Overview

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.

Eligibility

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.