Carfilzomib, Lenalidomide, and Dexamethasone for Smoldering Multiple Myeloma

Background:

* Multiple myeloma is a blood cancer that affects the plasma cells. These cells help produce antibodies and fight infection. Smoldering multiple myeloma (SMM) is a related condition that may develop into multiple myeloma. The current standard of care for SMM is close follow-up without treatment until multiple myeloma develops. However, researchers are studying possible treatments for SMM itself. One possible treatment involves a combination of cancer treatment drugs.
* Lenalidomide is a drug that may help reduce or prevent the growth of cancer cells. Dexamethasone is a steroid that is often given with other anti-cancer drugs. These two drugs are an approved treatment for multiple myeloma that has not responded to at least one other treatment. Carfilzomib is an experimental drug that has been effective in treating multiple myeloma. Researchers want to combine these three drugs to see if they are a safe and effective treatment for SMM.

Objectives:

- To see if carfilzomib, lenalidomide, and dexamethasone are a safe and effective treatment for smoldering multiple myeloma.

Eligibility:

- Individuals at least 18 years of age who have SMM that is likely to progress to multiple myeloma.

Design:

* Participants will be screened with a physical exam and medical history. They will also have blood and urine tests, and baseline bone marrow scans. Bone marrow samples will also be collected.
* Participants will have eight 28-day cycles of treatment with the three study drugs. The drugs will be given as tablets or as infusions. Treatment will be monitored with frequent blood tests and study visits.
* After the first four cycles, participants who are eligible for a stem cell transplant will have their stem cells collected and stored for future use.
* At the end of eight cycles, participants whose disease has not progressed will have up to 12 more cycles of treatment with lenalidomide tablets alone.

Background:

Smoldering multiple myeloma (SMM) is a precursor condition to multiple myeloma (MM) defined by the clinical parameters of M-protein \>= 3.0 g/dL or bone marrow plasma cells \>= 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.

The current standard of care for SMM is close follow-up without treatment until symptomatic MM develops. However, International Myeloma Working Group (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 cyclophosphamide, lenalidomide, and dexamethasone (CRd) in patients with high-risk SMM, focusing on the

Minimal residual disease (MRD(-) Complete Response (CR) rate

Eligibility:

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

Serum M-protein \>=3 g/dl and/or bone marrow plasma cells \>=10 % and \< 60%

Absence of anemia: Hemoglobin \>10 g/dl

Absence of renal failure: serum creatinine \< 2.0 mg/dL.

Absence of hypercalcemia: Calcium (Ca) \< 10.5 mg/dl or 2.65 mmol/L

Absence of lytic bone lesion

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

Measurable disease

High-risk SMM per Mayo Clinic, Spanish Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA), or the Rajkumar, Landgren, Mateos criteria

Age \>=18 years

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

Adequate laboratory parameters as defined in the protocol

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 serum protein electrophoresis (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 fluorodeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT)

This single arm pilot study will plan on initially enrolling 12 evaluable patients to detect a very good partial response (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. Accrual will then be extended to a total of 50 evaluable patients in order to estimate the MRD(-) CR rate with reasonable precision. To allow for a number of inevaluable patients and screen failures, the accrual ceiling will be set at 63.

Eligibility Criteria:
* INCLUSION CRITERIA:

Patients must have histologically or cytologically confirmed Smoldering Multiple Myeloma confirmed by the Laboratory of Pathology, national Cancer Institute (NCI) or the Department of Laboratory Medicine, Clinical Center (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: Calcium (Ca) \<10.5 mg/dl
* Absence of lytic bone lesion on X-ray, computed tomography (CT), or positron-emission tomography (PET)/CT and not more than 1 lesion on spinal magnetic resonance imaging (MRI). (NOTE: At the discretion of the investigator, PET/CT may replace MRI in patients who have a contraindication to 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

NOTE: As of Amendment L (version date 05/17/2018), the primary endpoint is minimal residual disease (MRD(-) Complete Response (CR) rate; therefore, per the discretion of the Principal Investigator, patients without measurable disease (e.g., M-spike \<1) may also be enrolled. This is in line with the most recent International Myeloma Working Group (IMWG) multiple myeloma (MM) response criteria.

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.

Eastern Cooperative Oncology Group (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

NOTE: At the discretion of the investigator, patients with an ANC of 0.5 K/uL \<1.0 K/uL may also be enrolled if clinically appropriate (e.g., patients with a baseline neutropenia that is chronic and that does not cause complications)

* platelets greater than or equal to 75 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
* aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) less than or equal to 3.0 times institutional upper limit of normal
* Serum creatinine less than or equal to 1.5 X institutional ULN. If serum creatinine is above 1.5 X ULN, Creatinine Clearance (CrCl) or estimated glomerular filtration rate (eGFR) (estimated glomerular filtration rate) must be greater than or equal to 50 ml/min.

  * Creatinine clearance (CrCl) will be calculated by Cockcroft-Gault method. CrCl (calculated) = (140 - Age) x Mass (in kilograms) x \[0.85 if Female\] 72 x Serum Creatinine (in mg/dL).
  * eGFR will be calculated by either of the following well established formulas: modification of diet in renal disease (MDRD) or the chronic kidney disease (CKD)-epidemiology collaboration (EPI) (institutional standard) equations
* CrCl may also be determined by measuring a 24 hour urine collection. The measured CrCl must be greater than or equal to 50 ml/min.

In addition to having Smoldering Multiple Myeloma (SMM), patients must also be classified as 'high-risk SMM' per Mayo Clinic or Spanish Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA) criteria.

Criteria set forward by Rajkumar, Landgren, Mateos\[14\] 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
* Immunoglobulin A (IgA) SMM
* Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes
* Serum involved/uninvolved free light chain (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 bone marrow plasma cells (BMPCs) 50%-60%
* Abnormal plasma cells (PCs) 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 Risk Evaluation and Mitigation Strategy (REMS).

The effects of carfilzomib and lenalidomide on the developing human fetus are unknown. The immunomodulatory agents used in this trial (i.e., lenalidomide) 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. In regard to carfilzomib, FCBP and their male partners must agree to use at least one method of effective contraception for at least 30 days after the

last dose of carfilzomib and males must agree to use contraception and not to donate sperm for at least 90 days after the last dose of carfilzomib.

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, in addition to patients with known allergy to sulfobutyl ether \<=- cyclodextrin (Captisol).

Uncontrolled hypertension or diabetes

Pregnant or lactating females. Pregnant women are excluded from this study. The effects of carfilzomib on a developing human fetus are unknown. Lenalidomide is teratogenic with unknown potential for abortifacient effects. Breastfeeding women and women planning on breastfeeding may not participate. No studies of carfilzomib have been conducted on breast feeding women and it is not known if it is excreted in milk. 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.

Significant cardiovascular disease with New York Heart Association (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 gastrointestinal (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 2 years or if, at the clinical discretion of the investigator, the risks of this study do not outweigh the potential benefits on a case to case basis.

Major surgery within 1 month prior to enrollment.