This is a randomized, Phase 2 study involving two arms evaluating the efficacy and safety of
ixazomib alone and the combination of both ixazomib and lenalidomide as maintenance therapy
for patients with multiple myeloma who have achieved at least partial response (PR) or better
after receiving a bortezomib- and lenalidomide-containing combination front-line therapy.
Patients who have achieved PR or better on a bortezomib- and lenalidomide-containing
combination therapy will be randomized to receive maintenance therapy with 28-day cycles of
either ixazomib alone or the combination of ixazomib and lenalidomide. If steroids were part
of the patient's qualifying regimen, steroids will be administered using the same drug(s),
schedule(s) and dose(s) as those of the last treatment cycle of the bortezomib-,
lenalidomide- and steroid-containing regimen. Ixazomib will be administered per orem (PO) at
3 mg on days 1, 8 and 15 of 28-day cycles. Lenalidomide will be taken PO, once daily at the
same dose as the last treatment on days 1 through 28 of the 28-day cycles. Patients will
start the randomized maintenance therapy after receiving a minimum of 6 cycles of a
bortezomib- and lenalidomide-containing combination treatment but may have received up to 8
cycles if they continued to show improvement in their response after the first 6 cycles.
During cycle 1, patients will have clinical laboratory tests weekly (days 1, 8, 15 and 22)
and MM disease assessments on day 22 to monitor for efficacy and potential toxicity.
Beginning with cycle 2, patients will have clinical laboratory tests performed twice a month
and MM disease assessments once a month. Patients will be treated until documentation of PD
or if subject meets any of the treatment discontinuation criteria.
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female patients 18 years or older.
2. Patients must be receiving a frontline bortezomib- and lenalidomide-containing regimen
for treatment of disease
3. Patients must meet the following clinical laboratory criteria:
- Absolute neutrophil count (ANC) grater or equal 1,000/mm3 and platelet count
greater or equal 75,000/mm3. Platelet transfusions to help patients meet
eligibility criteria are not allowed within 7 days prior to screening platelets
or at investigator's discretion.
- Hemoglobin ≥ 8.0 g/dL. Use of erythropoietic stimulating factors and red blood
cell (RBC) transfusions per institutional guidelines is allowed; however, most
recent RBC transfusion must have been at least 7 days prior to obtaining
screening hemoglobin or at investigator's discretion.
- Total bilirubin less or equal 1.5 times the upper limit of the normal range
- Calculated or measured creatinine clearance greater or equal 30 mL/min.
Calculation is based on a standard Cockcroft and Gault formula (Section 14.2).
- AST (SGOT) and ALT (SGPT) less or equal 3 x ULN or less or equal 5 x ULN if
hepatic metastases are present.
- LVEF ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of
evaluation. Mitigated Acquisition Scan (MUGA) is acceptable if ECHO is not
4. Patients must be transplant ineligible as determined by the treating physician.
5. Patients must have a life-expectancy of more than 6 months.
6. Patients must have a confirmed diagnosis of MM.
7. Patients receiving front-line therapy must have achieved at least PR and have
completed at least 6 cycles of treatment.
8. The disease must have reached a plateau phase at the end of front-line treatment as
demonstrated bythe same response (using IMWG criteria) in three consecutive tests with
at least three weeks between each test.
9. Patients must have received frontline treatment within 8 weeks of enrollment.
10. Patient can adhere to the study visit schedule and other protocol requirements.
11. Patient Eastern Cooperative Oncology Group (ECOG) performance status is ≤ 2.
12. Patients must voluntarily give written consent before any study related procedure not
part of standard medical care is performed, with the understanding that consent may be
withdrawn by the patient at any time without prejudice to future medical care.
13. Female patients must be postmenopausal for at least 1 year before screening visit OR
surgically sterile. If patient is female of childbeating potential (FCBP), patient
must agree to practice two 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. FCBP must also adhere to the guidelines of any treatment-specific
pregnancy prevention program AND 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.
14. Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree
to one of the following:
- To practice effective barrier contraception during the entire study treatment
period and through 90 days after the last dose of study drug
- 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
- Patients meeting any of the following exclusion criteria are not to be enrolled in the
1. Patient is currently progressing on a bortezomib- and lenalidomide-containing
2. Patients who have received more than 1 line of therapy (thus non-frontline
3. Patients who were exposed to ixazomib during frontline therapy.
4. Patient has ¬> Grade 3 peripheral neuropathy or Grade 2 with pain during the
5. Patient has known gastrointestinal disease or gastrointestinal procedure that
could interfere with the oral absorption or tolerance of ixazomib including
6. Female patients who are lactating or have a positive serum pregnancy test during
the screening period.
7. Major surgery within 14 days before enrollment or at investigator's discretion.
8. Patients undergoing stem cell therapy (SCT) or those who are planned for SCT.
9. Radiotherapy within 14 days before enrollment or investigator's discretion. If
the involved field is small, 7 days or investigator's discretion will be
considered a sufficient interval between treatment and administration of the
study drugs. Receipt of localized radiation therapy does not preclude enrollment.
10. Infection requiring systemic antibiotic therapy or other serious infection such
as known active hepatitis B or C virus infection, known human immunodeficiency
virus (HIV) positive within 14 days before of study enrollment or at
11. Evidence of current uncontrolled cardiovascular conditions, including
uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic
congestive heart failure, NYHA Class III or IV heart failure, unstable angina,
clinically significant pericardial disease or myocardial infarction within the
past 6 months, unless subject has a pacemaker. Prior to study entry, any ECG
abnormality at Screening must be documented by the investigator as not medically
12. Frontline therapy within 14 days or at investigator's discretion of the first
dose of study drugs.
13. Systemic treatment, within 14 days before or at investigator's discretion of the
first dose of study drugs, with strong CYP3A inducers (rifampin, rifapentine,
rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort or
14. Any serious medical or psychiatric illness that could, in the investigator's
opinion, potentially interfere with the completion of treatment according to this
15. Known allergy to any of the study medications, their analogues, or excipients in
the various formulations of any agent.
16. 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 non-melanoma skin cancer or carcinoma in situ of any type are not
excluded if they have undergone complete resection.
17. Participation in other clinical trials throughout the duration of this trial.
18. Patient has been diagnosed with:
1. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy,
monoclonal protein (M protein) and skin changes (POEMS) syndrome3.
2. Primary amyloidosis
3. Plasma cell leukemia.
4. Severe hypercalcemia, i.e., serum calcium ≥ 12 mg/dL (3.0 mmol/L) corrected