N Engl J Med
Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.
Abstract
Background
Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.
Methods
We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.
Results
A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.
Conclusions
Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).
Related Questions
Do you continue daratumumab beyond 24 months in first line treatment of amyloidosis?
This is an important and common clinical question, and one for which prospective data are currently limited. For background, the ANDROMEDA clinical trial (Kastritis et al., PMID 34192431) demonstrated that the addition of daratumumab to cyclophosphamide, bortezomib, and dexamethasone (CyBorD) signif...
How would you approach management and monitoring of AL amyloidosis with isolated renal involvement?
This is tough for sure, and my first question would be to ask how the renal biopsy was determined to be AL amyloidosis. Sometimes typing isn't required if the pattern is overwhelmingly lambda-restricted or kappa-restricted by immunofluorescence... but in this case, mass spectrometry typing may be wo...
How do you approach initial treatment for AL amyloidosis with excess plasmacytosis in the bone marrow, that has cardiac involvement and is not a transplant candidate?
This is the mirror image of an earlier question on theMednet, namely how we would approach MM treatment in someone who was incidentally diagnosed with AL amyloidosis:https://www.themednet.org/question/13482Here, it's how we would approach AL amyloidosis with someone well over 10% bone marrow plasma ...
How would one alter therapy in a transplant-ineligible AL amyloidosis with less than a complete response to six cycles of Dara-CyBorD?
If the patient has achieved deep VGPR (but perhaps not CR due to interference of dara), it is probably reasonable to continue dara maintenance as per ANDROMEDA as long as the patient is also clinically improving. If the response has not reached this level or the patient has not had evidence of impro...
How do you approach treating a patient with IgM-AL amyloidosis?
Good question. As pointed out, about 5% of lymphomas have a diagnosis of lymphoplasmacytic lymphoma (aka Waldenstroms) instead of a plasma cell dyscrasia. Small burdens of LPL can be difficult to detect unless specific testing is done (e.g., flow for clonal B cells) and intraclonal differentiation (...