Carfilzomib, Lenalidomide, and Dexamethasone for Smoldering Multiple Myeloma

BACKGROUND:

- SMM is a precursor condition to MM defined by the clinical parameters of M-protein
greater than or equal to 3.0 g/dL or bone marrow plasma cells greater than or equal to
10% and absence of end organ disease.

- Risk of progression of high risk SMM at 5 years is 72-75% with median time to
progression <2 years.1-2

- The current standard of care for SMM is close follow-up without treatment until
symptomatic

MM develops. However, IMWG states "Preventive clinical trials need to be considered for
patients with high risk smoldering myeloma".

- Carfilzomib is a new proteasome inhibitor with potent anti-MM effects

OBJECTIVES:

- To assess the response rate of CRd in patients with high-risk SMM

ELIGIBILITY:

- SMM according to the International Myeloma Working Group definition 3 i.e.:

- Serum M-protein greater than or equal to 3 g/dl and/or bone marrow plasma cells
greater than or equal to 10 % and less than 60%,

- Absence of anemia: Hemoglobin >10 g/dl

- Absence of renal failure: serum creatinine < 2.0 mg/dL. Absence of hypercalcemia:
Ca <10.5 mg/dl or 2.65 mmol/L

- Absence of lytic bone lesion

- Involved/un-involved light chain ration must be less than 100

- Measurable disease

- High-risk SMM per Mayo Clinic, Spanish PETHEMA, or the Rajkumar, Landgren Mateos
criteria

- Age greater than or equal to 18 years

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Adequate laboratory parameters as defined in the protocol

- An allowance for patients with an ANC of 0.5 K/uL <1.0 K/uL added at the discretion of
the investigator (e.g., patients with a baseline

neutropenia that is chronic and that does not cause complications).

DESIGN:

- Single arm pilot trial of combination therapy (carfilzomib, lenalidomide, and

dexamethasone) for high risk smoldering multiple myeloma

- Patients will receive 8 cycles of induction combination therapy of CRd

- Each cycle consists of 28-days

- After 4 cycles of therapy, transplant eligible patients may choose to undergo stem cell
collection

- After 8 cycles of CRd, patients will receive lenalidomide extended dosing (phase I) for
12 cycles. After 12 cycles, patients will have the option to continue extended dosing
(phase II) for one additional year.

- Patients will have routine blood work with SPEP and free light chains monthly during the
induction phase. Laboratory evaluations may be spread out to every 3 months during the
maintenance and follow-up phases.

- Pre-treatment, post-treatment and follow-up bone marrow biopsies will be obtained for
confirmation of diagnosis, response and correlative studies

- Patients will also undergo evaluation for minimal residual disease at regular interval
time points, using multi-parametric flow cytometry and FDG PET-CT

- This single arm pilot study will plan on initially enrolling 12 evaluable patients to
detect a VGPR from baseline. A replicate cohort of 16 evaluable patients will then be
enrolled in order to more precisely define the response rate to the CRd regimen in this
population.

- INCLUSION CRITERIA:

Patients must have histologically or cytologically confirmed Smoldering Multiple Myeloma
confirmed by the Laboratory of Pathology, NCI or the Department of Laboratory Medicine, CC
based on the International Myeloma Working Group Criteria:

- Serum M-protein greater than or equal to 3 g/dl and/or bone marrow plasma cells
greater than or equal 10% and <60%

- Absence of anemia: Hemoglobin >10 g/dl

- Absence of renal failure: serum creatinine < 2.0 mg/dL Absence of hypercalcemia: Ca
<10.5 mg/dl

- Absence of lytic bone lesion on X-ray, CT, or PET/CT and not more than 1 lesion on
spinal MRI

- Involved-un-involved light chain ratio must be <100

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

- Serum monoclonal protein greater than or equal to 1.0 g/dl

- Urine monoclonal protein >200 mg/24 hour

- Serum immunoglobulin free light chain >10 mg/dL AND abnormal kappa/lambda ratio

Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of carfilzomib in combination with lenalidomide in patients
<18 years of age, children are excluded from this study, but may be eligible for future
pediatric trials.

ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).

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

- absolute neutrophil count (ANC) greater than or equal to1.0 K/uL

- platelets greater than or equal to75 K/uL

- hemoglobin greater than or equal to 8 g/dL(transfusions are permissible)

- total bilirubin less than or equal to 1.5 times institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) less than or equal to 3.0 times institutional upper limit of
normal

- Creatinine Clearance greater than or equal to 60 ml/min. CrCl will be calculated by
Cockcroft Gault method. CrCl (calculated) = (140 Age) times Mass (in kilograms) times
[0.85 if Female] 72 times Serum Creatinine (in mg/dL). If calculated CrCl based on
Cockcroft-Gault method is <60 mL/min, patient will have a 24 hr urine collection to
measure CrCl. The measured CrCl must also be greater than or equal to 60 ml/min.

In addition to having SMM, patients must also be classified as high-risk SMM per Mayo
Clinic or Spanish PETHEMA criteria

Criteria set forward by Rajkumar, Landgren, Mateos may also be used to define high risk
disease, namely clonal bone marrow plasma cells greater than or equal to 10% and any one or
more of the following:

- Serum M protein greater than or equal to 30g/L

- IgA SMM

- Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes

- Serum involved/uninvolved FLC ratio greater than or equal to 8 (but less than 100)

- Progressive increase in M protein level (evolving type of SMM; increase in serum M
protein by greater than or equal to 25% on 2 successive evaluations within a 6-month
period)

- Clonal BMPCs 50%-60%

- Abnormal PC immunophenotype (greater than or equal to 95% of BMPCs are clonal) and
reduction of greater than or equal to 1 uninvolved immunoglobulin isotypes

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

- Increased circulating PCs

- MRI with diffuse abnormalities or 1 focal lesion

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

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

The effects of carfilzomib and lenalidomide on the developing human fetus are unknown. For
this reason and because immunomodulatory agents as well as other therapeutic agents used in
this trial are known to be teratogenic, women of childbearing potential and men must agree
to use adequate contraception. Females of childbearing potential (FCBP) must have a
negative serum or urine pregnancy test within 10 - 14 days and again within 24 hours prior
to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) 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.
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 successful vasectomy. All
patients must be counseled at a minimum of every 28 days about pregnancy precautions and
risks of fetal exposure. Should a woman become pregnant or suspect she is pregnant while
she or her partner is participating in this study, she should inform her treating physician
immediately.

Ability of subject to understand and the willingness to sign a written informed consent
document.

EXCLUSION CRITERIA:

Patients who are receiving any other investigational agents.

Concurrent systemic treatment or prior therapy within 4 weeks for SMM

- Treatment with corticosteroids for other indications is permitted

Patients with a diagnosis of MM as defined by the 2014 IMWH diagnostic criteria.

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

History of allergic reactions attributed to compounds of similar chemical or biologic
composition to carfilzomib or lenalidomide agents used in study, such as bortezomib or
thalidomide.

Uncontrolled hypertension or diabetes

Pregnant or lactating females. Pregnant women are excluded from this study because
Carfilzomib/Lenalidomide are agents with the potential for teratogenic or abortifacient
effects. Because there is an unknown but potential risk for adverse events in nursing
infants secondary to treatment of the mother with Carfilzomib/Lenalidomide, breastfeeding
should be discontinued if the mother is treated with Carfilzomib/Lenalidomide. These
potential risks may also apply to other agents used in this study

Significant cardiovascular disease with NYHA Class II, III or IV symptoms, or hypertrophic
cardiomegaly, or restrictive cardiomegaly, or myocardial infarction within 3 months prior
to enrollment, or unstable angina, or unstable arrhythmia

Active hepatitis B or C infection

Has refractory GI disease with refractory nausea/vomiting, inflammatory bowel disease, or
bowel resection that would prevent absorption

Significant neuropathy >Grade 2 at the time of first dose or within 14 days of enrollment

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 within 2 weeks that would limit
compliance with study requirements.

History of other malignancy (apart from basal cell carcinoma of the skin, or in situ cervix
carcinoma) except if the patient has been free of symptoms and without active therapy
during at least 5years

Major surgery within 1 month prior to enrollment