Sirolimus Pre-conditioning on T Cell Activity and T-cell Engaging Bispecific Antibody Efficacy in Multiple Myeloma

Impact of Sirolimus Pre-conditioning on T Cell Activity and T-cell Engaging Bispecific Antibody Efficacy in Multiple Myeloma

This is a single center, single arm Phase Ib study with expansion cohort designed to establish the safety and physiologic effects of sirolimus pre-conditioning followed by T-cell engaging bispecific antibody therapy.

Study Overview

• Status: Recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Sirolimus; Biological: Teclistamab; Biological: Talquetamb

Detailed Description

This is a Phase Ib trial with expansion cohort to assess the safety and estimate the preliminary efficacy of sirolimus pre-conditioning prior to treatment with a T-cell engaging bispecific antibody in patients with relapsed / refractory multiple myeloma previously exposed to T-cell engager therapy. Following Phase Ib, the study will enroll an expansion cohort to test the hypothesis that sirolimus pre-conditioning will result in an increase in the Teffector: Texhausted -cell ratio.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Christopher Strouse, MD; Phone Number: (319) 356-0489; Email: christopher-strouse@uiowa.edu

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa Health Care
      • Contact: Christopher Strouse, MD; Phone Number: (319) 356-0489; Email: christopher-strouse@uiowa.edu
      • Contact: Christopher Strouse, MD; Phone Number: 319-356-0489; Email: christopher-strouse@uiowa.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

To be eligible to participate in this study, an individual must meet all of the following criteria:

• Willingness and ability to provide signed and dated informed consent form.
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Aged 18 years of older.
• Diagnosis with multiple myeloma, per IMWG Consensus Criteria.20
• Planned for treatment with teclistamab, or talquetamab per standard of care, label indications.15

• Prior exposure to any of the following types of T-cell engaging therapies.

  1. Anti-BCMA x CD3 bispecific antibody (for example: teclistamab, elranatamab)
  2. Anti-GPRC5d x CD3 bispecific antibody (for example: talquetamab)
  3. Anti-GPRC5d x CD3 x CD38 trispecific antibody
  4. Anti-BCMA x CD3 x CD38 trispecific antibody
  5. Anti-BCMA x CD3 x GPRC5d trispecific antibody
  6. Anti-BCMA chimeric antigen T-cell (for example: idecabtagene vicleucel, ciltacabtagene autoleucel)
  7. Anti-FcRL5 x CD3 bispecific antibody
• Required clinical laboratory values during screening phase

Hematologic Parameters Hemoglobin ≥7.0 g/dL; Platelets ≥25 x 109/L; Absolute Lymphocyte Count ≥0.2 x 109/L

Chemistries AST/ALT < 5 x the ULN; Total Bilirubin < 3 x the ULN

• Ability to take oral medication and be willing to adhere to the sirolimus pre-conditioning regimen.
• ECOG performance status of 0, 1, or 2 (KPS of >50).
• For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner per section5.3.
• Agreement to adhere to Lifestyle Considerations (see section 5.3) throughout study duration.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

• Participants whose multiple myeloma is progressing at a rapid pace requiring immediate anti-myeloma therapy per assessment by the principal investigator or enrolling investigator are excluded.

• Excluded concomitant medication exposures:

  • Exposure to corticosteroids within 1 week of treatment start
  • Exposure to calcineurin inhibitor or mTOR inhibitors (tacrolimus, everolimus, temsirolimus, sirolimus)
  • Immunomodulatory monoclonal antibodies targeting tumor necrosis factor alpha (e.g. infliximab), interleukin 6 (e.g. siltuximab),
  • Janus kinase inhibitors (e.g. ruxolitinib)
  • Any other investigational drug within 28 days
• History of allogeneic hematopoietic cell transplantation.

• Excluded concurrent medical conditions:

  • Active uncontrolled infection within 7 days prior to treatment start
  • Uncontrolled thrombotic event within 3 months of treatment start
  • Acute myocardial infarction or acute coronary syndrome within 6 months of start of treatment
  • Uncontrolled inflammatory bowel disease
  • Active hepatitis B virus, hepatitis C virus, or Human Immunodeficiency Virus infection
  • Uncontrolled rheumatologic conditions

  • Use of ACE-inhibitor therapy within 1 week of treatment start

    • Patients found to be taking ace-inhibitor therapy during screening can be included if the ace-inhibitor is substituted for an angiotensin receptor blocking agent. (https://drug-interactions.medicine.iu.edu/main-table)
    • CYP3A4/p-gp inhibitors and inducers for 7 days prior to sirolimus doses and 7 days after sirolimus doses(see appendix A for list)
  • Any other current active malignancy or history of metastatic malignancy that has the potential to interfere with the safety or efficacy assessment of the investigational intervention
• Pregnancy or lactation.
• Known allergic reactions to study agent (sirolimus).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Sirolimus in combination with teclistamab or talquetamab; This study is designed to test changes in immune cell populations of patients with multiple myeloma exposed to short pre-conditioning with sirolimus prior to teclistamab or talquetamab. Safety of the combination will also be assessed.

Drug: Sirolimus; Sirolimus is an immunosuppressant drug. Sirolimus binds to FK binding protein 12 and inhibits mTOR. This then suppresses T-cell proliferation and inhibits progression from G1 to S phase of the cell cycle.; Other Names: Rapamycin; Biological: Teclistamab; Teclistamab is a bispecific antibody that binds the CD3 receptor on T-cells and the B-cell maturation antigen on multiple myeloma cells and healthy B-lineage cells.; Other Names: Tecvayli; Biological: Talquetamb; Talquetamab is a bispecific antibody that binds the CD3 receptor on T-cells and the GPRC5d receptor on multiple myeloma cells.; Other Names: Talvey

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase Ib: Dose limiting toxicities (DLTs) as measured by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0	The incidence of treatment-emergent adverse events will be summarized by system organ class and/or preferred term, type of adverse event, severity (based on NCI CTCAE v5.0) grades), and relation to study treatment. The most severe grade per participant will be reported. Adverse events leading to premature discontinuation from the study intervention and serious treatment-emergent adverse events will be presented in tabular form.	From treatment initiation through 30 days post last dose of study treatment
Expansion Cohort: Participants change in the Teffector: Texhausted cell ratio	Testing the null hypothesis H0: ΔPost-Pre = 0 versus the alternative H1: ΔPost-Pre ≠ 0. Results will be used as preliminary estimates to inform a subsequent larger trial.	From treatment initiation through 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participant change in the following T-cell subsets: T-regulatory; T-Effector Memory (T-EM); T-Effector Memory expressing RA (T-EMRA)	The within participant change in the following T-cell subsets will be estimated: T-regulatory, T-EM, T-EMRA. Mixed effects regression models will be utilized to estimate changes. Random effects will be included to account for the longitudinally correlated nature of repeated measurements. Graphical plots of the estimated mean and associated 95% confidence intervals by time point in the study will be produced.	From treatment initiation through 3 months
The proportion of participants with grade 3 or higher CRS	The rate of grade ≥3 CRS will be defined as the proportion of participants who develop grade 3 or higher CRS. The rate of grade ≥3 CRS will be reported as a binomial proportion along with a two-sided 95% confidence interval.	From treatment initiation through 3 months
The proportion of participants with grade 3 or highter ICANS	The rate of grade ≥3 ICAN will be defined as the proportion of participants who develop grade 3 or higher ICAN. The rate of grade ≥3 ICAN will be reported as a binomial proportion along with a two-sided 95% confidence interval.	From treatment initiation through 3 months
The proportion of participants with a very good partial response (VGPR) or better at 3 months	The 3-month response rate will be defined as the proportion of participants with a very good partial response (VGPR) or better at 3 months. The 3-month response rate will be reported as a binomial proportion along with a two-sided 95% confidence interval.	Three months after the initiation of treatment

Collaborators and Investigators

• Sponsor: Christopher Strouse
• Investigators: Principal Investigator: Christopher Strouse, MD, University of Iowa

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2026
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): October 1, 2029

Study Registration Dates

• First Submitted: May 5, 2026
• First Submitted That Met QC Criteria: May 5, 2026
• First Posted (Actual): May 12, 2026

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: June 2, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Neoplasms, Plasma Cell; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Hemic and Lymphatic Diseases; Multiple Myeloma; Organic Chemicals; Macrolides; Lactones; Sirolimus
• Other Study ID Numbers: 202601163

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No