External Beam Radiation Therapy in Combination With Talquetamab for the Treatment of Multiple Myeloma Patients With Extramedullary Disease

NCT ID: NCT06572605

Last Updated: 2025-09-19

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-08-29
• Study Completion Date: 2030-01-18

Brief Summary

This phase I/II trial tests the safety and effectiveness of extramedullary disease (EMD)-directed external beam radiation therapy (EBRT) in combination with talquetamab for the treatment of multiple myeloma patients with extramedullary disease. Extramedullary disease in multiple myeloma involves the infiltration of organs and soft tissues by malignant plasma cells and has proven difficult to treat. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink cancers. EBRT is a type of radiation therapy that delivers high-energy beams to the cancer from outside of the body. In this trial, the EBRT will be directed to a site of extramedullary disease. Talquetamab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Combining EMD-directed EBRT with talquetamab may be safe, tolerable, and/or effective in treating multiple myeloma patients with extramedullary disease.

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of single-field, palliative, extramedullary disease (EMD)-directed external beam radiotherapy (EMD-EBRT) in combination with talquetamab as assessed by incidence of adverse events (AEs) throughout the trial and unexpected toxicities (UTs) during step-up and cycle 1. (Phase 1b) II. To evaluate the systemic anti-tumor activity/preliminary efficacy of EMD-EBRT in combination with talquetamab as assessed by EMD-modified overall response rate (ORR). (Phase 2)

SECONDARY OBJECTIVE:

I. To additionally evaluate efficacy through International Myeloma Working Group (IMWG) overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

EXPLORATORY OBJECTIVES:

I. To assess the impact of EMD-EBRT combined with talquetamab on peripheral blood immune cell populations.

II. To assess the spatial transcriptomic changes in the medullary and extramedullary tumor microenvironment in response to EMD-EBRT combined with talquetamab.

OUTLINE:

STEP-UP PERIOD: Patients undergo EMD-EBRT once daily (QD) for 5 treatment fractions on weekdays (Monday to Friday), and receive talquetamab subcutaneously (SC) starting after the first fraction of EMD-EBRT and continuing every 2-4 days for up to 3 step-up doses in the absence of unacceptable toxicity.

SUBSEQUENT TREATMENT: Starting 2-7 days after step-up dose 3, patients receive talquetamab SC on days 1 and 15 of each cycle. Cycles repeat every 28 days for up to a maximum of 13 total cycles in the absence of disease progression or unacceptable toxicity.

Patients also undergo computed tomography (CT) and/or positron emission tomography (PET)/CT and collection of blood samples throughout the trial and undergo image-guided EMD biopsy at screening and on study. Patients undergo bone marrow biopsy/aspiration at screening and optionally at end of treatment.

After completion of study treatment, patients are followed up every 28 days for up to 12 months.

Conditions

Extramedullary Disease in Multiple Myeloma; Multiple Myeloma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (EDM-EBRT, talquetamab)

STEP-UP PERIOD: Patients undergo EMD-EBRT QD for 5 treatment fractions on weekdays (Monday to Friday), and receive talquetamab SC starting after the first fraction of EMD-EBRT and continuing every 2-4 days for up to 3 step-up doses in the absence of unacceptable toxicity.

SUBSEQUENT TREATMENT: Starting 2-7 days after step-up dose 3, patients receive talquetamab SC on days 1 and 15 of each cycle. Cycles repeat every 28 days for up to a maximum of 13 total cycles in the absence of disease progression or unacceptable toxicity.

Patients also undergo CT and/or PET/CT and collection of blood samples throughout the trial and undergo image-guided EMD biopsy at screening and on study. Patients undergo bone marrow biopsy/aspiration at screening and optionally at end of treatment.

Group Type: EXPERIMENTAL

Biospecimen Collection

Intervention Type: PROCEDURE

Undergo collection of blood samples

Bone Marrow Aspiration

Intervention Type: PROCEDURE

Undergo bone marrow aspiration

Bone Marrow Biopsy

Intervention Type: PROCEDURE

Undergo bone marrow biopsy

Computed Tomography

Intervention Type: PROCEDURE

Undergo CT and/or PET/CT

Electronic Health Record Review

Intervention Type: OTHER

Ancillary studies

External Beam Radiation Therapy

Intervention Type: RADIATION

Undergo EMD-EBRT

Image Guided Biopsy

Intervention Type: PROCEDURE

Undergo image-guided EMD biopsy

Positron Emission Tomography

Intervention Type: PROCEDURE

Undergo PET/CT

Talquetamab

Intervention Type: BIOLOGICAL

Given SC

Interventions

Biospecimen Collection

Undergo collection of blood samples

Intervention Type: PROCEDURE

Bone Marrow Aspiration

Undergo bone marrow aspiration

Intervention Type: PROCEDURE

Bone Marrow Biopsy

Undergo bone marrow biopsy

Intervention Type: PROCEDURE

Computed Tomography

Undergo CT and/or PET/CT

Intervention Type: PROCEDURE

Electronic Health Record Review

Ancillary studies

Intervention Type: OTHER

External Beam Radiation Therapy

Undergo EMD-EBRT

Intervention Type: RADIATION

Image Guided Biopsy

Undergo image-guided EMD biopsy

Intervention Type: PROCEDURE

Positron Emission Tomography

Undergo PET/CT

Intervention Type: PROCEDURE

Talquetamab

Given SC

Intervention Type: BIOLOGICAL

Other Intervention Names

Biological Sample Collection; Biospecimen Collected; Specimen Collection; Biopsy of Bone Marrow; Biopsy, Bone Marrow; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized axial tomography (procedure); Computerized Tomography; Computerized Tomography (CT) scan; CT; CT Scan; tomography; Definitive Radiation Therapy; EBRT; External Beam Radiation; External Beam Radiotherapy; External Beam Radiotherapy (conventional); External Beam RT; external radiation; External Radiation Therapy; external-beam radiation; Radiation, External Beam; Teleradiotherapy; Teletherapy; Teletherapy Radiation; Image-Guided Biopsy; Imaging for Biopsy; Imaging Guided Biopsy; Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron emission tomography (procedure); Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging; PT; Anti-CD3/Anti-GPRC5D Bispecific Monoclonal Antibody JNJ-64407564; GPRC5D x CD3 Bispecific Antibody JNJ-64407564; GPRC5D x CD3 DuoBody Antibody JNJ-64407564; GPRC5D/CD3 DuoBody Antibody JNJ-64407564; Humanized GPRC5D x CD3 DuoBody Antibody JNJ-64407564; JNJ 64407564; JNJ-64407564; JNJ64407564; Talquetamab-tgvs

Eligibility Criteria

Inclusion Criteria

• Documented informed consent of the participant and/or legally authorized representative

• Assent, when appropriate, will be obtained per institutional guidelines
• Agreement to allow the use of archival tissue from diagnostic tumor biopsies

• If unavailable, exceptions may be granted with study principal investigator (PI) approval
• Age: ≥ 18 years
• Karnofsky performance status (KPS) ≥ 60%
• Diagnosis of multiple myeloma with extramedullary disease (EMD). EMD is defined as soft-tissue plasmacytomas NOT arising from skeletal lesions (i.e., the EMD is not contiguous with any bone/bony lesion)
• Measurable systemic disease defined as serum M-spike ≥ 0.5 g/dl, 24-hour urine M-spike ≥ 200 mg/24 hours (hr), involved serum free light chain (FLC) ≥ 10 mg/dl with abnormal FLC ratio, and/or a non-target plasmacytoma ≥ 2 cm in a single diameter (NOTE: Non-target plasmacytoma must not be included in the EMD-EBRT field)
• At least one site of EMD must have an indication for palliative radiation per the treating clinicians (e.g., including but not limited to pain, asymmetry, discomfort, threatening to vital structure, etc.)
• Target EMD site must be encompassed by one radiation field per treating radiation oncologist
• Subject must have received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody
• Fully recovered from the acute non-hematologic toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy
• Prior antitumor therapy must have been completed prior to enrollment as follows:

• ≥ 2 weeks for prior external beam radiotherapy (XRT) to non-target site
• ≥ 21 days for cytotoxic chemotherapy (systemic or intrathecal)
• ≥ 28 days for prior adoptive cell therapy or T-cell redirecting therapies
• ≥ 4 weeks or 5 half-lives (whichever is shorter) for other myeloma therapies
• Absolute neutrophil count (ANC) ≥ 1,000/mm^3 (prior growth factor support is permitted but must be without support for 7 days for granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF] and for 14 days for pegylated GCSF before the laboratory test)

• Two repeat tests are allowed. If the repeat test satisfies criteria, the participant may enroll provided all other criteria are met
• Platelets ≥ 50,000/mm^3

• NOTE: No transfusion support or thrombopoietin receptor agonist within 7 days before laboratory test
• Two repeat tests are allowed. If the repeat test satisfies criteria, the participant may enroll provided all other criteria are met
• Hemoglobin ≥ 8g/dL

• NOTE: No transfusion support or erythropoietin use within 7 days before the laboratory test
• Two repeat tests are allowed. If the repeat test satisfies criteria, the participant may enroll provided all other criteria are met
• Total bilirubin ≤ 2.0 X upper limit of normal (ULN) (unless has congenital bilirubinemia such as Gilbert's disease, in which case ≤ 1.5 × ULN is required)

• Two repeat tests are allowed. If the repeat test satisfies criteria, the participant may enroll provided all other criteria are met
• Aspartate aminotransferase (AST) ≤ 2.5 x ULN

• Two repeat tests are allowed. If the repeat test satisfies criteria, the participant may enroll provided all other criteria are met
• Alanine aminotransferase (ALT) ≤ 2.5 x ULN

• Two repeat tests are allowed. If the repeat test satisfies criteria, the participant may enroll provided all other criteria are met
• Creatinine clearance of ≥ 30 mL/min per 24 hour urine test or the Cockcroft-Gault formula

• Two repeat tests are allowed. If the repeat test satisfies criteria, the participant may enroll provided all other criteria are met
• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

• If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Two repeat tests are allowed. If the repeat test satisfies criteria, the participant may enroll provided all other criteria are met
• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of talquetamab

• Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Exclusion Criteria

• Prior irradiation to target EMD site or field
• Prior GPRC5D therapy
• Prior radiopharmaceutical therapy
• Patients who have received previous radiation to > 25% of their bone marrow
• Prior allogeneic hematopoietic cell transplantation within the past 6 months or prior autologous hematopoietic cell transplantation within the past 12 weeks
• A maximum cumulative dose of corticosteroids of ≥ 140 mg of prednisone or equivalent within 14-day period before the first dose of study drug (does not include pre-treatment medications)
• Major surgery within 2 weeks prior to the start of administration of study treatment, or will not have fully recovered from surgery, or has major surgery planned during the time the participant is expected to be treated in the study, or within 2 weeks after administration of the last dose of study treatment

• Note: Participants with planned surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery. If there is a question whether a procedure is considered a major surgery, the investigator must consult with the appropriate representative at Janssen and resolve any issues before enrolling a participant in the study
• Ongoing or active infection
• Severe persistent asthma or severe chronic obstructive pulmonary disease (COPD)
• Presence of the following cardiac conditions:

• New York Heart Association stage III or IV congestive heart failure
• Myocardial infarction or coronary artery bypass graft ≤ 6 months prior to randomization
• Uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormalities
• History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration
• History of severe non-ischemic cardiomyopathy
• Any of the following:

• Hepatitis B infection (i.e., hepatitis B virus surface antigen [HBsAg] or hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] positive). In the event the infection status is unclear, quantitative viral levels are necessary to determine the infection status
• Active hepatitis C infection as measured by positive hepatitis C virus [HCV]-ribonucleic acid [RNA] testing. Participants with a history of HCV antibody positivity must undergo HCV-RNA testing. If a participant with history of chronic hepatitis C infection (defined as both HCV antibody and HCV-RNA positive) completed antiviral therapy and has undetectable HCV-RNA for at least 12 weeks following the completion of therapy, the participant is eligible for the study
• Plasma cell leukemia (> 20% circulating plasma cells and/or > 2.0 x 10^9/L plasma cells) at the time of screening, Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes), or primary amyloid light chain amyloidosis
• Known active central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of multiple myeloma. If either is suspected, negative whole brain MRI and lumbar cytology are required
• Other active malignancy. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Stroke or seizure within 6 months prior to enrollment
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• If HIV positive, any of the following:

• Detectable viral load at screening
• CD4+ T cell count ≤ 300
• AIDS-defining opportunistic infection within 6 months of screening
• Changes in highly active antiretroviral therapy (HAART) due to resistance/progression that occurred within 3 months prior to screening
• Changes in HAART due to toxicity within 4 weeks prior to screening
• Females only: Pregnant or breastfeeding
• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

City of Hope Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Scott R Goldsmith

Role: PRINCIPAL_INVESTIGATOR

City of Hope Medical Center

Locations

City of Hope Medical Center

Duarte, California, United States

Site Status: RECRUITING

Countries

United States

Facility Contacts

Scott R. Goldsmith

Role: primary

sgoldsmith@coh.org

626-218-2405

Other Identifiers

NCI-2024-06707

Identifier Type: REGISTRY

Identifier Source: secondary_id

23931

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA033572

Identifier Type: NIH

Identifier Source: secondary_id

View Link

23931

Identifier Type: -

Identifier Source: org_study_id