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Director, John Conant Davis Myeloma and Amyloid Program
Tufts Medical Center
Professor of Medicine and Pathology
Tufts University School of Medicine
Raymond L. Comenzo, MD has disclosed that he received funds for research support from Alnylam, Caelum/Alexion, Janssen, and Sanofi, consulting fees from Abbvie/Genentech, Caelum/Alexion, Janssen, Karyopharm, Sanofi, and Takeda, and royalty from Janssen.
In this commentary, I provide an overview of systemic light-chain (AL) amyloidosis and its historical treatment. Then I discuss the importance of the 2021 FDA approval of subcutaneous daratumumab for use in combination with cyclophosphamide, bortezomib, and dexamethasone (VCd, or CyBorD) in newly diagnosed patients with AL amyloidosis and share my perspective on how the treatment landscape may evolve in the future.
What Is AL Amyloidosis? How Has It Been Treated Historically?
AL amyloidosis is a protein misfolding disorder in which clonal CD38+ plasma cells produce abnormal immunoglobulin light chains that aggregate to form amyloid fibrils that deposit in tissues and organs. When deposits of these misfolded proteins become massive, they cause organ dysfunction; mortality associated with AL amyloidosis is most often due to cardiac damage. Currently, 20% to 30% of patients newly diagnosed with AL amyloidosis die within 6 months.
The treatment landscape for AL amyloidosis has evolved significantly. Historically, the combination of oral melphalan and prednisone was used in an attempt to control production of pathologic light chains by reducing the plasma cell burden in the bone marrow. In the 1990s, high-dose melphalan followed by stem cell transplantation began to be used in multiple myeloma. Subsequently, stem cell transplantation was also used in systemic AL amyloidosis with some success. Initially, because of organ damage, mortality rates with stem cell transplantation in some centers approached 20% for patients with AL amyloidosis. Today, patient selection has been refined to exclude patients with more severe cardiac damage and multiple organ involvement, and the mortality rate is approximately 2%. Unfortunately, only one quarter of newly diagnosed patients with AL amyloidosis are candidates for stem cell transplantation.
With the development of the proteasome inhibitor bortezomib and its approval for use in multiple myeloma in 2003, researchers also explored the use of bortezomib for treatment of systemic AL amyloidosis. Initially, bortezomib was a success in the relapsed setting and then in the upfront setting with the combination of VCd. Bortezomib-based combinations greatly help control the plasma cell disease. However, adverse events associated with bortezomib complicate its use and require dose reductions in some instances. Moreover, not all patients with AL amyloidosis respond to bortezomib-based combinations, with overall response rates of approximately 50% to 60% and an approximate complete response rate of 30% to 35%. In patients who respond, the persistence of pathologic light chains means that the organs continue to deteriorate even after treatment, but at a slower pace. With these advances in treatment, the median survival for patients diagnosed with AL amyloidosis, as of 2010, is approximately 3-4 years.
Anti-CD38 Monoclonal Antibodies in AL Amyloidosis
With the development of monoclonal antibody therapy for multiple myeloma, trials also began to assess use the anti-CD38 antibody daratumumab to treat systemic AL amyloidosis, initially in the relapsed setting. Unusual for plasma cell diseases, intravenous daratumumab was active as a single agent for patients with AL amyloidosis.
Subsequently, the randomized phase III ANDROMEDA trial evaluated subcutaneous daratumumab plus VCd vs VCd alone in newly diagnosed patients (N = 388) with systemic AL amyloidosis. Initial results were presented at the European Hematology Association Virtual Congress in 2020 and later published in the New England Journal of Medicine in 2021. In this analysis at a median follow-up of 11.4 months, the hematologic complete response rate (primary endpoint) was 53% with daratumumab plus VCd vs 18.1% with VCd alone, and patients who received daratumumab plus VCd had longer survival free from major organ deterioration or hematologic progression vs those who received VCd alone (HR: 0.58; 95% CI: 0.36-0.93; P = .02). More recently at the 2021 ASCO Virtual Annual Meeting, data from a 20.3-month follow-up from the ANDROMEDA trial were presented. The hematologic complete response rate was 59% with the daratumumab plus VCd combination vs 19% with VCd alone (odds ratio: 5.9; 95% CI: 3.7-9.4; P <.0001). However, renal and cardiac response rates for daratumumab plus VCd were 57% for both endpoints, compared with 27% and 28%, respectively, for the VCd arm. In January 2021, the FDA approved subcutaneous daratumumab for use in combination with VCd in newly diagnosed patients with AL amyloidosis. This approval has revolutionized our treatment of patients in the United States—it is the first drug approved for AL amyloidosis.
How I’m Using Daratumumab Plus VCd in the Clinic
In my clinic, I recently saw a patient with newly diagnosed AL amyloidosis. He had amyloid deposits in his abdominal fat, 20% plasma cells in his bone marrow, a serum free lambda light-chain level of 300 mg/L, and stage II cardiac disease. He also had significant gastrointestinal involvement as well, based on his history of recent weight loss.
When encountering a patient like this, the approval of daratumumab plus VCd is a real game changer. I was able to get approval for his treatment within 48 hours. Now that there is an FDA-approved regimen for AL amyloidosis, getting patients treated is much easier. Before this, we would need to argue with insurance companies that a patient with amyloidosis has myeloma based on a percentage of plasma cells in the bone marrow to get access to treatments typically used for multiple myeloma. Daratumumab also changes things because of the ease of its application as a 15-mL subcutaneous injection rather than intravenous administration.
I have another patient with AL amyloidosis who has been on the cardiomyopathy unit for 2 weeks with an ejection fraction of 20%. He only has amyloid fibrils in his heart and is being considered for a heart transplant. For him, I prescribed daratumumab, which he is receiving with a modest dose of methylprednisolone as well as dobutamine drip to maintain cardiac output.
For this patient, I did not prescribe VCd with daratumumab due to the modest risk of cardiovascular complications with the combination approach. However, in my experience, single-agent daratumumab is safe even in a patient with serious cardiac complications. There is little to no risk of cardiac complications associated with subcutaneous daratumumab plus 100 mg methylprednisolone, with premedication comprising montelukast 10 mg and diphenhydramine 25 mg as prophylaxis for infusion-related reactions. My expectation is that he will tolerate the medicine extremely well and that this combination will likely reduce the lambda light-chain level in his blood. Once he is stable, we can resume therapy with daratumumab plus VCd to control the overall plasma cell disease and get him listed for a heart transplant.
Daratumumab has revolutionized the treatment of patients with AL amyloidosis: It is approved in combination with VCd for therapy and is also safe with a small dose of steroids. During the past 35 years, treatment of this disease has progressed from melphalan/prednisone to melphalan/dexamethasone to stem cell transplantation to bortezomib (and other proteasome inhibitors). And yet, the approval of daratumumab in this setting is, to paraphrase Neil Armstrong, a giant leap for the portion of mankind that suffers from AL amyloidosis. I am grateful for the patients and their families who participated in the ANDROMEDA trial and for the coinvestigators in this study. I feel very fortunate to have observed these meaningful improvements during the course of my clinical career.
In the future, I think we will continue to see agents with novel mechanisms being used to manage and treat AL amyloidosis. For example, agents are being developed to resorb amyloid, that is, remove it from the tissues. In 2021, the FDA approved aducanumab, an antibody against amyloid plaques in patients with Alzheimer disease. The approval was controversial, but there is proof of principle here that antibodies can remove amyloid. A phase III trial (NCT04512235) is currently recruiting to test CAEL-101, a monoclonal antibody targeting amyloid fibrils, in combination with VCd in patients with stage IIIa AL amyloidosis. I also believe that a dual-antibody approach might be effective, perhaps using daratumumab plus an anti-BCMA antibody–drug conjugate or an antibody directed at another cell surface marker on amyloidosis plasma cells for these patients.
What questions do you have about managing patients with AL amyloidosis in your clinical practice? Please answer the poll and share your thoughts and questions on amyloidosis in the discussion box below.
For a deeper look at current amyloidosis treatment, watch for our module with an associated downloadable slideset (coming soon).