Management of light chain amyloidosis.

1. LIGHT CHAIN AMYLOIDOSIS- AN
UPDATE
Dr Kunal Chhattani
Clinical Hematologist, Nagpur

2. AGENDA
1. Diagnosis and Workup
2. Treatment [Daratumumab]

3. INTRODUCTION
 Systemic immunoglobulin light chain (AL)
amyloidosis is caused by the conversion of light
chains (LCs) from their soluble states into highly
organized fibrillar aggregates that deposit in
tissues, resulting in progressive organ damage and
dysfunction.
 -Merlini G et al. Nat Rev Dis Primers. 2018; 4(1):38.

4.  The light chain protein, instead of conforming to the
α-helical configuration of most proteins, misfolds
and forms a β-pleated sheet.
 Weiss BM et al. Increased serum free light chains precede the presentation of immunoglobulin light
chain amyloidosis. J Clin Oncol. 2014;32(25):2699-2704.

5.  Immunoglobulin light chain (AL) amyloidosis is the
most common type of systemic amyloidosis,
accounting for approximately 70% of all systemic
amyloidosis.
 Palladini G, Merlini G: What is new in diagnosis and management of light chain
amyloidosis? Blood 128:159-168, 2016

6.  AL amyloidosis is most frequently encountered in
the elderly population with a mean age of diagnosis
of approximately 60 years and an incidence that
increases with age.
 Quock TP, Yan T, Chang E, et al: Epidemiology of AL amyloidosis: A realworld study
using US claims data. Blood Adv 2:1046-1053, 2018

7.  About 3% to 5% of patients with a known precursor
PC disorder will progress to AL amyloidosis.
 However, even in referral centers, it takes a median
time of almost 1 year to reach the diagnosis, based
on signs or symptoms, in patients with preexisting
PC dyscrasias.
 Kourelis TV et al. Am J Hematol. 2014;89(11):1051-1054.

8. PRESENTATION
Palladini
2022,ASH

9. Palladini
2020 ASH

10. PROCEED WITH-
 Serum and Urine Protein Electrophoresis and
Immunofixation assay
 Free light chain measurement.

11. IF MONOCLONAL COMPONENT DETECTED
Palladini
2020,ASH

12. STAGING
Palladini
2020 ASH

13. 1. Suspect on presentation
2. Monoclonal component
3. Tissue Diagnosis
4. Typing of Amyloidosis
5. Staging

14. FOLLOW UP OF MGUS- RECOMMENDATION
Palladini
2020 ASH

15. CYTOGENETICS
 Translocation t(11;14), present in 61% of
amyloidosis patients, is associated with an adverse
impact on progression-free survival.
 Predicts a lower response rate to bortezomib based
therapies.
 The adverse impact of this translocation can be
overcome with melphalan, stem cell transplantation,
and daratumumab.
 The presence of t(11;14) should always raise the
possibility of venetoclax as a therapeutic option.
-Ozga M, et al. Cancer Med. 2021;10(3):965-973.

16.  Gain 1q, deletion 14q, and deletion 1p appear to
have an adverse prognostic effect.
 Hyperdiploidy seen in 38% of patients is associated
with worse progression free and overall survival.
-Ozga M, et al. Cancer Med. 2021;10(3):965-973.

17. RESPONSE CRITERIA
Palladini

18. TREATMENT

19. TREATMENT
 Chemotherapy for the treatment of amyloidosis was
introduced in 1972 in the form of melphalan and
prednisone.
 Bortezomib is the backbone of frontline therapy in
amyloidosis.
 On January 15, 2021 daratumumab became the
first drug approved by the FDA for the treatment of
AL amyloidosis.
-Kastritis E et al. Daratumumab-based treatment for immunoglobulin light-chain
amyloidosis. N Engl J Med. 2021;385(1):46-58.

21.  Patients with newly diagnosed AL amyloidosis were
randomly assigned to receive six cycles of
bortezomib, cyclophosphamide, and
dexamethasone either alone (control group) or with
subcutaneous daratumumab followed by single-
agent daratumumab every 4 weeks for up to 24
cycles (daratumumab group).
 The primary end point was a hematologic complete
response.

22.  A total of 388 patients underwent randomization.
 The percentage of patients who had a hematologic
complete response was significantly higher in the
daratumumab group than in the control group
(53.3% vs. 18.1%)
 Survival free from major organ deterioration or
hematologic progression favored the daratumumab
group. P=0.02.
 At 6 months, more cardiac and renal responses
occurred in the daratumumab group than in the
control group (41.5% vs. 22.2% and 53.0% vs.
23.9%, respectively).

24.  The four most common grade 3 or 4 adverse
events were lymphopenia (13.0% in the
daratumumab group and 10.1% in the control
group), pneumonia (7.8% and 4.3%, respectively),
cardiac failure (6.2% and 4.8%), and diarrhea
(5.7% and 3.7%).
 A total of 56 patients died (27 in the daratumumab
group and 29 in the control group), most due to
amyloidosis-related cardiomyopathy

28. NEWLY DIAGNOSED HSCT ELIGIBLE PATIENTS
Gertz et.al.
2022 AJH

29.  If Daratumumab is not available, CyBorD is an
acceptable option.
Gertz et.al.
2022 AJH

30. NEWLY DIAGNOSED HSCT INELIGIBLE
PATIENTS
Gertz et.al.
2022 AJH

31.  6 cycles of DaraCyBorD followed by Dara
monotherapy completing 24 cycles
 If Dara not available, CyBorD or BMDex for 6-12
cycles is an acceptable option.
 If <PR after 2 cycles or <VGPR after 4 cycles,
consider changing therapy, unless organ responses
are seen.
Gertz et.al.
2022 AJH

32. Gertz et.al.
2022 AJH

33. NEWER AGENTS
Theodorakakou et.al.,
Hemato 2022

34. Theodorakakou et.al.,
Hemato 2022

35. CONT’D

36. ANTI FIBRIL THERAPY- STILL IN TRIAL PHASE
Palladini
2022 ASH

37. TAKE HOME MESSAGE
 High index of suspicion.
 Search for monoclonal component as early as
possible.
 Look for signs and symptoms of Amyloidosis in
case of MGUS and abnormal light chain ratio.
 Advanced cardiac involvement is the major
determinant of poor outcomes.
 Treatment is Anti-Clone therapy only.
 Dara-CyBorD is the new standard of care.

38. THANK YOU