A Study of CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone) Plus Daratumumab in People With Monoclonal Gammopathy of Renal Significance (MGRS)
- Conditions
- Multiple MyelomaMonoclonal Gammopathy of Renal Significance
- Interventions
- Registration Number
- NCT06083922
- Lead Sponsor
- Memorial Sloan Kettering Cancer Center
- Brief Summary
The purpose of this study is to find out whether cyclophosphamide, bortezomib, dexamethasone (CyBorD) with daratumumab SC is a safe treatment combination for MGRS-associated kidney disease including cast nephropathy associated with multiple myeloma. In addition, the researchers will find out whether the study drug combination is an effective treatment for these conditions.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 61
Inclusion criteria for cast nephropathy associated with MM:
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Subjects must have a confirmed diagnosis of NDMM as per standard IMWG criteria
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Subjects must have measurable disease, defined as meeting at least 1 of the following criteria ≤ 14 days prior to registration:
- A monoclonal Immunoglobulin (M-protein) concentration on serum protein electrophoresis (SPEP) of ≥ 0.5 g/dL.
- Measurable urinary light chain secretion by quantitative analysis using urine protein electrophoresis (UPEP) of ≥ 200 mg/24 hours.
- Involved serum free light chain (FLC) level ≥ 10 mg/dL, provided the serum FLC ratio is abnormal.
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eGFR must be <40 ml/min/1.73m2
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Subjects must have histologically confirmed diagnosis of monoclonal gammopathy associated CN by kidney biopsy OR If a kidney biopsy is not available, a percentage of urine albumin excretion (%UAE) < 25 % AND FLC > 50 mg/dL
Inclusion criteria for other MGRS associated renal diseases
- Histologically confirmed diagnosis of MGRS-associated renal disease by kidney biopsy
- Presence of monoclonal gammopathy by serum protein electrophoresis, Immunofixation, or Free Light Chain Assay
- Evidence of plasma cell dyscrasia by bone marrow biopsy confirming clonal plasma cell population
- eGFR <40 ml/min/1.73m2 or 24h urine total protein > 1gm
Inclusion criteria for both cast nephropathy associated with MM and other MGRS associated renal diseases
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Subjects must be ≥ 18 years of age at time of registration.
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Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 ≤ 14 days prior to registration.
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No evidence of unequivocal recent nephrotoxic exposure (NSAIDs, radiocontrast...)
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No evidence of obstructive nephropathy by ultrasound
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Subjects must have adequate hematology laboratory values within 14 days prior to registration defined by the following:
- Neutrophils ≥ 1.0 × 10^9 /L (Patients cannot have received G-CSF or GM-CSF within 1 week of screening or pegfilgrastim within 2 weeks of screening to meet eligibility).
- Platelets ≥ 100 × 10^9 /L for run-in and 75 × 10^9 /L for phase II (Note: Platelet support is not permitted to help participants meet eligibility criteria).
- hemoglobin ≥ 7.5 g/dL without prior red blood cells [RBC] transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted.
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Subjects must have adequate hepatic function laboratory values ≤ 14 days prior to registration:
- Aspartate aminotransferase (AST), alkaline phosphatase (AP) or alanine aminotransferase (ALT) ≤ 3 × the upper limit of normal (ULN)
- Total bilirubin ≤ 1.5 x ULN except for patients with a history of elevated total bilirubin, such as in Gilbert's.
- Hepatic Child-Pugh score at worse A (patients are eligible for the phase 2 part but not for the Run-in-Period of the trial).
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Female patients will have to satisfy the following criteria:
- Be postmenopausal for at least 1 year Prior to registration visit, OR
- Be surgically sterile, OR
- If of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR
- Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception). If patient is female and of childbearing potential, she must have a negative serum beta human chorionic gonadotropin (β-HCG) test < 14 days prior to registration and consent to ongoing pregnancy testing during the course of the study.
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Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following
- Practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
- Practice true abstinence when this is in line with the preferred and usual lifestyle of he subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception).
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Subjects must have the willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, study procedures, and research procedures.
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MGRS associated with diseases other than plasma cell dyscrasia (e.g. CLL, B-cell neoplasm, Waldenstrom's macroglobulinemia...)
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Plasma cell leukemia, AL amyloidosis, or POEMS syndrome.
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Treatment with prior drugs aimed at the plasma cell dyscrasia.
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Treatment with prior or concurrent investigational agents aimed at the plasma cell dyscrasia.
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Female patients who are lactating or have a positive serum pregnancy test during the screening period.
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Major surgery ≤ 14 days before registration.
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Focal radiation therapy within 14 days prior to registration with the exception of palliative- radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma.
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Disease-related central nervous system involvement.
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The subject has uncontrolled significant intercurrent illness including, but not limited to, ongoing or active infection.
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Clinically significant cardiac disease, including:
- Myocardial infarction within 6 months before randomization, or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV)
- Uncontrolled cardiac arrhythmia
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Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
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Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
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Concurrent malignancy except for treated non-melanoma skin cancer, cervical carcinoma in situ and low-risk prostate CA being monitored without treatment.
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Grade 2 or higher peripheral neuropathy on clinical examination during the screening period.
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Chemotherapy ≤ 14 days of registration.
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Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic halflives, whichever is longer.
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Patients with known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal; moderate or severe persistent asthma within the past 2 years. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is <50% of predicted normal
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Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate.
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Patients who have a contraindication to the use of any form of anticoagulation or antiplatelet agents.
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The use of strong CYP3A4 and CYP1A2 inducers or inhibitors will not be allowed while patients are treated on this study.
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Patients with Hepatic Child-Pugh score B and C. Note that patients with Hepatic Child-Pugh score A are excluded from the Run-in-Period of the trial
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Patient is:
- Known history of human immunodeficiency virus (HIV) and those who are seropositive for HIV.
- Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
- Seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
- Vaccination with live attenuated vaccines within 4 weeks of first study agent administration.
- Plasmapheresis within 28 days before randomization.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Arm A will include patients with cast nephropathy Cyclophosphamide Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment. Arm B will include all other MGRS associated diseases with the exclusion of AL amyloidosis Dexamethasone Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment. Arm B will include all other MGRS associated diseases with the exclusion of AL amyloidosis Cyclophosphamide Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment. Arm A will include patients with cast nephropathy Bortezomib Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment. Arm A will include patients with cast nephropathy Dexamethasone Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment. Arm A will include patients with cast nephropathy Daratumumab Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment. Arm B will include all other MGRS associated diseases with the exclusion of AL amyloidosis Bortezomib Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment. Arm B will include all other MGRS associated diseases with the exclusion of AL amyloidosis Daratumumab Planned 8 cycles of CyBorD-Dara SC, treatment will be left to the discretion of the treating physician. It is recommended that patients eligible for ASCT undergo ASCT after 8 cycles of induction and that patient ineligible for ASCT, continue maintenance Bortezomib/Dexamethasone administered every other week with daratumumab SC administered every 4 weeks, for a period of 2 years from start of treatment.
- Primary Outcome Measures
Name Time Method Run-in Phase- Dose-limiting toxicity (DLT) rates 2 years Any participant in the run-in-phase who received at least ≥ 75% of the planned doses of the combination regimen in cycle one will be evaluated for DLTs using NCI-CTCAE.
Pilot study (Cohort B) best renal response 2 years For patients with a decreased eGFR \<50mL/min/1.73 m2 with or without significant proteinuria (UTP\>0.5 gm/24h) at presentation, renal response will be assessed using IMWG renal response criteria
Phase II (Cohort A) best renal response 2 years For patients with a decreased eGFR \<50mL/min/1.73 m2 with or without significant proteinuria (UTP\>0.5 gm/24h) at presentation, Assessment of renal response will be based on both the IMWG criteria for patient with decreased eGFR and the amyloid criteria for patients with proteinuria.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (10)
Tufts Medical Center (Data Collection Only)
🇺🇸Boston, Massachusetts, United States
Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)
🇺🇸Basking Ridge, New Jersey, United States
Memorial Sloan Kettering Monmouth (Limited Protocol Activities)
🇺🇸Middletown, New Jersey, United States
Memorial Sloan Kettering Bergen (Limited Protocol Activities)
🇺🇸Montvale, New Jersey, United States
Memorial Sloan Kettering Cancer Center Suffolk - Commack (Limited Protocol Activities)
🇺🇸Commack, New York, United States
Memorial Sloan Kettering Westchester (Limited Protocol Activities)
🇺🇸Harrison, New York, United States
Weill Cornell Medical Center (Data Collection Only)
🇺🇸New York, New York, United States
Mount Sinai Hospital (Data Collection Only)
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center (All Protocol Activities)
🇺🇸New York, New York, United States
Memorial Sloan Kettering Nassau (Limited Protocol Activities)
🇺🇸Uniondale, New York, United States