SUMMARY

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• CRS has been reported as an adverse event (AE) in the MonumenTAL-1, MonumenTAL-2, TRIMM-2, and RedirecTT-1 studies.^1-6
• MonumenTAL-1 (MMY1001) is an ongoing, open-label, phase 1/2 study evaluating the efficacy and safety of TALVEY in patients with relapsed or refractory multiple myeloma (RRMM) after ≥3 prior lines of therapy (LOTs), including a proteasome inhibitor (PI), an immunomodulatory drug, and an anti-CD38 monoclonal antibody.^3,6-14
  • Schinke et al (2024)¹⁵ presented the efficacy and safety results from a subgroup analysis in Black patients who received TALVEY at the recommended phase 2 doses (RP2Ds) of 0.4 mg/kg subcutaneous (SC) weekly (QW) or 0.8 mg/kg SC every other week (Q2W). CRS events were reported in Black patients.
  • Schinke et al (2024)¹⁰ reported findings from the MonumenTAL-1 study on the effects of prophylactic tocilizumab in mitigating CRS following TALVEY treatment, with a median follow-up of 4.4 months (range, 0.3-8.8 months). The use of prophylactic tocilizumab and post-dose dexamethasone appeared to reduce both the incidence and severity of CRS across different levels of disease burden.
  • Morillo et al (2024)¹¹ evaluated the impact of reduced number of step-up doses (SUDs) of TALVEY (0.8 mg/kg Q2W) on CRS parameters by comparing two alternative TALVEY Q2W SUD cohorts (Group 1: n=6; Group 2: n=12) with the global cohort receiving 0.8 mg/kg Q2W TALVEY (N=154).
  • Chari et al (2024)¹² published the clinical management of AEs in patients with RRMM treated with TALVEY in the MonumenTAL-1 study. CRS events were reported in the QW, Q2W, and prior T-cell redirection (TCR) cohorts.
  • Schinke et al (2023)⁶ presented the updated efficacy and safety results from the MonumenTAL-1 study at a median follow-up of 18.8 months for the 0.4 mg/kg SC QW cohort, 12.7 months for the 0.8 mg/kg SC Q2W cohort, and 14.8 months for the prior TCR therapy exposed cohort. Any-grade CRS events were reported in QW, Q2W, and prior TCR cohorts.
  • Jakubowiak et al (2023)¹³ presented updated efficacy and safety results in patients with prior TCR, including an additional 19 patients enrolled in the MonumenTAL-1 study since the prior analysis, at a median follow-up of 18.4 months for the overall prior TCR cohort, 18.4 months for the prior chimeric antigen receptor-modified T-cells (CAR-T) cohort, and 16.3 months for the prior bispecific antibody (BsAb) cohorts, respectively. Any-grade CRS events were reported in the overall prior TCR group.
  • Krishnan et al (2023)¹⁴ evaluated the efficacy and safety of TALVEY in key high-risk and prior B-cell maturation antigen (BCMA) therapy subgroups of patients from the MonumenTAL-1 study. CRS-related AEs of the high-risk subgroups are described below.
  • Per protocol, CRS is a systemic inflammatory response mediated by the activation of T lymphocytes. The specific mode-of-action of TALVEY is based on the binding and activation of T cells and the release of cytokines in the tumor environment leading to AEs of CRS. Dose delays were the primary method for managing CRS-related AEs in the phase 2 portion of the MonumenTAL-1 study protocol.⁷
• MonumenTAL-2 (MMY1004) is an ongoing, phase 1b, multi-arm, open-label study evaluating TALVEY in combination with other anticancer therapies in patients with multiple myeloma (MM).^6,16-18 Janssen does not recommend the use of TALVEY in a manner that is inconsistent with the approved labeling.
  • Cohort D is evaluating the efficacy and safety of TALVEY in combination with DARZALEX FASPRO^® and lenalidomide in 34 patients with newly diagnosed multiple myeloma (NDMM).¹⁸
    • Nooka et al (2024)¹⁸ presented the initial efficacy and safety results of the TALVEY 0.6 mg/kg Q2W + DARZALEX FASPRO + lenalidomide cohort at a median follow-up of 13.2 months (range, 10.0-14.6) and the TALVEY 0.8 mg/kg every 4 weeks (Q4W) + DARZALEX FASPRO + lenalidomide cohort at a median follow-up of 5.8 months (range, 1.7 [denotes patients who died]-12.0). CRS events were reported in both cohorts.
  • Cohort E is evaluating the safety and efficacy of TALVEY in combination with pomalidomide in 35 patients with RRMM.⁵
    • Searle et al (2024)⁵ presented the updated efficacy and safety results of TALVEY in combination with pomalidomide from the MonumenTAL-2 study at a median follow-up of 16.8 months (range, 1.2-25.1). Any-grade CRS events were reported.
• TRIMM-2 (MMY1002) is an ongoing, phase 1b, multicohort open-label study evaluating the efficacy and safety of DARZALEX FASPRO regimens in combination with TECVAYLI^® or TALVEY in patients with RRMM.^1,19,20 Janssen does not recommend the use of TECVAYLI, TALVEY, or DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
  • Bahlis et al (2024)²⁰presented the efficacy and safety results of the TALVEY 0.4 mg/kg QW + DARZALEX FASPRO + pomalidomide and TALVEY 0.8 mg/kg Q2W + DARZALEX FASPRO + pomalidomide cohorts at a median follow-up of 15.8 months (range, 3.2-37.9) and 17.5 months (range, 0.2-37.7), respectively. CRS events were reported in the TALVEY + DARZALEX FASPRO + pomalidomide cohorts.
  • Dholaria et al (2023)¹ presented the updated efficacy and safety results from the TALVEY + DARZALEX FASPRO cohorts at a median follow-up of 16.8 months for the TALVEY 0.4 mg/kg QW + DARZALEX FASPRO cohort and 15.0 months for the TALVEY 0.8 mg/kg Q2W + DARZALEX FASPRO cohort. Any-grade CRS events were reported in the TALVEY + DARZALEX FASPRO cohorts.
• RedirecTT-1 (MMY1003) is an ongoing, open-label, phase 1b/2 study evaluating the safety and efficacy of TALVEY and TECVAYLI in patients with RRMM.^2,21,22 Janssen does not recommend the use of TALVEY and TECVAYLI in a manner that is inconsistent with the approved labeling.
  • Cohen et al (2024)²² presented the updated efficacy and safety results in the evaluated cohorts, including in patients with extramedullary disease (EMD) at a median follow-up of 20.3 months for the all-dose levels cohort and 18.2 months (range, 0.7-27.0) for the TALVEY and TECVAYLI recommended phase 2 regimen (RP2R) cohort. CRS events were reported in the all-dose levels and RP2R cohorts.
• Other relevant literature has been identified in addition to the data summarized above:
  • A case report related to CRS.²³
  • Nursing and advance practice practitioner’s considerations for management of CRS.²⁴

PRODUCT LABELING

• TALVEY (talquetamab-tgvs) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/TALVEY-pi.pdf.
• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf.
• TECVAYLI (teclistamab-cqyv) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/TECVAYLI-pi.pdf.

CLINICAL DATA - Monumental-1 Study

MonumenTAL-1 (MMY1001; NCT03399799, NCT04634552) is a phase 1/2 study of TALVEY in patients with RRMM.^8,9

The study was conducted in 3 parts; the primary objectives are listed below⁶:

• Part 1 (phase 1; dose escalation): to characterize the safety of TALVEY and determine the RP2Ds and schedule.
• Part 2 (phase 1; dose expansion): to further characterize the safety of TALVEY at the RP2Ds.
• Part 3 (phase 2): to evaluate the efficacy of TALVEY at the RP2Ds.

Study Design/Methods (Phase 2)

Patients were enrolled into 1 of the following 3 cohorts^6,13:

• TCR naïve: 0.4 mg/kg SC QW, not previously exposed to TCR such as CAR-T or BsAbs (prior BCMA antibody-drug conjugate [ADC] allowed).
• TCR naïve: 0.8 mg/kg SC Q2W, not previously exposed to TCRs (prior BCMA ADC allowed).
• Prior TCR: 0.4 mg/kg SC QW or 0.8 mg/kg SC Q2W, have been previously exposed to TCRs.
  • Among the prior TCR-exposed cohort, patients were divided based on the type of TCR (CAR-T, BsAb, or CAR-T and BsAb).
• Key eligibility criteria (Part 3; Phase 2):
  • Measurable MM.¹³
  • ≥3 prior LOTs including a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.¹³
  • Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2.¹³
• Key exclusion criteria (Part 3; Phase 2):
  • Prior grade 3 or higher CRS (per Lee criteria 2014²⁵) related to any TCR or any prior G protein-coupled receptor, class C, group 5, member D (GPRC5D)-targeting therapy.⁷
  • Received cumulative dose of corticosteroids equivalent to ≥140 mg of prednisone within 14 days prior to study drug (not including premedication).⁷
• Primary endpoint: overall response rate (ORR).⁶
• Key secondary endpoints: duration of response (DOR), progression-free survival (PFS), overall survival, safety, immunogenicity, and pharmacodynamics.⁶
• Dosing
  • TALVEY 0.4 mg/kg SC QW and 0.8 mg/kg SC Q2W treatment dose schedule is based on a 28-day cycle.⁷
  • SUD for 0.4 mg/kg SC QW⁷:
    • Week 1: SUDs of TALVEY (0.01 mg/kg and 0.06 mg/kg SC).
    • Cycles 1+: TALVEY 0.4 mg/kg SC QW until progressive disease or unacceptable toxicity.
  • SUD for 0.8 mg/kg SC Q2W⁷:
    • Week 1: SUDs of TALVEY (0.01 mg/kg, 0.06 mg/kg, and 0.3 mg/kg SC).
    • Cycles 1+: TALVEY 0.8 mg/kg SC Q2W until progressive disease or unacceptable toxicity.
  • Premedications: dexamethasone, acetaminophen, and diphenhydramine were required to be administered for each SUDs and for the first full treatment dose of TALVEY.⁷
  • Patients were required to be hospitalized for at least 48 hours from the start of the injection for each SUDs and the first full treatment dose of TALVEY.⁷

Schinke et al (2024)¹⁵ presented the efficacy and safety results from a subgroup analysis in Black patients who received TALVEY at RP2Ds of 0.4 mg/kg SC QW or 0.8 mg/kg SC Q2W in phase 1/2 of the MonumenTAL-1 study. Results specific to CRS are summarized below.

Results

Treatment Disposition

• Overall, 29 (10%) Black patients and 254 (86%) White patients from the MonumenTAL-1 study were assessed.
• The median follow-up was 26 months for the Black subgroup and 31 months for the White subgroup.

Safety

• Details on CRS events are summarized in Table: MonumenTAL-1 Study: Incidence of CRS in Black vs White Patients.

Schinke et al (2024)¹⁰ presented findings from the MonumenTAL-1 study on the effects of prophylactic tocilizumab in mitigating CRS following TALVEY treatment.

Results

Treatment Disposition, Baseline Demographics, and Disease Characteristics

• A total of 12 patients were included in this analysis, and the median duration of follow-up was 4.4 months (range, 0.3-8.8).
• Baseline characteristics of patients are presented in Table: MonumenTAL-1 Study (Prophylactic Tocilizumab Cohort): Baseline Characteristics.

Safety

CRS Incidence, Severity, Timing, and Treatment

• The incidence of CRS in the prophylactic tocilizumab cohort is presented in Table: MonumenTAL-1 Study (Prophylactic Tocilizumab Cohort): Incidence of CRS in the Prophylactic Tocilizumab Cohort.
• Median CRS onset was 2.0 days (range, 2-12), with a median duration of 2 days (range, 1-6), due to 1 patient experiencing CRS at cycle 2, day 1.
• Grade 1 CRS events occurred during step-up dosing through cycle 1 in 2 patients (16.7% in cycle 1); 1 patient (8.3%) experienced a grade 1 CRS event at cycle 2 day 1, and 1 patient (8.3%) had a recurrent grade 1 CRS event during SUD.
  • All 3 patients received treatment for CRS, including tocilizumab (n=2) and paracetamol (n=3).
• Prophylactic tocilizumab and post-dose dexamethasone appeared to reduce CRS incidence and severity across varying disease burdens. See Table: MonumenTAL-1 Study (Prophylactic Tocilizumab Cohort): Baseline Characteristics of Patients With and Without CRS.
• One patient (8.3%) with 80% bone marrow plasma cells (BMPCs) developed immune effector cell-associated neurotoxicity syndrome (ICANS; grade 2; concomitant with CRS).

Morillo et al (2024)¹¹ presented the impact of fewer SUDs on CRS parameters, in the alternative TALVEY Q2W SUD and global TALVEY 0.8 mg/kg Q2W cohorts.

Results

Treatment Disposition

• In MonumenTAL-1, alternative SUD groups were added to the 0.8 mg/kg Q2W schedule.
• A total of 18 patients were included in this analysis to evaluate alternative TALVEY Q2W SUD regimens.
  • Group 1 (n=6): week 1 SUD of TALVEY (0.03 mg/kg and 0.2 mg/kg SC); cycle 1, day 1 of TALVEY (0.8 mg/kg SC Q2W).^7,11
  • Group 2 (n=12): week 1 SUD of TALVEY (0.06 mg/kg and 0.4 mg/kg SC); cycle 1, day 1 of TALVEY (0.8 mg/kg SC Q2W).^7,11
  • Patients in both Group 1 and 2 could switch to 0.8 mg/kg Q4W at confirmed partial response or better (≥PR).
• The median duration of follow-up was 6.7 months (range, 2.2-9.9).
• Most patients had high-risk cytogenetics (10/18) and were triple-class refractory (11/18), being refractory to the last LOT (11/18). Three patients had extramedullary plasmacytomas.

Safety

CRS Incidence, Severity, Timing, and Treatment

• Summary of CRS events in the alternative SUD and global TALVEY Q2W cohorts is presented in the Table: MonumenTAL-1 Study: Summary of CRS Events in Alternative TALVEY Q2W SUD and Global TALVEY Q2W Cohorts.
  • At a median follow-up of 23.4 months (range, 0.2-37.4), the rates of grade 1 and 3 CRS events were consistent between the alternative TALVEY Q2W SUD and global TALVEY Q2W cohorts.
  • The rate of grade 2 events was higher in the alternative TALVEY Q2W SUD cohort. See Table: MonumenTAL-1 Study: CRS Incidence and Severity in Alternative TALVEY Q2W SUD and Global TALVEY Q2W Cohorts.
• Incidence of CRS in the SUD phase in all 3 cohorts are presented in Table: MonumenTAL-1 Study: CRS Timing in Alternative TALVEY Q2W SUD and Global TALVEY Q2W Cohorts.
• Tocilizumab was administered for CRS in 77.8% of patients in the alternative TALVEY Q2W SUD cohort and in 37.0% of patients in the global TALVEY Q2W cohort. Patients who received tocilizumab did not experience any subsequent grade 2 event.
• During the first SUD, 1 patient (8.3%) in group 2 experienced grade 1 neurotoxicity concurrent with CRS, which resolved without TALVEY discontinuation.
• None of the patients in the alternative TALVEY Q2W SUD cohorts discontinued TALVEY due to CRS; however, 1 patient in the global TALVEY Q2W cohort discontinued TALVEY due to CRS.

Chari et al (2024)¹² published the clinical management of AEs in patients with RRMM treated with TALVEY in the MonumenTAL-1 study. Results specific to CRS events are summarized below.

Results

Safety

• In MonumenTAL-1, 79.0% (n=113) of patients in the 0.4 mg/kg QW cohort, 74.5% (n=108) of patients in the 0.8 mg/kg Q2W cohort, and 76.5% (n=39) of patients in the prior TCR cohorts had CRS per the American Society for Transplantation and Cellular Therapy (ASTCT) criteria.
• Most CRS events were grade 1/2 that occurred with SUD and the first full dose. Almost all cases of CRS were resolved.
• Median duration of each CRS event was 14.5-20.4 hours across all the 3 cohorts. See Table: MonumenTAL-1 Study: CRS Events Associated With TALVEY.
• Patients rarely had CRS at or beyond cycle 2, with 5 patients each in the 0.4 mg/kg QW and 0.8 mg/kg Q2W cohorts and 2 patients in the prior TCR cohorts having a CRS event at or beyond cycle 2.
• One patient in the 0.8 mg/kg Q2W cohort discontinued treatment due to CRS.

Supportive Measures/Management

• Early CRS experience led to premedication and dosing modifications to mitigate CRS events with TCR. See Table: MonumenTAL-1 Study: Most Common Supportive Measures and Concomitant Treatments for CRS Events for additional details.
• TALVEY administration protocol includes administering SUD before the first full dose, and using the pretreatment with a glucocorticoid, antihistamine, and antipyretic. In the MonumenTAL-1 study, patients were hospitalized for a minimum of 48 hours during the SUD injections and the administration of the first full dose.
• The healthcare team must be aware of CRS signs and symptoms, including fever, tachypnea, headache, tachycardia, hypotension, rash, hypoxia, and/or multi-organ dysfunction, during TALVEY treatment, especially during SUD and the first cycle.
  • During TALVEY initiation, frequent monitoring for fever (≥38.3°C) is necessary to detect CRS.
  • Early CRS symptoms should be distinguished from infection and hemophagocytic lymphohistiocytosis, especially in patients with a high disease burden who are not responding to initial CRS management.
  • Severe CRS management requires a multi-departmental approach.
  • A detailed medical history, physical work-up, and additional imaging may be required to differentiate CRS from other causes of fever and from injection-site or systemic administration-related reactions.
• Upon confirming CRS, patients should be closely monitored and treated according to institutional protocols, CRS treatment guidelines, and the product label.
• TALVEY treatment should be held until CRS resolves, and discontinuation may be considered in severe cases.
• Tocilizumab reduced CRS recurrence in the MonumenTAL-1 study. Across the three cohorts, 23-26% of patients who received tocilizumab experienced a subsequent CRS event, compared to 42-52% of those who did not receive tocilizumab. The impact of prophylactic tocilizumab administration before TALVEY was not assessed.
• Almost all events associated with TALVEY were fully resolved through appropriate and timely management.

Schinke et al (2023)⁶ presented the updated efficacy and safety results from the phase 2 portion of the MonumenTAL-1 study. Results specific to CRS events are summarized below.

Results

Treatment Disposition

• Overall, 143 patients were included in the 0.4 mg/kg SC QW cohort, 145 patients in the 0.8 mg/kg SC Q2W cohort, and 51 patients in the prior TCR cohort.
• The median duration of follow-up was 18.8 months for the 0.4 mg/kg SC QW cohort, 12.7 months for the 0.8 mg/kg SC Q2W cohort, and 14.8 months for the prior TCR cohort.

Safety

• The incidence of any grade CRS reported in patients in the 0.4 mg/kg SC QW, 0.8 mg/kg SC Q2W, and prior TCR cohorts is presented in Table: MonumenTAL-1 (Phase 2) Study: Incidence of CRS.^6,26

Jakubowiak et al (2023)¹³ presented the updated efficacy and safety results in patients with prior TCR, including an additional 19 patients enrolled in the MonumenTAL-1 study since the prior analysis. Results specific to CRS events are summarized below.

Results

Treatment Disposition

• A total of 70 patients with prior TCR were enrolled; 67 patients (95.7%) were exposed to BCMA-targeting TCR.
• The median duration of follow-up was 18.4 months for the overall prior TCR cohort and the prior CAR-T cohort and 16.3 months for the prior BsAb cohort, respectively.

Safety

• The incidence of CRS in patients with prior TCR is presented in Table: MonumenTAL-1 Study: CRS Events (Prior TCR).
  • Patients with prior exposure to CAR-T had similar rates of CRS when compared with patients with prior exposure to BsAb.

Krishnan et al (2023)¹⁴ evaluated the efficacy and safety of TALVEY in key high-risk and prior BCMA therapy subgroups of patients from the phase 1/2 MonumenTAL-1 study. Results specific to CRS events are summarized below.

Results

Treatment Disposition

• Overall, 143 patients in the 0.4 mg/kg SC QW cohort and 145 patients in the 0.8 mg/kg SC Q2W cohort were included in the subgroup analyses.
  • Subgroups of patients with high-risk features included ≥75 years of age, high-risk cytogenetics (del(17p), t(4;14), and/or t(14;16)), International Staging System (ISS) stage III, renal impairment (baseline function ≤60 mL/min/1.73 m²), triple-class refractory (to a PI, immunomodulatory drug, and anti-CD38 monoclonal antibody), and EMD ≥1 (including soft tissue plasmacytomas).
  • Subgroups of patients with prior BCMA therapies included TCR-naïve BCMA ADC exposed in the 0.4 mg/kg SC QW TALVEY dose, TCR-naïve BCMA ADC exposed in the 0.8 mg/kg SC Q2W TALVEY dose, and TCR-exposed (includes BCMA ADC, BCMA CAR-T, and BCMA BsAb) QW and Q2W dosing.

Safety

• CRS-related AEs observed in the high-risk patient subgroups are summarized in Table: MonumenTAL-1 Study: Summary of CRS-related AEs in High-risk Subgroups.
• CRS-related AEs observed in the prior BCMA therapies subgroups are summarized in Table: MonumenTAL-1 Study: Summary of CRS-related AEs in Prior BCMA Subgroups.

MonumenTAL-1 Study Protocol (Part 3) - Description and Management of CRS

• As the specific mode-of-action of TALVEY is based on the binding and activation of T cells and the release of cytokines in the tumor environment, AEs of CRS should be anticipated.^7,25
• To reduce the risk of CRS, patients should receive SUDs of TALVEY. Per protocol, patients should also receive premedications (glucocorticoid, antihistamine, and antipyretic) prior to each SUD and the first treatment dose of TALVEY.⁷

Description

• Clinical symptoms indicative of CRS may include but are not limited to fever (with or without rigors), arthralgia, nausea, vomiting, tachycardia, hypotension, headache, confusion, tremor, and delirium.⁷
• At first sign of CRS (such as fever) patients should be immediately hospitalized for evaluation.⁷
• Potentially life-threatening complications of CRS may include cardiac dysfunction, adult respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).⁷
• In the MonumenTAL-1 study (phase 2, Part 3), CRS and CRS symptoms were captured as an AE of special interest and graded per the ASTCT grading system.⁷

Monitoring

• Patients should be closely monitored for early signs and symptoms indicative of CRS.⁷
• Patients were monitored before and after the administration of TALVEY and as clinically indicated. Monitoring included vital signs (including temperature) and oxygen saturation.⁷
• Laboratory testing for coagulation will be conducted during cycle 1 (and as clinically indicated) to monitor for DIC, a manifestation of CRS.⁷

Management

• Recommendations for the clinical management of CRS were provided in the protocol (see Table: MonumenTAL-1 Study Protocol: Guidelines for the Management of CRS) and were symptom-driven.⁷
• Trained clinical personnel should be prepared to intervene in the event of CRS. Resources necessary for resuscitation (ie, agents such as epinephrine and aerosolized bronchodilator; medical equipment such as oxygen, tracheostomy equipment, and a defibrillator) should be readily available. Vital signs and laboratory parameters must be monitored at regular intervals until normalized.⁷
• Treatment with tocilizumab is included for the clinical management of CRS, therefore tocilizumab or alternate treatment must be available prior to administration of TALVEY.⁷
• Per protocol: Hospitalization requirements are defined as⁷ :
  • At first signs of CRS (such as fever) patient should be immediately hospitalized for evaluation (if not already hospitalized).
  • If a patient develops grade 2/3 CRS during the preceding dose that does not resolve to baseline or improve to grade ≤1 in 48 hours, then the 2 subsequent doses require hospitalization for at least 36 hours from the start of injection.

MonumenTAL-1 Study Protocol (Part 3) - Dose Modification Guidance

• Dose delays were the primary method for managing AEs in Part 3 (phase 2) of the MonumenTAL-1 study. If a dose interruption is ≥28 days, treatment must be permanently discontinued unless continuation is agreed in consultation with the sponsor after a review of safety and efficacy. Repeat of SUDs and pretreatment medication may be required.⁷
• Select criteria for a dose delay in phase 2, Part 3 related to CRS were⁷:
  • Ongoing grade 1, 2, or first occurrence of grade 3 CRS: CRS must be completely resolved prior to the next dose.
  • Following a dose delay, CRS must fully resolve and there should be no evidence of serious bacterial, viral, or fungal infection before the next administration of TALVEY.
• Criteria for dose delays due to TALVEY-related toxicities are as follows⁷:
  • Grade ≥3 clinically significant non-hematologic toxicities (i.e., associated with an AE and/or require intervention).
  • If toxicity occurs during SUD administration:
    • The toxicity must resolve to baseline or grade ≤1 and there must be no evidence of serious bacterial, viral, or fungal infection before proceeding to the next SUD (if more than one SUD is to be administered) or to cycle 1 day 1.
    • One further attempt at SUD is allowed within 28 days of any SUD.

MonumenTAL-1 Study Protocol (Part 3) - Discontinuation of Treatment Related to CRS

• A patient’s study treatment in Part 3 (phase 2) was permanently discontinued if the patient presented with a second occurrence of grade 3 CRS or any occurrence of grade 4 CRS.⁷

MonumenTAL-1 Study Protocol (Part 3) - Key Prohibited Medications Related to CRS

• Corticosteroids in excess of 10 mg daily of prednisone (or equivalent) for more than 14 days are prohibited, other than for the management of AEs where no other treatment options are available and in consultation with the sponsor. Dexamethasone should not be administered as a pretreatment medication after cycle 1 day 1, except for patients who experience grade ≥2 CRS.⁷
• Other immunosuppressant agents unless used as protocol-specified pretreatment medications or to treat an AE (eg, CRS).⁷
• Cytochrome P450 substrates with narrow therapeutic index should be used with caution during the first 48 hours after the first dose of TALVEY administration and during any events of CRS.⁷
• For patients receiving warfarin, investigators should consider switching from warfarin to a different anticoagulant. For patients who cannot switch to a different anticoagulant and who experience CRS, coagulation parameters should be monitored closely during a CRS event and until CRS symptoms resolve.⁷
• The use of myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor, should be avoided during CRS.²⁷

CLINICAL DATA - Monumental-2 study

MonumenTAL-2 (MMY1004; clinicaltrials.gov identifier NCT05050097) is an ongoing, phase 1b, multi-arm, open-label study evaluating TALVEY in combination with other anticancer therapies in patients with MM.^16-18 Summarized below are CRS events in Cohort D and Cohort E.

Study Design/Methods

• Key eligibility criteria:
  • Cohort D: measurable MM, NDMM, ECOG PS of 0-1, and transplant ineligible or not intended for transplant.¹⁸
  • Cohort E: measurable MM; ≥2 prior LOTs, including a PI and an immunomodulatory drug; ECOG PS of 0-1; prior pomalidomide and prior TCR (CAR-T and BsAb) permitted; and no prior GPRC5D-targeted therapy.¹⁶
• Primary endpoint for Cohort D and Cohort E: safety; AEs assessed per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, except for CRS and ICANS, which were graded per ASTCT guidelines.^16,18

Cohort D

Nooka et al (2024)¹⁸ presented the initial efficacy and safety results of the TALVEY 0.6 mg/kg Q2W + DARZALEX FASPRO + lenalidomide and TALVEY 0.8 mg/kg Q4W + DARZALEX FASPRO + lenalidomide cohorts from the MonumenTAL-2 study. Results specific to CRS events are summarized below.

Results

Treatment Disposition

• Overall, 8 patients were included in the TALVEY 0.6 mg/kg Q2W + DARZALEX FASPRO + lenalidomide cohort and 26 patients were included in the TALVEY 0.8 mg/kg Q4W + DARZALEX FASPRO + lenalidomide cohort.
• The median follow-up was 13.2 months (range, 10.0-14.6) for the TALVEY 0.6 mg/kg Q2W + DARZALEX FASPRO + lenalidomide cohort and 5.8 months (range, 1.7 [denotes patients who died]-12.0) for the TALVEY 0.8 mg/kg Q4W + DARZALEX FASPRO + lenalidomide cohort.

Safety

• CRS events are summarized in Table: MonumenTAL-2 Study (Cohort D): Summary of CRS Events.

Cohort E

Searle et al (2024)⁵ presented the updated efficacy and safety results of TALVEY in combination with pomalidomide from the MonumenTAL-2 study. Results specific to CRS events are summarized below.

Results

Treatment Disposition

• Overall, 16 patients were included in the TALVEY 0.4 mg/kg QW + pomalidomide cohort and 19 patients were included in the TALVEY 0.8 mg/kg Q2W + pomalidomide cohort.
• The median follow-up was 16.8 months (range, 1.2-25.1).
• Prior treatments included the following: CAR-T (8.6%), BsAb (2.9%), anti-CD38 antibody (74.3%), and pomalidomide (22.9%).

Safety

• CRS reported at a data cutoff date of April 22, 2024, is summarized in Table: MonumenTAL-2 (Cohort E) Study: Summary of CRS Events.

CLINICAL DATA - TRIMM-2 STUDY - TALVEY + DArZALEX FASPRO COHORT

TRIMM-2 (MMY1002; clinicaltrials.gov identifier: NCT04108195) is an ongoing, phase 1b, 2-part, multicohort, open-label study evaluating DARZALEX FASPRO regimens in combination with bispecific TCR antibodies in patients with RRMM.^1,19,20

Study Design/Methods

• Key eligibility criteria¹:
  • Double refractory to a PI and an immunomodulatory drug or received ≥3 prior LOTs (including a PI and an immunomodulatory drug).
  • Treatment with an anti-CD38 monoclonal antibody (>90 days prior allowed) including anti-CD38 refractory patients.
  • Prior BsAb and CAR-T were allowed.
• Key primary endpoints¹:
  • Part 1: identify the RP2D for each treatment combination.
  • Part 2: safety and tolerability at the selected RP2D of each treatment combination.
  • Antitumor activity.

Bahlis et al (2024)²⁰ presented the efficacy and safety results of the TALVEY 0.4 mg/kg QW + DARZALEX FASPRO + pomalidomide and TALVEY 0.8 mg/kg Q2W + DARZALEX FASPRO + pomalidomide cohorts at a median follow-up of 15.8 months (range, 3.2-37.9) and 17.5 months (range, 0.2-37.7), respectively.

Study Design/Methods

• Dosing:
  • TALVEY: 2-3 SUDs before receiving the first full doses of either 0.4 mg/kg SC QW or 0.8 mg/kg SC Q2W.
    • The dose frequency could be reduced from QW to Q2W after cycle 4 if patients achieved PR and from Q2W to Q4W after cycle 8 if they achieved very good partial response (VGPR).
  • DARZALEX FASPRO 1800 mg SC: cycles 1-2, QW; cycles 3-6, Q2W; cycles 7+, Q4W.
  • Pomalidomide 2 mg PO: Starting cycle 2. The dosage may be lowered due to hematologic AEs.

Results

Treatment Disposition

• Overall, 18 patients were included in the TALVEY 0.4 mg/kg QW + DARZALEX FASPRO + pomalidomide cohort and 59 patients were included in the TALVEY 0.8 mg/kg Q2W + DARZALEX FASPRO + pomalidomide cohort.
• The median duration of follow-up was 15.8 months (range, 3.2-37.9) for the TALVEY 0.4 mg/kg QW + DARZALEX FASPRO + pomalidomide cohort and 17.5 months (range, 0.2-37.7) for the TALVEY 0.8 mg/kg Q2W + DARZALEX FASPRO + pomalidomide cohort.

Safety

• CRS occurred mostly during step-up and cycle 1 dosing. No grade ≥3 CRS was reported. All CRS events resolved.
• The incidence, timing/duration, and supportive measures used for management of CRS are summarized in the Table: TRIMM-2 Study (TALVEY + DARZALEX FASPRO + Pomalidomide Cohort): CRS Events.

Dholaria et al (2023)¹ presented the updated results of the TRIMM-2 study. Results specific to CRS events reported in patients receiving TALVEY and DARZALEX FASPRO are summarized below.

Study Design/Methods

• Dosing:
  • TALVEY: 1-3 SUDs within 1 week before receiving the full doses of either 0.4 mg/kg SC QW or 0.8 mg/kg SC Q2W.
    • The dose frequency of TALVEY could be reduced from QW to Q2W after 4 cycles if patients achieved PR and further from Q2W to Q4W after 8 cycles if they achieved VGPR.
  • DARZALEX FASPRO 1800 mg SC: cycles 1-2, QW; cycles 3-6, Q2W; cycles 7+, Q4W.

Results

Treatment Disposition

• Overall, 14 patients were included in the TALVEY 0.4 mg/kg QW + DARZALEX FASPRO 1800 mg Q4W cohort and 51 patients in the TALVEY 0.8 mg/kg Q2W + DARZALEX FASPRO 1800 mg Q4W cohort.
• The median duration of follow-up was 16.8 months (range, 1.9-31.0) for the TALVEY 0.4 mg/kg QW + DARZALEX FASPRO 1800 mg Q4W cohort and 15.0 months (range, 1.0-23.3) for the TALVEY 0.8 mg/kg Q2W + DARZALEX FASPRO 1800 mg Q4W cohort.

Safety

• CRS occurred mostly during step-up and cycle 1 doses only. No grade 3/4 CRS or discontinuations due to CRS were reported.
• The incidence, timing/duration, and supportive measures used for management of CRS are summarized in the Table: TRIMM-2 Study: CRS Events.

CLINICAL DATA - redirectt-1 STUDY - TALVEY + tecvayli COHORT

RedirecTT-1 (MMY1003; clinicaltrials.gov identifier: NCT04586426) is an ongoing, open-label, phase 1b/2 study evaluating the safety and effectiveness of the combination of TALVEY and TECVAYLI in patients with RRMM.^2,21,22

Study Design/Methods

Key inclusion criteria: relapsed or refractory or intolerant to established therapies including the last LOT; prior exposure to a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.²²

• Primary endpoints: safety, identify RP2R(s), and schedule.²²
• Dosing: eligible patients received varying dose levels of TALVEY and TECVAYLI to determine the RP2R dose and schedule of the combination.²²
  • All dose levels: Five varying dose levels of TECVAYLI and TALVEY.
  • RP2R: TECVAYLI 3.0 mg/kg SC Q2W plus TALVEY 0.8 mg/kg SC Q2W.

Cohen et al (2024)²² presented the updated efficacy and safety results for the all dose levels cohort and the TALVEY and TECVAYLI RP2R cohort in the RedirecTT-1 study, including patients with EMD.

Results

Treatment Disposition

• Overall, 94 patients were included in the all dose levels cohort and 44 patients were in the RP2R cohort.
• The median duration of follow-up was 20.3 months in the all dose levels cohort and 18.2 months (range, 0.7-27.0) in the RP2R cohort.

Safety

• Details on CRS occurrence and management are presented in Table: RedirecTT-1 Study (TALVEY + TECVAYLI Cohort): Incidence and Management of CRS.
• Most CRS events occurred during SUD and cycle 1 day 1 doses. All CRS events recovered.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 09 January 2025.