Daratumumab, Carfilzomib, Lenalidomide, and Low-dose Dexamethasone in Treating Participants with Newly-diagnosed, Multiple Myeloma
This phase II trial studies how well daratumumab, carfilzomib, lenalidomide, and low-dose dexamethasone work in treating participants with newly-diagnosed multiple myeloma. Daratumumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Anti-inflammatory drugs, such as low-dose dexamethasone lower the body’s immune response and are used with other drugs in the treatment of some types of cancer. Giving daratumumab, carfilzomib, lenalidomide, and low-dose dexamethasone may work better in treating participants with newly-diagnosed multiple myeloma.
Inclusion Criteria
- Newly diagnosed, previously untreated myeloma requiring systemic chemotherapy * Prior treatment of hypercalcemia or spinal cord compression or active and/or aggressively progressing myeloma with corticosteroids or lenalidomide or bortezomib-based regimens does not disqualify the patient (the treatment dose should not exceed the equivalent of 160 mg of dexamethasone in a 4 week period or not more than 1 cycle of proteasome inhibitors and immunomodulatory drug [PI/IMiD] based therapy)
- Both transplant and non-transplant candidates are eligible
- Diagnosis of symptomatic multiple myeloma as per current International Myeloma Working Group (IMWG) uniform criteria prior to initial treatment
- Monoclonal plasma cells in the bone marrow (BM) >= 10% or presence of a biopsy-proven plasmacytoma
- Measurable disease, prior to initial treatment including any emergent treatment of myeloma. Measurable disease will be indicated by one or more of the following: * Serum M-protein >= 1 g/dL * Urine M-protein >= 200 mg/24 hours * If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable * Serum freelite measurable disease as per current IMWG criteria
- Bone marrow specimen will be required at study entry; available deoxyribonucleic acid (DNA) sample from pre-induction BM will be used for calibration step for MRD evaluation by gene sequencing
- Males and females ≥ 18 years of age
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Bilirubin =< 1.5 x upper limit of normal (ULN)
- Aspirate aminotransferase (AST) =< 3 x ULN
- Alanine aminotransferase (ALT) =< 3 x ULN
- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
- Hemoglobin >= 8 g/dL
- Platelet count >= 75 x 10^9/L
- Calculated creatinine clearance (by Cockcroft-Gault) >= 50 mL/min or serum creatinine below 2 g/dL
- Females of child-bearing potential (FCBP) must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to initiating lenalidomide; the first pregnancy test must be performed within 10-14 days before and the second pregnancy test must be performed within 24 hours before lenalidomide is prescribed for cycle 1 (prescriptions must be filled within 7 days)
- FCBP must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study; and 3) for at least 30 days after discontinuation from the study
- Male subjects must agree to use 1 highly-effective method of contraception and 1 effective method of contraception at the same time during sexual contact with females of childbearing potential while participating in the study and for at least 90 days following discontinuation from the study even if he has undergone a successful vasectomy
- All study participants in the US must be consented to and registered into the mandatory Revlimid REMS program and be willing and able to comply with the requirements of Revlimid REMS
- Voluntary written informed consent
Exclusion Criteria
- Frail non-transplant candidates, defined as in Palumbo et al, Blood 2015
- Non-secretory or hyposecretory multiple myeloma, prior to initial treatment defined as < 1.0 g/dL M-protein in serum, < 200 mg/24 hr urine M-protein, and no measurable disease as per IMWG by Freelite
- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
- Amyloidosis
- Plasma cell leukemia
- Waldenstrom’s macroglobulinemia or IgM myeloma
- Radiotherapy to multiple sites or immunotherapy within 4 weeks before start of protocol treatment (localized radiotherapy to a single site at least 1 week before start is permissible)
- Participation in an investigational therapeutic study within 3 weeks or within 5 drug half-lives (t1/2) prior to first dose, whichever time is greater
- Patients not able to tolerate daratumumab, carfilzomib, lenalidomide or dexamethasone
- Peripheral neuropathy >= grade 2 at screening
- Diarrhea > grade 1 in the absence of antidiarrheals
- Central nervous system (CNS) involvement
- Pregnant or lactating females
- Major surgery within 3 weeks prior to first dose
- Myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
- Prior or concurrent pulmonary embolism
- Known moderate or severe persistent asthma or known chronic obstructive pulmonary disease (COPD) * Known or suspected chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal * Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification ** Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study
- Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead electrocardiograph (ECG) during screening
- Uncontrolled hypertension or diabetes
- Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
- Known seropositive for or active viral infection with human immunodeficiency virus (HIV) or hepatitis C virus (HCV)
- Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]); subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction [PCR] measurement of hepatitis B virus [HBV] deoxyribonucleic acid [DNA] levels; those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
- Non-hematologic malignancy or non-myeloma hematologic malignancy within the past 3 years except a) adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix, or prostate cancer < Gleason grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone
- Any clinically significant medical disease or condition that, in the investigator’s opinion, may interfere with protocol adherence or a subject’s ability to give informed consent
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03500445.
PRIMARY OBJECTIVE:
I. To evaluate the rate of stringent complete response (sCR) response as well as the rate of minimal residual negative disease (MRD) by next generation gene sequencing (NGS) at the end of 8 cycles of low dose dexamethasone (D-KRd).
SECONDARY OBJECTIVES:
I. Rate of MRD by next generation gene sequencing (NGS) by clonoSEQ (Adaptive Biotechnologies) at the end of cycle 8 and at the end of cycle 24, and then yearly for as long as no progressive disease (PD), the first 2 years is required by study and optional thereafter per standard of care (SOC).
II. Duration of response (DOR), progression free survival (PFS), time to progression (TTP), and overall survival (OS).
III. Overall response rate defined as partial response or better (> partial response [PR]) including the rate of very good partial response (VGPR) or better (> VGPR) and near complete response or better (sCR/complete response [CR]/near complete response [nCR]) across entire treatment in high risk and low risk patients at indicated time points and as best response.
IV. Safety and tolerability of combination of D-KRd.
EXPLORATORY OBJECTIVE:
I. To conduct gene expression profiling (GEP), proteomics, ribonucleic acid sequencing (RNASeq), and gene sequencing studies on pre-treatment patient samples to evaluate the correlation between treatment outcome and pre-treatment patient profile.
OUTLINE:
INDUCTION: Participants receive lenalidomide orally (PO) once daily (QD) on days 1-21, dexamethasone intravenously (IV) or PO QD on days 1, 8, 15, and 22, carfilzomib IV on days 1, 2, 8, 9, 15, and 16, and daratumumab subcutaneously (SC) on days 1, 8, and 15 of courses 1 and 2 and days 1 and 15 of course 3 and 4. Courses repeat every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION: Beginning 3 months after stem cell transplant, participants receive lenalidomide PO QD on days 1-21, dexamethasone IV or PO QD on days 1, 8, 15, and 22, carfilzomib IV on days 1, 2, 8, 9, 15, and 16, and daratumumab SC on days 1 and 15. Courses repeat every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Participants receive lenalidomide PO QD on days 1-21, dexamethasone IV or PO QD on days 1, 8, 15, and 22, carfilzomib IV on days 1, 2, 15, and 16, and daratumumab SC on day 1. Courses repeat every 28 days for up to 16 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up at 30 days and then every 3 months.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Chicago Comprehensive Cancer Center
Principal InvestigatorBenjamin A Derman
- Primary IDIRB17-1097
- Secondary IDsNCI-2018-00626
- ClinicalTrials.gov IDNCT03500445