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.

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.

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).