2021 EHA Big Coffee Interview Professor Cao Xinxin: Interpretation of Research Progress in Light Chain Amyloidosis

Light chain type (AL) amyloidosis is a disease in which the light chain of monoclonal immunoglobulin is misfolded to form amyloid, which is deposited in tissues and organs, causing tissue structure damage, organ dysfunction, and progressive progress.
It is mainly related to clonal plasma It is related to abnormal cell proliferation
.

In recent years, the application of new drugs such as proteasome inhibitor (PI) and CD38 monoclonal antibody has greatly improved the prognosis of AL amyloidosis
.

On the occasion of the 26th Annual Meeting of the European Society of Hematology (EHA), Yimaitong has the honor to invite Professor Xinxin Cao from Peking Union Medical College Hospital to share the latest research progress on AL amyloidosis at this EHA conference
.

Q1: The current treatments for AL amyloidosis all target clonal plasma cells.
The current treatment goal is high-quality hematological relief
.

Patients with rapid hematological remission have a better prognosis, but relevant data are limited
.

In response to this, what data does this EHA meeting provide as support? Professor Xinxin Cao presented two posters at this EHA conference that demonstrated the impact of rapid hematological remission on the prognosis of AL amyloidosis patients
.

[EP1000] The first is a retrospective study from London, UK, which included 1133 patients with AL amyloidosis who used bortezomib as the first-line treatment between 2010 and 2019.
The results of the study showed that the 1-month hematological remission rates were respectively They were: complete remission (CR) 11.
5%, very good partial remission (VGPR) 22.
6%, partial remission (PR) 21.
1%, and no remission (NR) 31.
1%
.

The median OS of patients with ≥VGPR at 1 month has not yet reached, while the median OS of patients with only PR or NR was 60 months and 32 months, respectively, and the difference between the two groups was statistically significant
.

Further analysis also found that patients with CR and affected serum free light chain (iFLC) <20mg/L had significantly better survival than those with CR but iFLC>20mg/L
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At the same time, the study also found that in all patients with Mayo staging, the prognosis of patients who reached ≥VGPR in 1 month was better than that of patients who did not achieve VGPR
.

[EP1053] Another poster is a study from Italy.
A total of 52 high-risk patients in Mayo2012 stage III and IV who received first-line treatment with bortezomib were enrolled.
On the 30th day of treatment, 11 patients had CR and 12 patients Patients received VGPR, 14 patients and 15 patients received PR and NR, respectively.
The median OS of patients ≥VGPR was 43 months, while the median OS of PR patients was 24 months, and the median OS of NR patients was only 11 Month, the difference between groups is also statistically significant
.

The study also found that some patients who got PR and NR on the 30th day could still get VGPR after 6 months of treatment, suggesting that patients who only got PR on the 30th day may not need to change the treatment plan
.

[Experts' comments] The goal of treatment for AL amyloidosis is always faster and deeper hematological relief.
Combining the above two posters, it can be seen that patients who get ≥VGPR after a course of treatment do have better survival
.

The previous data of Peking Union Medical College Hospital also suggests that patients who have achieved ≥PR hematology curative effect in one course of treatment have a better prognosis
.

Therefore, for patients who fail to achieve PR after a course of treatment, the treatment plan should be replaced earlier in order to achieve faster remission
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Q2: In the 2021 NCCN guidelines and CSCO guidelines for diagnosis and treatment of hematological malignancies, daratumumab combined with CyBorD (cyclophosphamide, bortezomib, dexamethasone) are included in the newly diagnosed AL amyloidosis category Recommended
.

At this year's EHA meeting, what are the new developments in the treatment of AL amyloidosis with daratumumab? Professor Xinxin Cao has updated two research data on the treatment of AL amyloidosis with daratumumab in this year's EHA
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[S189] This article is a long-term follow-up update of the "Andromeda" study, comparing the efficacy of daratumomab combined with VCd (bortezomib + cyclophosphamide + dexamethasone) and VCd
.

As of November 2020, the median treatment time of the two groups was 18.
5 and 5.
3 months, respectively
.

After prolonging the follow-up time, the analysis found that whether it was CR rate, VGPR rate, median time ≥ VGPR, or cardiac remission rate and renal remission rate, the daratumumab+VCd group was significantly better than the VCd group
.

In terms of adverse reactions, there were no unpredictable adverse reactions in the daratumomab+VCd group, and no grade 3/4 adverse events with an incidence of ≥5%
.

[EP1036] The other is a multi-center phase II clinical study from Europe.
It is planned to enroll 40 newly diagnosed Mayo2004 IIIb AL amyloidosis patients from 4 countries and receive first-line treatment with daratumomab.
For patients who have not achieved VGPR or PR patients who have not achieved cardiac/renal remission, the investigator may decide to add bortezomib and low-dose dexamethasone treatment starting from the fourth cycle
.

As of January 31, 2021, a total of 7 patients were enrolled, with a median age of 65 years and a median of 13 cycles of treatment
.

4 patients are still receiving treatment, including 1 PR, 2 VGPR, and 1 MRD-negative CR
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Three patients died due to disease complications during treatment; no patients died of treatment-related cardiac complications
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The 6-month OS rate was 57.
1%
.

This early analysis showed that Dara monotherapy is safe, and there are no treatment-related safety events or any signs of cardiotoxicity in stage IIIb patients
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The research is continuing, and as more patients are enrolled, there will be more safety and efficacy data
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[Experts' comments] At present, 20 patients with primary AL amyloidosis in Peking Union Medical College Hospital have received treatment with daratumomab-containing regimen.
Among them, only one patient was NR, and the other 19 patients received hematology.
Remission, the fastest time to remission is about 7 days, that is, hematology effect is achieved after one dose of daratumumab treatment
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However, while obtaining good curative effects, the 6-month mortality rate is still about 30%.
It can be seen that the treatment of Mayo2004 IIIb or Mayo2012 IV patients is very difficult
.

In all previous studies of daratumumab, almost no patients in Mayo2004 phase IIIb were enrolled, so for these ultra-high-risk AL amyloidosis patients, how to choose daratumumab and which drugs should be combined for treatment , Is the current clinical problem that needs to be solved urgently
.

Peking Union Medical College Hospital is carrying out a clinical trial using daratumomab combined with bortezomib and dexamethasone to treat patients with Mayo2004 phase III amyloidosis.
It is hoped that this clinical trial can solve this part of the problem
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Q3: The ideal treatment goal for AL amyloidosis is to remove amyloid deposits and obtain organ relief
.

There are currently some drugs that target amyloid deposits in the development stage
.

At this EHA meeting, what are the latest developments in these drugs? Professor Cao Xinxin has two posters at this EHA conference that reported the same study of the amyloid-targeted monoclonal antibody CAEL101.
The study is divided into two parts, including Mayo phase I, II and IIIa AL amyloid For degenerative patients, part A is treated with CAEL101 combined with VCd regimen, and part B is treated with CAEL101 combined with daratumomab and VCd regimen
.

[EP1017] The first poster mainly reported the safety of using the maximum tolerated dose of 1000 mg/m2 CAEL-101 combined with VCd or combined with daratumumab + VCd
.

A total of 22 patients were enrolled in the study, of which stage I patients accounted for 9.
1%, stage II patients accounted for 68.
2%, stage IIIa patients accounted for 22.
7%, 72.
7% of patients had cardiac involvement, and 68.
2% of patients had received at least one anti-plasma Cell disease treatment
.

During the 4-week safety observation period, the overall safety of the patient was good, and the most common adverse events included nausea, constipation, rash, and fatigue
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In this study, there was no treatment-related death case, and only one death case from septic pneumonia, but it was considered unrelated to the study drug
.

It can be seen that CAEL101 combined with VCd or combined with daratumumab + VCd is safe and tolerable for patients with AL amyloidosis
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[EP1018] Another poster reported the safety long-term follow-up results of Part A of the study.
A total of 13 patients were enrolled, and the median treatment was 38 weeks.
Common adverse reactions included diarrhea (46.
2%), nausea (46.
2%), Skin rash (38.
5%) and anemia (38.
5%)
.

Through NT-proBNP and cTnT assessment, no patients progressed, and the heart disease was stable
.

Overall, the safety of CAEL101 is good, but its efficacy needs further research and verification.
There are currently two ongoing phase III clinical trials that are evaluating CAEL-101 in Mayo IIIa and IIIb patients with AL amyloidosis.
Safety and effectiveness
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[Expert's Comment] At present, the core treatment of AL amyloidosis is mainly the treatment of clonal plasma cells
.

In addition, supportive treatment is very important for patient management in clinical work, especially for patients with heart involvement
.

Doctors need to instruct patients to manage their water load and educate patients to monitor their weight every day.
If weight gains may need to increase the use of diuretics; for patients with orthostatic hypotension, doctors need to instruct patients to exercise slowly to prevent orthostatic hypotension
.

It needs to be emphasized that hematological remission is the basis of organ remission
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Therefore, there is an urgent need for drugs targeting amyloidosis in clinics to enable patients to achieve organ remission faster and better.
It is hoped that new drugs such as CAEL101 can be put into clinical application as soon as possible to benefit more patients with AL amyloidosis
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Professor Xinxin Cao, Deputy Chief Physician, Department of Hematology, Peking Union Medical College Hospital, and supervisor of master's students, Member of the Hematology Branch of the Chinese Medical Association, Member of the Tissue Cell Disease Committee of the Chinese Medical Doctor Association, Member of the Hematology Specialist Branch of the Beijing Medical Association, Member of the Hematology Society of Beijing Medical Association Youth Committee of China Anti-Cancer The main professional direction of the young members of the Association's Hematology Oncology Committee: plasma cell, histiocytoma, "read the original text", we make progress