D-VCd Rises as the New Standard of Care in Newly Diagnosed AL Amyloidosis

Jonathan L. Kaufman, MD

The emergence of the 4-drug regimen composed of subcutaneous daratumumab and hyaluronidase-fihj (Darzalex Faspro), bortezomib (Velcade), cyclophosphamide, and dexamethasone (D-VCd) has shifted the standard of care for patients with light chain (AL) amyloidosis with the exception of those with significant cardiac involvement, according to Jonathan L. Kaufman, MD. For those who have high-risk cardiac features, novel monoclonal antibodies have started to pick up momentum.

The quadruplet regimen was approved by the FDA in January 2021 for patients with newly diagnosed AL amyloidosis based on data from the phase 3 ANDROMEDA study (NCT03201965).¹ Results indicated that the regimen elicited a 53% hematologic complete response (CR) rate vs 18% with VCd alone.2 Moreover, the D-VCd regimen was found to yield higher rates of best hematologic response at any time vs VCd alone, at 56.9% and 18.7%, respectively (odds ratio, 5.68; 95% CI, 3.58-9.00; P <.0001).

“This provides us with, for the first time, a proven single standard of care for patients with newly diagnosed AL amyloidosis, [except for] those who have significant cardiac involvement; those patients were excluded from the study,” said Kaufman, medical director and section chief of the Ambulatory Infusion Centers at Emory University’s Winship Cancer Institute. “We still need to spend time and energy figuring out what the best therapy [is for those patients]. However, for all other patients, we can say the current standard of care is subcutaneous D-VCd. This is really going to call into question the role of autologous transplant in amyloidosis. We will probably see a significant decline in the use of transplant over the next several years.”

In an interview with OncLive® during an Institutional Perspective in Cancer webinar on amyloidosis, Kaufman further discussed the significance of subcutaneous D-VCd in the treatment of patients with AL amyloidosis, remaining questions with the approach, and emerging strategies for those with high-risk cardiac features. At Emory, he also serves the School of Medicine as an associate professor in the Department of Hematology and Medical Oncology and as interim director of the Division of Hematology.

OncLive^®: What are the recent updates regarding new therapies for AL amyloidosis?

Kaufman: It’s an exciting time for the management of AL amyloidosis. Just recently, we had an FDA approval for the up-front combination of subcutaneous D-VCd. The reality is that we have been getting better at treating [patients with] amyloidosis over the past several years, better able to risk stratify them and understand who is appropriate for transplant. [Applying] our newer myeloma therapies to amyloidosis [has] really made a great impact. However, we still have challenges ahead of us, particularly in the patients who have significant cardiac involvement. With new research, hopefully we can improve their outcomes, too.

What are some of the challenges faced when diagnosing a patient with this disease?

Amyloidosis is actually an incredibly challenging diagnosis to make. It is the type of diagnosis that if you never think about it, you will never make the diagnosis. It is very important that you at least consider the diagnosis of amyloidosis for any patient who has new-onset monoclonal gammopathy. You look for [symptoms such as] heart failure with preserved ejection fraction, nephrotic-range proteinuria, isolated elevated alkaline phosphatase, or purpura. If you have made the diagnosis of myeloma and the patient has an enormous amount of toxicity associated [with] treatment, particularly gastrointestinal effects, that should also be a clue that there is underlying amyloidosis.

The other challenge with amyloidosis [has to do with its subtypes]. Obviously, as a group that treats a lot of myeloma, we focus primarily on AL amyloidosis, but it is very important [to consider] that many other types of amyloidosis [exist, including those] for which good treatment options are available. Understanding [and] making the accurate diagnosis, especially with regard to transthyretin amyloidosis, is incredibly important.

Historically, this has been a condition with limited treatment options. Could you expand on how the field has turned to the myeloma arsenal for additional approaches?

Conceptually, the treatment of [patients with] amyloidosis is really all the same: You are trying to drive down the abnormal protein that is causing the clinical features of amyloidosis. I primarily focus on AL amyloidosis and ways to drive down the light chain that is causing amyloidosis [and] to get rid of the abnormal plasma cells.

That proof of principle—that eliminating the abnormal plasma cells will ultimately improve outcomes in amyloidosis—was proven in a randomized study many years ago which looked at the combination of melphalan and prednisone, [which] was superior to colchicine. At the time, we thought colchicine was going to remove amyloid from the organs. What [investigators] noted was that melphalan and prednisone, the earliest effective therapy for plasma cell disorders, was clearly beneficial from a survival standpoint in amyloidosis. Since then, we have been refining our treatment and using more of the myeloma therapies like autologous transplant and, now, monoclonal antibodies.

What has been the impact of the FDA approval of subcutaneous D-VCd in newly diagnosed AL amyloidosis? What was learned from the phase 3 ANDROMEDA study?

The primary end point of this study was hematologic CR. The key to these patients living a long time is 2-fold: deep responses measured by hematologic CR and improvement in organ function. A clear benefit was observed with subcutaneous D-VCd over VCd alone. Of the patients in the [experimental] arm, 53% achieved a hematologic CR vs 18% [of those] in the [control arm]. Additionally, an improvement in organ function [was observed] in the patients who had the 4-drug [regimen].

The real question is [whether we] can identify a group of patients who should still receive autologous transplant and not conventional therapy as an outpatient. [That could be] patients who have low disease burden and renal-only amyloidosis. I have patients in my clinic today who I did a single transplant on and 10, 13, or 15 years later are still in remission and have never received any other therapy. Now that we have extremely effective therapies with high CR rates, what is the role of autologous transplant?

Were any unexpected or notable toxicities associated with this quadruplet regimen?

The toxicities are well characterized with all these drugs. There was not really any unexpected toxicity [reported with the regimen]. We do see more upper-respiratory tract infections with the combination, [as well as more] neutropenia and more pneumonia. However, the benefit so far [with this approach] outweighs those additional risks. It is, however, important to note that when we add subcutaneous daratumumab, we are adding increased risk of infections, and we do have to be conscientious about that.

The question that I have when I look at these data is: Could we remove some of the therapy? Do we need cyclophosphamide as part of this treatment? Could we more comfortably modify the dose of bortezomib? [We still have many] questions with this regimen.

What clinical research is being conducted for high-risk cardiac patients?

That is an incredibly timely question. [A potential agent is] a monoclonal antibody, NEOD-001, that binds to the amyloid protein and either remove the amyloid from the organ or interact with the toxic amyloid protein. A phase 3 randomized trial was conducted that ended up being negative, but a post hoc analysis of the patients [with] high-risk cardiac [features indicated] a survival advantage. [Therefore], the company has been given the go-ahead to do another randomized trial just in these patients [with] high-risk cardiac features, where the monoclonal antibody will be combined with standard therapy and compared with standard therapy alone to see whether the survival advantage observed [in this subset] is real. That is exciting.

The other thing is something that we have done at our site, which has been led by my colleague, Craig C. Hofmeister, MD, MPH, of Winship Cancer Institute: It’s [to take] a slow-go [approach]. We have 4 drugs available, but maybe the high-risk patients cannot tolerate all 4 drugs at one time. [In] this study, we are using another monoclonal antibody that targets CD38, isatuximab-irfc [Sarclisa]. Here, you start with isatuximab. Instead of starting with 4 drugs and tapering down based on toxicity, we start with 1 drug and build up based on tolerance.

References

1. Genmab announces that Janssen has been granted US FDA approval for DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) for patients with newly diagnosed light-chain (AL) amyloidosis. News release. Genmab A/S. January 15, 2021. Accessed March 17, 2021. http://bit.ly/38P8hlc
2. Comenzo RL, Kastritis E, Minnema MC, et al. Reduction in absolute involved free light chain and difference between involved and uninvolved free light chain is associated with prolonged major organ deterioration progression-free survival in patients with newly diagnosed AL amyloidosis receiving bortezomib, cyclophosphamide, and dexamethasone with or without daratumumab: results from ANDROMEDA. Blood. 2020;136(suppl 1):48-50. doi:10.1182/blood-2020-137582