Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for the Treatment of Newly Diagnosed Multiple Myeloma in Elderly Patients
- Newly diagnosed, untreated, symptomatic multiple myeloma (MM) as defined by standard criteria: * Clonal bone marrow plasma cells >= 10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma-defining events: ** Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: *** Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper limit of normal or > 2.75 mmol/L (>= 11 mg/dL) and/or *** Renal insufficiency: creatinine clearance < 40 mL per min or serum creatinine > 177 umol/L (> 2 mg/dL) and/or, *** Anemia: hemoglobin value of > 20 g/L (> 2 g/100 mL)below the lower limit of normal, or a hemoglobin value < 100 g/L (10 g/100 mL) and/or, *** Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT (if bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement) Any one or more of the following biomarkers of malignancy: ** Clonal bone marrow plasma cell percentage* >= 60% or ** Serum free light chain (FLC) ratio greater than or equal to 100 provided involved FLC level is 100 mg/L or higher, or ** More than one focal lesion on magnetic resonance imaging (MRI)** * Clonality should be established by showing kappa/lambda-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used. ** Each focal lesion must be 5 mm or more in size
- Age >= 70 and ineligible for autologous hematopoietic stem cell transplantation (defined as age, >= 80 or age < 80 with cardiac/pulmonary/ or other comorbidities deemed by investigator likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation). Frailty will also be assessed by the IMWG frailty score, but scores will not be used as part of the inclusion criteria
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Patients must have measurable disease defined by at least 1 of the following 3 measurements: * Serum M-protein >= 1 g/dL (10 g/L) or >= 0.5 g/dL if IgA * Urine M-protein >= 200 mg/24 hours * Serum free light chain assay: involved free light chain level > 10 mg/dL (> 100 mg/L) provided the serum free light chain ratio is abnormal
- Due to the teratogenicity of lenalidomide and the lack of adequate reproductive toxicity data for daratumumab, if a male subject is sexually active with a woman of child bearing potential, in addition to the user independent highly effective method of contraception, a male or female condom with or without spermicide, diaphragm, or cervical cap is required. Male condom and female condom should not be used together (due to risk of failure with friction)
- During the study (including during dose interruptions), and for 4 weeks following discontinuation of lenalidomide, and if receiving daratumumab, for 3 months after the last dose, in addition to the user independent highly effective method of contraception (even if he has undergone a successful vasectomy), a man * Who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception (i.e., latex or synthetic condom with spermicidal foam/gel/film/cream/suppository) * Who is sexually active with a woman who is pregnant must use a latex or synthetic condom * Must agree not to donate sperm
- Willing and able to adhere to the prohibitions and restrictions specified in this protocol and referenced in the informed consent form (ICF)
- Must sign an ICF (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study
- Peripheral neuropathy grade 2 or >= grade 1 with pain on clinical examination during the screening period
- Kidney failure with creatinine clearance (CrCl) =< 15 mL/min by Cockcroft-Gault
- Significant cardiac disease as determined by the investigator including: * Known or suspected cardiac amyloidosis * Congestive heart failure of class III or IV of the New York Heart Association (NYHA) classification * Uncontrolled angina, hypertension or arrhythmia * Myocardial infarction in the past 6 months * Any uncontrolled or severe cardiovascular disease * Corrected QT interval (QTc) > 470 milliseconds (msec) on a 12-lead electrocardiogram (ECG) obtained during the screening period. If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG or by manual calculation. If QTc on subsequent ECG remains above this value, per PI discretion to determine risk for significant cardiac disease
- Prior cerebrovascular event with persistent neurologic deficit
- Subject is: * 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 viremia at least 12 weeks after completion of antiviral therapy)
- Human immunodeficiency virus infection (HIV screening will be performed as indicated per principal investigator [PI] discretion)
- Any medical conditions that, in the investigator’s opinion, would impose excessive risk to the subject
- Prior or concurrent malignancy, except for the following: * Adequately treated basal cell or squamous cell skin cancer * Cervical carcinoma in situ * Adequately treated stage I or II cancer from which the subject is currently in complete remission * Or any other cancer from which the subject has been disease-free for >= 3 years
- Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing
- Males sexually active with females of childbearing potential who do not agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form (ICF) through 90 days after the last dose of study drug, or do not agree to practice true abstinence
- Central nervous system involvement
- Diagnosis of primary amyloidosis (with the exception of patients whose amyloidosis has been documented as a complication of MM, who will be evaluated on a case-by-case basis for trial participation)
- Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study drug administration
- Known chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal (for subjects > 65 years old FEV1 < 50% or diffusion capacity of the lung for carbon monoxide [DLCO] < 50%). Note: FEV1 testing is required for subjects suspected of having chronic obstructive pulmonary disease and subjects must be excluded if FEV1 < 50% of predicted normal
- Known moderate or severe persistent asthma within the past 2 years or currently has uncontrolled asthma of any classification. Note: Subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study
- Persistent corrected serum calcium >= 14 mg/dL within 2 weeks of enrollment (despite appropriate measure such a short course of steroids, bisphosphonates, hydration, calcitonin)
- Absolute neutrophil count < 1000 cells/mm^3. No growth factors allowed within 1 week of enrollment
- Platelets < 75,000 cell/mm^3 (75 x 10^9/L). Qualifying laboratory value must occur at most recent measurement before enrollment and must be no more than 14 days before enrollment. No transfusions are allowed within 72 hours prior to study drug administration
- Hemoglobin < 8 g/dL. Qualifying laboratory value must occur at most recent measurement before enrollment and must be no more than 14 days before enrollment. No transfusions are allowed within 72 hours before qualifying laboratory value
- Total bilirubin >= 1.5 x upper limit of normal (ULN), unless known have Gilbert’s syndrome in which case 3 x ULN
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >= 3 x ULN
- Major surgery or radiation therapy within 14 days before study drug administration
- Kyphoplasty or vertebroplasty within 1 week of cycle 1 day 1 (C1D1)
- Administration of anti-myeloma chemotherapy, biological, immunotherapy, or investigational agent (therapeutic or diagnostic) within 3 weeks before enrollment; however, a cumulative dose of =< 160 mg dexamethasone or equivalent during screening is permitted
- Non-steroidal anti-inflammatory drugs (NSAIDs), IV contrast, aminoglycosides, or other potentially nephrotoxic drugs within 2 weeks of C1D1, except aspirin
- Known hypersensitivity to bortezomib, lenalidomide, dexamethasone, or daratumumab
I. To evaluate the efficacy of rate of very good partial response (VGPR) or better of subcutaneous daratumumab and hyaluronidase-fihj (daratumumab) in combination with dose-attenuated bortezomib, lenalidomide, and dexamethasone for elderly subjects with newly diagnosed multiple myeloma.
I. To evaluate the efficacy of this regimen using best overall response rate (ORR), including stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), and clinical benefit rate (CBR).
II. To evaluate duration of and time to ORR (>= PR), >= VGPR, >= CR and sCR.
III. To evaluate clinical outcomes including: time to progression (TTP), progression-free survival (PFS), overall survival (OS), and duration of response (DOR).
IV. To evaluate association between clinical outcomes of time to progression (TTP), progression-free survival (PFS), overall survival (OS), and duration of response (DOR) and International Myeloma Working Group (IMWG) frailty score classifications previously developed by Palumbo A. et al: fit (score = 0), intermediate (score = 1), and frail (score >= 2), gait speed, and quality of life Assessment with MyPOS (Myeloma Patient Outcome Scale).
V. To assess the safety and tolerability and tabulate all toxicities of this regimen overall and according to IMWG frailty score classifications previously developed by Palumbo A. et al: fit (score=0), intermediate (score=1), and frail (score >= 2), gait speed, and quality of life assessment with MyPOS (Myeloma Patient Outcome Scale).
I. To identify gene signatures associated with response to therapy.
II. To identify biomarkers that may predict response to therapy.
Patients receive daratumumab and hyaluronidase-fihj subcutaneously (SC) over 3-5 minutes on days 1, 8, 15 and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, and every 28 days of subsequent cycles. Patients also receive lenalidomide orally (PO) on days 1-21, bortezomib SC on days 1, 8 and 15, dexamethasone PO or intravenously (IV) on days 1, 8, 15 and 22. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive daratumumab and hyaluronidase-fihj SC over 3-5 minutes and dexamethasone PO or IV on day 1. Patients also receive lenalidomide PO on days 1-21 or ixazomib PO on days 1, 8 and 15. Treatment repeats every 28 days. All patients will continue maintenance treatment until disease progression or unacceptable toxicity, except daratumumab maintenance will be discontinued after 2 years if subjects remain on maintenance treatment at that time.
After completion of study treatment, patients are followed up at 30 days, every 3 months for up to 1 year.
Trial Phase Phase II
Trial Type Treatment
Icahn School of Medicine at Mount Sinai
- Primary ID 19-0944
- Secondary IDs NCI-2019-07317, 19-01894
- Clinicaltrials.gov ID NCT04052880