Dara-CyBorD vs CyBorD in Newly Diagnosed AL Amyloidosis| Hans Lee, MD | #ASH2024

Hi, my name is Hans Lee from MD Anderson Cancer Center in Houston, Texas, where I focus on the treatment of multiple myeloma in light chain amyloidosis. At this year's Ash 2024 meeting, the final results of the phase three Andromeda study was presented by my colleague and co-investigator Doctor Efstathios Kastritis. Just as a little brief background, this was a phase three randomized study evaluating the use of daratumumab, cyclophosphamide, bortezomib, and dexamethasone for six cycles, followed by daratumumab monotherapy every four weeks for a total of 24 months versus cyclophosphamide, bortezomib, and dexamethasone, otherwise known as CyBorD, for six cycles for newly diagnosed light chain AL amyloidosis.

The initial results of the primary endpoint of this study was reported approximately three years ago, which to demonstrate significant improvement of complete hematologic response rates in the dara CyBorD arm versus CyBorD, and this led to the regulatory approval of dara CyBorD for newly diagnosed light chain amyloidosis and established dara CyBorD as a standard of care for the treatment of newly diagnosed AL amyloidosis in this particular setting.

At this year's meeting, the five year follow up and the final analysis was reported, and this was important in the field because they reported on a couple key secondary endpoints, including overall survival and major organ deterioration, progression free survival, which was a composite endpoint evaluating end stage cardiac disease, end stage renal disease, hematologic disease progression and overall survival.

So nearly 400 patients were randomized in the study to either receive dara CyBorD or CyBorD with newly diagnosed Al amyloidosis, approximately 70% of patients had cardiac involvement at baseline. Approximately 60% of patients had baseline renal involvement, and with the additional five year follow up, what it did show was that there's a deepening of hematologic response rates in the dara CyBorD arm, and about 60% versus, a complete hematologic response rate of 19% in the CyBorD arm.

So nearly tripling of complete hematologic response rate with the addition of dara to the CyBorD backbone. In addition, the cardiac and renal response rates were 2 to 3 fold higher with dara CyBorD versus CyBorD, alone with longer follow up. And looking at some of the key secondary endpoints, including overall survival and major organ deterioration, progression free survival with the addition of daratumumab to CyBorD, there are significant improvement of both overall survival and major organ deterioration.

Progression free survival with dara CyBorD versus CyBorD alone, and this was pretty consistent across all major pre-specified subgroup analyses. Finally, when looking at the safety profile with longer follow up, there's really no new safety signal seen, with the addition of, dara, daratumumab to the CyBorD backbone, small increase in, infection rate and grade one and grade two upper respiratory infections and pneumonia.

But overall, this is a very safe and well tolerated regimen in this particular patient population. So in summary, with the five year, follow up, in the final analysis of Andromeda, these results really establish and reconfirm that dara CyBorD is the standard of care for newly diagnosed and amyloidosis, with both an overall survival benefit, and a major organ deterioration progression free survival benefit with the use of daratumumab with CyBorD versus CyBorD alone.

This was a, a new endpoint developed for this specific study. And so their unique characteristics of light chain amyloidosis patients there are different than multiple myeloma that have special considerations when considering the endpoints of progression free survival. In particular, amyloidosis patients can have involvement of specific organs, most critically the heart and the kidneys. And so again, this, composite endpoint not only looked at death and progression, by hematological response, as you know, it's typical, progression criteria but also organ deterioration.

And this also looked at cardiac or end stage cardiac disease and end stage renal disease.

So the definition of end stage cardiac disease for the major organ deterioration progression free survival endpoint had three criteria; cardiac transplantation, the use of a left ventricular assist device, and a use of intra-aortic balloon pump, which signified end stage cardiac disease.

So the definition of end stage renal disease for this composite endpoint was basically onset of hemodialysis or kidney transplantation.

I think one of the really game changing, medicines actually for light chain amyloidosis has been anti-CD38 monoclonal antibody based therapy with daratumumab and there have been previous studies showing, retrospective analysis looking at the use of both single agent daratumumab and daratumumab combination in patients with previously treated light chain amyloidosis.

And so if a patient has not received daratumumab and has relapsed, certainly I think using a daratumumab based regimen would be my go to in this particular setting. And even if a patient has been exposed but not refractory to daratumumab, their retreatment with an anti CD38 like daratumumab would be a very reasonable option in this context.

There's been tremendous progress in the treatment of light chain amyloidosis over the last 3 to 5 years, particularly with introduction of daratumumab to the CyBorD backbone. I think this has really been sort of a landmark, monumental sort of study for the field. And given that this is the first time there's actually a drug approved uniquely for light chain amyloidosis, which is, you know, sort of unprecedented and the first time.

And I think more progress is being made with other therapies, in, light chain amyloidosis. So I think the field, is very promising and I’m really excited with what's moving forward with the research?