Background:
SMM is a precursor condition to 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, 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; 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: 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 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 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.
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.
- 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. (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 MRD(-) 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 IMWG
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.
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 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
- 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 eGFR (estimated glomerular filtration
rate) must be greater than or equal to 50 ml/min.
- 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 SMM, patients must also be classified as 'high-risk SMM' per Mayo
Clinic or Spanish 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
- 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 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 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 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.
