Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone for the Treatment of Newly Diagnosed Multiple Myeloma
- Newly diagnosed patients with histologically confirmed multiple myeloma (MM) based on the following criteria: * Clonal plasma cells in the bone marrow * Measurable disease within the past 4 weeks defined by any one of the following: * Serum monoclonal protein >= 1.0 g/dL * Urine monoclonal protein >= 200 mg/24 hour * Involved serum immunoglobulin free light chain >= 10 mg/dL AND abnormal kappa/lambda ratio
- Evidence of underlying end organ damage and/or myeloma defining event attributed to underlying plasma cell proliferative disorder meeting at least one of the following (Note: Myeloma defining event does not need to be based on repeat testing done at screening, if previous pathology, radiology etc. confirm diagnosis of myeloma per International Myeloma Working Group [IMWG]): * Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) above upper limit of normal or >= 2.75 mmol/L (11 mg/dL) * Anemia: hemoglobin value < 10 g/dL or > 2 g/dL below lower limit of normal * Bone disease: >= 1 lytic lesions on skeletal X-ray, computed tomography (CT), or positron emission tomography (PET)-CT. For patients with 1 lytic lesion, bone marrow should demonstrate >= 10% clonal plasma cells * Clonal bone marrow plasma cell percentage >= 60% * Involved/un-involved serum free light chain ratio >= 100 and involved free light chain >= 100 mg/L * > 1 focal lesion on magnetic resonance imaging study (lesion must be > 5 mm) in size * For patients with 1 lytic lesion, bone marrow should demonstrate >= 10% clonal plasma cells
- Creatinine clearance >= 60 ml/min. Creatinine clearance (CrCl) can be measured or estimated using Cockcroft-Gault method, Modification of Diet in Renal Disease (MDRD), or Chronic Kidney Disease (CKD)-Epidemiology (EPI) formulae
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Absolute neutrophil count (ANC) >= 1.0 K/uL, unless if cytopenias are deemed to be due disease at discretion of clinical investigator. Transfusions and growth factors are permissible
- Hemoglobin >= 8 g/dL, unless if cytopenias are deemed to be due disease at discretion of clinical investigator. Transfusions and growth factors are permissible
- Platelet count >= 75 K/uL, unless if cytopenias are deemed to be due disease at discretion of clinical investigator. Transfusions and growth factors are permissible
- Bilirubin < 1.5 x the upper limit of normal (ULN)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN
- All study participants must be able to tolerate one of the following thromboprophylactic strategies: aspirin, low molecular weight heparin or warfarin (Coumadin) or alternative anti-coagulant
- All study participants must be registered into the mandatory electronic Risk Evaluation and Mitigation Strategy (eREMS) program and be willing and able to comply with the requirements of REMS
- 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 * A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
- Patients receiving > 1 cycle of prior treatment or concurrent systemic treatment for multiple myeloma: * Treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with current or prior corticosteroids is permitted * Bone targeting agents are permitted * Concurrent or prior treatment with corticosteroids for indications other than multiple myeloma is permitted * Prior treatment with radiotherapy is permitted * Prior MM treatments, such as immunomodulatory imide drugs (IMIDs) or non-MM drugs in clinical trials for smoldering myeloma is permitted with a washout period of 2 weeks from last dose. Smoldering patients previously treated with carfilzomib are excluded * Patients with measurable disease who received up to one cycle of any therapy within 60 days with a washout period of 2 weeks from last dose (on a trial or outside a trial) are eligible (Note: Measurable disease is defined as one or more of the following: Serum monoclonal protein >= 1.0 g/dL, urine monoclonal protein >= 200 mg/24 hour and/ or involved serum immunoglobulin free light chain >= 10 mg/dL AND abnormal kappa/lambda ratio)
- Plasma cell leukemia
- Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome
- Has known chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal (note that FEV1 testing is required for subjects suspected of having chronic obstructive pulmonary disease and subjects must be excluded if FEV1 < 50% of predicted normal)
- Pregnant or lactating females. Because there is a potential risk for adverse events nursing infants secondary to treatment of the mother with carfilzomib in combination with lenalidomide. These potential risks may also apply to other agents used in this study
- Uncontrolled hypertension (i.e. systolic blood pressure [BP] > 160 mmHg, diastolic BP > 100 mmHg) or diabetes
- Active hepatitis B or C infection
- Subject is: * Seropositive for human immunodeficiency virus (HIV) * 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 * 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)
- Significant cardiovascular disease with New York Heart Association (NYHA) class III or IV symptoms, symptomatic ischemia, current uncontrolled arrhythmias, screening electrocardiogram (ECG) with corrected QT interval (QTc) of > 470 msec, pericardial disease, or myocardial infarction within 4 months prior to randomization and left ventricular ejection fraction (EF) =< 40% assessed by transthoracic echocardiogram (ECHO), current unstable angina as determined by history and physical exam, hypertrophic cardiomyopathy or restrictive cardiomyopathy
- Pulmonary hypertension
- Has refractory gastrointestinal (GI) disease with refractory nausea/vomiting, inflammatory bowel disease, or bowel resection that would prevent absorption of oral agents
- Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance with study requirements
- Significant neuropathy >= grade 3 or grade 2 neuropathy with pain at baseline
- Contraindication to any concomitant medication, including antivirals or anticoagulation
- Major surgery within 3 weeks prior to first dose
I. To compare the rates of minimal residual disease (MRD) negativity for patients who receive bortezomib, lenalidomide, dexamethasone (VRD) (Arm A) to patients who receive carfilzomib, lenalidomide, and dexamethasone (KRD) (Arm B) and for patients who receive VRD (Arm A) to patients who received KRD + daratumumab (DARA) (Arm C).
I. To compare overall survival, progression-free survival, and event-free survival in patients achieving partial response (PR) or less within the first 4 cycles of therapy, across the treatment arms (Arm A versus [vs] Arm B, Arm A vs Arm C).
II. To compare the rates of PR or better, very good partial response (VGPR) or better, complete response (CR) and stringent complete response (sCR) across the treatment arms (Arm A vs Arm B, Arm A vs Arm C).
III. To compare the rate of MRD-negativity as a best response after the completion of eight cycles of therapy across the treatment arms (Arm A vs Arm B, Arm A vs Arm C).
IV. To compare the safety and tolerability of the three treatment arms.
V. To compare MRD assessments in bone marrow versus blood with different techniques.
I. To explore clinical outcomes by cytogenetic risk groups.
II. With the myTYPE gene panel, explore whether any mutations appear to be associated with response to therapy or toxicity.
III. With the myTYPE gene panel, evaluate the samples collected at the time of disease progression or during an ongoing response and compare them to the pre-treatment baseline samples to explore whether pathways leading to emergence of resistance to the drug regimen can be identified.
IV. To obtain and store biosamples for future testing, and store leftover samples for future studies of potential biomarkers of prognosis and outcome.
V. To explore associations of symptom burden of lenalidomide-related diarrhea (including, but not limited to, grade and duration of diarrhea) and the potential role of the gut microbiota in the pathoetiology of lenalidomide-related diarrhea (Memorial Sloan Kettering [MSK] patients only).
OUTLINE: Patients are randomized to 1 of 3 arms.
ARM A (VRD): Patients receive bortezomib subcutaneously (SC) or intravenously (IV) on days 1, 4, 8, and 11, dexamethasone orally (PO) or IV on days 1, 4, 8, and 11, and lenalidomide PO on days 1-14. Treatment repeats every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
ARM B (KRD): Patients receive carfilzomib IV over 30 minutes on days 1, 8, and 15, dexamethasone PO or IV on days 1, 8, and 15, and lenalidomide PO on days 1-21. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
ARM C (KRD+DARA): Patients receive daratumumab IV on days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6 and day 1 of subsequent cycles. Patients also receive carfilzomib IV over 30 minutes on days 2, 8, and 15 of cycle 1, and days 1, 8, and 15 of subsequent cycles, dexamethasone PO or IV on days 1, 2, 8, 15 and 22 of cycle 1, days 1, 8, 15, and 22 of cycle 2 and days 1, 8, and 15 of subsequent cycles, and lenalidomide PO on days 2-21 of cycle 1 and days 1-21 of subsequent cycles. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Response assessment is measured after 4 cycles of therapy. Patients with progressive disease receive no additional study treatment.
In all arms, patients who are MRD positive and do not have progressive disease after 4 cycles of therapy, undergo autologous stem cell transplantation (ASCT) after 8 cycles of treatment, then receive lenalidomide for 2 years, and patients who are MRD negative receive lenalidomide for 2 years in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up until the end of maintenance therapy for a total of 3 years.
Trial Phase Phase II
Trial Type Treatment
Memorial Sloan Kettering Cancer Center
Neha S. Korde
- Primary ID 19-339
- Secondary IDs NCI-2020-01093
- Clinicaltrials.gov ID NCT04268498