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REAL WORLD DATA ON THE EFFICACY AND SAFETY OF DARATUMUMAB FOR TREATMENT OF
RELAPSED REFRACTORY AL AMYLOIDOSIS:A MULTI-SITE RETROSPECTIVE STUDY
Tamir Shragai1, Moshe Gatt2, Noa Lavie3, Iuliana Vaxman4, Tamar Tadmor5, Ory Rouvio5, Miri Zektser6, Shai Levi1, Irit Avivi1, Yael C Cohen1
1Tel-Aviv Sourasky Medical Center, Tel-Aviv; 2Hadassah medical center, Jerusalem; 3Rambam Health Care Campus, Haifa; 4Rabin Medical Center, Petah-Tikvah; 5Hematology, Bnei-Zion medical center, Haifa.
6Soroka University Medical Center , Beer-Sheva, Israel
AL Amyloidosis• Plasma cell (PC) dyscrasia; Small, usually indolent PC clone synthesizes an unstable,
misfolded light chain (LC), which is prone to aggregate and form amyloid fibrils
• Causes systemic toxicity and devastating organ dysfunction1,2:
• Heart 75% (restrictive cardiomyopathy)
• kidney 65% (albuminuria→ renal failure)
• Soft tissue 15% (carpal tunnel syndrome, macroglossia…)
• Hepatic 15%
• Neuropathy 10% (peripheral and/or autonomic )
• Gastrointestinal tract 5%
• Other: coagulation / lungs / … any tissue except CNS
• Either primary or secondary to Myeloma
• Incidence 6-12/1 million per year2,3;
• Prevalence (primary AL): 5.8 / 100,000 3
1Merlini, Hematology 20172Gertz, Leukemia & Lymphoma 20183Duhamel, Blood 2017
Treatment approach: Similar regimens as Myeloma
Goal: eliminate PC clone → achieve organ response
=VCD
https://www.msmart.org/treating-al
Prognosis depends on degree of organ dysfunctionand transplant eligibility
Kumar JCO 2012
Revised MAYO score: • FLC-diff >18 mg/dL• cTnT > 0.025 ng/mL• NT-ProBNP > 1,800 pg/mL
Each 1 point
AL Amyloidosis
MM
post ASCT AL Vs MM
Dispenzieri BMT 2013
Stage 4: med OS 6 months
Tתאי
Clinical trials - Daratumumab for R/R AL amyloidosis
Study N Follow-up(months)
%MM
Study design DARATx
Hem ORR
Organ ORR(C/R/L )ɸ %
PFS(median /10 months)
OS
Kaufman1 25 7 NA retrospective monoTx 76% NA NA/ NA NA
Roussel2 30 (24*) NA NA Phase 2 monoTx 63% NA NA/ NA NA
Kimmich3 32 4.5 100 retrospective monoTx 72% 25/50/NA 9.5/NA NR
48 7.9 retrospective monoTx 65% NA 9.5/NA NR
Abeykoon4 44 (30*) 10.2 0 retrospective 22 monoTx22 comb
83% 44/27/0 NR/ 89% NR
* no. of patients included in the final analysis; ɸ cardiac / renal / liver; monoTx – monotherapy; comb – combination; NA – not available; NR – not reached
1kaufman Blood 20172 Roussel Blood 20173 Kimmich Blood 20174 Abeykoon Leukemia 2019
Daratumumab efficacy in AL amyloidosis:deep and durable responses
kaufman Blood 2017 Kimmich Blood 2017Roussel Blood 2017
REAL WORLD DATA ON THE EFFICACY AND SAFETY OF DARATUMUMAB FOR TREATMENT OF RELAPSED/ REFRACTORY AL AMYLOIDOSIS: A MULTI-SITE RETROSPECTIVE STUDY
Study Rationale based on –
• Recent evidence from phase 2 trial of safety and efficacy of DARA in AL
• Availability of daratumumab (health basket / insurance / compassionate)
• Unmet medical need
Daratumumab has recently been incorporated in the routine treatment of AL amyloidosis
Real word evidence provides important complimentary data to that of clinical trials:
• Broad (rather than high selective) target patient population, including patients with severe organ dysfunction
• Variable combination therapy
STUDY GOAL: Analyze real-world outcomes of DARA alone and in combinations for the treatment of AL
amyloidosis, among a multi-site cohort in the Israeli Myeloma centers
Methods
• A retrospective multi-center cohort study
• Population:• Adult patients (>18 years) with histopathological evidence of amyloidosis
• Either primary AL or secondary to Myeloma
• Treated with Daratumumab as monotherapy or in combination.
* Data was collected with RedCAP eCRF
Specific Objectives
• To assess & analyze -
• Patient characteristics
• Treatment patterns
• Hematological Response
• Organ response
• PFS
• OS
• Safety and tolerability
Study endpoints: Treatment Response
• Hematological response was assessed according to Comenzo et al.
• Organ response*:• Cardiac: NT proBNP, BNP, EF, NYHA
• Renal: proteinuria, CCT
• Hepatic: ALKP level
* Response was defined as >30% improvement in the marker’s level.
Comenzo, Leukemia 2012Muchtar, Leukemia 2018
Hematologic response criteria
Comenzo, Leukemia 2012
Results
• 6 clinical sites:• Hadassah; Tel-Aviv Sourasky; Rambam; Bnei-Zion, Rabin; Soroka
• 45 patients identified, 42 evaluable for analysis
• Median follow-up: 10 months (range 2-36).
Patients Characteristics
Age at diagnosis, years
median (range) 59 (34-90)
Age at initiation of DARA, years
median (range) 63.3 (47.2-90)
Males n (%) 26 (62)
Myeloma defining event n (%) 7 (17)
FISH t(11:14 ) n (%) 8 (19)
BM plasmocytosis at diagnosis, %
median (range) 15 (2-100)
Paraprotein type n (%)
Light chain only
IgG
IgA
IgM
27 (66)
11 (27)
5 (12)
1 (2)
Light chain type n (%)
kappa
Lambda
18 (39)
26 (56)
dFLC mg/L median (range) 435.9 (0.3-8763)
Revised Mayo score ≥ 3 n (%) 21 (50)
Organ Involvement
Number of involved organsInvolved Organs
0
10
20
30
40
50
60
70
80
heart kidney PNS GI softtissue
liver other
pat
ien
ts %
4-organs 1-organ
3-organs 2-organs
1 organ: 29%
2 organs: 24%3 organs: 24%
4 organs or more: 24%
Organ Involvement: biomarkers
n
NTproBNP pg/ml
median (range)
24 2700
(480-35,000)
NYHA, n (%)
I
II
III
IV
27
3 (11)
3 (11)
14 (52)
7 (26)
EF %,
median (range)
11 40 (15-65)
n
Proteinuria (mg/24h) median (range)
11 3000 (500-11,700)
Creatinine mg/dL
median (range)
10 1.5
(0.5-3.6)
Cardiac (n=30) Renal (n=25)
Prior treatment lines: Number of previous
treatment lines
med (range)
2 (1-7)
Induction Regimen: VCDVRDMelphalanRd
33431
Previous drug N (%)exposed
N (%)Refractory
Pis:BortezomibCarfilzomibIxazomib
42 (100)5 (12)1 (2)
27 (64)4 (10)
IMiDs: LenalidomideThalidomidePomalidomide
16 (38)9 (21)9 (21)
12 (29)4 (10)8 (19)
Cyclophosphamide 37 (88) 20 (48)
Elotuzumab 2 (5) 1 (2)
Low dose melphalan 7 (17) 3 (7)
HDM/ASCT 5 (12) 3 (7)
Doxycycline 10 (24) 6 (14)
Daratumumab Treatment
• Initiated at median of 16 (2-168) months after diagnosis.
• 11(26%) patients treated as monotherapy, 31 (74%) in combination with other drugs:
• 25 IMiDs (21 lenalidomide, 3 pomalidomide, 1 thalidomide)
• 10 PIs (10 bortezomib, 3 ixazomib)
• 2 Cyclophosphamide.
Hematological Response
63% (26)
22% (9)
15% (6)
ORR 85%(35/41) CR / VGPR
PR
SD /PD
Median time to response: 2 months (range 0.5- 10)Median duration of response: 9 months (range 1-26)
Hematological Response
-100
-80
-60
-40
-20
0
20
40
60
80
100
Monotherapy Combination Therapy
dFL
C%
Ch
ange
800% 200%
Hematological Response
-100
-80
-60
-40
-20
0
20
40
60
80
100
DARA 2nd line
DARA ≥ 3 line
Monotherapy Combination Therapy
dFL
C%
Ch
ange
800% 200%
Cardiac Response
• ORR 57 % (13 of 23 evaluable patients)
• Median time to respond: 5 months (range:1-10)
% Change in NTproBNP
Median change:-702 pg/ml , (-9417 to + 2265)
Improvement in NYHA
n=13 57%
n=14%
n=9 39%
Median improvement:-1 point
n=343%
n=114%
n=343%
Change in EF
Median improvement:+5%
-100
-50
0
50
100
150
200
Renal Response
• Renal responses, as reported by the treating physician, were in 9/17 (53%)
• Median time to response of 6 months
• Median improvement of proteinuria reported for 9 Pts was 2300 mg (57%)
-100
-80
-60
-40
-20
0
% c
han
ge p
rote
inu
ria
Progression-Free and Overall Survivalsince DARA start
PFS OS
12 month PFS 69% 12 month OS 78%
Adverse events
• 32 (76%) remain on Tx
• No patients discontinued d/t
toxicity
• 7 discontinued d/t PD
• No treatment related deaths,
8 Pts in total have died
0 5 10 15 20 25 30 35 40 45 50
nausea-vomiting
DVT-PE
neurotox
other toxicity
Bili increase
neutropenic infection
rash
Infusion - hypersensitivity
diarrhea
renal
cardiovasc tox
Dyspnea
peripheral neuropathy
pneumonia
other infection
All events grade 3/4%
Summary
• We report real world outcomes of 42 PTs with AL amyloidosis, who received DARA with additional anti-myeloma drug combinations, as their second or subsequent line of therapy
• Almost all Pts (85%) achieved a hematologic response, and over half achieved cardiac and/or renal responses
• Safety profile appears typical for this patient population
• While phase 3 clinical trial results will determine the role of DARA in the treatment guideline for AL amyloidosis, our data suggest a favorable safety tolerability and efficacy profile of DARA among nonselective AL amyloidosis patients in a real world setting
Thanks to all contributing investigators !
Dr Moshe Gatt Hadassah Medical Center, Jerusalem
Dr Noa Lavie Rambam Health Care campus, Haifa
Dr Iuliana Vaxman Rabin Medical Center, Petah-Tikvah
Prof Tamar Tadmor Bnei-Zion medical center, Haifa
Dr Ory Rouvio and Dr Miri Zektser Soroka University Medical center, Beer-Sheva
Dr Yael C. Cohen and Prof Irit Avivi Tel-Aviv Sourasky Medical Center
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