Study of CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone) plus Daratumumab in Newly Diagnosed Multiple Melanoma Patients with Cast Nephropathy or Monoclonal Gammopathy of Renal Significance (MGRS)

Inclusion Criteria

• CAST NEPHROPATHY ASSOCIATED WITH MULTIPLE MYELOMA (MM) (CLOSED 03/11/2025):
• Subjects must have a confirmed diagnosis of newly diagnosed (ND)MM 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
• Estimated glomerular filtration rate (eGFR) must be < 50 ml/min/1.73m^2
• Subjects must have histologically confirmed diagnosis of monoclonal gammopathy associated cast nephropathy (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
• 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, or presence of monoclonal gammopathy by immuno-fluorescence of kidney biopsy
• Evidence of plasma cell dyscrasia by bone marrow biopsy confirming clonal plasma cell population or normal bone marrow biopsy
• eGFR < 50 ml/min/1.73m^2 or 24 hour (h) urine total protein > 1gm
• 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 (nonsteroidal antiinflammatory drugs [NSAIDs], radiocontrast…)
• No evidence of obstructive nephropathy by ultrasound
• Neutrophils ≥ 1.0 × 10^9/L (within 14 days prior to registration) (Patients cannot have received granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage [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 (within 14 days prior to registration) (Note: Platelet support is not permitted to help participants meet eligibility criteria)
• Hemoglobin ≥ 7.5 g/dL (within 14 days prior to registration) without prior red blood cells (RBC) transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted
• Aspartate aminotransferase (AST), alkaline phosphatase (AP) or alanine aminotransferase (ALT) ≤ 3 × the upper limit of normal (ULN) (≤ 14 days prior to registration)
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with a history of elevated total bilirubin, such as in Gilbert’s (≤ 14 days prior to registration)
• Hepatic Child-Pugh score at worse A (≤ 14 days prior to registration) (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 (beta- human chorionic gonadotropin [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 the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
• Subjects must be willing to refrain from egg/sperm donation through 90 days after the last dose of study drug
• 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. chronic lymphocytic leukemia [CLL], B-cell neoplasm, Waldenstrom’s macroglobulinemia…)
• Plasma cell leukemia, amyloid light chain (AL) amyloidosis, or polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin (POEMS) syndrome
• Treatment with more than 1 cycle of 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 cancer (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 half-lives, 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
• 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 (i.e., 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) deoxyribonucleic acid (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