Talquetamab for Multiple Myeloma

Overseen By Lupita Chen

Age: 65+

Sex: Any

Trial Phase: Phase 2

Sponsor: Larysa Sanchez

Must not be taking: T-cell-engaging antibodies

Disqualifiers: Active CNS involvement, Plasma cell leukemia, Active malignancies, Uncontrolled diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

23 Participants Needed

Trial Summary

What is the purpose of this trial?

Induction therapy approaches in recent years have evolved, now utilizing triple or quadruple drug regimens in the majority of patients. By combining anti-CD38 antibodies, proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and steroids, patients achieve longer remissions with their first- and second-line therapies but also become refractory to most or all three major drug classes earlier. For patients who are refractory to at least 3 of the commonly administered PIs and IMiDs, occurring after 2 lines of therapy in many, the median overall survival is only 5 months. Elderly, frail patients are not often candidates at this point for aggressive therapies like stem cell transplantation and CAR T-cell therapy thus necessitating effective yet tolerable treatments for elderly patients in early relapse (1-3 prior therapy). Talquetamab is a GPRC5DxCD3 bispecific antibody that redirects patients' T cells to myeloma cells which express GPRC5D. In the phase 1 MonumenTAL-1, heavily pretreated patients with a median of 6 prior lines of therapy attained a 70% response rate with 405 μg/kg of subcutaneous (SC) talquetamab. Importantly, subcutaneous talquetamab was found to be tolerable for the treated population, which included 28% of patients aged ≥70, with only three patients experiencing dose-limiting toxicities in the form of grade 3 rashes which responded to steroids. The anti-CD38 antibody daratumumab eliminates CD38-positive T and B regulatory cells, potentiates the activity of bispecific antibodies like talquetamab, and may improve its efficacy when used in combination. The aim of this study will be to assess the efficacy and safety of treating elderly patients with relapsed/refractory multiple myeloma with at least ≥2 prior lines of therapy with subcutaneous talquetamab. Patients who have progressive disease on talquetamab or who fail to respond after 3 cycles will have subcutaneous daratumumab added to their regimen.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, certain prior treatments, like monoclonal antibody treatment for multiple myeloma, must be stopped at least 21 days before the study. It's best to discuss your specific medications with the trial team.

Is Talquetamab safe for humans?

Talquetamab has been shown to be generally well-tolerated in humans, but it can cause some side effects like skin, mouth, and nail issues. It has fewer infections compared to similar treatments, making it a promising option for multiple myeloma patients. ^{1 2 3 4 5}

How is the drug Talquetamab different from other treatments for multiple myeloma?

Talquetamab is unique because it is a first-in-class bispecific antibody that targets a specific protein (GPRC5D) found on cancerous plasma cells, while also engaging T-cells to activate an immune response. This approach is different from traditional treatments and offers a new option for patients with relapsed or refractory multiple myeloma. ^{1 3 6 7 8}

Research Team

Larysa Sanchez, MD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

This trial is for elderly patients with multiple myeloma who have experienced an early relapse after 1-3 prior therapies. They should not be candidates for aggressive treatments like stem cell transplantation and must have been refractory to at least three major drug classes.

Inclusion Criteria

Clinical laboratory values meeting specific criteria during the Screening Phase

Human immunodeficiency virus-positive participants meeting specific criteria

Agreement to wear a condom and not donate sperm for reproduction

Exclusion Criteria

I have not recently had cancer treatment or been in a drug trial.

I am not allergic to the drugs used in this study.

Specific medical conditions or diseases likely to interfere with study procedures

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Participants receive talquetamab SC monotherapy starting with three step-up doses followed by the standard 800 μg/kg dose every other week. Cycles are 28 days long.

12 weeks

Monthly response assessment

Treatment Part 2

For participants who proceed to part 2, talquetamab is continued and daratumumab is added. Daratumumab is administered weekly for 2 cycles, every other week for 4 cycles, then monthly.

Up to 36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Daratumumab
• Talquetamab

Trial Overview The study tests subcutaneous Talquetamab, a new antibody that targets myeloma cells, in these patients. If there's no improvement after three cycles, Daratumumab will be added. The goal is to find an effective yet tolerable treatment for this group.

Participant Groups

Group I: Talquetamab SC monotherapy Experimental Treatment 1 Intervention

In part 1, patients will receive talquetamab SC monotherapy starting with three step-up doses followed by the standard 800 μg/kg dose every other week. Cycles will be 28 days long. Response will be assessed monthly according to IMWG criteria, and patients who have PD after completing at least 1 cycle of talquetamab or who fail to attain ≥ PR after completion of cycle 3 will proceed to part 2 only if not previously refractory to an anti-CD38 monoclonal antibody. Patients refractory to an anti-CD38 mAb will not be allowed in Part 2. patients who are refractory to an anti-CD38 mAb and PD at any point will be taken off study and not proceed to Part 2. patients who are refractory to an anti-CD38 mAb and achieve a response \<PR after 3 cycles (stable disease or minimal response) will continue on talquetamab monotherapy until PD or be taken off study per investigator discretion if it is deemed that subject will not continue to derive clinical benefit from talquetamab monotherapy.

Group II: Talqeutemab SC + Daratumumab SC Experimental Treatment 2 Interventions

For participants who proceed to part 2, talquetamab will be continued at 800 μg/kg every other week but daratumumab will be initiated at the standard dose (weekly for 2 cycles, every other week for 4 cycles, monthly thereafter). In part 2, participants will continue talquetamab and daratumumab until PD, unacceptable toxicity or other reasons for discontinuing treatment, withdrawal from study. Patients in part 1 and part 2 who achieve VGPR or better after receiving at least 4 cycles of talquetamab in the respective part can be transitioned to every 4 week dosing.

Who Is Running the Clinical Trial?

Larysa Sanchez

Lead Sponsor

Trials

2

Recruited

40+

Janssen Research & Development, LLC

Industry Sponsor

Trials

1,022

Recruited

6,408,000+

Giacomo Salvadore

Janssen Research & Development, LLC

Chief Medical Officer since 2023

MD from the University of Rome, Tor Vergata

Ricardo Attar

Janssen Research & Development, LLC

Chief Executive Officer since 2008

PhD in Molecular Biology from the University of Buenos Aires

Findings from Research

Talquetamab, a bispecific T-cell engager targeting GPRC5D and CD3, has received accelerated approval in the USA and conditional marketing authorization in the EU for treating adults with relapsed or refractory multiple myeloma, highlighting its potential as a new treatment option.

This approval marks a significant milestone in the development of talquetamab, indicating its efficacy and safety in addressing a challenging form of cancer that has not responded to previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talquetamab: First Approval. Keam, SJ.[2023]

Daratumumab, an anti-CD38 monoclonal antibody, has significantly improved treatment outcomes for multiple myeloma (MM), showing enhanced progression-free survival and response rates in relapsed/refractory cases when combined with other therapies, as demonstrated in several key clinical trials.

In newly diagnosed patients, daratumumab has also shown an overall survival benefit when added to frontline treatment regimens, indicating its effectiveness in both early and advanced stages of MM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daratumumab for the Treatment of Multiple Myeloma: A Review of Clinical Applicability and Operational Considerations. Arnall, JR., Maples, KT., Harvey, RD., et al.[2022]

Talquetamab, a bispecific antibody targeting GPRC5D and CD3, shows similar efficacy and durability of response in treating relapsed or refractory multiple myeloma compared to teclistamab, the first bispecific antibody approved for this condition.

While talquetamab has a lower incidence of infections than teclistamab, it presents unique side effects related to skin, oral, and nails, yet remains a well-tolerated and effective treatment option for patients with heavily pretreated multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talquetamab in multiple myeloma. Liu, L., Krishnan, A.[2023]

Belantamab mafodotin (BLENREP) received accelerated FDA approval for treating relapsed or refractory multiple myeloma in adults who have undergone at least four prior therapies, showing an overall response rate of 31% to 34% in the DREAMM-2 trial with 2.5 or 3.4 mg/kg doses.

The most common side effect was keratopathy, affecting 71% to 77% of patients, leading to a boxed warning for ocular toxicity, indicating the need for careful monitoring and a restricted distribution program.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Belantamab Mafodotin for Patients with Relapsed or Refractory Multiple Myeloma. Baines, AC., Ershler, R., Kanapuru, B., et al.[2023]

Belantamab mafodotin is a newly approved treatment for relapsed or refractory multiple myeloma, showing an overall response rate of 31% and a median progression-free survival of 2.9 months in patients who have undergone at least four prior therapies.

While the treatment is generally well tolerated, it is associated with notable ocular toxicities, which require careful management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Ocular Toxicity in Patients Receiving Belantamab Mafodotin. Lu, R., Morphey, A., Diaz, F., et al.[2023]

In the MonumenTAL-1 trial, nearly 75% of the 288 patients with relapsed/refractory multiple myeloma showed significant anticancer effects from the investigational drug talquetamab.

Talquetamab is a first-in-class bispecific antibody that targets GPRC5D on malignant plasma cells while sparing normal cells, effectively activating T cells to mount an immune response against the cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MonumenTAL Results for Talquetamab in Myeloma. [2023]

Three new bispecific antibodies—teclistamab, elranatamab, and talquetamab—have received accelerated FDA approval for treating relapsed/refractory multiple myeloma, indicating their potential efficacy in this challenging condition.

While these agents show promise, the medical community is currently awaiting results from randomized phase III clinical trials to better understand their effectiveness compared to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Embarrassment of Riches: Three FDA-Approved Bispecific Antibodies for Relapsed Refractory Multiple Myeloma. Firestone, R., Lesokhin, AM., Usmani, SZ.[2023]

In the phase 1 MonumenTAL-1 study involving patients with refractory or relapsed multiple myeloma, two doses of talquetamab (405 μg/kg weekly and 800 μg/kg every other week) were found to be well tolerated, with most side effects being mild or moderate, including cytokine release syndrome (CRS).

The treatment showed promising efficacy, with most participants experiencing a reduction in cancer signs and a median duration of response of 8-10 months, indicating talquetamab's potential as a new option for patients who have not responded to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plain language summary of the MonumenTAL-1 study of talquetamab in people with relapsed or refractory multiple myeloma. Chari, A., Askari, E., Caers, J., et al.[2023]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Talquetamab: First Approval. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Daratumumab for the Treatment of Multiple Myeloma: A Review of Clinical Applicability and Operational Considerations. [2022]

3. Italy pubmed.ncbi.nlm.nih.gov

Talquetamab in multiple myeloma. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Belantamab Mafodotin for Patients with Relapsed or Refractory Multiple Myeloma. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Management of Ocular Toxicity in Patients Receiving Belantamab Mafodotin. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

MonumenTAL Results for Talquetamab in Myeloma. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

An Embarrassment of Riches: Three FDA-Approved Bispecific Antibodies for Relapsed Refractory Multiple Myeloma. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Plain language summary of the MonumenTAL-1 study of talquetamab in people with relapsed or refractory multiple myeloma. [2023]