This phase III trial compares the effect of adding a stem cell transplant with melphalan after completing chemotherapy with daratumumab, cyclophosphamide, bortezomib and dexamethasone (Dara-VCD) versus chemotherapy with Dara-VCD alone for treating patients with newly diagnosed amyloid light chain (AL) amyloidosis. Melphalan is a chemotherapy given prior to a stem cell transplant. Giving chemotherapy before a peripheral blood stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. The stem cells are then returned to the patients to replace the blood forming cells that were destroyed by the chemotherapy. Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Chemotherapy drugs, such as cyclophosphamide 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. Dexamethasone is in a class of medications called corticosteroids. It is used to lower the body's immune response to help stop the growth of cancer cells. Giving a stem cell transplant with melphalan after Dara-VCD may kill more cancer cells in patients with newly diagnosed AL amyloidosis.
STEP 1: Participants must have systemic AL amyloidosis which is biopsy proven and includes histologically-confirmed by positive Congo red stain with green birefringence on polarized light microscopy, OR characteristic appearance by electron microscopy AND confirmatory AL amyloid typing (mass spectrometry-based proteomic analysis or immunofluorescence). If there is question regarding diagnosis, consult study chairs prior to registration
Positive monoclonal serum immunofixation electrophoresis
Positive monoclonal urine immunofixation electrophoresis
Monoclonal plasma cells in bone marrow In addition, participants must also have a difference between the involved and uninvolved free light chain (dFLC) >= 2 mg/dL
None
Sequential
Autologous Hematopoietic Stem Cell Transplantation
Procedure/SurgeryGiven IV
Biopsy
Procedure/SurgeryUndergo fat pad biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood and urine specimen collection
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow aspiration
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow biopsy
Bortezomib
DrugGiven SC
Computed Tomography
Procedure/SurgeryUndergo CT scan
Cyclophosphamide
DrugGiven PO or IV
Daratumumab and Hyaluronidase-fihj
DrugGiven SC
Dexamethasone
DrugGiven PO or IV
Echocardiography
Procedure/SurgeryUndergo echocardiography
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Melphalan
DrugGiven IV
Positron Emission Tomography
Procedure/SurgeryUndergo PET-CT
Stem Cell Isolation
Procedure/SurgeryUndergo stem cell collection
Survey Administration
Other interventionAncillary study
Major organ deterioration progression-free survival (PFS)
Will be performed using a stratified log-rank test for comparison between study arms. The analyses will be stratified according to Mayo 2012 Prognostic Staging System for Light Chain Amyloidosis (Stage 1 versus \[vs.\] 2-3), hematological response following 2 cycles of daratumumab, cyclophosphamide, bortezomib and dexamethasone (Dara-VCD) induction (partial response \[PR\] or worse vs. very good partial response \[VGPR\] or better), and presence of t(11;14) by interphase fluorescence in situ hybridization \[iFISH\] (yes vs. no). All eligible participants will be considered in analyses of the primary endpoint, according to their assigned arm at randomization.
Overall survival
Will be performed using a stratified log-rank test for comparison between arms, with stratification according to Mayo 2012 Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. \[VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
Hematologic PFS
Will be performed using a stratified log-rank test for comparison between arms, with stratification according to Mayo 2012 Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
Cardiac and renal organ response rates
Progression will be defined based on objective evidence of worsening of organ dysfunction due to AL amyloid. Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
Measurable residual disease (MRD) negativity rate
Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
Bone marrow Next Generation Flow based MRD negativity rates
Comparisons of MRD negativity rates between arms will be made using a stratified Cochran-Mantel-Haenszel test, with analyses stratified according to European modification of the Mayo Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3a), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
Change in physical function as assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS)-29+2 physical function domain
Analysis will be conducted using multiple linear regression analysis, adjusting for the clinical study-specified stratification factors (which are also anticipated to influence QOL endpoints), and the baseline score as covariates.
Change in PROMIS-29 fatigue domain score
Analysis will be conducted using linear regression, adjusting for the clinical study-specified stratification factors and the baseline PROMIS-29 fatigue domain score as covariates. Additionally, will conduct longitudinal modeling of the physical function domain score over time (through 12 months from registration Step 3). For longitudinal modeling, linear mixed models will be used.
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SWOG Cancer Research Network
Lead sponsor
National Cancer Institute (NCI)
Collaborator
