PRIMARY OBJECTIVE:
I. To determine the ≥ very good partial response (VGPR) rate after 8 cycles in subjects
treated with daratumumab, ixazomib and dexamethasone (DId) versus (vs) daratumumab,
bortezomib and dexamethasone (DVd) followed by DId among newly diagnosed myeloma patients
(NDMM).
SECONDARY OBJECTIVES:
I. To estimate the proportion of subjects with successful stem cell mobilization after
receiving 3 cycles of treatment in both arms (DId x 8 vs DVd x 3 then DId x 5).
II. To establish safety among patients receiving the combination of DId and DVd then DId.
III. To obtain anti-tumor activity (best response rates: overall response rate [ORR], VGPR,
complete response [CR], stringent complete response [sCR] and minimal residual of disease
[MRD] negativity) in patients treated with these combinations.
IV. Progression free survival (PFS), progression free survival 2 (PFS2), duration of response
(DOR), time to progression (TTP), determine the time to next therapy (TTNT).
V. Overall survival (OS).
VI. Engraftment parameters among the autologous stem cell transplant (ASCT) group.
VII. Determine whether tumor response and PFS may change in subgroups with different
prognosis according to current prognostic factors.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I:
INDUCTION: Patients receive dexamethasone intravenously (IV) and orally (PO) on days 1, 8,
15, and 22, daratumumab IV on days 1, 8, 15, and 22 of cycles 1-2 and on days 1 and 15 of
cycles 3-8, and ixazomib PO on days 1, 8, and 15. Treatment repeats every 28 days for 8
cycles in the absence of disease progression or unacceptable toxicity. Eligible patients then
undergo stem cell transplant per standard of care. Patients who have at least stable disease
after induction and patients who have undergone transplant continue to Maintenance.
MAINTENANCE: Patients receive dexamethasone IV and PO on days 1, 8, 15, and 22, daratumumab
IV on day 1, and ixazomib PO on days 1, 8, and 15. Cycles repeat every 28 days for up to 24
months in the absence of disease progression or unacceptable toxicity.
ARM II:
INDUCTION CYCLES 1-3: Patients receive dexamethasone IV and PO on days 1, 8, and 15,
daratumumab IV on days 1, 8, and 15, and bortezomib subcutaneously (SC) on days 1, 4, 8, and
11. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or
unacceptable toxicity.
INDUCTION CYCLES 4-8: Patients receive dexamethasone IV and PO on days 1, 8, 15, and 22,
daratumumab IV on days 1 and 15, and ixazomib PO on days 1, 8, and 15. Treatment repeats
every 28 days for 5 cycles in the absence of disease progression or unacceptable toxicity.
Eligible patients then undergo stem cell transplant per standard of care. Patients who have
at least stable disease after induction and patients who have undergone transplant continue
to Maintenance.
MAINTENANCE: Patients receive dexamethasone IV on day 1, daratumumab IV on day 1, and
ixazomib PO on days 1, 8, and 15. Cycles repeat every 28 days for up to 24 months in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months.
Inclusion Criteria:
- Patients must meet the following criteria on screening examination to be eligible to
participate in the study. All laboratory assessments should be performed within 21
days of initiation of protocol therapy unless otherwise specified. Subject is, in the
investigator's opinion, willing and able to comply with the protocol requirements
- Subject has given voluntary signed written informed consent before performance of any
study-related procedure that is not part of normal medical care, with the
understanding that consent may be withdrawn by the subject at any time without
prejudice to their future medical care
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
- Have documented multiple myeloma as defined by the International Myeloma Working Group
(IMWG) 2014 criteria including: Clonal bone marrow plasma cells ≥ 10% (If bone marrow
has less than 10% clonal plasma cells, more than one bone lesion is required to
distinguish from solitary plasmacytoma with minimal marrow involvement). In addition,
the patient must meet one of the criteria in d1 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) < 40 mL/min (measured or
estimated by validated equations) or serum creatinine > 177 umol/L (> 2
mg/dL)
- Anemia: hemoglobin value of > 20 g/L below the lower limit of normal, or a
hemoglobin value < 100 g/L
- Bone lesions: 1 or more osteolytic lesions on skeletal radiography, computed
tomography (CT), or magnetic resonance imaging (MRI)
- Clonality should be established by showing kappa/lambda-light-chain
restriction on flow cytometry, immunohistochemistry, or
immunofluorescence. Bone marrow plasma cell percentage should
preferably be estimated from a core biopsy specimen; in case of a
disparity between the aspirate and core biopsy, the highest value
should be used
- Any one or more of the following:
- Clonal bone marrow plasma cell percentage ≥ 60%
- Clonality should be established by showing kappa/lambda-light-chain
restriction on flow cytometry, immunohistochemistry, or
immunofluorescence. Bone marrow plasma cell percentage should
preferably be estimated from a core biopsy specimen; in case of a
disparity between the aspirate and core biopsy, the highest value
should be used
- Involved:uninvolved serum free light chain (FLC) ratio > 100
- These values are based on the serum Freelite assay (The Binding Site
Group, Birmingham, UK). The involved FLC must be ≥ 100 mg/L
- > 1 focal lesions on MRI studies; Each focal lesion must be 5 mm or more in
size
- 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.
Note: All attempts should be made to determine eligibility of the subject based
on the central laboratory results of screening blood and urine M-protein
measurements. In exceptional circumstances, the local laboratory results for
blood and urine M-protein measurements may be used to determine eligibility, but
only if the results are clearly (eg, 25% or more) above the thresholds for
measurability; or
- Immunoglobulin A (IgA), immunoglobulin D (IgD), immunoglobulin E (IgE), or
immunoglobulin M (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
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/m²
each dosing equivalent 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 [eg, calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
of contraception.)
- Females of childbearing potential (FCBP) must have a negative serum or urine
pregnancy test with a sensitivity of at least 50 milli-International Unit
(mIU)/mL within 10-14 days prior to and again within 24 hours of starting study
drugs
- Male patients, even if surgically sterilized (ie, 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 (eg, calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
of contraception.)
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
- Renal insufficiency, defined as creatinine clearance ≤ 30 mL/min (either actual or
calculated value), within 21 days of initiation of protocol therapy. The
Cockcroft-Gault formula should be used for calculating creatinine clearance values
- Platelet count ≤ 75,000 cells/mm³ 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/mm³ 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
not 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.)
- Steroids more than 160 mg IV equivalents of dexamethasone or bortezomib > 2 doses of
1.3 mg/m² each dosing equivalents
- 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 chronic obstructive pulmonary disease with a forced expiratory volume in 1
second (FEV1) < 50% of predicted normal
- Has known 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 (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)
- 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
not excluded if they have undergone complete resection
- Known hypersensitivity to acyclovir or similar anti-viral drug
- Known 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 the
ixazomib
- Systemic treatment, within 14 days before the first dose of ixazomib, with strong
cytochrome P450, family 3, subfamily A (CYP3A) inducers (rifampin, rifapentine,
rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort
- 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
- Patients that have previously been treated with ixazomib, or participated in a study
with ixazomib whether treated with ixazomib or not
