Талкетамаб у японских пациентов с рецидивной/рефрактной множественной миеломой MonumenTAL-1 Учёба.

Introduction

Multiple myeloma (MM) is a hematologic cancer in which plasma cells proliferate excessively and overproduce abnormal immunoglobulins, leading to multiple organ system complications [ 1 ]. Globally, MM is the third most common hematologic malignancy with a 5-year prevalence of 6.8 per 100,000 individuals and approximately 121,388 deaths reported in 2022 [ 2 ]. In Asia, Japan has the highest incidence of MM, and incidence has steadily increased over time with more than 7000 new cases reported in 2019 [ 3 ]. Established therapies for the treatment of MM in Japan are generally consistent with the rest of the world and include immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs) [ 4 – 7 ]. In the relapsed/refractory setting, no consensus standard of care exists, although novel B-cell maturation antigen (BCMA)-targeting immunotherapies, including ciltacabtagene autoleucel and idecabtagene vicleucel (chimeric antigen receptor [CAR]-T cell therapies) and teclistamab and elranatamab (bispecific antibodies), have been approved in this setting in Japan [ 3 , 8 – 12 ]. Despite these newer therapies, MM remains incurable, and patients continue to experience cycles of remission and relapse, with each remission typically shorter than the last and each successive relapse with a poorer prognosis [ 13 – 15 ]. To address this unmet need, additional novel treatments are needed to expand treatment options for Japanese patients with relapsed/refractory MM (RRMM).

Talquetamab is a first-in-class, off-the-shelf, T-cell redirecting bispecific antibody that targets G protein–coupled receptor family C group 5 member D (GPRC5D) on myeloma cells and CD3 on T cells [ 16 , 17 ]. GPRC5D is an orphan receptor with no recognized ligand and is highly expressed in malignant plasma cells but rarely in normal plasma cells [ 18 ]. Talquetamab induces T-cell–mediated cytotoxicity by bringing activated CD3-expressing T cells into close proximity to GPRC5D-expressing myeloma cells, leading to T-cell activation and subsequent lysis of myeloma cells [ 16 – 18 ].

Talquetamab has been approved in both the United States and Europe for patients with triple-class exposed (to an IMiD, PI, and anti-CD38 mAb) RRMM based on results from the global phase 1/2 MonumenTAL-1 study ( NCT03399799 /NCT04636552) [ 16 , 17 ]. In MonumenTAL-1, talquetamab demonstrated high response rates of ≥ 69% in patients with triple-class exposed RRMM who received two recommended phase 2 doses (RP2Ds) of subcutaneous (SC) talquetamab: 0.4 mg/kg weekly (QW) or 0.8 mg/kg every other week (Q2W). Responses were rapid and durable: time to response (TTR) was 1.2 (QW) and 1.3 (Q2W) months, median duration of response (DOR) was 9.5 (QW) and 16.9 (Q2W) months, and 12-month overall survival (OS) rates were 76.4% (QW) and 76.8% (Q2W) [ 19 ]. Common adverse events (AEs) included cytokine release syndrome (CRS) and on-target, off-tumor (GPRC5D-related) AEs; however, talquetamab was generally tolerable and led to few treatment discontinuations (4.9% [QW] and 9.1% [Q2W]) [ 17 , 19 ].

A phase 1 analysis of talquetamab in 15 Japanese patients receiving three doses of talquetamab (0.135 mg/kg QW, 0.4 mg/kg QW, and 0.8 mg/kg Q2W) revealed no dose-limiting toxicities, deaths, or dose reductions/treatment discontinuations due to AEs. Common AEs included neutropenia, lymphopenia, CRS, and GPRC5D-related AEs, similar to the global MonumenTAL-1 study, and overall response rate (ORR) was 60.0% (0.4 mg/kg QW) and 83.3% (0.8 mg/kg Q2W) [ 19 , 20 ]. Here, we report outcomes with talquetamab 0.4 mg/kg QW in Japanese patients enrolled in a separate phase 2 cohort of the MonumenTAL-1 study.

Materials and methods

Study design and patients

The methodology of MonumenTAL-1 was previously published [ 19 , 21 ]. Briefly, MonumenTAL-1 is a first-in-human, phase 1/2, open-label, multicenter study of talquetamab monotherapy in patients with RRMM. The phase 1 dose escalation and expansion portion of the study identified two RP2Ds: SC talquetamab 0.4 mg/kg QW and 0.8 mg/kg Q2W [ 21 ]. In phase 2, efficacy and safety were further assessed in patients receiving the RP2Ds of talquetamab. Eligible patients in phase 2 were aged ≥ 18 years, had measurable MM per International Myeloma Working Group (IMWG) criteria [ 22 ], had ≥ 3 prior lines of therapy (≥ 1 PI, ≥ 1 IMiD, and ≥ 1 anti-CD38 mAb), had documented progressive disease based on IMWG 2016 criteria, and had an Eastern Cooperative Oncology Group performance status ≤ 2. Patients enrolled in the global cohorts included those who were naive or exposed to prior T-cell redirection therapies, such as CAR-T and bispecific antibodies; prior exposure to antibody–drug conjugates was permitted. Patients from Japan with no prior exposure to T-cell redirection therapies were enrolled in a separate phase 2 cohort of MonumenTAL-1, referred to as the Japan cohort.

This study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines of the International Council for Harmonisation. Study protocol and amendments were approved by the institutional review board at each site, and all authors affirm that the study was conducted in accordance with the protocol. All patients provided written informed consent.

Treatment

Patients in the Japan cohort received SC talquetamab 0.4 mg/kg QW. To mitigate the risk of CRS, patients received two step-up doses (0.01 mg/kg and 0.06 mg/kg) of talquetamab and pretreatment medications (glucocorticoid, antihistamine, and antipyretic) prior to step-up doses and initial full treatment dose. Hospitalization for ≥ 48 h was required from the start of each step-up dose and first full treatment dose. Patients received treatment until disease progression, unacceptable toxicity, withdrawal of consent, or end of study.

Endpoints and assessments

The primary endpoint for the Japan cohort was ORR. Key secondary endpoints included DOR, rate of very good partial response or better (≥ VGPR), rate of complete response or better (≥ CR), rate of stringent complete reponse (sCR), TTR, progression-free survival (PFS), OS, incidence of AEs, and pharmacokinetics (PK).

ORR was defined as the proportion of patients who achieved a partial response or better according to IMWG 2016 consensus criteria [ 22 ]. Disease response and progression were assessed by an independent review committee. CRS and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded by American Society for Transplantation and Cellular Therapy criteria [ 23 ]. All other AEs were graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Serial PK serum samples were collected from Cycle 1 until Cycle 13 and at the end of treatment. Serum concentrations of talquetamab were analyzed using a validated, specific, and sensitive immunoassay method with a lower limit of qualification of 0.5 ng/mL.

Efficacy and safety analyses were based on a data cutoff date of September 2024. PK analyses were based on a data cutoff date of May 2024.

Statistical analyses

Efficacy and safety data were analyzed in Japanese patients who received at least one dose of talquetamab. ORR and 95% exact confidence intervals (CIs) were calculated; statistical significance was considered achieved if the lower limit of the two-sided 95% CI of the ORR was > 30%. The Kaplan–Meier method was used to analyze DOR, PFS, and OS. Data were summarized using descriptive statistics.

Results

Patients

Between July 2022 and December 2023, 36 patients were enrolled in the talquetamab 0.4 mg/kg QW Japan cohort. The median age was 70.5 years, and the majority of patients were male (55.6%). Patients had a median of 3.5 prior lines of therapy (range 3–13). Extramedullary disease, defined as soft tissue plasmacytomas not associated with bone, was present in two (5.6%) patients. Thirteen (39.4%) patients had high-risk cytogenetics, defined as the presence of del(17p), t(4;14), and/or t(14;16), consistent with the 2015 Revised International Staging System [ 24 ]. Most patients were triple-class refractory (25 [69.4%]); eight (22.2%) were penta-drug refractory and 35 (97.2%) were refractory to the last line of therapy (Table 1 ).

Efficacy

As of September 2024, median follow-up was 13.4 (range 0.6–24.7) months. ORR (95% CI) was 77.8% (60.8–89.9) with 72.2% (54.8–85.8) of patients achieving ≥ VGPR, 55.6% (38.1–72.1) achieving ≥ CR, and 47.2% (30.4–64.5) achieving sCR (Fig. 1 ).

Among the 28 responders to talquetamab, the median (range) time to first response was 1.2 (1.1–3.0) months, the median time to best response was 4.5 (1.2–11.2) months, and the median time to ≥ VGPR was 2.1 (1.1–7.6) months. The median DOR was not reached (NR) (95% CI 10.2–not estimable [NE]) with 71.4% of patients censored (Fig. 2 a). Responses deepened over time (Fig. 2 b). The 9-month DOR rate (95% CI) was 88.7% (68.8–96.2), and the 12-month DOR rate was 66.4% (40.9–82.9).

The median PFS was 15.5 (95% CI 11.3–NE) months with 63.9% of patients censored (Fig. 3 a). The 9-month PFS rate (95% CI) was 75.4% (56.5–86.9), and the 12-month PFS rate was 56.3% (34.8–73.2). The median OS was NR (95% CI 15.2–NE) with 75.0% of patients censored (Fig. 3 b). The 9-month OS rate (95% CI) was 85.6% (68.8–93.7), and the 12-month OS rate was 74.1% (54.3–86.3).

Safety

The most common AEs in the Japan cohort were taste-related AEs, CRS, and skin-related (non-rash) AEs. The most common grade 3/4 AEs were hematologic toxicities (Table 2 ).

CRS occurred in 75.0% of patients (Table 2 ). All events were grade 1 (58.3%) or 2 (16.7%) and were largely confined to step-up and Cycle 1 Day 1 doses, with few events occurring on or after Cycle 2 (8.3%). Median time to onset of CRS was 30.5 h, and median duration of CRS was 12.5 h (Supplementary Table 1). Supportive measures were given to 26 (72.2%) patients and included tocilizumab (61.1%), acetaminophen (44.4%), and intravenous fluids (25.0%). Recurrent CRS events occurred in 36.1% of patients, were all grade 1/2, and mostly occurred during step-up and Cycle 1 Day 1 doses. A small proportion of patients (5.6%) had a worse grade during any subsequent CRS event. Median time to onset of recurrent CRS was 30.9 h, and median duration of recurrent CRS was 12.3 h. Cycle delays or dose modifications due to CRS occurred in six (16.7%) patients. All CRS events resolved, and no patients discontinued treatment due to CRS.

No patients reported an ICANS event. The only neurotoxicity event was a grade 1 headache.

On-target, off-tumor (GPRC5D-related) AEs included taste-, skin- (non-rash), nail-, and rash-related AEs. Taste-related AEs were the most common AE reported with talquetamab (80.6%) (Table 2 ). Taste-related AEs were reported as a grouped term that included dysgeusia, ageusia, hypogeusia, and taste disorder, which all have a maximum grade of 2 per CTCAE. Median time to onset of taste-related AEs was 11 days, and median duration was 195 days (Supplementary Table 2). More detailed information on taste-related AEs, including the specific toxicity and patient experience of the toxicity, is shown in Table 3 . Dose modifications (i.e., dose delays, skips, or reductions) due to taste-related AEs occurred in one (2.8%) patient; 31% of events resolved at the time of data cutoff, and no patients discontinued treatment due to taste-related AEs. Weight decrease was reported in eight (22.2%) patients; of these, three (8.3%) had grade 3 events. Following talquetamab treatment, weight decreased until Cycle 4, then began to stabilize. This trend was similar irrespective of whether patients had taste-related events, although numbers are small (Fig. 4 ).

Skin-related (non-rash) AEs were reported as a grouped term that included skin exfoliation, dry skin, pruritus, and palmar-plantar erythrodysesthesia syndrome (Fig. 5 a–c), and occurred in 66.7% of patients (Table 2 ). All events were low grade (1/2). Median time to onset of skin-related (non-rash) AEs was 21 days, and median duration was 46 days (Supplementary Table 2). Dose modifications due to skin-related (non-rash) AEs occurred in two (5.6%) patients; 42.1% of events resolved at the time of data cutoff, and no patients discontinued treatment due to skin-related (non-rash) AEs.

Nail-related AEs were reported as a grouped term that included nail discoloration, nail disorder, onycholysis, onychomadesis, onychoclasis, nail dystrophy, nail toxicity, and nail ridging (Fig. 5 d and e), and occurred in 55.6% of patients (Table 2 ). All were low grade (1/2). Median time to onset of nail-related AEs was 51 days, and median duration was 109 days (Supplementary Table 2). No dose modifications were required for nail-related AEs; 33.3% of events were resolved at the time of data cutoff, and no patients discontinued treatment due to nail-related AEs.

Rash-related AEs were reported as a grouped term that included rash, maculopapular rash, erythematous rash, and erythema (Fig. 5 f), and occurred in 36.1% of patients (Table 2 ). The majority were grade 1/2. Median time to onset of rash-related AEs was 15 days, and median duration was 36 days (Supplementary Table 2). Dose modifications due to rash-related AEs occurred in two (5.6%) patients; most events resolved (88.9%), and no patients discontinued treatment due to rash-related AEs.

Hematologic AEs occurring in ≥ 25% of patients included lymphopenia (47.2%), neutropenia (38.9%), anemia (27.8%), and thrombocytopenia (25.0%). The most common grade 3/4 hematologic AEs were lymphopenia (47.2%) and neutropenia (27.8%) (Table 2 ).

Infections occurred in 19 (52.8%) patients; pneumonia and upper respiratory tract infections were the most common. Grade 3/4 infections occurred in six (16.7%) patients (Table 2 ) (one of which resulted in death [grade 5 pneumonia]); excluding the grade 5 infection, grade 3/4 infections included pneumonia (two patients; 5.6%), otitis media, sepsis, and staphylococcal sepsis (one patient each; 2.8% each). Three (8.9%) patients had COVID-19; all were grade 1/2. Grade ≥ 3 infections generally occurred in the first 6–9 months of treatment and then declined thereafter (Fig. 6 ). Opportunistic infections occurred in one patient (grade 2 cytomegalovirus infection); the infection resolved and talquetamab was continued without any dose modifications. Hypogammaglobulinemia was reported in three (8.3%) patients.

Fifteen (41.7%) patients reported serious AEs, seven (19.4%) of which were considered by the investigator as related to talquetamab. Grade 5 AEs occurred in three (8.3%) patients; of these, two patients had respiratory failure (not attributed to talquetamab) and one patient had interstitial lung disease (not attributed to talquetamab) and pneumonia (attributed to talquetamab). There were no dose reductions due to AEs. AEs resulted in treatment discontinuation in one (2.8%) patient (staphylococcal sepsis).

Pharmacokinetics

The mean trough concentration (C trough ) was higher than the 90% maximal effective concentration values identified in an ex vivo cytotoxicity assay from first target dose.

Discussion

In this phase 2 analysis of Japanese patients with triple-class exposed RRMM receiving the novel agent talquetamab in the MonumenTAL-1 study, a high ORR (77.8%) was observed, and responses were deep (72.2% ≥ VGPR; 55.6% ≥ CR) and durable (median DOR was NR, 12-month DOR rate was 66.4%, median PFS was 15.5 months, and 12-month PFS rate was 56.3%). Efficacy outcomes in the Japan cohort were generally consistent with the global MonumenTAL-1 QW cohort [ 19 ]. These data are impressive considering the current treatment landscape for patients with RRMM, in which no consensus standard of care exists [ 25 ]. This is underscored by a recent real-world analysis that identified more than 100 unique regimens used in the treatment of patients with triple-class exposed RRMM who experienced poor treatment outcomes (ORR 31.8%; median PFS 4.6 months) [ 26 ]. In indirect treatment comparisons utilizing the global MonumenTAL-1 cohorts, talquetamab has demonstrated superior efficacy compared with standard treatment regimens (real-world physician’s choice) in triple-class exposed RRMM, further supporting talquetamab as a compelling treatment in this setting [ 27 , 28 ].

Similar to the global MonumenTAL-1 population, CRS was one of the most commonly reported AEs in the Japan cohort. CRS is characterized by systemic immune activation, including excessive elevation of cytokines and inflammatory processes that can be triggered by infections or T-cell redirecting therapies, such as CAR-T and bispecific antibodies. Symptoms of CRS range from low-grade fever to serious multi-organ failure and may affect patient outcomes and quality of life [ 23 , 29 ]. Generally, CRS is less frequent, less severe, has an earlier onset, and has a shorter duration in patients treated with bispecific antibodies compared with CAR-T therapies [ 29 – 32 ]. In the Japan cohort, CRS events generally occurred early during step-up and Cycle 1 Day 1 doses, were all low grade (1/2), and did not result in treatment discontinuations; these data closely align with the global MonumenTAL-1 cohorts and are consistent with other T-cell redirecting bispecific antibodies in RRMM [ 33 , 34 ]. Although guidance exists to manage CRS [ 35 ], additional strategies to mitigate CRS are being investigated, including prophylactic tocilizumab use and alternative step-up dosing schedules [ 36 , 37 ]. In a small cohort of patients (N = 12) from the global MonumenTAL-1 study who received prophylactic tocilizumab, incidence and severity of CRS were reduced without impacting antimyeloma activity [ 37 ]. Although preliminary, this strategy may potentially facilitate outpatient administration of talquetamab, thereby improving both safety and convenience of talquetamab, reducing burden of hospitalization, and elevating patient experience.

GPRC5D-related AEs, including taste-, skin- (non-rash), nail- and rash-related AEs, are common with talquetamab and have previously been described in the global MonumenTAL-1 cohorts [ 19 , 38 ]. These on-target, off-tumor AEs may be related to the expression pattern of GPRC5D, which has been found in epithelial tissues, including hair, skin cells associated with hair follicle-specific keratin, eccrine glands, and filiform papillae on the tongue. GPRC5D expression is also believed to occur in the nailbed of humans due to expression reported in the nailbeds of mice [ 18 , 39 – 42 ].

Similar to the global MonumenTAL-1 cohorts, GPRC5D-related AEs in the Japan cohort were common and mostly low grade; none resulted in treatment discontinuation, and few dose modifications were required. The most common treatments used to manage taste-related AEs in the Japan cohort were consistent with those in the global cohorts and included anti-infective, anti-inflammatory, and corticosteroid oral medications (Supplementary Table 2). In the global MonumenTAL-1 study, dose modifications were implemented in 7.7% of patients across cohorts and based on investigator experience, they appear to be the most effective strategy in managing taste-related AEs [ 38 ]. In the Japan cohort, dose modifications were also implemented in 1 (2.8%) patient to manage taste-related AEs. The novelty and subjectivity of taste-related AEs with talquetamab, as well as limitations of CTCAE grading that defines a maximum severity as 2, have posed challenges to identifying and managing taste-related AEs [ 43 ]. To contribute to our understanding, we captured the taste disorder experience of ten patients in the Japan cohort (Table 3 ), which highlighted the variability of each patient’s experience. A recently initiated study, TALISMAN, is assessing strategies to mitigate and manage taste-related toxicities due to talquetamab, and will provide needed data on taste-related assessment tools as well as the impact of taste-related AEs on patient experience [ 44 ].

Taste-related toxicities may have an impact on diet given the potential change to patients’ experience of food taste or food interest, and thus an impact on weight. However, preliminary investigation into the association of weight loss with taste-related toxicities in the Japan cohort indicated that weight loss occurred regardless of whether patients experienced taste-related AEs. This outcome is similar to what has been observed in the global MonumenTAL-1 cohorts, which assessed weight loss in association with a broader group of oral toxicities (including taste-related toxicities) [ 45 ]. Studies are ongoing to further characterize and understand weight loss with talquetamab. Early referral to a nutritionist should be considered to provide guidance on maintaining a balanced diet and weight with talquetamab [ 38 ].

In terms of dermatologic GPRC5D-related AEs, the incidence, severity, timing, and dose modifications for skin- (non-rash), nail-, and rash-related AEs were similar between the Japan cohort and the global MonumenTAL-1 cohorts. Management of dermatologic GPRC5D-related AEs largely mirrored that of the global population, with common approaches including use of topical steroids, petroleum based moisturizers, and oral antihistamines (Supplementary Table 2). Topical heparin, mucopolysaccharide polysulfate cream, and crotamiton were additionally used in the Japan cohort due to variations in product availability and institutional protocols. Images of dermatologic GPRC5D-related AEs in the Japan cohort are presented here (Fig. 5 ) and may help clinicians to identify these toxicities promptly. Investigation in the global MonumenTAL-1 population has indicated that although dermatologic GPRC5D-related AEs may impact quality of life, they are typically mild and generally resolve, with the exception of nail-related toxicities due to slower growth of nails [ 38 ].

In the Japan cohort, the incidence and timing of infections (generally restricted to the first 6 months of treatment) were comparable to the global MonumenTAL-1 population. Of note, like the global MonumenTAL-1 population, the rate of grade 3/4 infections (16.7%) was lower in the Japan cohort than rates observed in published studies of BCMA-targeting bispecific antibodies (40‒55%) [ 19 , 33 , 46 ]. Unlike BCMA, GPRC5D expression is restricted to malignant plasma cells with limited expression on other hematopoietic cells, including cells across the continuum of the B-cell lineage [ 18 , 41 , 42 ]. We have previously shown no decreases in B-cell counts or polyclonal immunoglobulin G concentration following talquetamab treatment in the global MonumenTAL-1 study [ 47 ]. Together, these data continue to support talquetamab as a B-cell–sparing treatment that allows for preservation of humoral immune function to permit better control of infections [ 47 ].

There are some limitations to this study, including the single-arm study design and relatively small sample size of the Japan cohort. Although the Japan cohort had a relatively short follow-up period, data collection is ongoing. While the 0.8 mg/kg Q2W dose was not studied in this analysis, the safety and efficacy of the Q2W dose were assessed in a separate Japan phase 1 study (n = 6), and response was observed in five of six Japanese patients [ 20 ].

In conclusion, efficacy and safety results with talquetamab among Japanese patients with triple-class exposed RRMM who participated in the MonumenTAL-1 study were generally consistent with the global MonumenTAL-1 population [ 19 ]: talquetamab demonstrated rapid, deep, and durable responses, with low rates of discontinuations due to AEs, none of which were due to on-target, off-tumor AEs. Overall, these data support use of talquetamab as a novel immunotherapy for Japanese patients with triple-class exposed RRMM.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 76 KB)

Acknowledgements

This study was funded by Johnson & Johnson. The authors thank all the patients who participated in this study and their families and caregivers. The authors also thank the physicians and nurses who cared for the patients as well as the staff at the clinical sites, and the supporting scientific staff. Editorial and medical writing support was provided by Michelle Yang, PharmD, of Eloquent Scientific Solutions, and funded by Johnson & Johnson.

Author contributions

Shigeki Ito: conceptualization; investigation; data curation; writing—original draft; and writing—review & editing. Yoshiaki Kuroda: conceptualization; investigation; data curation; writing—original draft; and writing—review & editing. Kazutaka Sunami: conceptualization; investigation; data curation; writing—original draft; and writing—review & editing. Kosei Matsue: conceptualization; investigation; data curation; writing—original draft; and writing—review & editing. Kazunori Imada: conceptualization; investigation; data curation; writing—original draft; and writing—review & editing. Hideto Tamura: conceptualization; investigation; data curation; writing—original draft; and writing—review & editing. Ei Fujikawa: methodology; data curation; formal analysis; visualization; and writing—review and editing. Hiroshi Yamazaki: methodology; data curation; formal analysis; visualization; and writing—review and editing. Mikihiro Takamoto: methodology; data curation; formal analysis; visualization; and writing—review and editing. Lixia Pei: methodology; data curation; formal analysis; visualization; and writing—review and editing. Xiang Qin: methodology; data curation; formal analysis; visualization; and writing—review and editing. Tara J. Masterson: methodology; data curation; formal analysis; visualization; and writing—review and editing. Michela Campagna: methodology; data curation; formal analysis; visualization; and writing—review and editing. Veronique Vreys: methodology; data curation; formal analysis; visualization; and writing—review and editing. Bonnie W. Lau: methodology; data curation; formal analysis; visualization; and writing—review and editing. Yasushi Takamatsu: conceptualization; investigation; data curation; writing—original draft; and writing—review & editing.

Funding

This study was funded by Johnson & Johnson.

Data availability

The data sharing policy of Johnson & Johnson is available at https://www.jnj.com/innovativemedicine/node/87 . As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu .

Declarations

Conflict of interest

Shigeki Ito has received honoraria from Sano, Pzer, Johnson & Johnson, Chugai, Takeda, and BMS; has received research funding from AbbVie, GSK, and Kissei; and is an editor of the International Journal of Hematology. Yoshiaki Kuroda has received research funding and participates in a speakers bureau for Johnson & Johnson, Takeda Pharmaceuticals, Bristol Myers Squibb, Sano, SymBio Pharmaceuticals, ONO PHARMACEUTICAL, AstraZeneca, ASAHI KASEI PHARMA, and Amgen. Kazutaka Sunami has received research funding from Sano, Pzer, Ono Pharmaceutical, Novartis, Mitsubishi Tanabe, Kyowa-Kirin, Incyte, GSK, Chugai, BMS, BeiGene, and AbbVie; and has received honoraria and research funding from Johnson & Johnson. Kosei Matsue has received trust research/joint research funds from AstraZeneca; and has received honoraria from Johnson & Johnson, BMS, and Takeda. Kazunori Imada has received honoraria from Johnson & Johnson K.K., Towa Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Alexion Pharmaceuticals, Inc., AbbVie GK., Astellas Pharma Inc., Amgen K.K., AstraZeneca K.K., and DAIICHI SANKYO Co., Ltd.; has received other honoraria from Genmab K.K., Chugai Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., Ono Pharmaceutical Co. Ltd., Otuka Pharmaceutical Co. Ltd. and Pzer Japan Inc.; and has received patents & royalties honoraria from Gilead Sciences K.K., PharmaEssentia Japan KK, Kyowa Kirin Co., Ltd., Novartis Pharma K.K., Sano K.K., Asahi Kasei Pharma, Nippon Kayaku Co., Ltd., Nippon Shinyaku Co., Ltd., and Eisai Co., Ltd. Hideto Tamura has participated in a speakers bureau for Bristol Meyers Squib; has received honoraria from Ono Pharmaceutical and Sano; has received consultation fees for Sanofi, AbbVie, and Johnson & Johnson; has received remuneration for lectures for Johnson & Johnson, BMS, Sanofi, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; and has received a scholarship fund from Fujipharm Co., Ltd. Ei Fujikawa, Hiroshi Yamazaki, Mikihiro Takamoto, Lixia Pei, Xiang Qin, Tara J. Masterson, Michela Campagna, Veronique Vreys, and Bonnie W Lau are current employees of Johnson & Johnson and hold equity in a publicly-traded company. Yasushi Takamatsu has received speaking fees from AstraZeneca and Sanofi; and has received scholarship or grant donations from Chugai Pharmaceutical, Takeda Pharmaceuticals, and Astellas Pharma.

Ethics approval

Registry and the registration number of the study: clinicaltrials.gov ; NCT03732820 . The study was conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Guidelines of the International Council for Harmonisation. The protocol and amendments were approved by the institutional review board at each study site.

Informed consent

All patients provided written informed consent. Written consent for the publication of the medical photographs was obtained from the patient(s).

Footnotes

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References

1. van de Donk N, Pawlyn C, Yong KL. Multiple myeloma. Lancet. 2021;397(10272):410–27. 10.1016/s0140-6736(21)00135-5.

2. Globocan 2022 World Fact Sheet. Available from: https://gco.iarc.who.int/media/globocan/factsheets/populations/900-world-fact-sheet.pdf

3. Iida S, Ito S, Yokoyama H, Ishida T, Nagai Y, Handa H, et al. Elranatamab in Japanese patients with relapsed/refractory multiple myeloma: results from MagnetisMM-2 and MagnetisMM-3. Jpn J Clin Oncol. 2024;54(9):991–1000. 10.1093/jjco/hyae068.

4. Holstein SA. Current frontline treatment of multiple myeloma. Oncology (Williston Park). 2022;36(7):430–41. 10.46883/2022.25920967.

5. Moreau P, Richardson PG, Cavo M, Orlowski RZ, San Miguel JF, Palumbo A, et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood. 2012;120(5):947–59. 10.1182/blood-2012-04-403733.

6. Moribe T, Xu L, Take K, Yonemoto N, Suzuki K. Real-world treatment trends and triple class exposed status in newly diagnosed multiple myeloma patients in Japan: a retrospective claims database study. PLoS ONE. 2024;19(9):e0310333. 10.1371/journal.pone.0310333.

7. van de Donk N, Richardson PG, Malavasi F. CD38 antibodies in multiple myeloma: back to the future. Blood. 2018;131(1):13–29. 10.1182/blood-2017-06-740944.

8. Bristol Myers Squibb’s Abecma® becomes first CAR T approved for use in earlier lines of therapy for patients with relapsed or refractory multiple myeloma in Japan [press release]. December 6, 2023. Available from: https://news.bms.com/news/details/2023/Bristol-Myers-Squibbs-Abecma-Becomes-First-CAR-T-Approved-for-Use-in-Earlier-Lines-of-Therapy-for-Patients-with-Relapsed-or-Refractory-Multiple-Myeloma-in-Japan/default.aspx

9. ELREXFIO (elranatamab) for the treatment of multiple myeloma, USA. Available from: https://www.clinicaltrialsarena.com/projects/elrexfio-elranatamab-multiple-myeloma-usa/#:~:text=Following%20this%2C%20the%20drug%20received,in%20Japan%20in%20March%202024

10. EISAI obtains manufacturing and marketing approval for “TECVAYLI® subcutaneous injection 30 mg” and “ TECVAYLI® 153 mg” for relapsed or refractory multiple myeloma. Available from: https://www.janssen.com/japan/press-release/20241227

11. Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002–14. 10.1056/NEJMoa2213614.

12. Shibayama H, Itagaki M, Handa H, Yokoyama A, Saito A, Kosugi S, et al. Primary analysis of a prospective cohort study of Japanese patients with plasma cell neoplasms in the novel drug era (2016–2021). Int J Hematol. 2024;119(6):707–21. 10.1007/s12185-024-03754-8.

13. Kumar SK, Dimopoulos MA, Kastritis E, Terpos E, Nahi H, Goldschmidt H, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017;31(11):2443–8. 10.1038/leu.2017.138.

14. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373(13):1207–19. 10.1056/NEJMoa1506348.

15. Zhang X, Zhang H, Lan H, Wu J, Xiao Y. CAR-T cell therapy in multiple myeloma: current limitations and potential strategies. Front Immunol. 2023;14:1101495. 10.3389/fimmu.2023.1101495.

16. TALVEY. Summary of product characteristics: Janssen Biologics B.V; 2023. Available from: https://www.ema.europa.eu/en/documents/product-information/talvey-epar-product-information_en.pdf

17. TALVEY ® (talquetamab-tgvs) [prescribing information]. Horsham, PA, USA: Janssen Biotech, Inc.; 2023

18. Rodriguez-Otero P, van de Donk N, Pillarisetti K, Cornax I, Vishwamitra D, Gray K, et al. GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review. Blood Cancer J. 2024;14(1):24. 10.1038/s41408-023-00966-9.

19. Chari A, Touzeau C, Schinke C, Minnema MC, Berdeja JG, Oriol A, et al. Safety and activity of talquetamab in patients with relapsed or refractory multiple myeloma (MonumenTAL-1): a multicentre, open-label, phase 1–2 study. Lancet Haematol. 2025. 10.1016/s2352-3026(24)00385-5.

20. Iida S, Sunami K, Ito S, Yuda J, Fujikawa E, Takamoto M, et al. Phase 1 study of talquetamab, a humanized GPRC5D x CD3 bispecific antibody, in Japanese patients with relapsed/refractory MM. Int J Hematol. 2025. 10.1007/s12185-025-03991-5.

21. Chari A, Minnema MC, Berdeja JG, Oriol A, van de Donk N, Rodriguez-Otero P, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387(24):2232–44. 10.1056/NEJMoa2204591.

22. Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328–46. 10.1016/s1470-2045(16)30206-6.

23. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625–38. 10.1016/j.bbmt.2018.12.758.

24. Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863–9. 10.1200/jco.2015.61.2267.

25. Mateos MV, Weisel K, De Stefano V, Goldschmidt H, Delforge M, Mohty M, et al. LocoMMotion: a study of real-life current standards of care in triple-class exposed patients with relapsed/refractory multiple myeloma - 2-year follow-up (final analysis). Leukemia. 2024;38(12):2554–60. 10.1038/s41375-024-02404-6.

26. Weisel K, Mateos MV, Gonzalez Garcia ME, Bittrich M, Lindsey-Hill J, De Stefano V, et al. Standard of care outcomes in the last 3 years in patients with triple-class exposed relapsed/refractory multiple myeloma: the first pooled analysis of LocoMMotion and MoMMent trials. Presented at: The 20th International Myeloma Society (IMS) Annual Meeting; September 27–30, 2023; Athens, Greece

27. Einsele H, Moreau P, Bahlis N, Bhutani M, Vincent L, Karlin L, et al. Comparative efficacy of talquetamab vs. current treatments in the LocoMMotion and MoMMent studies in patients with triple-class-exposed relapsed/refractory multiple myeloma. Adv Ther. 2024;41(4):1576–93. 10.1007/s12325-024-02797-x.

28. Ye JC, Biran N, Nair S, Lin X, Qi K, Londhe A, et al. Talquetamab versus real-world physician’s choice treatment: comparative effectiveness in patients with triple-class exposed relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2025;25(2):124-34.e5. 10.1016/j.clml.2024.08.003.

29. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6(1):56. 10.1186/s40425-018-0343-9.

30. Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med. 2020;383(23):2255–73. 10.1056/NEJMra2026131.

31. Kim J, Cho J, Lee MH, Yoon SE, Kim WS, Kim SJ. CAR T cells vs bispecific antibody as third- or later-line large B-cell lymphoma therapy: a meta-analysis. Blood. 2024;144(6):629–38. 10.1182/blood.2023023419.

32. Shah D, Soper B, Shopland L. Cytokine release syndrome and cancer immunotherapies - historical challenges and promising futures. Front Immunol. 2023;14:1190379. 10.3389/fimmu.2023.1190379.

33. Lesokhin AM, Tomasson MH, Arnulf B, Bahlis NJ, Miles Prince H, Niesvizky R, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 2023;29(9):2259–67. 10.1038/s41591-023-02528-9.

34. Moreau P, Garfall AL, van de Donk N, Nahi H, San-Miguel JF, Oriol A, et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2022;387(6):495–505. 10.1056/NEJMoa2203478.

35. Rodriguez-Otero P, Usmani S, Cohen AD, van de Donk N, Leleu X, Gállego Pérez-Larraya J, et al. International Myeloma Working Group immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell-engaging bispecific antibodies in multiple myeloma. Lancet Oncol. 2024;25(5):e205–16. 10.1016/s1470-2045(24)00043-3.

36. Morillo D, Martinez Chamorro C, Mateos MV, Costa LJ, Minnema MC, Sanchez L, et al. Cytokine release syndrome in patients receiving alternative step-up doses of talquetamab for relapsed/refractory multiple myeloma: results from the phase 1/2 MonumenTAL-1 study. Presented at: The 21st International Myeloma Society (IMS) Annual Meeting September 25–28, 2024; Rio de Janeiro, Brazil

37. Schinke C, Vij R, Jagannath S, Sanchez L, Pianko M, Jakubowiak A, et al. Prophylactic tocilizumab to mitigate cytokine release syndrome in patients receiving talquetamab for relapsed/refractory multiple myeloma: results from the phase 1/2 MonumenTAL-1 study. Presented at: The 21st International Myeloma Society (IMS) Annual Meeting; September 25–28, 2024; Rio de Janeiro, Brazil

38. Chari A, Krishnan A, Rasche L, Ye JC, Garfall A, Popat R, et al. Clinical management of patients with relapsed/refractory multiple myeloma treated with talquetamab. Clin Lymphoma Myeloma Leuk. 2024;24(10):665-93.e14. 10.1016/j.clml.2024.05.003.

39. Goldsmith RB, et al. Normal human tissue expression of G protein–coupled receptor class C group 5 member D (GPRC5D), a promising novel target for multiple myeloma, is restricted to plasma cells and hard keratinized tissues. The International Myeloma Workshop. Vienna, Austria; 2021

40. Hasselbalch Riley C, Hutchings M, Yoon S, Koh Y, et al. RG6234, a novel GPRC5D T-cell engaging bispecific antibody, induces rapid responses in patients with relapsed/refractory multiple myeloma: preliminary results from a first-in-human trial. Presented at: The European Hematology Association (EHA) Annual Meeting; June 9–12, 2022; Vienna, Austria

41. Smith EL, Harrington K, Staehr M, Masakayan R, Jones J, Long TJ, et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med. 2019;11(485):eaau7746. 10.1126/scitranslmed.aau7746.

42. Verkleij CPM, Broekmans MEC, van Duin M, Frerichs KA, Kuiper R, de Jonge AV, et al. Preclinical activity and determinants of response of the GPRC5DxCD3 bispecific antibody talquetamab in multiple myeloma. Blood Adv. 2021;5(8):2196–215. 10.1182/bloodadvances.2020003805.

43. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Available from: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf

44. Popat R, Laheij A, van de Donk N. Prophylactic interventions for oral toxicities with the GPRC5D×CD3 bispecific antibody talquetamab in relapsed/refractory multiple myeloma: an open-label, phase 2, randomized study (TALISMAN). Presented at: The 21st International Myeloma Society (IMS) Annual Meeting; September 25–28, 2024; Rio de Janeiro, Brazil

45. Rasche L, Schinke C, Touzeau C, Minnema MC, van de Donk NWCJ, Rodriguez-Otero P, et al. Long-term efficacy and safety results from the phase 1/2 MonumenTAL-1 study of talquetamab, a GPRC5D×CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma. Presented at: The European Hematology Association (EHA) Hybrid Congress; June 13–16, 2024; Madrid, Spain

46. Garfall AL, Nooka AK, van de Donk NWCJ, Moreau P, Bhutani M, Oriol A, et al. Long-term follow-up from the phase 1/2 MajesTEC-1 trial of teclistamab in patients with relapsed/refractory multiple myeloma. Presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 31–June 4, 2024; Chicago, IL, USA & Virtual

47. Rodriguez-Otero P, Schinke C, Chari A, et al. Analysis of infections and parameters of humoral immunity in patients with relapsed/refractory multiple myeloma treated with talquetamab monotherapy in MonumenTAL-1. Presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 2–6, 2023; Chicago, IL, USA & Virtual

Associated Data

Supplementary Materials

Supplementary file1 (DOCX 76 KB)

Data Availability Statement

The data sharing policy of Johnson & Johnson is available at https://www.jnj.com/innovativemedicine/node/87 . As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu .