Multiple Myeloma, Smoldering Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, Smoldering Multiple Myeloma, Chemotherapy, Immunotherapy
Brief summary
The goal of this research study is to test if ciltacabtagene autoleucel (cilta-cel) is safe and effective in treating participants with high-risk, smoldering myeloma. The names of the treatment interventions used in this study are: * Cilta-cel (or chimeric antigen receptor T cells) * Cyclophosphamide (a lymphodepleting chemotherapy) * Fludarabine (a lymphodepleting chemotherapy)
Detailed description
This is a Phase II study to test the safety and effectiveness of study therapy cilta-cel in treating participants with high-risk smoldering multiple myeloma (SMM). T cells are a part of a person's immune system which usually helps fight infection and prevents/fights cancer cells. The U.S. Food and Drug Administration (FDA) has approved cilta-cel as a treatment for relapsed and refractory multiple myeloma but not specifically for smoldering myeloma. The research study procedures include screening for eligibility, study treatment including evaluations, blood collections, radiologic scans of tumors, bone marrow biopsies, and follow-up visits. Participation in this study is expected to last about 15 years. It is expected that about 20 people will take part in this research study. This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational therapy to learn whether the therapy works in treating a specific disease. "Investigational" means that the therapy is being studied. Janssen Research & Development, LLC is supporting this research study by providing the study treatment and funding.
Interventions
Genetically modified autologous T-cell immunotherapy, via intravenous infusion per protocol.
DRUGCyclophosphamide
Lymphodepleting conditioning regimen, nitrogen mustard-derivative, via intravenous infusion per standard care.
DRUGFludarabine Phosphate
Lymphodepleting conditioning regimen, synthetic purine nucleoside, via intravenous infusion per standard care.
Sponsors
Dana-Farber Cancer Institute
Janssen Research & Development, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \> 18 years. * High-risk SMM with ≤40% plasma cells in the bone marrow and with high-risk criteria defined as having 1 of the following 2 criteria: 1. High-risk per "20-2-20" Criteria defined as presence of any two of the following: * Serum M-protein ≥ 2 gm/dL * Involved to uninvolved free light chain (FLC) ratio≥ 20 * Bone marrow PC% ≥ 20% to \<40%. * OR total score of 9 using the following scoring system: * FLC Ratio * \>10-25 = 2 * \>25-40 = 3 * \> 40 = 5 * Serum M-protein (g/dL) * \>1.5-3 = 3 * \>3 = 4 * BMPC% * \>15-20 = 2 * \>20-30 = 3 * \>30-40 = 5 * \>40 = 6 * FISH abnormality (t(4,14), t(14,16), 1q gain, or del13q = 2 2. Presence of ≥10% BMPC and at least one of the following: * Evolving pattern: * eMP (≥10% increase in serum M-protein ) over a 6 month period OR; * Evolving change in hemoglobin (eHb) ≥ 0.5 g/dl decrease over a 12 months period OR; * Progressive Involved light chain increase \>10% over a 6 month period along with a light chain ration \> 8 * Abnormal PC immunophenotype (≥95% of BMPCs are clonal) and reduction of ≥1 uninvolved immunoglobulin isotype. (Only IgG; IgA and IgM will be considered) High risk cytogenetics defined as presence of t(4;14), t(14;16), t(14;20), 17p deletion, TP53 mutation, 1q21 gain * No evidence of CRAB criteria\* or new criteria of active MM (SLIM-CRAB) which including the following: * Increased calcium levels: Corrected serum calcium \>0.25 mmol/L (\>1mg/dL) above the upper limit of normal or \>2.75 mmol/L (\>11mg/dL); * Renal insufficiency (attributable to myeloma); * Anemia (Hgb 2g/dL below the lower limit of normal or \<10g/dL); * Bone lesions (lytic lesions or generalized osteoporosis with compression fractures) * No evidence of the following new criteria for active MM including the following: * Bone marrow plasma cells \>60% * Serum involved/uninvolved FLC ratio ≥100 * MRI with more than one focal lesion * Participants with CRAB criteria that are attributable to conditions other than the disease under study may be eligible after discussion with the Sponsor Investigator. * ECOG Performance Status (PS) 0 or 1 (Appendix 8) * The following laboratory values obtained \< 28 days prior to registration: * ANC \>1000/mL * PLT \>75,000/mL * Total bilirubin ≤ 2.0 mg/dL (If total is elevated check direct and if normal patient is eligible.) * AST \<2.5 x institutional upper limit of normal (ULN) * ALT \<2.5 x institutional upper limit of normal (ULN) * Estimated creatinine clearance CrCl ≥60 mL/min (Cockcroft Gault equation). * Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. * Women of childbearing potential must have a negative pregnancy test at screening. * When a woman is of childbearing potential, the following are required: • Subject must agree to practice a highly effective method of contraception (failure rate of \<1% per year when used consistently and correctly) and agree to remain on a highly effective method of contraception from the time of signing the informed consent form (ICF) until 1 year after receiving a cilta-cel infusion. Examples of highly effective contraceptives include: * user-independent methods: 1) implantable progestogen-only hormone contraception associated with inhibition of ovulation; 2) intrauterine device; intrauterine hormone- releasing system; 3) vasectomized partner. * user-dependent methods: 1) combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral or intravaginal or transdermal; 2) progestogen-only hormone contraception associated with inhibition of ovulation (oral or injectable). * In addition to the highly effective method of contraception, a man: * Who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception (eg, condom with spermicidal foam/gel/film/cream/suppository) from the time of signing the ICF until 1 year after receiving a cilta-cel infusion. * Who is sexually active with a woman who is pregnant must use a condom. Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively, during the study and for 1 year after the last dose of study treatment. Note: Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of the contraceptive method.
Exclusion criteria
* Prior SMM directed therapy. * Symptomatic Multiple Myeloma or any evidence of CRAB criteria, including presence of myeloma defining events (MDE). Any prior therapy for active Myeloma should also be excluded. Bisphosphonates are not excluded. * Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational. Prior therapy with bisphosphonate is allowed. Prior radiation therapy to a solitary plasmacytoma is allowed but had to be at least 1 year prior to enrollment on the trial. Prior clinical trials or therapy for smoldering MM or MGUS are not allowed per
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Dose Limiting Toxicities (DLT) | 24 months | Incidence of Dose Limiting Toxicities (DLTs) during the first 28 days after anti-BCMA CAR-T cell administration. Dose-Limiting Toxicities (DLTs) will be defined as follows: * Grade 4 non-hematologic toxicity of any duration including Grade 4 CRS and ICANS * Grade 3 CRS that does not improve to a grade 2 or less in 72 hours following adequate therapy. * Grade 3 neurological toxicity of any duration * Grade 3 toxicity of any duration involving vital organs (cardiac, pulmonary). Exceptions can be made if associated with CRS. * Other Grade 3 toxicity lasting \> 72 hours. Exceptions may be made for Grade 3 abnormal hepatic or renal function tests that improve to grade 2 or less within 7 days. * Grade 3 hypersensitivity reaction that is not reversible to Grade 2 or less within 24 hours * Grade 4 neutropenia or thrombocytopenia lasting more than 28 days |
| Nature of Dose Limiting Toxicities (DLT) | 24 months | Nature of Dose Limiting Toxicities (DLTs) during the first 28 days after anti-BCMA CAR-T cell administration. Dose-Limiting Toxicities (DLTs) will be defined as follows: * Grade 4 non-hematologic toxicity of any duration including Grade 4 CRS and ICANS * Grade 3 CRS that does not improve to a grade 2 or less in 72 hours following adequate therapy. * Grade 3 neurological toxicity of any duration * Grade 3 toxicity of any duration involving vital organs (cardiac, pulmonary). Exceptions can be made if associated with CRS. * Other Grade 3 toxicity lasting \> 72 hours. Exceptions may be made for Grade 3 abnormal hepatic or renal function tests that improve to grade 2 or less within 7 days. * Grade 3 hypersensitivity reaction that is not reversible to Grade 2 or less within 24 hours * Grade 4 neutropenia or thrombocytopenia lasting more than 28 days |
| Incidence of Adverse Events (AEs) | 24 months | Adverse events with onset or worsening on or after date of first dose of study treatment. AEs with onset or worsening on or after date of first dose of study treatment. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening, and Grade 5= Death related to AE. SAE is any untoward medical occurrence that results in any of the following outcomes: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect; suspected transmission of any infectious agent via a medicinal product or medically important. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Manufacture Success Rate (Feasibility) | 24 months | Defined as number of subjects treated with planned target dose divided by total number of subjects treated, and it is done to evaluate the feasibility of the manufacturing process |
| Overall Response Rate (ORR) | 6 months | Defined by the proportion of subjects with the best overall response (BOR). It is the BOR of stringent complete response (sCR), Complete response (CR), VGPR (Very good partial response), and Partial response (PR) at month 3 and month 6 as determined using International Myeloma Working Group (IMWG) Criteria (Kumar et al, 2016). |
| Complete Response Rate | 3 months | Proportion of subjects with best overall response (BOR) of stringent complete response (sCR) or complete response (CR) at month 3 as determined by local investigator using International Myeloma Working Group (IMWG) Criteria (Kumar et al, 2016) |
| Duration of Response | 12 months from infusion of cellular product | Duration of response (DOR) to be assessed, and DOR defined as the time from achievement of stringent complete response (sCR), Complete response (CR), VGPR (Very good partial response), and Partial response (PR) to relapse or death due to multiple myeloma. |
| Cmax of BCMA CAR-T Cells | 24 months | Cmax of BCMA analyzed through qPCR-detected transgene of CAR-T concentrations over time in peripheral blood and bone marrow. |
| Tmax of BMCA CAR-T cells | 24 months | Tmax of BCMA analyzed through qPCR-detected transgene of CAR-T concentrations over time in peripheral blood and bone marrow. |
| AUC of BCMA CAR-T cells | 24 months | AUC of BCMA analyzed through qPCR-detected transgene of CAR-T concentrations over time in peripheral blood and bone marrow. |
| Clast of BCMA CAR-T cells | 24 months | Clast of BCMA analyzed through qPCR-detected transgene of CAR-T concentrations over time in peripheral blood and bone marrow. |
| Number of patients with pre-existing and treatment induced immunogenicity of BMCA CAR-T | 24 months | Both cellular and humoral of pre-existing and treatment induced immunogenicity for BCMA CAR-T cellular therapy in smoldering myeloma (SMM). |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORIrene Ghobrial, MD
Dana-Farber Cancer Institute
Outcome results
None listed