Ixazomib (MLN9708) and Dexamethasone in High Risk Smoldering Multiple Myeloma: A Clinical and Correlative Pilot Study

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed Smoldering Multiple
Myeloma confirmed by Department of Pathology, based on the International Myeloma
Working Group Criteria

- Serum M-protein ≥3 g/dl and/or bone marrow plasma cells ≥10 %,

- Absence of anemia attributed to the plasma cell disorder*: Hemoglobin >10 g/dl or not
more than 2g/dL below the lower limit of normal

- Absence of renal failure attributed to the plasma cell disorder*: calculated
creatinine clearance (according to Cockcroft-Gault method, MDRD, or CKD-EPI formulae)
> 30 mL/min (or alternatively based on standard creatinine level criteria of 2 mg/dl)

- Absence of hypercalcemia attributed to the plasma cell disorder* (: Ca < 10.5 mg/dl or
≤ 2.5 mmol/L

- Absence of lytic bone lesion

- Absence of Clonal bone marrow plasma cell percentage ≥60%

- Absence of Involved: uninvolved serum free light chain ratio ≥100

- Absence >1 focal lesions on MRI studies

* To be determined based on clinical and laboratory assessment by the primary
oncologist

- "High-risk SMM" per Mayo Clinic or Spanish PETHEMA criteria

- Measurable disease within the past 4 weeks defined by any one of the following

- Serum monoclonal protein ≥ 1.0 g/dl

- Urine monoclonal protein >200 mg/24 hour

- Serum immunoglobulin free light chain >10 mg/dL AND abnormal kappa/lambda ratio
(reference 0.26-1.65)

- Age ≥18 years

- ECOG performance status 0, 1, or 2.

- Ability to give informed consent.

- Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count ≥1.0 K/μL

- Platelets ≥ 75 K/μL (Platelet transfusions to help patients meet eligibility criteria
are not allowed within 3 days before study enrollment.)

- Hemoglobin > 10 g/dL(transfusions are not permissible)

- Total bilirubin ≤1.5 X institutional upper limit of normal AST(SGOT)/ALT(SGPT) ≤ 3.0 X
institutional upper limit of normal

- Female patients who:

- Are postmenopausal for at least 24 months 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.)

- Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:

- 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:

- Participation in other clinical trials, including those with other investigational
agents not included in this trial and throughout the duration of this trial; within at
least 5 half-lives of previous therapy for smoldering myeloma at start of this trial.

- Prior therapy for SMM with a proteasome inhibitor.

- Patients with a diagnosis of MM per standard IMWG criteria

- Contraindication to any concomitant medication, including antivirals, anticoagulation
prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy.

- Known allergy to any of the study medications, their analogues, or excipients in the
various formulations of any agent.

- Uncontrolled hypertension or diabetes.

- Females patients who are lactating or have a positive serum pregnancy test during the
screening period.

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

- Patient has ≥ Grade 1 peripheral neuropathy with pain on clinical examination during
the screening period.

- 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 study enrollment, with strong inhibitors of
CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A
(clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone,
posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin,
carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.

- Ongoing or active systemic infection, known human immunodeficiency virus (HIV)
positive, known active hepatitis B virus hepatitis, or known active hepatitis C virus
hepatitis.

- Co-morbid systemic illnesses or other severe concurrent disease that, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens.

- Psychiatric illness/social situation that would limit compliance with study
requirements.

- QTc > 470 milliseconds (msec) on a 12-lead EKG obtained during the Screening period.
If a machine reading is above this value, the EKG should be reviewed by a qualified
reader and confirmed on a subsequent EKG.

- 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.

- Failure to have fully recovered (ie, ≤ Grade 1 toxicity) from the reversible effects
of prior chemotherapy.

- Inability to swallow oral medication, inability or unwillingness to comply with the
drug administration requirements or GI procedure that could interfere with the oral
absorption or tolerance of treatment.

- Major surgery within 14 days prior to enrollment.

- 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.

- Central nervous system involvement (based on clinical assessment).

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

- No current anti-myeloma bisphosphonate therapy (however, prior bisphosphonates and/or
bisphosphonate therapy due to osteoporosis is allowed).

- Patients with Paget's disease of the bone.

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