53.8%), and in 32 patients from T‐cell redirection cohort (62.7%). All events were of G1‐G2. Few dose modifications and no discontinuation were observed.

Rare AEs included tumor lysis syndrome (TLS); a single patient from the 0.8 mg/kg Q2W cohort, with a high disease burden (90% bone marrow plasma cells via biopsy of 90% and 60% via aspirate at baseline) showed a G3–G4 TLS. TLS prophylaxis is recommended especially in high‐risk patients due to significant disease burden. One patient from the prior T‐cell redirection cohort experienced a G2 hemophagocytic lymphohistiocytosis [50]. Alopecia was observed across all cohorts as a rare and low‐grade AE. While ataxia occurred in one patient, differently from the more frequent incidence observed in CAR‐T therapies [57].

Potential immune‐mediated AEs emerged from the trial. Tumor flare and pseudo‐progression were observed, as highlighted by a case report involving a 61‐year‐old woman. Recognizing the possibility of this clinical syndrome is crucial, as early discontinuation of treatment due to perceived progression could adversely impact the patient outcome [58, 59].

A summary of safety data from the MonumenTAL‐1 trial on talquetamab treatment across various dosage regimens is described in Table 1.

In real‐world settings, the safety profile of talquetamab observed in the MonumenTAL‐1 trial has been confirmed; however, physicians have reported the emergence of new toxicities not previously reported [60, 61, 62].

5.1. Management of Adverse Events

Since the first talquetamab administration requires close monitoring, it is mandatory to conduct it in a clinical setting with immediate access to critical care units, the capacity to perform neurologic evaluation, and the availability of supportive measures, including tocilizumab, oxygen, corticosteroids, and vasopressors [47, 63].

To optimize the management and prevention of CRS, the talquetamab administration protocol incorporated step‐up dosing before the first full dose for each cohort. The step‐up doses were set at 0.01 and 0.06 mg/kg for doses 1 and 2, respectively, at both dose levels. For the 0.8 mg/kg Q2W cohort, a third step‐up dose was administered, with 0.03 mg/kg for the FDA schedule and 0.04 mg/kg for the EMA schedule. Additionally, premedication with glucocorticoid, antihistamine, and antipyretic was required to further mitigate the risk of CRS. The MonumenTAL‐1 trial protocol required a minimum of 48 h of hospitalization, starting from the first infusion of the step‐up dose through to the first full dose. This allowed for close monitoring of patients to detect early signs and symptoms of CRS and to differentiate them from other AEs, such as infections. To enhance patient outcomes, CRS management guidelines were published, aiming to improve the quality of life and, consequently, the efficacy of the treatment [29, 34, 35, 43, 47, 48].

Management of ICANS adhered to ICE score, and established guidelines, incorporating supportive therapies such as corticosteroids, tocilizumab, levetiracetam, and anakinra, in alignment with existing literature recommendations [29, 34, 35, 43, 44, 45, 46, 47, 64, 65].

Infections remain a significant challenge in MM patients receiving immunotherapies. The prevention of herpes infections with acyclovir or valacyclovir is regularly employed. Patients are encouraged to get Herpes Zoster, COVID‐19, and influenza vaccination before treatment initiation. Monitoring for hypogammaglobulinemia and administration of intravenous immunoglobulin (IVIG) have also been recommended for recurrent infections or levels below 400 mg/dL [47, 63]. To manage neutropenia, filgrastim should be considered.

Nail toxicities may be managed with topical moisturizers, topical corticosteroids, emollients, nail soaks, and protective nail coverings. Grade 3 rashes could be managed with topical or oral corticosteroids and talquetamab may be restarted in the majority of patients. Xerosis and pruritis may also take advantage of topical steroids and oral antihistamines [47, 63].

Dysgeusia and other oral AEs that may lead to significant malnourishment and weight loss need close monitoring. Dysgeusia can be managed with mouth rinses, such as salt water or liquid corticosteroids, pain medications, and short courses of oral corticosteroids [47, 53, 54, 55, 56, 63].

Dry mouth/xerostomia instead needs xylitol and sorbitol to support dental health, artificial saliva, and glycerol for the lubrification of the food, as well as lysozyme, lactoferrin, and lactoperoxidase as antibacterial agents. Fluconazole as candidiasis prophylaxis is always administered [47, 53, 54, 55, 56, 63].

6. Ongoing Clinical Studies

Pre‐clinical studies have shown an emerging mechanism of resistance after treatment with BCMA or GPRC5D‐targeting BsAbs. Most cases involve mutational events in target proteins, which interfere with the BsAbs receptor binding [66]. However, emerging preclinical data from BsAbs CAR‐T constructs direct against both BCMA and GPRC5D, showed superior results compared to single‐target therapies [67, 68].

Ongoing trials are primarily exploring combination therapies with talquetamab to enhance efficacy while ensuring safety. Key ongoing trials are summarized in Table 2.

TABLE 2.

Overview of key clinical trials involving talquetamab in multiple myeloma.

Trial ID	Phase	Population	Intervention/treatment	Outcome measures
TRIMM‐2 study (NCT04108195) [72, 73]	1b/2	RRMM (≥ 3 previous LOTs)	Dara + Tal ± Pom Versus Dara + Tec ± Pom	Part1: DLT Part2: AEs and SAEs
TRIMM‐3 trial (NCT05338775) [75]	1b	RRMM	Tal+Tec+PD‐1 inhibitor	AEs
RedirecTT‐1 study (NCT04586426) [74]	1/2	RRMM	Tal+Tec ± Dara	Part 1: DLT Part 2: AEs and SAEs Part 3: ORR
MonumenTAL‐2 (NCT05050097)	1b	MM	Tal+Carf versus Tal+Carf + Dara versus Tal+len versus Tal+Len+Dara versus Tal+Pom	AEs
MonumenTAL‐3 trial (NCT05455320)	3	RRMM [≥ 1 LOTs]	Talq/Dara versus Talq/ Dara/Pom versus DPd	PFS
MonumenTAL‐6 trial (NCT06208150)	3	RRMM [1–4 LOTs with an Anti‐CD38 Antibody and Lenalidomide]	Tal‐p or Tal‐Tec versus EPd or PVd	PFS
MajesTEC‐7 trial (NCT05552222)	3	NDMM	Tec/Dara/Len versus Talq/Dara/Len versus DRd	PFS Sustained MRD‐negative CR
GEM‐TECTAL trial (NCT05849610)	2	DNHRMM	DaraVRd followed by Tec/Dara or Talq/Dara	MRD negative CR rate

Abbreviations: AEs, Adverse Events; Carf, carfilzomib; CR, complete response; Dara, daratumumab; DaraVRd, daratumumab, bortezomib, lenalidomide and dexamethasone; DLT, Dose Limiting Toxicity; DNHRMM, de novo high‐risk multiple myeloma patients; DPd, daratumumab, pomalidomide, dexamethasone; DRd, daratumumab, lenalidomide and dexamethasone; EPd, elotuzumab, pomalidomide, and dexamethasone; Len, lenalidomide; LOTs, lines of therapies; MRD, measurable residual disease; NDMM, newly diagnosed multiple myeloma; ORR, Overall Response Rate; PFS, progression‐free survival; Pom, pomalidomide; PVd, pomalidomide, bortezomib, and dexamethasone; RRMM, relapsed/refractory multiple myeloma; SAEs, Serious Adverse Events; Tal, talquetamab; Tec, teclistamab.

The TRiMM‐2 study (NCT04108195) is a trial that evaluated the use of talquetamab in combination with daratumumab, with or without pomalidomide, in RRMM patients. Phase 1 established the RP2Ds for each combination and assessed safety profiles. The rationale for combining talquetamab and daratumumab stems from pre‐clinical findings where daratumumab‐mediated depletion of CD38‐expressing Tregs enhanced talquetamab's efficacy in killing MM cells. In mouse models, daratumumab‐induced reduction of NADase activity in CD38‐expressing cells increased immune activity [17, 26, 27, 43, 69].

Enrolled patients had received at least three LOTs or were refractory to a PI and an IMiD. Before therapies with an anti‐CD38 > 90 days, other BsAbs and CAR‐T cells were also enrolled. Patients were treated with s.c. talquetamab (0.4 QW or 0.8 mg/kg Q2W) plus daratumumab 1800 mg per protocol.

Safety data revealed that 78.8% of patients experienced G1 and G2 CRS, with some treated requiring tocilizumab treatment. ICANS was reported in 4.6% of patients (G1–G2). Among oral AEs related to GPRC5D, dysgeusia, dry mouth, and stomatitis were the most common, with G3–G4 in 3% of cases. Dermatological AEs were reported in 81.5% of patients (G3–G4: 9%) and nail AEs in 66% (G3–G4: 1.5%). Hematologic toxicities, including neutropenia, lymphopenia, and thrombocytopenia, were also frequent.

The most frequent infection was pneumonia (26% of patients). Efficacy data showed an ORR of 80% in anti‐CD38 mAb‐refractory patients treated with 0.4 mg/kg QW, and an ORR of 79% in patients previously exposed to CAR‐T therapy [70, 71, 72, 73].

The MonumenTAL‐2 (NCT05050097) is a multi‐arm phase 1b study of talquetamab administered with other anticancer agents in RRMM patients to establish the safety dose level of each regimen. Talquetamab was administered in five different experimental treatment combinations, including carfilzomib, daratumumab, lenalidomide, and pomalidomide.

The RedirecTT‐1 study (NCT04586426) is a phase 1b/2 trial, that was designed to test the combination of two BsAbs, teclistamab and talquetamab.

The trial included dose escalation and expansion phases to establish the recommended Phase 2 regimen(s) (RP2R[s]), assess safety, and establish efficacy in RRMM patients and those with extramedullary disease. The safety profile was consistent with other trials, with CRS being the most frequent AE (76.3%). Other AEs included dysgeusia, skin toxicity, nail disorders, infections, and febrile neutropenia. Drug‐related discontinuation occurred in 6.5% of patients. Efficacy data showed an ORR of 96.3% at the RP2R, with 40.7% achieving at least VGPR. In patients with extramedullary disease, the ORR was 85.7% [74].

The TRIMM‐3 trial (NCT05338775) is a phase 1 trial evaluating talquetamab and teclistamab in combination with a Programmed Cell Death receptor‐1 (PD‐1) inhibitor in RRMM patients. The primary end‐points were to determine the dosage of the PD‐1 inhibitor and the safety and tolerability of each combination [75].

Additional trials are exploring other combination therapies with talquetamab in RRMM patients, including the phase I trial (NCT06348108) assessing talquetamab with iberdomide and dexamethasone in tiple class exposed (TCE) RRMM patients.

Ongoing Phase III clinical trials, including the MonumenTAL‐6 trial (NCT06208150) and MonumenTAL‐3 trial (NCT05455320), are evaluating various talquetamab‐based regimens against standard treatments in RRMM. Specifically, the MonumenTAL‐6 trial compares talquetamab in combination with pomalidomide (Tal‐P) and with teclistamab (Tal‐Tec) against the investigator's choice of either elotuzumab, pomalidomide, and dexamethasone (EPd) or pomalidomide, bortezomib, and dexamethasone (PVd). The patient population consists of individuals with RRMM who have undergone 1–4 prior lines of therapy, including an anti‐CD38 monoclonal antibody and lenalidomide. Additional trials are currently investigating talquetamab in other disease settings and patient populations. The MonumenTAL‐3 trial compares subcutaneous talquetamab with daratumumab and pomalidomide (Tal‐DP), talquetamab with daratumumab (Tal‐D), and the combination of daratumumab, pomalidomide, and dexamethasone (DPd) in RRMM patients who have received at least one prior line of therapy.

The NCT06066346 trial is designed to evaluate the talquetamab treatment efficacy, specifically assessing the ORR in RRMM patients who have previously undergone BCMA‐targeted CAR T‐cell therapy.

The OPTIMMAL trial (NCT06461988) is an ongoing phase II clinical trial, enrolling a total of 30 patients, aimed at evaluating the efficacy of talquetamab in combination with lenalidomide as maintenance therapy following stem cell transplant. The primary end‐point of the study is to assess the CR rate at 12 months. Additionally, the trial will investigate the safety of the combination treatment, as well as monitor longitudinal patient‐reported outcomes related to symptoms and quality of life.

In newly diagnosed MM patients, eligible for high‐dose therapy, the TALTEC trial (NCT06505369), a phase 2, open‐label, multicentre, non‐randomized trial, is evaluating the efficacy of T‐cell redirection therapy, using a sequential combination of talquetamab and teclistamab during a consolidation phase, following induction phase with Dara‐VRd. The primary objective is to determine the ability of this regimen to enhance MRD‐negative CR rate in this setting of patients.

Conversely, in newly diagnosed MM patients, who are either ineligible or not intended for autologous stem cell transplant as initial therapy, the MajesTEC‐7 trial (NCT05552222), is a phase 3 randomized study that is designed to compare the efficacy of teclistamab in combination with subcutaneous daratumumab and lenalidomide (Tec‐DR), as well as talquetamab combined with subcutaneous daratumumab and lenalidomide (Tal‐DR) versus the standard regimen of subcutaneous daratumumab, lenalidomide and dexamethasone (DRd). The primary end‐point is PFS.

The MonumenTAL‐8 trial (NCT06550895) is an ongoing phase II trial designed to evaluate the safety of the combination of ciltacabtagene autoleucel (Cilta‐cel) and talquetamab in high‐risk MM patients, divided into three different cohorts. Cohort 1 includes RRMM patients who will receive cilta‐cel and talquetamab as consolidation following CAR‐T treatment, cohort 2 includes newly diagnosed MM (NDMM) patients who will undergo induction therapy with DRd followed by cilta‐cel and multiple cycles of Talquetamab as consolidation treatment, cohort 3 involves RRMM patients receiving talquetamab as bridging to cilta‐cel therapy.

Several other ongoing trials are investigating in newly diagnosed MM population. The IFM 2022–01 trial (NCT06353022) is testing T‐cell redirection therapy based on MRD status, comparing MRD‐negative standard‐risk patients to MRD‐positive high‐risk patients. The aMMbition trial (NCT06577025) evaluates sequences of treatment in NDMM patients, comparing the combination of ciltacel and talquetamab with daratumumab, and teclistamab with daratumumab, following induction therapy with daratumumab, bortezomib, lenalidomide, and dexamethasone. The GEM‐TECTAL trial (NCT05849610) focuses on high‐risk NDMM patients and aims to evaluate the efficacy and the safety of teclistamab plus daratumumab and talquetamab plus daratumumab as intensification treatment, with MRD‐negative CR as the primary outcome.

In smoldering myeloma, talquetamab is being tested to limit disease progression. The REVIVE study (NCT06100237) is a phase 2 immune‐oncology trial designed to assess the efficacy of talquetamab and daratumumab (Tal‐Dar) or teclistamab and daratumumab (Tec‐Dara) in preventing the progression to active MM with the MRD as a primary endpoint.

Several trials aim to optimize the administration and management of talquetamab. The NCT05972135 is a phase 2 designed to assess the safety of outpatient administration of teclistamab or talquetamab in MM in the post‐marketing setting, focusing on the incidence of CRS during the first two treatment cycles.

The Talisman trial (NCT06500884) aims to minimize oral AEs related to talquetamab, exploring preventing measures to enhance tolerability.

In addition to clinical trials, studies are examining the real‐world efficacy of talquetamab. The REALiTEC/TAL (NCT06285318) is a retrospective trial evaluating the clinical outcomes in RRMM patients receiving the T‐cell redirecting therapy with either talquetamab or teclistamab.

Furthermore, two observational real‐world studies, LocoMMotion (NCT04035226) and MoMMent (NCT05160584) utilize adjusted comparisons to assess the relative effectiveness of talquetamab versus real‐world physician's choice of therapy [76].

7. Discussion

In recent decades, a long list of non‐targeted therapies has been approved for the treatment of MM, which has significantly improved patient survival by effectively targeting myeloma cells. Despite their efficacy in slowing disease progression, the non‐specific action of these treatments limits their long‐term tolerability. Targeted therapies, which focus on specific molecules or pathways critical to myeloma cell survival and proliferation, offer a more refined approach. By selectively attacking tumor cells while sparing normal tissues, these drugs promise to reduce adverse effects and improve patient outcomes. Consequently, the development of targeted treatments is essential for optimizing therapeutic strategies in MM, providing the potential for more effective disease control with a reduced risk of toxicity [77].

Efficacy data from the pivotal trials of BsAbs teclistamab, elranatamab, and talquetamab demonstrated robust clinical responses, leading to their accelerated approval as shown in Table 3.

TABLE 3.

Bispecific antibodies pivotal trials.

Bispecific antibody	Pivotal trial	Phase	Target	Administration	LOTs (median)	ORRs	mDOR (months)	CRS any grade	ICANS G3
Teclistamab [23]	MajesTEC‐1 (NCT03145181/NCT04557098)	1–2	BCMA	S.C. QW	4 (5)	63%	18.4	72.1%	2.4%
Elranatamab [25]	MagnetisMM (NCT03269136 /NCT04649359/NCT05014412)	2	BCMA	S.C. QW or Q2W	2 (7)	61%	NR	57.7%	7%
Talquetamab [27, 43]	Monumen TAL‐1 (NCT03399799)	2	GPRC5D	S.C. QW or Q2W	2 (6) for 0.4 mg/kg	68%	7.8–10.2	78.4%	6%
					2 (5) for 0.8 mg/kg

Abbreviations: BCMA, B‐cell maturation antigen; class C, group 5 member D; CRS, cytokine release syndrome; GPRC5D, G‐protein coupled receptor; ICANS, immune effector cell associated neurotoxicity syndrome; IV, intravenous; LOTs, lines of previous therapies; mDOR, median duration of response; NR, not reached; ORR, Overall response rate; Q2W, every 2 weeks; QW, weekly; SC, subcutaneous.

As per pivotal trial data, talquetamab represents a significant advancement in the treatment of RRMM. Its dual‐targeting mechanism, engaging both CD3 on T‐cells and GPRC5D on myeloma cells, offers a novel therapeutic strategy, facilitating potent T‐cell activation and subsequent tumor cell lysis. This approach is especially beneficial for patients who have developed resistance to BCMA‐targeting therapies, which are a mainstay in the current treatment landscape [36, 43, 44, 67, 78].

One of the most compelling aspects of talquetamab is its demonstrated efficacy in heavily pretreated populations. The MonumenTAL‐1 trial showed an impressive ORR of approximately 70%, even among patients who had failed BCMA‐targeted therapies. This high response rate is particularly significant, as RRMM patients are notoriously difficult to treat due to the development of resistance to multiple prior therapies. Talquetamab's efficacy in this context positions it as a valuable option for patients with limited treatment choices [27, 43, 44].

Despite its efficacy, talquetamab does have a safety profile that requires careful management. CRS is a common side effect, occurring in 40% of patients, and up to 80% of those receiving certain doses. However, the predictability of CRS and its generally manageable nature within a controlled clinical environment make this side effect less concerning when appropriately managed.

A unique feature of talquetamab is its “on‐target off‐tumor” effects, which include dysgeusia (taste alterations), skin‐related issues, and nail‐related toxicities. Although these AEs are usually non‐severe and rarely lead to treatment discontinuation, they can negatively impact the patient's quality of life, especially with long‐term treatment. Addressing these toxicities through supportive care is crucial, as these side effects might influence patient adherence and satisfaction with the therapy [47, 63].

Real‐world evidence has added further support to talquetamab's clinical utility. Studies comparing talquetamab to real‐world physicians' choice of therapy (RWPC) have demonstrated its superior effectiveness, underscoring its potential as a valuable tool in the treatment of RRMM [76]. The availability of such real‐world data is particularly important, as it reflects the drug's performance outside the controlled setting of clinical trials, giving clinicians greater confidence in its use across broader patient populations.

One of the major advantages of talquetamab is its potential role as an alternative to CAR‐T cell therapy for patients with rapidly progressing diseases. CAR‐T cell therapy, while highly effective, often requires a significant lead time for cell manufacturing, which may not be feasible for patients with aggressive disease who require immediate intervention. Talquetamab, administered subcutaneously and without the need for such delays, offers a timely therapeutic option, allowing clinicians to act more quickly in critical cases. Moreover, the toxicity profile of CAR‐T therapy is often more severe, which is an important consideration for elderly or frail patients. In this patient population, talquetamab's more manageable side effect profile may make it a more suitable option.

Nevertheless, talquetamab does come with certain limitations. The long‐term durability of responses remains uncertain, as data are still emerging. While initial outcomes are promising, the question of how patients will respond over time, particularly those who progress on talquetamab, is yet to be fully answered [79]. Additionally, the optimal sequencing of talquetamab with other therapies, such as BCMA‐targeting agents and CAR‐T cells, remains a critical clinical question. Mechanisms of resistance, including antigen escape and downregulation of BCMA, complicate the landscape, and more research is needed to determine the best therapeutic order.

In addition to BCMA, other promising therapeutic targets are being investigated for MM, showing potential in both monotherapy and combination regimens.

Forimtamig (RG6234) is a unique BsAb that binds CD3 on T cells and GPRC5D on plasma cells, with a distinct bivalent binding to the N‐terminus of GPRC5D. This higher affinity binding compared to conventional 1 + 1 formats, promotes more stable immunological synapse formation, enhancing T‐cell activation and tumor cell killing. Based on promising preclinical results, an ongoing phase 1 trial is assessing the safety and pharmacokinetics of escalating doses in RRMM patients. Preliminary results show an ORR of 71.4% for intravenous and 60.4% for subcutaneous administration, with CR/sCR rates of 28.5% and 18.8%, respectively [28, 58, 80, 81].

Cevostamab, another BsAb, targets Fc receptor‐homolog 5 (FcRH5) and CD3 and is currently under evaluation in RRMM patients who have previously received prior anti‐BCMA therapies, including anti‐BCMA antibody‐drug conjugates, CAR T cells, and anti‐BCMA BsAbs [30, 82].

Trispecifc antibodies (TsAbs) targeting two different tumor antigens are emerging as a potential strategy. The tri‐specific antibody JNJ‐ 79635322 targets CD3 on T‐cells and BCMA and GPRC5D on tumor cells, aiming to reduce ‘on target/off tumor’ toxicity.

Another TsAb, SAR442257, binds not only CD3 but also CD38 and CD28 [83]. The interaction with CD28 provides a costimulatory signal to T‐cells, which helps to prevent T‐cell exhaustion and may enhance the durability of the immune response against tumor cells [83].

Additionally, ISB 2001, which targets CD3, CD38, and BCMA, has shown promising activity in preclinical MM models [84].

Finally, cost and accessibility also pose challenges for talquetamab. Like many novel therapies, its high cost may limit its availability to some patients, particularly in healthcare systems with limited resources. The requirement for inpatient monitoring during the step‐up phase adds to the overall treatment burden, both in terms of cost and healthcare logistics. Ensuring that talquetamab is accessible to a broad patient population while managing these financial and practical challenges will be key to its long‐term success.

In conclusion, talquetamab is a highly promising therapeutic option for RRMM patients, particularly those who have few remaining treatment choices. Its novel targeting mechanism, impressive efficacy in heavily pretreated populations, and relatively manageable safety profile make it a valuable addition to the MM treatment landscape. However, its role in the broader therapeutic context will continue to evolve as more data become available on long‐term outcomes, optimal sequencing strategies, and real‐world applications. As these factors are clarified, talquetamab is likely to play an increasingly central role in the treatment of RRMM, offering new hope to patients facing a challenging and relapsing disease.

Author Contributions

All authors contributed to the manuscript and were involved in revisions and proofreading. All authors approved the submitted version.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The authors have nothing to report.