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