Overview
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.
Principal investigator
Eligibility criteria
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).
* 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).
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