Wave of Therapies Being Developed in AL Amyloidosis Space

Sandy W. Wong, MD

Immunoglobulin light chain amyloidosis (AL amyloidosis), known as the most common form of systemic amyloidosis and associated with an underlying plasma cell dyscrasia, is frequently difficult to recognize because it presents similarly to a variety of other hematologic disorders.

However, explains Sandy W. Wong, MD, therapeutic developments for AL amyloidosis have recently been emerging to include plasma cell treatment and anti-amyloid fibril therapy to propel this field into a more positive direction.

For example, a prospective phase II study presented during the 2017 ASH Annual Meeting showed that the CD38-directed monoclonal antibody daratumumab (Darzalex) was found to induce deep and rapid hematological responses in pretreated patients with AL amyloidosis.¹ Among 24 evaluable patients, the hematologic complete response rate was 17%, 29% experienced a very good partial response, and 17% achieved a partial response. The overall response rate was 63%.

There have also been early-phase studies with anti-amyloid fibril therapy. NEOD001, a monoclonal antibody, was well tolerated in a first-in-human study of 27 patients with AL amyloidosis. Of 14 cardiac-evaluable patients, 8 (57%) met the criteria for cardiac response and 6 (43%) had stable disease. Of 15 renal-evaluable patients, 9 (60%) met the criteria for renal response and 6 patients (40%) had stable disease.²

OncLive: What developments have we recently seen in this field?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Wong, an assistant clinical professor in the Division of Hematology/Oncology, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed some of these therapeutic advancements and recent data that have shown excitement in this landscape.Wong: The developments have basically been separated into 2 major categories. One is anti-plasma cell therapy and the other one is anti-amyloid fibril therapy. In terms of the anti-plasma therapies, the new development has been the publication of the phase I trial for ixazomib in AL amyloidosis. It looks to be quite an active drug with a relatively good safety profile.

The other drug that has also made its headlines in AL amyloidosis has also been pomalidomide (Pomalyst). That trial was also published this year. It does also have a good safety profile as well as a good efficacy profile. The anti-plasma cell therapies have really made the splash.

The most prominent one that garnered a lot of people’s attention is daratumumab. There were early reports of [using] daratumumab in this disease; the first report was published early last year by Dr Morie A. Gertz. He presented 2 cases in his paper that was published in Blood. Earlier [in 2017], there was a retrospective study looking at the response rates of daratumumab, which were very impressive.

Most recently, at the 2017 ASH Annual Meeting, there were actually 2 prospective trials that were presented in an oral session, as well as 2 retrospective studies in poster form that also showed the preliminary safety profile of daratumumab and preliminary efficacy profiles. It is a very exciting time. We have 3 drugs that have made an initial splash in the world of AL amyloidosis in terms of plasma cell therapy.

The other class of agents include the anti-amyloid fibril treatments, and none of these are FDA approved yet. One of them that has been published is NEOD001, which is a drug that is an anti-amyloid fibril monoclonal antibody against the amyloid fibrosis themselves in an effort to clean up the amyloid deposits in the body to allow organ recovery. That antibody is very interesting because the first paper that was published was in the Journal of Clinical Oncology a couple of years ago as a phase I trial; it looks like it is very safe to give. Preliminary [findings show that] there does seem to be cardiac, renal, and neurologic responses to that drug, so that is really exciting.

The other anti-amyloid fibril therapy is 111F4. Now, it has been renamed to CAEL-101 and that was actually presented at the 2017 ASH Annual Meeting. It was a final analysis of the phase I study with this drug and looks similar to NEOD001; it looks quite safe and there are preliminary signals of efficacy, which are very exciting.

What are some of the risk factors for this condition? How does it typically present?

With the third anti-amyloid fibril therapy, there has been a retrospective study published this past year. It is about doxycycline, which is a pretty common antibiotic that is used in clinical practice. Interestingly, it does seem to have anti-amyloid fibrils properties; these are all very exciting drugs being studied in AL amyloidosis this past year. How it presents is one of the challenges in diagnosing this disease. It is a great mimicker of a lot of common conditions. In AL amyloidosis, approximately 60% to 70% of patients have cardiac involvement and/or renal involvement, and when it affects the heart, it causes an infiltrative cardiomyopathy so patients can have heart failure, swelling in their legs, and shortness of breath—especially of exertion. These are, essentially, heart failure symptoms and oftentimes it can be talked up to other causes.

You mentioned an initial splash with some agents, such as ixazomib, pomalidomide, and daratumumab. Is there room for other known drugs, such as elotuzumab (Empliciti) or lenalidomide (Revlimid)?

A lot of people don’t think of AL amyloidosis. If it affects the kidneys, it can cause decreases in the filtration rate of the kidneys. It can also cause spilling of protein into the urine, as well. Again, these can be attributed to other causes, so, unfortunately, this disease is not diagnosed until late in its course. AL amyloidosis could also deposit in other organs in the body, such as the gut, the liver, and the peripheral nerves. Every AL amyloidosis patient is unique and different, and everyone has a unique pattern of organ involvement. That also contributes to the trickiness of diagnosing this disease. Lenalidomide has been studied in AL amyloidosis, and it does look to be an effective agent, as well. The problem with the immunomodulatory agents (IMiDs) is they can cause side effects that are more pronounced compared with what is being used in myeloma. For example, IMiDs cause a rise in the cardio biomarkers; it can also cause more fatigue than you would expect and it could also cause fluid retention. Lenalidomide does look like it is efficacious, but you have to be careful of the side effects it can cause.

Is there a rationale to study immunotherapy in AL amyloidosis?

Elotuzumab, in combination with lenalidomide and dexamethasone with or without cyclophosphamide, is actually being studied right now. We eagerly anticipate the results of that trial. I definitely think there is a lot of room to study immunotherapy. Immunotherapy has really garnered a lot of people’s attention, especially in the myeloma world. Thus far, the response rates are really impressive; however, toxicity remains an issue that as the field evolves, it is learning to deal with.

In the AL amyloidosis world, it deserves study in a select group of patients. There are patients who, you treat them with first-line chemotherapy and they go into remission, and they’re in remission for some time. However, there are patients with AL amyloidosis in whom you try multiple lines of therapy, and it’s difficult to get them into a remission or deep enough remission to see an organ response. Those patients will be the ones that [could] benefit most from more advanced treatments, such as [immunotherapy].

In terms of toxicity from the immunotherapy trials I have seen—and it depends which trial—if it were to move into the AL amyloidosis space, we would have to [ask], “What is the safety profile of these drugs, and would we be able to find the right patient to match them with the appropriate drug?”

I like to think about this disease as there being a factory that is making the light chains, and there are other organs involved and each and every organ needs to be interrogated to see which pattern of organ involvement they have. As this disease moves on, it is important to keep in mind how these organs are doing. Are they getting better? Have they stabilized? That is important to not lose track of because the pattern of organ recovery can be very disparate between organs of the same person. If they are not making adequate organ recovery, there needs to be a consideration for clinical trials, specially with the anti-amyloid fibril therapies that, so far, look very promising.

References

1. Roussel M, Stoppa AM, Perrot A, et al. A prospective phase II of daratumumab in previously-treated systemic light-chain (al) amyloidosis. In: Proceedings from the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 508.
2. Gertz MA, Landau H, Comenzo RL, et al. First-in-human phase I/II study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction. J Clin Oncol. 2016;34(10):1097-1103. doi: 10.1200/JCO.2015.63.6530.