A Phase 2 Study of Subcutaneous Daratumumab in Combination With Dose-Attenuated Bortezomib, Lenalidomide, and Dexamethasone in Elderly Newly Diagnosed Multiple Myeloma Patients
A Phase 2 Study of Subcutaneous Daratumumab in Combination With Dose-Attenuated Bortezomib, Lenalidomide, and Dexamethasone in Elderly Newly Diagnosed Multiple Myeloma Patients
This is a single center, open-label, phase 2 study in elderly (age ≥ 70) subjects with newly diagnosed multiple myeloma who are transplant ineligible. Subjects will receive subcutaneous daratumumab, dose-attenuated bortezomib, revlimid, and dexamethasone until confirmed disease progression, discontinuation of study treatment due to unacceptable drug toxicity, or other reasons. Throughout the study, subjects will be monitored closely for adverse events, laboratory abnormalities, and clinical response.
This is a single center, open-label, phase 2 study in elderly (age ≥ 70) subjects with newly diagnosed multiple myeloma who are transplant ineligible. The main study consists of the following phases: a 28-day screening phase; followed by initial therapy with 12 cycles of daratumumab in combination with dose-attenuated VRd; and a maintenance phase that starts after Cycle 12 of therapy. Cycles are 28 days in length. Treatment can continue until disease progression or unacceptable toxicity. After 12 cycles of initial therapy, maintenance therapy will begin with 28 day cycles of daratumumab with either lenalidomide or ixazomib and the choice of maintenance therapy will be based on cytogenetic risk status at diagnosis. All subjects will continue maintenance treatment until disease progression, except maintenance daratumumab will be discontinued after 2 years if subjects remain on maintenance treatment at that time. All subjects will be followed in the longterm follow-up for at least 1 year after last dose of study treatment and will continue until death, withdrawal of consent for study participation, or the end of study definition is met. The end of study is defined as when all subjects have completed at least 1 year of long-term follow up and until death, withdrawal of consent for study participation, or 5 years after first patient begins daratumumab therapy, whichever occurs first.
Inclusion Criteria:
Newly diagnosed, untreated, symptomatic 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 (> 1mg/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 µmol/L (>2 mg/dL) and/or,
Anemia: hemoglobin value of >20 g/L (>2g/100 mL)below the lower limit of normal, or a hemoglobin value <100 g/L (10g/100 mL) and/or,
Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or 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:
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).
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
Patients must have measurable disease defined by at least 1 of the following 3 measurements:
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:
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.
Exclusion Criteria:
Peripheral neuropathy > Grade 2 or >Grade 1 with pain on clinical examination during the Screening period.
Kidney failure with CrCl ≤ 15 mL/min by Cockfraft Gault
Significant cardiac disease as determined by the investigator including:
Prior cerebrovascular event with persistent neurologic deficit.
Subject is:
Human immunodeficiency virus infection
Any medical conditions that, in the investigator's opinion, would impose excessive risk to the subject.
Prior or concurrent malignancy, except for the following:
Known 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 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/mm3. No growth factors allowed within 1 week of enrollment.
Platelets < 75,000 cell/mm3 (75 x 109/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 ULN, unless known have Gilbert's syndrome in which case 3 x ULN).
AST or ALT ≥ 3 x ULN.
Major surgery or radiation therapy within 14 days before study drug administration.
Kyphoplasty or vertebroplasty within 1 week of enrollment.
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.
NSAIDs, IV contrast, aminoglycosides, or other potentially nephrotoxic drugs within 2 weeks of enrollment, except aspirin.
Known hypersensitivity to bortezomib, lenalidomide, dexamethasone, or daratumumab