PRIMARY OBJECTIVE:
I. To determine the proportion of patients with newly diagnosed myeloma and acute kidney
injury (AKI) who have renal function recovery following 2 cycles (6 weeks) of treatment with
a daratumumab-based induction regimen.
SECONDARY OBJECTIVES:
I. Overall response rate at the end of 2 and 4 cycles of therapy. II. Adverse event profile
of the combination in patients with AKI. III. Pharmacokinetic parameters of maximum
concentration (Cmax), area under the curve (AUC), time to maximum concentration (tmax),
clearance, and half life (t1/2) of daratumumab in combination treatment in the AKI
population.
IV. Global assessment of renal function at cycle initiation including creatinine clearance
(CrCl).
V. Timeline of changes in pharmacodynamic markers of light chains, urine paraprotein, and
serum paraprotein measures.
OUTLINE:
Patients receive daratumumab intravenously (IV) weekly of cycles 1-3 and on day 1 only of
cycle 4, bortezomib subcutaneously (SC) on days 1, 4, 8, and 11, and dexamethasone IV or
orally (PO) on days 1-4 of cycle 1 and on day 1 of cycles 2-4 and PO on days 8 and 15 of all
cycles. Beginning cycle 2, patients may also receive lenalidomide PO daily on days 1-14 or
thalidomide PO once daily (QD) on days 1-21. Treatment repeats every 21 days for 4 cycles in
the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
Inclusion Criteria:
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
- Creatinine clearance < 30 mL/min by Cockcroft-Gault (C-G), 24 hour urine collection or
the Modification of Diet in Renal Disease (MDRD) methods. The same method used for
inclusion will be used for renal response assessment
- Documented multiple myeloma as defined by the International Myeloma Working Group
(IMWG) 2014 criteria including: Clonal bone marrow plasma cells >= 10%. In addition,
the patient must meet one of the criteria in day (d)1 or d2:
- Evidence of end organ damage that can be attributed to the underlying plasma cell
proliferative disorder, specifically (one or more of the following):
- Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper
limit of normal (ULN) or > 2.75 mmol/L (>11 mg/dL)
- Renal insufficiency: creatinine clearance (CrCl) < 30 mL/min
- Anemia: hemoglobin value of > 2 g/dL below the lower limit of normal, or a
hemoglobin value < 10 g/L
- Bone lesions: 1 or more osteolytic lesions on skeletal radiography, computed
tomography (CT), or magnetic resonance imaging (MRI)
- Measurable disease as defined by any of the following:
- Serum M-protein level >= 1.0 g/dL or urine M-protein level >= 200 mg/24 hours.
- IgA, IgD, IgE, or IgM multiple myeloma: serum M-protein level >= 0.5 g/dL or
urine M-protein level >= 200 mg/24 hours; or
- Light chain multiple myeloma without measurable disease in the urine: serum Ig
free light chain (FLC) >= 10 mg/dL and abnormal serum Ig kappa/lambda FLC ratio
- Prior treatment to stabilize the patient with steroids up to 160 mg IV equivalents of
dexamethasone is allowed
- Prior treatment to stabilize the patient with bortezomib up to 2 doses of 1.3 mg/m^2
is allowed
- Subject agrees to refrain from blood donations during therapy on study and for 8 weeks
after therapy is completed
- Female patients who:
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- If they are 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.)
- Are not planning to donate eggs during the period of study and up to 3 months
after the last dose of study drug
- Females of childbearing potential (FCBP) must have a negative serum or urine
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior
to and again within 24 hours of starting study drugs
- Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree
to one of the following:
- Agree to practice effective barrier contraception during the entire study
treatment period and 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.) and
- Agree to no sperm donation during the period of study and up to 3 months after
the last dose of study drug
Exclusion Criteria:
- Diagnosed with smoldering multiple myeloma (MM), monoclonal gammopathy of undetermined
significance, Waldenstrom's macroglobulinemia, polyneuropathy, organomegaly,
endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, amyloidosis
or primary or secondary plasma cell leukemia
- Participant has >= grade 3 peripheral neuropathy, or grade 2 with pain on clinical
examination within 21 days before initiation of protocol therapy
- Plasmapheresis within 28 days
- Platelet count =< 75,000 cells/mm^3 at time of screening evaluation. Platelet
transfusions to help patients meet eligibility criteria are not allowed within 3 days
before study enrollment
- Participants with an absolute neutrophil count (ANC) =< 1000 cells/mm^3 at time of
screening evaluation. Growth factors may not be used to meet ANC eligibility criteria
within 14 days of obtaining screening evaluation
- Participants with hemoglobin level < 7.0 g/dL, at time of screening. Transfusion may
be used to meet eligibility criteria within 7 days of obtaining screening evaluation
- Participants with hepatic impairment, defined as bilirubin >= 1.5 x institutional
upper limit of normal (ULN) or aspartate aminotransferase (AST) (serum
glutamic-oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT) (serum
glutamate pyruvate transaminase [SGPT]), or alkaline phosphatase >= 3 x institutional
ULN, within 21 days of initiation of protocol therapy
- Patients may be receiving concomitant therapy with bisphosphonates and low dose
corticosteroids (e.g., prednisone up to but no more than 10 mg p.o. once daily [q.d.]
or its equivalent) for symptom management and comorbid conditions. Doses of
corticosteroid should be stable for at least 7 days prior to study treatment.)
- Steroids160 mg IV equivalents of dexamethasone or bortezomib > 2 doses of 1.3 mg/m^2.
- Known significant cardiac abnormalities including:
- Congestive heart failure, New York Heart Association (NYHA) class III or IV
- Uncontrolled angina, arrhythmia or hypertension
- Myocardial infarction within the past six months
- Any other uncontrolled or severe cardiovascular condition
- Prior cerebrovascular event with residual neurologic deficit
- Known history of chronic obstructive pulmonary disease with a forced expiratory volume
in 1 second (FEV1) < 50% of predicted normal
- Has known history of moderate or severe persistent asthma within the past 2 years, or
currently has uncontrolled asthma of any classification
- Serious, intercurrent illness including, but not limited to, clinically relevant
active infection, uncontrolled diabetes mellitus, or serious co-morbid medical
conditions such as chronic restrictive pulmonary disease, and cirrhosis
- Seropositive for human immunodeficiency virus (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 a viremia at least 12 weeks after completion of antiviral therapy)
- Any condition, including laboratory abnormalities, that in the opinion of the
investigator places the subject at unacceptable risk if he/she were to participate in
the study
- Diagnosed or treated for another malignancy within 2 years before study enrollment or
previously diagnosed with another malignancy and have any evidence of residual
disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are
allowed if they have undergone complete resection
- Known hypersensitivity to acyclovir or similar anti-viral drug
- Known severe intolerance to steroid therapy
- Participants with known central nervous system (CNS) involvement
- Poor tolerability or known allergy to any of the study drugs or compounds of similar
chemical or biologic composition to dexamethasone, boron or mannitol
- Female participants pregnant or breast-feeding
- Participants who have undergone major surgery =< 4 weeks prior to starting study drug
or who have not recovered from side effects of the surgery
- Participants with any significant history of non-compliance to medical regimens or
unwilling or unable to comply with the instructions given to him/her by the study
staff
- Prior exposure to anti-CD38 therapy
- Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days
will be considered a sufficient interval between treatment and administration of study
medications
- Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol
- Participation in other clinical trials, including those with other investigational
agents not included in this trial, within 30 days of the start of this trial and
throughout the duration of this trial
