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.