Daratumumab, Lenalidomide, Dexamethasone and Bortezomib for the Treatment of Patients with Newly Diagnosed Multiple Myeloma
This phase II trial tests how well daratumumab, lenalidomide, bortezomib and dexamethasone work in treating patients with newly diagnosed multiple myeloma who are minimal residual disease (MRD) positive after initial treatment. 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 and bortezomib, work in different ways to stop the growth of tumor 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. Giving daratumumab, lenalidomide, bortezomib, and dexamethasone together may work better compared to lenalidomide, bortezomib, and dexamethasone alone in treating patients with multiple myeloma.
Inclusion Criteria
- Participants >= 18 years of age or of legal age of consent per local regulations (whichever is greater)
- Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care
- Eastern Cooperative Oncology Group (ECOG) status of =< 2 and able to tolerate all applicable treatments per investigator’s evaluation and standard institutional criteria
- Both transplant eligible and ineligible myeloma patients can be included in this study. If applicable, participant should be able to tolerate all treatments per investigator’s evaluation, including high dose chemotherapy and autologous stem cell transplant (ASCT) based on standard criteria at the institution where this treatment will be administered
- Participant must have a diagnosis of active MM according to International Myeloma Working Group (IMWG) diagnostic criteria, which require the following findings: * Clonal bone marrow plasma cells >= 10% or biopsy proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events (end organ damage that can be attributed to the underlying multiple myeloma): ** Hypercalcemia: serum calcium > 1 mg/dL higher than the upper limit of normal or serum calcium > 11 mg/dL ** Renal insufficiency: serum creatinine > 2 mg/dL or creatinine clearance < 40 mL/min ** Anemia: hemoglobin >= 2 g/dL below the lower limit of normal or hemoglobin < 10 g/dL ** Bone lesions: one or more osteolytic lesions on imaging studies ** One or more of the following biomarkers of malignancy: *** Clonal bone marrow plasma cell >= 60% *** Involved: uninvolved serum free light chain (FLC) ratio >= 100 *** > 1 focal lesion on MRI or PET/CT studies
- Participant must also have measurable disease as defined by at least one of the following: * Serum M protein >= 1 g/dL (except patients with IgD or IgA myeloma). For patients with IgD or IgA myeloma, a serum M-protein >= 0.5 g/dl will suffice, or * Urinary Bence-Jones protein >= 200 mg per 24 hours, or * Serum involved FLC >= 10 mg/dL with an abnormal FLC ratio
- Baseline bone marrow or tissue sample available for Clonality ID in ClonoSEQ
- Participant must be registered in and must comply with all requirements of Risk Evaluation and Mitigation Strategies (REMS) program for lenalidomide
- Female participant who: * Is post-menopausal for at least one year prior to study enrollment, OR * Is surgically sterile, OR * If of childbearing potential, must have a negative urine or serum pregnancy test with 10-14 days prior to and again within 24 hours of starting lenalidomide. They must also be willing to use TWO effective forms of contraception simultaneously from the time of signing the study consent until 90 days following the administration of the last dose of lenalidomide and 7 months following the administration of the last dose of bortezomib, OR * Agree to practice complete abstinence if that is aligned with their lifestyle, which does not include periodic abstinence or withdrawal
- Male participant, even if surgically sterilized, must agree to one of the following: * Agree to practice effective barrier contraception during the entire study treatment period and through 90 days following the last dose of lenalidomide and 4 months following the administration of the last dose of bortezomib, OR * Agree to practice complete abstinence if that is aligned with their lifestyle, which does not include periodic abstinence or withdrawal
Exclusion Criteria
- Diagnoses of smoldering MM (SMM), monoclonal gammopathy of undetermined significance (MGUS), non-secretory MM, plasma cell leukemia, amyloid light-chain (AL) amyloidosis, Waldenstrom’s macroglobulinemia, or polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. History of SMM and/or MGUS is not excluded
- Known disease involvement of the central nervous system (CNS)
- History of prior hematopoietic stem cell transplant or organ transplant of any type
- Received more than one cycle of anti-myeloma therapy prior to enrollment. Up to one cycle of myeloma therapy is allowed. Concomitant treatment is allowed with low dose corticosteroids and bisphosphonates. The dose of corticosteroids for myeloma treatment should not exceed the equivalent of 160 mg of dexamethasone over a two-week period before initiation of protocol. Prednisone up to but no more than 10 mg po daily or its equivalent is allowed, for symptom management and comorbid conditions
- Significant renal insufficiency, defined as creatinine clearance < 30 ml/min per Cockcroft-Gault formula
- Hepatic impairment, defined as bilirubin > 1.5 x institutional upper limit of normal (ULN) or
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]), or alkaline phosphatase > 3 x institutional ULN
- Growth factor may not be used to meet absolute neutrophil count (ANC) eligibility criteria. Absolute neutrophil count (ANC) < 1000 cells/mm^3 within 7 days of enrollment
- Hemoglobin (Hgb) < 8 g/dL within 7 days of enrollment
- Platelet count < 75,000 cells/mm^3 within 7 days of enrollment. Transfusion may not be used to meet platelet eligibility criteria
- Any condition, including laboratory abnormalities, that in the opinion of the investigator places the subject at unacceptable risk if subject were to participate in the study
- Major surgery =< 2 weeks prior to starting study drug or who have not recovered from complications of the surgery
- Clinically significant uncontrolled peripheral neuropathy, defined as symptoms limiting activities of daily living (basic ADLs)
- Symptomatic uncontrolled cardiac disease including congestive heart failure with New York Heart Association class III-IV symptoms, arrhythmia, unstable angina or myocardial infarction within the past six months, or any other uncontrolled or severe cardiovascular condition
- Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal
- Clinically uncontrolled asthma of any classification or known moderate or severe persistent asthma within the past two years
- Serious intercurrent illness including but not limited to clinically relevant cerebrovascular disease, uncontrolled diabetes mellitus, cirrhosis, pulmonary disease
- Active autoimmune process or other disease requiring systemic immunosuppressive, monoclonal antibody, small molecule, or radiation therapy. However, local radiation for myeloma related symptomatic treatment is allowed
- Participant 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 ** Participants 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)
- History of additional active malignancy in the past five years (not including squamous cell or basal cell carcinoma of the skin or in situ cervical cancer). However, malignancy treated with curative intent with < 5% chance of disease relapse / recurrence in the next two years is allowed
- Known drug contraindication to study required medications (including steroids) or appropriate prophylactic medications (e.g. acyclovir, aspirin, warfarin or low molecular weight heparin)
- Women with a positive pregnancy test during the screening period prior to study initiation or who are lactating
- Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial
- Any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given
- Participants using strong CYP3A4 inducers are excluded unless the inducer can be switched to an alternative agent while receiving Bortezomib
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04140162.
PRIMARY OBJECTIVE:
I. To determine the rate of MRD negativity after daratumumab-based induction and consolidation therapy if necessary in both transplant eligible and ineligible newly diagnosed multiple myeloma (MM) patients.
SECONDARY OBJECTIVES:
I. To describe the overall survival (OS) of patients who received daratumumab-based combination regimen.
II. To describe the progression free survival (PFS) of patients who received daratumumab-based combination regimen.
III. To describe the rate of MRD conversion after consolidation in patients who were MRD positive after initial induction.
IV. To describe duration of sustained MRD negativity at time points of post-induction, post-consolidation, and post-1 year maintenance.
V. To determine the quality of life of patients enrolled on the study as reflected in patient reported outcomes.
VI. To evaluate the safety and tolerability of daratumumab-based combination regimens in both transplant eligible and ineligible patient populations.
VII. To estimate the proportion of patients with a successful stem cell mobilization after receiving daratumumab-based induction therapy.
EXPLORATORY OBJECTIVES:
I. To correlate bone marrow MRD status with imaging MRD results.
II. To correlate MRD status change with changes in immune phenotypes throughout treatment stages.
III. To describe MRD results and clinical outcome in patients with high risk cytogenetic features (including del17p), focusing on the persistent MRD status in the presence of baseline high risk cytogenetics by fluorescence in situ hybridization (FISH).
OUTLINE:
INDUCTION REGIMEN: Patients receive daratumumab intravenously (IV) or subcutaneously (SC) on days 1, 8, 15 and 22 of cycles 1-2 and days 1 and 15 of cycles 3-6, lenalidomide orally (PO) once daily (QD) on days 1-21, and dexamethasone PO or IV weekly. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve at least partial response (PR) may continue to receive treatment for up to 3 additional cycles. Patients who achieve less than PR receive consolidation regimen. Patients who do not achieve complete response (CR) or very good partial response (VGPR) after 6 cycles or those with CR or VGPR after 6 cycles who are MRD positive (+) receive consolidation regimen. Patients with CR or VGPR after 6 cycles who are MRD negative (-) receive maintenance regimen.
CONSOLIDATION REGIMEN: Patients receive daratumumab IV or SC on day 1, lenalidomide PO QD on days 1-21, dexamethasone PO or IV weekly and bortezomib SC on days 1, 8,15 and 22. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients who do not achieve CR or VGPR or those who achieve CR or VGPR and are MRD+ undergo stem cell transplantation followed by maintenance regimen. Patients with CR or VGPR and are MRD- or those who are MRD+ and did not undergo stem cell transplantation receive maintenance regimen.
MAINTENANCE REGIMEN: Patients receive daratumumab IV or SC on day 1 every 8 weeks and lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. After 13 cycles, patients then receive lenalidomide PO QD on days 1-21 in the absence of disease progression or unacceptable toxicity.
Patients also undergo echocardiography (ECHO) at screening and undergo bone marrow aspiration/bone marrow biopsy, collection of blood samples, and positron emission tomography (PET)/computed tomography (CT) or magnetic resonance imaging (MRI) during screening and on study.
After completion of study treatment, patients are followed up every 3 months for up to 3 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Michigan Rogel Cancer Center
Principal InvestigatorErica Leigh Campagnaro
- Primary IDUMCC 2018.056
- Secondary IDsNCI-2019-05319
- ClinicalTrials.gov IDNCT04140162