Article

Daratumumab Plus CyBorD Poised to Change Frontline AL Amyloidosis Care

Author(s):

Sandy Wong, MD, discusses the ANDROMEDA trial, the need for further investigation of venetoclax, and research with anti-amyloid fibril drugs in light chain amyloidosis.

Sandy Wong, MD

Sandy Wong, MD

The addition of daratumumab (Darzalex)to cyclophosphamide, bortezomib (Velcade) and dexamethasone (CyBorD) elicited impressive responses in patients with light chain (AL) amyloidosis, which might warrant a regulatory approval, according to Sandy Wong, MD, and several novel approaches are also improving outcomes in the relapsed/refractory setting.

In the phase 3, open-label ANDROMEDA study, patients with AL amyloidosis who received daratumumab plus CyBorD experienced a complete response (CR) rate of 53% versus 18% in those who received CyBorD alone (95% CI, 3.2-8.2; P <.0001).

Wong explained that the 6-month cardiac response rate was 42% in the daratumumab arm and 22% in the control arm (P = .0029); additionally, the 6-month renal response rates were 54% and 27%, respectively (P < 0.0001). These data were very exciting for patients who are unable to tolerate induction therapy or are transplant ineligible, said Wong.

“Many exciting [approaches are] being developed for AL amyloidosis,” said Wong. “The frontline space is really going to be changed because of what we saw from the ANDROMEDA study. We're all eagerly anticipating, hopefully, an FDA approval. That would be amazing because it would be the first approved treatment for this disease in this setting.”

In the relapsed/refractory setting, several investigational agents are under exploration. For example, after venetoclax (Venclexta) demonstrated a signal of activity in patients with multiple myeloma who harbored t(11;14), investigators have sought to evaluate its use in amyloidosis, as almost half of the patients have this cytogenetic abnormality at diagnosis, said Wong. Additionally, the anti-amyloid fibril drug CAEL-101 is showing promising tolerability in early-phase research.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Multiple Myeloma, Wong, a blood disease specialist and assistant clinical professor in the Division of Hematology/Oncology of the Helen Diller Family Comprehensive Cancer Center, at the University of California, San Francisco (UCSF), further discussed the ANDROMEDA trial, the need for further investigation of venetoclax, and research with anti-amyloid fibril drugs, in AL amyloidosis.

OncLive®: Could you provide a brief overview of the key updates in amyloidosis? How has care evolved in recent years?

Wong: The treatment of amyloid light-chain (AL) amyloidosis has really improved over the past several decades, especially with regard to [options for] patients who are transplant ineligible. When we look at bortezomib-based therapies, we look at the hematologic response, which in amyloidosis, a very good partial response (VGPR) or better is considered acceptable. Around 43% of patients obtain a VGPR or better [with this approach, according to a] large, retrospective study; this is fair, but certainly, there's room for improvement. However, the organ responses reported from that study were really dismal, with 17% of patients achieving a cardiac response and 25% of patients achieving a renal response.

This is really the basis of the ANDROMEDA study, which was presented this year at the European Hematology Association Congress. This is a phase 3 study that randomized patients to subcutaneous daratumumab plus CyBorD versus CyBorD. Patients who were in the experimental arm went on to receive a maximum total of 24 cycles of subcutaneous daratumumab after their initial 6 cycles of daratumumab/CyBorD. In the CyBorD arm, after the 6 cycles, patients went on to observation. This was a patient population for which future transplant was not planned. They had a very nice spread of patients who had heart and kidney involvement, which is what you see in the typical population.

What really made a very impressive mark in amyloidosis was that they achieved amazing responses on the experimental arm. The primary end point was a hematologic CR. Fifty-three percent of patients on the experimental arm had a hematologic CR as a best response compared with 18% of patients who received CyBorD. If you look at patients who achieved a VGPR or better, it was 92% of patients in the experimental arm compared with 49% of patients in the CyBorD arm. Then, the organ responses were double with the daratumumab/CyBorD arm versus CyBorD.

These were very impressive data that were presented and shined a light on what we can achieve in amyloidosis without stem cell transplant. However, there is still a role for stem cell transplant, especially for those who may not respond to this type of therapy. Updated results from a retrospective study showed that at 6 months, the renal response was 52% and the cardiac response was 42% [with transplant]. As such, there is still certainly a role for stem cell transplant, especially for patients who do not respond to daratumumab-based induction therapy.

In the relapsed/refractory setting, we have several drugs that can be used for AL amyloidosis, some of which are more toxic than others. Keep in mind that the toxicities of these drugs, which were borrowed from the multiple myeloma space, are more intense in the patients with amyloidosis because they are fragile and have multiorgan damage to start with.

One of the interesting drugs that is starting to be studied in amyloidosis, although not yet formally, is venetoclax. Venetoclax is a drug that is not yet been FDA approved for myeloma but has been approved for lymphoma. In myeloma, it tends to [be effective in] patients who have t(11;14). This cytogenetic abnormality actually occurs in a very high percentage of patients with AL amyloidosis; close to half of the patients at diagnosis have t(11;14). At UCSF, we have treated some patients with this and have seen some impressive hematological responses as well as organ responses.

Lastly, [it is important to mention the] anti-amyloid fibril drugs. In 2018, the development of both NEOD001 and anti-SAP monoclonal antibody were halted. Currently, there is an anti-amyloid fibril drug being studied called CAEL-101. We are all waiting to see what comes of this drug because, at least in early studies, it looks like there is some signal of efficacy.

What are you currently doing for your patients right now in the frontline space? How are applying recent updates to practice?

CyBorD has been the de facto frontline therapy for AL amyloidosis for a long time. When this study came out and the organ responses were recorded, it was so impressive that it begs the question as to why we are not [still using] it now. There are challenges because there is no FDA-approved regimen for AL amyloidosis; however, I have started to not give CyBorD as frontline therapy.

I'm actually able to sometimes get insurance approval for daratumumab, bortezomib, and dexamethasone; that has actually led to some pretty impressive responses, but the problem with that is insurance approval and the ability to gain access [to that regimen]. Hopefully, in the future that will not be an issue. Everyone hopes that daratumumab/CyBorD will be FDA-approved for AL amyloidosis, then our patients will not have to [face] the big hurdle to get access to daratumumab [for] frontline therapy.

Could you expand on the data supporting the use of daratumumab/CyBorD?

Daratumumab combined with CyBorD produces a very high percentage of CRs in patients with AL amyloidosis. In the study, 53% of patients achieved a hematologic CR [with daratumumab/CyBorD] compared with 18% of those who just received CyBorD. Ninety-two percent of patients who received daratumumab/CyBorD achieved a VGPR compared with 49% in the CyBorD arm; this was very statistically significant.

Lastly, the [last thing to mention] with this regimen is the organ response at 6 months. The cardiac response for daratumumab/CyBorD was 42% compared with 22%, which is also statistically significant. In terms of renal response, of those who received daratumumab/CyBorD, 54% achieved a renal response compared with 27%; this was also statistically significant.

Shifting to the relapsed/refractory setting, could you elaborate on the role of venetoclax?

Venetoclax is FDA approved for lymphoma and had been studied in myeloma. The signal [for activity] in myeloma is seen in patients who carry the t(11;14). Many of us are familiar with what happened with BELLINI, which was a phase 3 trial with either venetoclax combined with bortezomib/dexamethasone versus bortezomib/dexamethasone. Unfortunately, the patients in the venetoclax arm had worsened survival compared with the control arm. However, if you look at just the t(11;14) subset, a survival advantage [was observed with the agent]. Because of that, the agent is being further studied in multiple myeloma.

However, for patients with AL amyloidosis, this drug is particularly interesting because of the high percentage of patients with a t(11;14). Some have been using [venetoclax] for AL amyloidosis, oftentimes in the relapsed or refractory setting. We have done that as well and have so far seen hematologic responses, as well as organ responses.

That being said, this drug needs to be formally studied. A phase 1 trial is being done with venetoclax in AL amyloidosis at Tufts Medical Center, but the hope is that more studies examining this drug in this particular space will be done.

How are you navigating among the available options in this crowded setting?

In terms of selecting treatments among this litany of drugs, it's great that we have so many, but how do we navigate this? We know in terms of hematologic and organ responses, and in terms of the toxicity profile, daratumumab and CyBorD are the drugs that really stand out. Stem cell transplant [is also an option] for those who are eligible. Obviously, only 25% of patients are transplant eligible, so that is a big barrier to autologous stem cell transplant. Immunomodulatory drugs are oftentimes raised because they are very familiar to us and because of their usage in multiple myeloma. However, the 1 warning with lenalidomide (Revlimid) and pomalidomide (Pomalyst) is that these drugs can cause symptoms of heart failure [in amyloidosis]; that is different from what we see in multiple myeloma. If these drugs are being used, we use them carefully and at a reduced dose to ensure that the patients tolerate [them] and don’t develop toxicity.

Carfilzomib (Kyprolis) is interesting; it is a proteasome inhibitor that was really developed to avoid the neuropathy that you see with bortezomib. However, results from a phase 1 study that were shared in an oral presentation at the ASH Annual Meeting several years ago demonstrated that when carfilzomib was used in patients with AL amyloidosis, patients experienced excess amount of cardiotoxicity with this drug compared with [what had been observed with its use in] myeloma. It seemed like more cardiotoxicities, even in patients who did not have involvement of the heart, so I would say to be very careful with carfilzomib.

Ixazomib (Ninlaro) is also very interesting; it was actually examined in a phase 3 study where patients were randomized to ixazomib/dexamethasone, or physician's choice. The physician's choice included lenalidomide/dexamethasone, melphalan/dexamethasone, cyclophosphamide/dexamethasone, and thalidomide (Thalomid)/dexamethasone. The study, unfortunately, did not meet its primary end point, although it seemed like there may be trends in terms of responses and organ responses in the ixazomib/dexamethasone arm compared with physician's choice. While [the benefit] was not determined to be statistically significant, what it does tell me is that it is a drug that we can reach for if it's tolerated by patients.

Could you discuss some of the data we've seen with the anti-amyloid fibril drugs that are emerging?

The anti-amyloid fibril space is 1 that has brought with it a lot of excitement, but also many challenges. The space was very much occupied with 2 drugs back in 2016-2017: NEOD001 and anti-SAP. It's important to understand what happened there to figure out where we go from here. The NEOD001 monoclonal antibody went through phase 1, 2, and 3 clinical trials. The phase 2 PRONTO study, which was done in [patients with AL amyloidosis who have persistent] cardiac [dysfunction], did not meet its primary end point. That prompted an interim futility analysis with the phase 3 program. [The agent] met the futility analysis and hence, the development [of the drug] was ultimately scrapped.

However, if you look at a subset analysis with just the patients with stage IV disease, who are truly the sickest of the group, it seems like there may have been a signal in terms of all-cause mortality in favor of those who received the NEOD001 drug compared with the placebo. That's really interesting to know, and this raises the question that perhaps the patients who benefit most from this type of therapy, may be those who really are the sickest. That's actually great because we've been wanting drugs for these types of patients because there's such a need to rescue them from the toxicities of their disease. That's really exciting and hopefully, we'll use that kind of knowledge to plan future trials with anti-amyloid fibril drugs.

You mentioned earlier that CAEL-101 is under investigation. Could you expand on what is known so far with its use in this patient population?

The CAEL-101 used to be known as 11-1F4. This is a monoclonal antibody, which unlike the NEOD001 drug, was actually raised toward amyloid light chains. We actually know the binding site for this particular monoclonal antibody is actually to an epitope that is only revealed when the light chains become amyloidogenic, which is really helpful to know because it means that it's not going to attach to the normal light chains. This drug has been demonstrated to attach to amyloid in the organs via imaging studies. That's also very helpful to understand that it actually is going to places where there is amyloid present.

[One] case was presented [with] a patient who had developed a rash after getting this drug. A biopsy showed that there is drug that is attached to the amyloid fibrils, causing an immune reaction in the skin. All that is very exciting because it demonstrates to us that we have a drug, we know where it binds, we know that it goes radiographically to places where there's amyloid, and there's also tissue-based evidence that this has happened in at least in 1 patient. That's really exciting to be able to demonstrate all those properties.

We are looking forward to seeing what comes of this drug. Certainly, in phase 1/2 studies, the safety of this drug has been determined; it’s very well-tolerated and we're all looking forward to what studies will examine this drug in the future.

Reference

Kastritis E, Palladini G, Minnema MC, et al. Subcutaneous daratumumab + cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients with newly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract LB2604.

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