Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized With NFKB2 Rearrangement

PRIMARY OBJECTIVES:

To test whether the NFKB2 rearrangement can guide the selection of treatment (ixazomib
[ixazomib citrate] plus dexamethasone [Id] or ixazomib plus lenalidomide and dexamethasone
[IRd]) by conducting the following comparisons:

I. To compare the response rate at 4 cycles between patients treated with Id and patients
treated with IRd and confirm the lack of significant difference in overall response.

II. To compare the response rate at 4 cycles between non-rearranged and rearranged NFKB2
treated with Id and confirm that NFKB2 rearrangement is associated with reduce response rate.

III. To compare the responses rate at 4 cycles of patients with rearranged NFKB2 treated with
Id or IRd and confirm that adding lenalidomide increases the response rate in this
population.

SECONDARY OBJECTIVES:

I. To determine time to treatment failure (TTF).

II. To determine the frequency and severity of adverse events (AE) in IRd treated cohort.

III. To identify novel transcribed mutations associated with Id and IRd resistance in
patients with multiple myeloma (MM).

IV. To determine the prevalence of NFKB2 rearrangement in relapsed/refractory MM patients
screened in the study.

V. To determine the prevalence of NFKB2 rearrangement according to the type of previous
therapies received in all patients screened in the study.

VI. To determine the toxicity profile of the study drugs according to the presence of NFKB2
rearrangement.

VII. Delineate transcribed mutations associated with relapse or refractoriness to Id or IRd
treatment by ribonucleic acid (RNA)-sequencing.

OUTLINE:

ARM A (UNMUTATED NFKB2 REARRANGEMENT): Patients receive ixazomib orally (PO) on days 1, 8,
and 15 and dexamethasone PO on days 1, 8, 15, and 22.

Patients with mutated NFKB2 rearrangement are randomized in to 1 of 2 treatment arms.

ARM B (MUTATED NFKB2 REARRANGEMENT): Patients receive ixazomib and dexamethasone as in arm A.

ARM C (MUTATED NFKB2 REARRANGEMENT): Patients receive ixazomib and dexamethasone as in arm A
and lenalidomide PO daily on days 1-21.

In all arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

Patients may proceed to autologous stem cell transplant after 4 courses of treatment.

After completion of study, patients are followed up monthly.

Inclusion Criteria:

- Voluntary written consent must be given before performance of any study related
procedure not part of standard medical care, with the understanding that consent may
be withdrawn by the patient at any time without prejudice to future medical care

- Females of childbearing potential (FCBP)* must have a negative serum or urine
pregnancy test with a sensitivity of at least 50 milli-International Units (mIU)/mL
within 10-14 days prior to and again within 24 hours of starting lenalidomide and
ixazomib and must either commit to continued abstinence from heterosexual intercourse
or begin TWO acceptable methods of birth control, one highly effective method and one
additional effective method AT THE SAME TIME, at least 28 days before she starts
taking lenalidomide through 90 days after the last dose of study drug; FCBP must also
agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual
contact with a FCBP even if they have had a vasectomy from the time of signing the
informed consent form through 90 days after the last dose of study drug; in the event
that the male patients choose to agree to practice true abstinence, this must follow
the timelines detailed above; all patients assigned to the lenalidomide treatment
group must be registered in and must comply with all requirements of the Revlimid Risk
Evaluation and Mitigation Strategy (REMS) program

- *A female of childbearing potential is a sexually mature woman who:

- 1) has not undergone a hysterectomy or bilateral oophorectomy; or

- 2) has not been naturally postmenopausal for at least 24 consecutive months

- Multiple myeloma diagnosed according to standard criteria either currently or at the
time of initial diagnosis

- The patient has confirmed relapsed or refractory MM

- For patients that relapse following a response to prior treatment with bortezomib or
carfilzomib, six months must have elapsed since the last dose of treatment

- The patient has received 1 to 3 prior lines of therapy. By definition, a single line
of therapy may consist of 1 or more agents, and may include induction, hematopoietic
stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a
single short course of steroids (ie, less than or equal to the equivalent of
dexamethasone 40 mg/day for 4 days) would not be considered prior lines of therapy

- Patients must have measurable disease defined by at least 1 of the following
measurements:

- Serum M-protein ≥ 1.0 g/dL (≥ 10 g/L) for an immunoglobulin (Ig)G myeloma, ≥ 0.1
g/dL for an immunoglobulin D (IgD) myeloma or 0.5 g/dL (≥ 5g/L) for an
immunoglobulin A (IgA) myeloma

- Urine light chain ≥ 200 mg/24 hours

- Serum free light chain ≥ 10 mg/dL provided the free light chain (FLC) ratio is
abnormal

- Patients with oligo- or non-secretory disease must have bone marrow involvement
with at least 30% plasmacytosis on aspiration

- Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
status 0, 1, or 2

- Absolute neutrophil count (ANC) ≥ 1,000/mm³

- Platelet count ≥ 75,000/mm³; in the case that platelets are between 50,000-75,000, the
patient can be enrolled if the plasma cell count in the bone marrow is superior to ≥
50%; to meet this hematological eligibility no transfusion support and hematological
growth factor are not allowed within 7 days before study enrollment

- Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN

- Serum creatinine ≤ 2.5 mg/dL or a calculated creatinine clearance ≥ 50 mL/min

Exclusion Criteria:

- The patient is refractory to carfilzomib or bortezomib; (refractory is defined as
patients who never achieved a response and progressed while on carfilzomib or
bortezomib or within 60 days of completing treatment)

- Prior treatment with any investigational proteasome inhibitor within 6 months of study
entry

- Female patients who are breast feeding or have a positive serum pregnancy test during
the screening period

- Failure to have fully recovered (ie, > grade 1 toxicity) from the reversible effects
of prior chemotherapy

- Diarrhea > grade 1 according to National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) version (v)4.03

- Prior chemotherapy and/or immunotherapy within 14 days before enrollment; major
surgery within 14 days before enrollment and minor surgery within 7 days prior to
cycle 1 day 1

- Radiotherapy within 14 days before enrollment; if the involved field covered ≤ 5% of
the bone marrow reserve, the patient may be enrolled irrespective of the end date of
radiotherapy

- Central nervous system involvement

- Infection requiring systemic antibiotic therapy or other serious infection within 14
days before study enrollment

- Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
unstable angina, or myocardial infarction within the past 6 months

- Systemic treatment, within 14 days before the first dose of ixazomib, with strong
cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A) inducers (rifampin,
rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo
biloba or St. John's wort

- Active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV)
positive

- Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially compromise the patient's ability to understand the patient information, to
give informed consent, to comply with the treatment according to this protocol or
complete 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 non-melanoma skin cancer or carcinoma in situ of any type are
not excluded if they have undergone complete resection

- Patient has ≥ grade 2 peripheral neuropathy or neuropathy with pain, regardless of
grade that is seen on clinical examination during the screening period

- Known intolerance to immunomodulatory drugs (IMiDs)

- History of allergic reaction/hypersensitivity to any of the study medications, their
analogues or excipients in the various formulations

- Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
absorption or tolerance of ixazomib or lenalidomide, including difficulty swallowing

- Participation in other clinical trials, including those with other investigational
agents not included in this trial, such as monoclonal antibodies, within 30 days of
the start of this trial and throughout the duration of this trial

- Corticosteroid doses > 10 mg/day of prednisone or equivalent within 14 days prior to
cycle 1 day 1

- Autologous or allogeneic stem cell or bone marrow transplant within 3 months prior to
cycle 1 day 1

- Cytotoxic therapy within 21 days prior to cycle 1 day (D) 1

- Patients that have previously been treated with ixazomib, or participated in a study
with ixazomib whether treated with ixazomib or not