A Study of CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone) Plus Daratumumab in People With Monoclonal Gammopathy of Renal Significance (MGRS)

Inclusion criteria

Inclusion criteria

for cast nephropathy associated with MM:

• Subjects must have a confirmed diagnosis of NDMM as per standard IMWG criteria
• 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.
• eGFR must be <40 ml/min/1.73m2
• 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

• Subjects must be ≥ 18 years of age at time of registration.
• Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 ≤ 14 days prior to registration.
• No evidence of unequivocal recent nephrotoxic exposure (NSAIDs, radiocontrast…)
• No evidence of obstructive nephropathy by ultrasound
• 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.
• 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).
• 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.
• 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).
• Subjects must have the willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, study procedures, and research procedures.

Exclusion criteria

• MGRS associated with diseases other than plasma cell dyscrasia (e.g. CLL, B-cell neoplasm, Waldenstrom's macroglobulinemia…)
• Plasma cell leukemia, AL amyloidosis, or POEMS syndrome.
• Treatment with prior drugs aimed at the plasma cell dyscrasia.
• Treatment with prior or concurrent investigational agents aimed at the plasma cell dyscrasia.
• Female patients who are lactating or have a positive serum pregnancy test during the screening period.
• Major surgery ≤ 14 days before registration.
• Focal radiation therapy within 14 days prior to registration with the exception of palliative- radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma.
• Disease-related central nervous system involvement.
• The subject has uncontrolled significant intercurrent illness including, but not limited to, ongoing or active infection.
• 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
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
• Concurrent malignancy except for treated non-melanoma skin cancer, cervical carcinoma in situ and low-risk prostate CA being monitored without treatment.
• Grade 2 or higher peripheral neuropathy on clinical examination during the screening period.
• Chemotherapy ≤ 14 days of registration.
• 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.
• 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
• 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.
• Patients who have a contraindication to the use of any form of anticoagulation or antiplatelet agents.
• The use of strong CYP3A4 and CYP1A2 inducers or inhibitors will not be allowed while patients are treated on this study.
• 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
• 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.