Carfilzomib or Bortezomib with Lenalidomide and Dexamethasone in Treating Patients with Newly Diagnosed Multiple Myeloma, COBRA Study
This phase III trial studies how well carfilzomib, lenalidomide, and dexamethasone work compared to bortezomib, lenalidomide, and dexamethasone in treating patients with newly diagnosed multiple myeloma. Drugs used in chemotherapy, such as carfilzomib, lenalidomide, and bortezomib, 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 dexamethasone lower the body’s immune response and are used with other drugs in the treatment of some types of cancer. The purpose of this trial is to compare two different drug regimens to determine if one works better at preventing worsening of disease in patients with multiple myeloma.
Inclusion Criteria
- Newly diagnosed, previously untreated myeloma requiring systemic chemotherapy per International Myeloma Working Group (IMWG) criteria: * Patients must have received no prior chemotherapy for this disease * Patients must have received no prior radiotherapy to a large area of the pelvis (more than half of the pelvis) * Prior steroid treatment is allowed provided treatment was not more than 2 weeks in duration and =< 160 mg dexamethasone * Patients must not have received any prior treatment with bortezomib or lenalidomide
- Both transplant and non-transplant candidates are eligible. Transplant candidates must agree at the time of consent to defer transplant to the end of study treatment. Patients who are non-transplant eligible due to frailty may not be enrolled. If patient proceeds to transplant, they will come off study
- Diagnosis of symptomatic multiple myeloma as per current IMWG uniform criteria prior to initial treatment
- Monoclonal plasma cells in the bone marrow (BM) 10% or presence of a biopsy-proven plasmacytoma
- Serum M-protein >= 1 g/dL
- Urine M-protein >= 200 mg/24 hours
- Involved serum free light chains >= 10 mg/dL provided that free light chain ratio is abnormal
- If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable
- 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 0-2
- Bilirubin =< 1.5 x upper limit of normal (ULN)
- Aspirate aminotransferase (AST) and 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
- Female of child birth 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 a latex condom 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 United States (US) and the European Union (EU) countries (excluding Poland) must be consented to and registered into the mandatory Revlimid Risk Evaluation and Mitigation (REMS) program and be willing and able to comply with the requirements of Revlimid REMS
- Subjects must comply with pregnancy prevention and counseling
- Voluntary written informed consent
Exclusion Criteria
- Frail, non-transplant candidates, per modified IMWG frailty score (age not counted as a scoring factor)
- 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 free light chain (FLC) < 10 mg/dL as per IMWG measured 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 bortezomib, carfilzomib, lenalidomide or dexamethasone
- Peripheral neuropathy >= grade 2 at screening
- Diarrhea > grade 1 in the absence of antidiarrheals
- Central nervous system (CNS) involvement
- Patients who cannot undergo or unwilling to take thromoprophylaxis
- Uncontrolled or symptomatic angina, arrhythmia, hypertension, chronic heart failure (CHF), ejection fraction (EF) < 40%, within 6 months prior to first dose
- 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
- Pulmonary embolism within 6 months prior to first dose
- Known moderate or severe persistent asthma or known chronic obstructive pulmonary disease (COPD)
- Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead electrocardiography (ECG) during screening
- Uncontrolled 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), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine or are asymptomatic HBV carriers are eligible
- 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 NCT03729804.
PRIMARY OBJECTIVE:
I. To compare the minimal residual disease (MRD) at 12 months after randomization and progression free survival (PFS).
SECONDARY OBJECTIVES:
I. To determine the status of MRD-negative disease at 8 and 24 months from randomization between the KRd and VRd arms.
II. To evaluate the duration of MRD-negative status between the two arms.
III. To compare the MRD-negative complete response status as best response between the two arms.
IV. To evaluate the efficacy (rate – overall response rate [ORR] – and sustainability – duration of response [DOR] – of partial response [PR], very good partial response [VGPR], complete response [CR], and stringent complete response [sCR]) across entire treatment in high risk and low risk patients and as best response of KRd versus (vs.) VRd after randomization.
V. Determine rates of improvement of the depth of response by at least one category according to International Myeloma Working Group (IMWG) response criteria.
VII. To compare overall survival.
VIII. To evaluate the safety and tolerability of KRd vs. VRd.
EXPLORATORY OBJECTIVES:
I. To evaluate the correlation between treatment outcome, using KRd or VRd, and pre-treatment profile using gene expression profiling (GEP), proteomics, ribonucleic acid sequencing (RNASeq), and gene sequencing.
II. To compare the MRD-negative disease status at 36, 48 and 60 months after randomization between the KRd and VRd arms.
III. To compare treatment response as assessed by mass spectrometry-based quantification of M-protein with response defined by conventional methods (IMWG criteria), using available baseline and serial follow-up serum samples.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I (KRd): Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21, carfilzomib intravenously (IV) over 30 minutes on days 1, 8, and 15 of cycles 1-12 and on days 1 and 15 of cycles 13-24, and dexamethasone PO or IV on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. After completion of 24 cycles, patients may continue with maintenance therapy and receive lenalidomide PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo buccal swab during screening and positron emission tomography (PET)/computed tomography (CT), bone marrow biopsy and aspiration, as well as blood sample collection throughout the study.
ARM II (VRd): Patients receive bortezomib subcutaneously (SC) on days 1, 4, 8, and 11 of cycles 1-8, dexamethasone PO or IV on days 1, 2, 4, 5, 8, 9, 11, and 12 of cycles 1-8 and on days 1, 8, 15, and 22 of cycles 9-26, and lenalidomide PO QD on days 1-14 of cycles 1-8 and on days 1-21 of cycles 9-26. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. After completion of 8 cycles of VRD and 18 cycles of lenalidomide and dexamethasone (Rd), patients may continue with maintenance therapy and receive lenalidomide PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo buccal swab during screening and PET/CT, bone marrow biopsy and aspiration, as well as blood sample collection throughout the study.
After completion of study treatment, patients are followed up for 30 days and until 26 months after the last accrued patient.
Trial PhasePhase III
Trial Typetreatment
Lead OrganizationUniversity of Chicago Comprehensive Cancer Center
Principal InvestigatorAndrzej J. Jakubowiak
- Primary IDIRB18-1243
- Secondary IDsNCI-2019-03373
- ClinicalTrials.gov IDNCT03729804