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AL Amyloidosis
Managing Light-Chain Amyloidosis: Experts Respond to Your Questions on Optimizing Care

Released: February 09, 2022

Expiration: February 08, 2023

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Immunoglobulin light-chain (AL) amyloidosis is the most common form of systemic amyloidosis. It is caused by the abnormal production of immunoglobulin light chains that produce amyloid fibrils, which can accumulate in organs and lead to damage, organ dysfunction, and mortality. This rare disease often is difficult to recognize and diagnose because of its nonspecific presentation and range of classifications, which makes early and accurate diagnosis critical. Various treatment options for patients with AL amyloidosis are used in the clinic, making treatment decisions challenging. In this commentary, experts Shaji K. Kumar, MD; Vaishali Sanchorawala, MD; and Ankit Kansagra, MD, answer the audience questions from a live webinar held in January 2022 to help guide improved management of AL amyloidosis.

You have indicated that light-chain characteristics such as glycosylation might identify patients at higher risk for the development of AL amyloidosis. Is a test for glycosylation of monoclonal paraproteins widely available?

Shaji K. Kumar, MD:
Individuals with monoclonal gammopathy of undetermined significance (MGUS) are clinically asymptomatic but show evidence of premalignant plasma cell proliferation and thus are at risk of developing AL amyloidosis. A recent study suggests that light-chain characteristics predispose patients with MGUS to developing AL amyloidosis, and the presence of N-glycosylated monoclonal protein was a risk factor for developing AL amyloidosis.

A test for glycosylation of monoclonal paraproteins is not routinely available, but you can test for glycosylation with mass spectrometry–based immunofixation. That is what we do in our lab, and I think more labs are starting to use this method. I hope this is something that will become more available as labs switch over to mass spectrometry–based paraprotein testing.

Can a diagnosis of AL amyloidosis still be made based on traditional tests, such as Congo red stain and immunohistochemistry?

Shaji K. Kumar, MD:
Before mass spectroscopy, immunohistochemistry and Congo red stain were the standards for diagnosing AL amyloidosis. So, these traditional analyses may be sufficient for diagnosis, but there is always an element of uncertainty. However, if a patient has amyloid deposits that with immunohistochemistry are clearly related to one light chain, I think that can be trusted for treatment purposes.

Vaishali Sanchorawala, MD:
I think immunohistochemistry or immunofluorescence on kidney biopsies are quite specific, and I would use them. However, the commercially available antibodies for histologic analysis are not uniformly accurate. The quality of the results may depend on the center or laboratory performing the tests.

Hematologic responses to therapy are typically rapid for AL amyloidosis. When would you expect organ responses?

Shaji K. Kumar, MD:
The newer therapies such as quadruplet combination of daratumumab (Dara), cyclophosphamide, bortezomib, and dexamethasone can produce a hematologic response within the first 1 or 2 cycles, but organ responses typically take longer. You can see kidneys continue to improve beyond the 12-month mark, and the median time to cardiac response—at least with older therapies such as melphalan, dexamethasone or bortezomib, cyclophosphamide, and dexamethasone—was longer than 6 months. It also is important to note that a complete hematologic response usually results in organ improvement.

The problem that we come across is when we are not seeing organ improvement in a patient who has not completely eliminated the paraprotein. In this situation, we start wondering whether there is sufficient depth of hematologic response. The next step will depend on the location and severity of the organ involvement. If a patient with significant cardiac involvement is not seeing a deep hematologic response in the beginning, you may want to change the therapy, whereas in cases of primarily renal involvement, if you continue to see a deepening response, you may be able to wait longer.

The ANDROMEDA trial revealed a higher percentage of serious cardiac adverse events in the Dara plus bortezomib/cyclophosphamide/dexamethasone (VCd) arm. Would you comment on this finding, and does it discourage you from using Dara plus VCd for patients with advanced cardiac disease?

Vaishali Sanchorawala, MD:
ANDROMEDA is a randomized, open-label phase III trial of SC Dara plus VCd vs VCd alone in patients with newly diagnosed AL amyloidosis. In this trial, patients with N-terminal pro‒brain natriuretic peptide >8500 ng/L or those with a New York Heart Association classification of stage IIIB disease were excluded. In clinical practice, I have used single‑agent SC Dara for patients with stage IIIB disease and then gradually escalated with the addition of VCd. Dexamethasone would be the last agent to be added if it is well tolerated.

The other part of the question is regarding the increased rates of serious fatal cardiac events. Cardiac‑related adverse events occurred in approximately 33% of patients receiving Dara plus VCd vs 22% of patients receiving VCd alone. The design of the clinical trial was such that patients receiving Dara plus VCd remained on therapy for 24 months compared with 6 months for patients receiving VCd. Therefore, related cardiac events, by the study design, occurred more commonly in the Dara plus VCd arm. However, when adjusted for exposure to therapy, the rates of cardiac events were comparable between the 2 arms. Furthermore, cardiac responses were seen more commonly in patients who received Dara plus VCd vs VCd alone (53% vs 24% at an 18-month follow-up, respectively). The early mortality at 60 days was comparable in both arms, and cardiac events occurred more commonly in patients who had baseline cardiac involvement. A manuscript about cardiac events in the ANDROMEDA trial is going to be published soon. In addition, a postmarket research clinical trial requested by the FDA to look more closely at this data will be starting soon.

What is the optimal amount of time to treat candidates for stem cell transplant (SCT) with Dara plus VCd?

Vaishali Sanchorawala, MD:
I am not a strong believer in induction therapy. Because the median time to hematologic response in Dara plus VCd is 60 days, 2‑4 cycles would be adequate for SCT. But if the patient has achieved a complete hematologic response with Dara plus VCd, I probably would not recommend SCT as consolidation, as we would for multiple myeloma. I would rather have the organs recover after Dara plus VCd and save SCT for later to treat a potential relapse.

What dosage of melphalan do you recommend for patients before they undergo SCT?

Vaishali Sanchorawala, MD:
The International Society of Amyloidosis and European Hematology Association recently published guidelines for high-dose chemotherapy and SCT for AL amyloidosis. The group recommended 200 mg/m2 of melphalan prior to SCT, specifically in the era of Dara plus VCd. A lower dose of melphalan reduces the rate of hematologic complete response, and the group did not think modified high‑dose melphalan should be offered unless patients have an estimated glomerular filtration rate of <30 mL/min/m2. Patients receiving dialysis who are going to be treated with SCT should probably get 140 (vs 200) mg/m2 of melphalan.

What is the best treatment for patients with AL amyloidosis who experience relapse?

Ankit Kansagra, MD:
Relapsed AL amyloidosis is the toughest situation in our clinics because we do not have great options for patients. Dr. Sanchorawala recommended SCT if the patient has not previously undergone this treatment. If the organs are functioning well, you could consider alkylating agents in some combination. The true and tested treatments for patients with AL amyloidosis who have relapses are immunomodulatory drugs and alkylators. Melphalan as an alkylating agent and pomalidomide or lenalidomide as an immunomodulatory drug could be considered.

When patients have a biochemical relapse but do not experience renal or cardiac progression, do you initiate therapy? Conversely, if patients experience end-organ progression but no hematologic progression, would you initiate therapy?

Ankit Kansagra, MD:
In the case of light-chain relapse in AL patients, I would look at the rapidity and time to increase, and I would carefully monitor them. If the serum free light chains go from 10 mg/dL to 20 mg/dL or 10 mg/dL to 30 mg/dL, I would probably wait before initiating therapy, but a persistent increase in the light chain over time would prompt me to change treatments.

In the opposite case—cardiac relapse (or any other organ relapse) with no significant hematologic progression—I would search for causes. Are there other factors at work here? We have had patients whose light chains were normal, but their renal proteinuria kept getting worse. That would be a good reason to consider treatment on a case-by-case basis.

Shaji K. Kumar, MD:
I agree with Dr. Kansagra. It is always good to think about the patient’s baseline numbers before initiating treatment in these situations. If you see somebody starting at 10 mg/dL, you don’t want to wait too long to take action, whereas if you saw a starting point of 1000 mg/dL, you might want to consider watchful waiting.

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