Multiple Myeloma, Relapsed/Refractory Multiple Myeloma
Conditions
Keywords
Multiple myeloma, Relapsed/refractory multiple myeloma, Iberdomide, CAR-T therapy, CC-220
Brief summary
This feasibility trial studies the efficacy of administering iberdomide (CC-220) as a priming agent prior to leukapheresis in patients with relapsed/refractory multiple myeloma (RRMM) who are already planned for standard-of-care CAR-T therapy. Giving iberdomide before CAR-T may improve T cell fitness which may improve CAR-T expansion kinetics and response after infusion.
Detailed description
In this feasibility study, patients with RRMM planned for standard of care CAR-T will be approached for consent for enrollment. Participating patients will receive one 28-day cycle of iberdomide at a dose of 1.0 mg daily, using a dosing schedule of 1.0 mg once daily for 21 days followed by 7 days off. After completion of the 28-day cycle, patients will proceed with leukapheresis on day 29 of therapy, with allowance for up to a 14-day delay in leukapheresis if needed. Blood samples will be collected on day 1 (prior to iberdomide exposure) and on the day of leukapheresis to compare T cell profiling before and after iberdomide priming. After leukapheresis, patients will proceed with standard of care management, including bridging therapy if indicated, until CAR-T infusion. After infusion, blood samples will be collected daily during initial hospitalization, then weekly for 1 month, and then monthly for up to 1 year. Blood samples will be evaluated for maximal CAR-T and ALC expansion and CAR-T persistence. Patients will be monitored per standard of care protocols for clinical efficacy and toxicity after CAR-T therapy for up to 1 year.
Interventions
PROCEDURECAR-T Infusion
Participants will receive an intravenous infusion of standard-of-care CAR-T therapy manufactured from the participant's previously collected cells
DRUGIberdomide
1.0mg iberdomide capsules administered orally, daily on days 1-21 of a 28-day cycle
PROCEDURECAR-T Leukapheresis
A procedure in which blood is collected and white blood cells (including T cells) are separated and collected. The remaining blood components are returned to the participant. The collected T cells will be used to manufacture the CAR-T cell therapy.
Sponsors
Shambavi Richard
Bristol-Myers Squibb
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject is ≥18 years of age at the time of signing the informed consent form (ICF). * Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. * Subject is willing and able to adhere to the study visit schedule and other protocol requirements. * All subjects must have documented diagnosis of MM and be eligible for commercial CAR-T therapy with either cilta-cel or ide-cel. * All subjects must have ≥2 prior lines of multiple myeloma directed therapy, as determined by their treating clinician * All patients must have ECOG Performance Status ≤ 2. * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy tests (minimum sensitivity 25 IU/L or equivalent units of hCG), at screening (10-14 days prior to start of study drug); another within 24 hours prior to the start of study drug. * Women must not be breastfeeding * WOCBP must agree to follow instructions for method(s) of contraception for 1 month (4 weeks) before the start of treatment with study drugs, for the duration of treatment with study drugs, and for a total of 1 month (4 weeks) after completion of iberdomide. * Males who are sexually active with WOCBP must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Iberdomide (CC-220) and for up to 90 days after discontinuing Iberdomide (CC-220), even if they have undergone a successful vasectomy. Male patients must not donate sperm. * Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, they must still undergo pregnancy testing as described in this section. * All subjects must agree not to share study medication.
Exclusion criteria
* Subjects with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), primary amyloidosis (no active multiple myeloma), Waldenström's macroglobulinemia, or POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) * Subjects with active plasma cell leukemia (defined as either 20% of peripheral blood white blood cell count comprised of plasma/CD138+ cells or an absolute plasma cell count of 2 x 109/L) * Subjects with active Central Nervous System involvement with multiple myeloma * Subjects with active multiple myeloma that cannot be safely managed with single-agent iberdomide for the duration of the priming period, per the discretion of the treating physician or PI * Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent form * Any serious concurrent medical conditions that may make the patient non-evaluable or put the patient's safety at risk, per the discretion of the treating physician or PI * Subjects with an active infection that requires parenteral anti-infective treatment within 7 days * Unable to tolerate thromboembolic prophylaxis while on iberdomide * Severe hypersensitivity reaction to prior IMiD (thalidomide, lenalidomide or pomalidomide) * Grade \> 2 peripheral neuropathy (per NCI CTCAE v5.0) * Patients with a positive PCR test for hepatitis B virus or hepatitis C virus indicating active infection. Patients with positive serologic testing indicating exposure will need confirmatory testing by PCR. * Patients with detectable HIV viral load or known acquired immunodeficiency syndrome (AIDS). * Prior or concurrent malignancy, except for the following: * Adequately treated basal cell or squamous cell skin cancer or in-situ carcinoma. * Non-muscle invasive bladder cancer treated within the last 24 months that is considered completely cured. * Localized prostate cancer (N0M0): * with a Gleason score of ≤6, treated within the last 24 months or untreated and under surveillance, * with a Gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence; or * any history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence per the discretion of the treating physician or PI * Non-invasive cervical cancer treated within the last 24 months that is considered completely cured. * Breast cancer: adequately treated lobular carcinoma in situ, or ductal carcinoma in situ, or history of localized breast cancer and receiving anti-hormonal agents and considered to have a very low risk of recurrence. * Any other cancer from which the subject has been disease free for \> 3 years prior to study entry, or considered cured with minimal risk of disease recurrence. * Prior treatment with Iberdomide (CC-220) within 6 months prior to enrollment * Prior allogeneic stem cell transplant except subjects who have completed the stem cell transplant \> 12 months prior to first dose of study drug, have no history of graft versus host disease, and are not on systemic immunosuppressive therapy * Major cardiac surgery within 8 weeks prior to the first dose of study drug; all other major surgery within 4 weeks prior to the first dose of study drug. * Subjects with following physical and laboratory test findings: * Absolute neutrophil count \< 1 x 109/L without growth factor support within 1 week, or absolute neutrophil count \< 0.5 x 109/L for patients with documented Duffy-null blood typing * Platelets \< 50 x 109/L without transfusion support within 1 week * Creatinine clearance \< 30 ml/min according to the Cockroft-Gault formula: * Female CrCl = \[(140 - age in years) x weight in kg x 0.85\] / \[72 x serum creatinine in mg/dl\] * Male CrCl = \[(140 - age in years) x weight in kg x 1.00\] / \[72 x serum creatinine in mg/dl\] * Total bilirubin ≥ 2 x ULN (≥ 3 x ULN if documented Gilbert's syndrome) * AST or ALT ≥ 3x ULN * Corrected serum calcium \> 13.5 mg/dL * Are also excluded: * Prisoners or subjects who are involuntarily incarcerated * Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with T cell effector memory (TEM) expansion following iberdomide priming. | On the day of leukapheresis, after completing iberdomide therapy on Day 29 | Proportion of patients with T cell effector memory (TEM) expansion following iberdomide priming, defined as an absolute increase of \>10 percentage points or a relative increase of \>50% in TEM cells. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Proportion of T cell subsets from baseline after iberdomide priming | On the day of leukapheresis, after completing iberdomide therapy on Day 29 | Proportion of T cell subsets (including terminally differentiated effector, exhausted, and activated T cells) present for each participant in the feasibility evaluable (FE) population at leukapheresis (Priming D29 after iberdomide) to baseline (Priming-D1). |
| Cmax with iberdomide priming prior to leukapheresis | After CAR-T infusion at Day 14, Day 28, Month 3, Month 6, Month 12 | Cmax is the highest measured concentration of iberdomide. Cmax will be assessed in the CAR-T evaluable (CARTE) population |
| Tmax with iberdomide priming prior to leukapheresis, | After CAR-T infusion at Day 14, Day 28, Month 3, Month 6, Month 12 | Time to reach Cmax. Tmax will be assessed in CAR-T (CARTE) population |
| AUC0-14 with iberdomide priming prior to leukapheresis | After CAR-T infusion at Day 14, Day 28, Month 3, Month 6, Month 12 | Total Exposure over time. AUC0-14 will be assessed in the CAR-T evaluable (CARTE) population. |
| CAR-T persistence with iberdomide priming prior to leukapheresis, | After CAR-T infusion at Day 14, Day 28, Month 3, Month 6, Month 12 | CAR-T persistence will track therapy effectiveness over time. CAR-T persistence will be assessed in the CAR-T evaluable (CARTE) population. |
| ALCmax with iberdomide priming prior to leukapheresis | After CAR-T infusion at Day 14, Day 28, Month 3, Month 6, Month 12 | Absolute Lymphocyte Count (ALC) is a key blood test measuring the exact number of lymphocytes. ALCmax measures the maximum count overtime. ALCmax will be assessed in the CAR-T evaluable (CARTE) population. |
| Time to ALCmax with iberdomide priming prior to leukapheresis | After CAR-T infusion at Day 14, Day 28, Month 3, Month 6, Month 12 | Time to reach absolute lymphocyte count maximum (ALCmax) in the CAR-T evaluable (CARTE) population. |
| Absolute lymphocyte count (ALC) expansion kinetics as a proxy for CAR-T expansion | After CAR-T infusion at Day 14, Day 28, Month 3, Month 6, Month 12 | — |
| Overall response rate | After CAR-T at Day 100 (~Month 3) and Month 12 | Overall response rate (ORR), defined as the proportion of patients that achieve at least a partial response according to IMWG criteria |
| Measurable residual disease | After CAR-T at Day 100 (~Month 3) and Month 12. Long-term follow-up for up to 5 years. | Rate of measurable residual disease (MRD)-negativity and MRD-negative complete response (CR) as defined by IMWG response criteria |
| Progression-free survival | After CAR-T at Day 100 (~Month 3) and Month 12. Long-term follow-up for up to 5 years. | Progression-free survival (PFS), defined as the time from CAR-T infusion until progression by IMWG response criteria or death |
| Overall survival | After CAR-T at Day 100 (~Month 3) and Month 12. Long-term follow-up for up to 5 years. | Overall survival (OS), defined as the time from CAR-T infusion until death |
| Duration of response | After CAR-T at Day 100 (~Month 3) and Month 12. Long-term follow-up for up to 5 years. | Duration of response (DOR), defined as time from first observed response after CAR-T until progression by IMWG criteria |
| Time to next treatment | After CAR-T at Day 100 (~Month 3) and Month 12. Long-term follow-up for up to 5 years. | Time to next treatment (TTNT), defined as the time from CAR-T infusion until initiation of the next line of myeloma-directed therapy for subsequent relapsed disease |
Countries
United States
Contacts
CONTACTVikram Madan, MPH
CONTACTRashmi Unawane
PRINCIPAL_INVESTIGATORShambavi Richard, MD
Icahn School of Medicine at Mount Sinai
Outcome results
None listed