Background:
Smoldering multiple myeloma (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.
Patients with high-risk SMM have a risk of progression to MM of 72-75% in 5 years with median
time to progression of <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) recommends Preventive
clinical trials need to be considered for patients with high risk smoldering myeloma.
Carfilzomib is a proteasome inhibitor and daratumumab is an anti-CD38 monoclonal antibody,
both with potent anti-MM effects.
Objectives:
To assess the remission rate of daratumumab, carfilzomib, and dexamethasone (DKd) in patients
with high-risk (HR) smoldering multiple myeloma (SMM) by determining the minimal residual
disease (MRD) negative complete response (CR) rate by up to 12 cycles of induction therapy
using flow cytometry.
Eligibility:
SMM according to the IMWG 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 lesions
<=1 focal lesion on MRI
Involved/un-involved light chain ratio <100
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
Design:
Single arm trial of combination therapy (daratumumab, carfilzomib, and dexamethasone)
followed by daratumumab maintenance monotherapy (DKd-D) for high-risk SMM
Participants will receive 8 cycles of DKd induction combination therapy. After 8 cycles,
participants who have not attained an MRD negative remission will receive 4 additional cycles
of DKd. Each cycle consists of 28-days.
After 4 cycles of induction therapy, transplant eligible participants may choose to undergo
stem cell collection for storage.
After induction with DKd, participants will receive daratumumab maintenance therapy for 24
cycles.
Participants will have routine blood work with SPEP and free light chains at the start of
each cycle during the induction phase. Laboratory evaluations may be spread out to every 3-6
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.
Participants will also undergo evaluation for MRD at regular interval time points, using
multi-parametric flow cytometry, FDG PET-CT, and Diffusion Weighted Whole Body (DW-MRI).
The statistical analysis of the primary endpoint, MRD negativity, will be performed at the
end of induction therapy.
- INCLUSION CRITERIA:
- Patients must have histologically or cytologically confirmed smoldering multiple
myeloma (SMM) based on the International Myeloma Working Group Criteria:
- 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
- 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 (unless involved light chain
is <=10 mg/dL)
- Measurable disease within the past 4 weeks defined by any one of the following:
- Serum monoclonal protein >= 0.5 g/dl
- Urine monoclonal protein >200 mg/24 hour
- Serum immunoglobulin free light chain >10 mg/dL AND abnormal kappa/lambda serum
free light chain ratio (reference 0.26-1.65)
- Because the primary endpoint is MRD (-) remission rate, per the discretion of the
Principal Investigator, patients without measurable disease in the serum (e.g.,
Mspike <0.5 g/dL) may also be enrolled. This is in line with the most recent IMWG
MM response criteria.
- Age >=18 years.
- ECOG performance status <=2 (Karnofsky >=60%).
- Patients must have adequate organ and marrow function as defined below:
- absolute neutrophil count (ANC) >=1.0 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 >=75 K/uL
- hemoglobin > =8 g/dL, for anemia not due to MM (transfusions are permissible)
- total bilirubin = <1.5 X institutional upper limit of normal
- AST(SGOT)/ALT(SGPT) =<3.0 X institutional upper limit of normal
- creatinine within normal institutional limits, OR
- If creatinine is outside of the normal limits, then creatinine Clearance (CrCl) or
Egfr (estimated glomerular filtration Rate) >=40 ml/min calculated by Cockcroft-Gault
method, modification of diet in renal disease (MDRD), or the chronic kidney disease
(CKD)-epidemiology collaboration (EPI) (institutional standard) equations.
-In addition to having SMM, patients must also be classified as high-risk SMM per at
least one of three criteria below:
- Criteria 1: Mayo Clinic, high-risk defined as:
- Bone marrow plasmacytosis >=10%,
- Serum monoclonal protein >=3 g/dL, AND
- Serum free light chain ratio of >=8 or <=0.125
- Criteria 2: Spanish PETHEMA, high-risk defined as:
- Immunoparesis (depression of one of the uninvolved immunoglobulin isotypes in the
total serum immunoglobulin assay, AND
- >=95% aberrant plasma cells on bone marrow aspirate flow cytometry
- Criteria 3: Rajkumar, Landgren, Mateos may also be used to define high risk disease,
namely clonal bone marrow plasma cells >=10% AND any one or more of the following:
- Serum M protein >=30g/L,
- IgA SMM,
- Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes,
- Serum involved/uninvolved FLC ratio >=8 (but <100),
- Progressive increase in M protein level (evolving type of SMM; increase in serum
M protein by >=25% on 2 successive evaluations within a 6-month period),
- Clonal BMPCs 50%-60%,
- Abnormal PC immunophenotype (>=95% of BMPCs are clonal) and reduction of >=1
uninvolved immunoglobulin isotypes,
- t(4;14) or del(17p) or 1q gain,
- Increased circulating PCs,
- MRI with diffuse abnormalities or 1 focal lesion, AND/OR PET-CT with focal lesion
with increased uptake without underlying osteolytic bone destruction
- The effects of carfilzomib and daratumumab on the developing human fetus are
unknown. For this reason, women of child-bearing potential (WOCBP) and men
must agree to use adequate contraception (hormonal or barrier method of
birth control; abstinence) prior to study entry and for 3 months after
daratumumab and/or 6 months after the last dose of carfilzomib, whichever is
longer. Males with female partners of reproductive potential must use
adequate contraception during treatment and for 3 months after stopping
daratumumab and/or carfilzomib. 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.
- Negative serum or urine pregnancy test at screening for WOCBP.
- 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.
- Prior therapy for SMM. At the discretion of the investigator, exceptions might be made
depending on prior treatments received and response to those treatments, provided that
by the start of protocol therapy, there will be a 4-week washout period. Exceptions
will not be made for patients who have received the current DKd with daratumumab
maintenance regimen nor any other regimen consisting of daratumumab and a proteasome
inhibitor (e.g., bortezomib, ixazomib). Treatment with corticosteroids for other
indications is permitted.
- Contraindication to any concomitant medication, including support/prophylaxis for
infusion reaction, antiviral, antibacterial, anticoagulation or tumor lysis given
prior to therapy.
- Patient has either of the following:
--Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume
in 1 second (FEV1) <50% of predicted normal. NOTE: FEV1 testing is required for
patients suspected of having COPD and subjects must be excluded if FEV1 is <50% of
predicted normal.
---Known moderate or severe persistent asthma within the past 2 years, or uncontrolled
asthma of any classification. NOTE: Subjects who currently have controlled
intermittent asthma or controlled mild persistent asthma are allowed to participate in
the study.
- Seropositive for human immunodeficiency virus (HIV). HIV-infected patients on
effective anti-retroviral therapy with undetectable viral load for at least the 3
months prior to enrollment are eligible for this trial.
- Active hepatitis B infection. NOTE: Patients who are hepatitis B surface antigen
(HbcsAg) or hepatitis B core antibody (HbcAb) positive will need to have a negative
HBV PCR result before enrollment. Those with a positive PCR for hepatitis B are
excluded.
- Seropositive for hepatitis C (except in the setting of a sustained virologic response
[SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).
- Peripheral neuropathy of any cause that is Grade 2 or higher
- History of inflammatory bowel disease
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to carfilzomib or daratumumab or other agents used in study.
- Current uncontrolled hypertension (chronic systolic blood pressures >160 mm Hg) or
diabetes (chronic clinical signs/symptoms of hyperglycemia and/or an A1c value >9%).
- 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.
- No studies of carfilzomib or daratumumab 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, breastfeeding should be discontinued if the mother is treated with
carfilzomib/daratumumab.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, unstable angina pectoris, cardiac arrhythmia, venous thromboembolic
disease, hemorrhage, pulmonary fibrosis, pneumonitis, or psychiatric illness/social
situations that would limit compliance with study requirements.
