Trial of Combination of Ixazomib and Lenalidomide and Dexamethasone in Smoldering Multiple Myeloma

This research study is a Phase II clinical trial, which tests the effectiveness of an
investigational drug(s). The investigational drugs used in this research study are Ixazomib,
Lenalidomide and Dexamethasone.

"Investigational" means that the FDA (the U.S. Food and Drug Administration) has not approved
the combination of Ixazomib, Lenalidomide and Dexamethasone as a treatment regimen for
Smoldering Multiple Myeloma. The purpose of this research study is to learn whether the
combination of Ixazomib, Lenalidomide, and Dexamethasone works in treating Smoldering
Multiple Myeloma.

Ixazomib is a drug that may kill or stop cancer cells from growing by blocking the proteasome
within the cell, which is responsible for degrading or breaking down a variety of proteins.
This type of drug is called a proteasome inhibitor. Lenalidomide is an immunomodulatory drug,
meaning it modifies the participant immune system to help fight the participant disease.
Dexamethasone is a steroid, which is usually combined with other drugs to enhance their
effects to fight the participant disease.

Ixazomib is approved by the FDA in combination with Lenalidomide and Dexamethasone for the
treatment of Multiple Myeloma and is currently being evaluated for use in the treatment of
several types of cancers. Both Lenalidomide and Dexamethasone have been previously approved
by the FDA for the treatment of Multiple Myeloma, as well as several other cancers.

Inclusion Criteria:

- Age ≥ 18 years.

- Must meet criteria of high risk smoldering MM based on the criteria described below:

- Definition of high-risk SMM:

--Bone marrow clonal plasma cells ≥10% and ≤60% and any one or more of the following:

- Serum M protein ≥3.0g/dL (IgA, IgG, IgM, or IgD)

- IgA SMM

- Immunoparesis with reduction of two uninvolved immunoglobulin isotypes

- Serum involved/uninvolved free light chain ratio ≥8 (but less than 100)

----Free Light Chain Smoldering Myeloma patients as defined in section 2.4 are
not excluded

- Progressive increase in M protein level (Evolving type of SMM)

----Increase in serum monoclonal protein by ≥10% on two successive evaluations
within a 6 month period

- Bone marrow clonal plasma cells 50-60%

- Abnormal plasma cell immunophenotype (≥95% of bone marrow plasma cells are
clonal) and reduction of one or more uninvolved immunoglobulin isotypes

- t (4;14) or del 17p or 1q gain

- Increased circulating plasma cells

- MRI with diffuse abnormalities or 1 focal lesion

- PET-CT with one focal lesion with increased uptake without underlying osteolytic
bone destruction

- Urine monoclonal light chain excretion ≥500 mg/24 hours

- ECOG Performance Status (PS) 0, 1, or 2 (Appendix A)

- The following laboratory values obtained ≤ 21 days prior to registration and confirmed
prior to the first dose of study drug:

- ANC ≥ 1000/uL

- PLT ≥ 75,000/uL. Platelet transfusions to help patients meet eligibility criteria
are not allowed within 3 days before study enrollment.

- Total bilirubin ≤ 1.5 mg/dL (If total is elevated check direct and if normal
patient is eligible.)

- AST ≤ 3 x institutional upper limit of normal (ULN)

- ALT ≤ 3 x institutional upper limit of normal (ULN)

- Calculated creatinine clearance ≥ 30 mL/min

- Ability to understand and the willingness to sign a written informed consent before
performance of any study-related procedure not part of normal medical care, with the
understanding that consent may be withdrawn by the subject at any time without
prejudice to future medical care.

- Female patients who are postmenopausal for at least 1 year before the screening visit
or are surgically sterile. Females of childbearing potential* must have a negative
serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14
days and again within 24 hours prior to prescribing lenalidomide for Cycle 1
(prescriptions must be filled within 7 days as required by Revlimid REMS®) 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. Female patients must agree to practice two effective methods of birth
control from the time of signing the informed consent form though 90 days after the
last dose of study drug

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

- Has not undergone a hysterectomy (the surgical removal of the uterus) or
bilateral oophorectomy (the surgical removal of both ovaries) or

- Has not been naturally postmenopausal (amenorrhea following cancer therapy does
not rule out childbearing potential) for at least 24 consecutive months (i.e.,
has had menses at any time during the preceding 24 consecutive months)

- All study participants must be registered into the mandatory Revlimid REMS® program,
and be willing and able to comply with the requirements of the REMS® program.

- Females of reproductive potential must adhere to the scheduled pregnancy testing as
required in the Revlimid REMS® program.

- Men must agree to use a latex condom during sexual contact with a female of
childbearing potential even if they have had a successful vasectomy 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:

- No evidence of CRAB* criteria or new criteria of active MM which including the
following:

- Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the upper
limit of normal or >.275 mmol/dL) related to MM

- Renal insufficiency (attributable to MM)

- Anemia (Hb 2g/dL below the lower limit of normal or <10g/dL) related to MM

- Bone lesions (lytic lesions or generalized osteoporosis with compression
fractures)

- Bone marrow plasma cells ≥60%

- Serum involved/uninvolved FLC ratio ≥100, provided the absolute level of the
involved free light chain is at least 100 mg/L and repeated twice

- MRI with two or more focal lesion that is at least 5 mm or greater in size

- Participants with CRAB criteria that are attributable to conditions other than the
disease under study may be eligible

- Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
considered investigational. Prior therapy with bisphosphonate is allowed. Prior
radiation therapy to a solitary plasmacytoma is allowed.

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

- Diagnosed or treated for another malignancy within 2 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant or nursing women will be excluded from the study because lenalidomide is an
agent with the potential for teratogenic or abortifacient effects.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ixazomib or lenalidomide.

- Known seropositive for or active viral infection with human immunodeficiency virus
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are
seropositive because of hepatitis B virus vaccine are eligible.

- Major surgery within 14 days before enrollment.

- Known Amyloid involvement.

- Myeloma-related central nervous system involvement.

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

- Known GI disease or GI procedure that could interfere with the oral absorption or
tolerance of ixazomib including difficulty swallowing.

- Grade 2 peripheral neuropathy or higher or grade 1 with pain on clinical examination
during the screening period.

- 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.

- Previous treatment with ixazomib, or participation in a study with ixazomib whether
treated with ixazomib or not.