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

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.

• Anti-BCMA x CD3 bispecific antibody (for example: teclistamab, elranatamab)
• Anti-GPRC5d x CD3 bispecific antibody (for example: talquetamab)
• Anti-GPRC5d x CD3 x CD38 trispecific antibody
• Anti-BCMA x CD3 x CD38 trispecific antibody
• Anti-BCMA x CD3 x GPRC5d trispecific antibody
• Anti-BCMA chimeric antigen T-cell (for example: idecabtagene vicleucel, ciltacabtagene autoleucel)
• 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).