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Update on treatment of AL
amyloidosis
Arnaud Jaccard
IKMG meeting, Montreal, May 2019
Disclosure of Conflict of Interest
Nature of relationship(s)Name of for-profit or not-for-profit organization(s)
Description of relationship(s)
Any direct financial payments including receipt of honoraria
Janssen, Celgene, Takeda, Amgen, Sanofi
Honoraria
Membership on advisory boards or speakers’ bureaus
Janssen Advisory board for Andromeda protocol
Funded grants or clinical trials
Celgene, Janssen Fundings of clinical trials
Patents on a drug, product or device
All other investments or relationships that could be seen by a reasonable, well-informed participant as having the potential to influence the content of the educational activity
◼ Since 2007
◼ Network: 2 centers(Limoges and Poitiers: Frank Bridoux) and 25 competence centers
◼ WeB conference: > 500 cases discussed since 2016
AL amyloidosis
> 90 % plasma cells usually IgG, IgA or free light chains
<10% other B-cell proliferationsusually IgM
MGUS or smoldering myeloma/ CRAB veryuncommun
Very low proliferative index : 0.7% (0-1.6)MM (1.6-3.6%) Blood Jan 25, 2011
Evolution to symptomatic multiple myeloma very rare
1596 patients with AL amyloidosis seen at theMayo Clinic : only 6 evolutions to a symptomatic multiple myeloma with lytic bone lesions orhypercalcemia(Rajkumar et al, 1994)
AL amyloidosis isa MGCS
◼ Light chain oligomers are toxic for the heart:
increased oxidant stress
Increased reactive radicals localized to the mitochondria
Cardiac AL amyloidosis is much more severe than TTR cardiacamyloidosis
Rapid improvement after hematologic response
62 year-old patient with severe cardiac and renal
amyloidosis, CR after one cycle of chemo (VCD)
4 months
NT-proBNP
62 year-old patient with severe cardiac and renal
amyloidosis, CR after one cycle of chemo (VCD)
4 months
Albumine
AL amyloidosis : treatment
◼ Clinical response is often slow (> 1 year). Treatment’s efficacycannot be monitored on clinical response
50 % drop
M-Dex
O1/2007 01/2011
Criteria for hematologic response
Response criteria: low dFLC
• BLOOD, 3 AUGUST 2017 x VOLUME 130, NUMBER 5
« low-dFLC partial response(dFLC <10 mg/L for patientswith a dFLC between 20 and50 mg/L), predicted overalland renal survival already at3 months after the start oftherapy »
Prognosis: depending on cardiac biomarkers and dFLC:
◼ Classic Mayo Staging (1) :
Stage 1 : normal NT-proBNP and troponin
Stage 2: only 1 elevated
Stage 3: both elevated
◼ European way (2):
Idem for 1 and 2
Stage 3a: NT-proBNP < 8500 ng/l
Stage 3 b : NT-proBNP > 8500 ng/l
◼ New Mayo staging (3):
Median NT-proBNT, dFLC, troponin
1, 2, 3 or 4 above the median value
years
years
years
517 patients of the French network
Median survival9,6 yrs5.6 yrs2,1 yrs
2.8 yrs0.4 yrs
5 yrs 81%5.9 yrs3.2 yrs1.4 yrs
1) Dispenzieri, A. et al. J. Clin.Oncol. 22, 3751–3757 (2004).2) Wechalekar, A. D. et al. Blood 121, 3420–3427 (2013).3) Kumar, S. et al. J. Clin. Oncol. 30, 989–995 (2012).
Improvement in survival since 2004
Median survival9,6 yrs5.6 yrs2,1 yrs
242 pts, 1979-2000Mayo Clinic, mainly MP
517 patients of the French network, Mdex, BMDex, VCD
Which treatment?
◼ Depending on the B cell proliferation type
Plasma cells (IgG, IgA, light chains) myeloma treatment
Other B-cell proliferation (IgM) lymphoma or
macroglobulinemia treatment
ASH 2018But
◼BM morphology in 71 patients with IgM AL :
pure plasma cell disorder (PPCD type) in 25% (n=18)
low-grade B-cell lymphoma (LGBCL) with plasmacyticfeatures (LPL type) in 62% (n=44)
◼Genetic:
MYD88 mutation, 88% (22/25) in the LPL type vs 0% inthe plasma cell type
t(11;14) 0% (0/18) in LPL type vs. 60% (9/15) in plasmacell type
Treatment of AL amyloidosis
◼ If the serum level of the amyloidogenic proteindecreases, involved organs are getting better, most ofthe time slowly, with different speed in different organs
◼ Liver > Kidney > heart > macroglossia
Kappa light chain
Gamma-GT
Chemotherapy is not directlyactive on
amyloidosis deposits
Relapse 3 years after ASCT Continuous CR 11 years after 5 cycles
of bortezomib and
dexamethasone
Al amyloidosis therapies, time line and response rates
1965 1995 2000 2003 2006 2012 2019
MP ASCT MDEX30% 65% 67%
Update in 2014: With a median follow-up of 6 years, in patients receiving full-dose dexamethasone, 30% of whom were cardiac stage I, 60% stage II or IIIa, and 10% stage IIIb, the median overall survival was 7.3 years. The hematologic response rate was 76%, with 31% of patients obtaining CR.Palladini G et al. Haematologica. 2014;99(4):743-750.
Al amyloidosis therapies, time line and response rates
1965 1995 2000 2005
MP ASCT MDEX30% 68% 67%
Survival according to arm
0
,2
,4
,6
,8
1
Sur
vie C
um.
0 10 20 30 40 50 60 70 80
months
3,906 1 0,0481
Chi-2 DDL P
56 months
22 months
M-Dex
HDM
Intent to treat
20 deaths
31 deaths
No more ASCT first line after 2007
Any advantage for ASCT 10 years after?
Pts surviving 6 months who received their allotted treatment
HDM (n = 29)
3 M-Dex (n = 37)
Landmark analysis, April 2016
TRM: 0%Feasibility: 100%
MDex
ASCT
Any advantage for ASCT 10 years after? PFS
Whole cohort Landmark analysis
MDex
ASCT
MDex
ASCT
French cohort: 478 ptsMDex +- bortezomib and VCD
Eligible for ASCT n=53: 3 year-survival: 90 %Non eligible for ASCT n=425: 3 year-survival: 61 %P =0,0015
Mdex: 53% Bort based: 26%
Mdex: 32% Bort based: 52%
Clinical Oncology 19, no. 14 (July 15 2001)
Amyloidosis and ASCT
◼ What are the good indications ?
Non responding patients with an IgM
Patients with a symptomatic multiple myeloma and no severe organ involvement
Young patients without severe organ involvement refractory to 2 lines of treatment (but with daratumumab and venetoclax ??)
Al amyloidosis therapies, time line and response rates
1965 1995 2000 2003 2006 2012 2019
MP ASCT MDEX Thalidomide Bortezomib CTD CyborD/VCD
30% 65% 65% 65% 80/94%
Therapeutic strategies after 2007 in France
2007 : M-Dex first line
2009 : M-Dex + bortezomib for non responding patients
after 3 cycles for patients without cardiac involvement
after 1 cycle for patients with cardiac involvement
2011: VCD (bortezomib, cyclophosphamide, dexamethasone) for Mayo stage III patients
Treatment : 6 to 9 months
Survival of refractory patients depending on Mayo staging
28
• The more severe the disease is, the faster you must obtain a response
130 patients< PR at 3 months
29
http//www.cr.amylose-al.frFrench consensus for non IgM AL amyloidosis
Why not bortezomib for all patients ?
M-Dex 6 cycles
Lambda light chain
January 2006 January 2018
How can we progress in 2019 ?
1) Response criteria
Am J Hematol. 2018 Jan;93(1):17-22
ASH 2018
MRD in AL amyloidosis
◼ Flow cytometry
Merlini ASH 2017
◼ 32 patients
◼ Time from CR to MRD: 33 month (5-178 months)
◼ 68% MRD neg
◼ Cardiac and renalimprovement associated to MRD neg (p=0,04)
Mayo Clinic
Proteomic
Organ responses: heart and kidneys
◼ Responses:
Partial : 30 to 59% drop
VGPR: > 60%
CR: NT-proBNP < 450 ng/l
How can we progress in 2019 ?
1) Response criteria
2) Other parameters outside cardiac involvement
Bone marrow studies:
◼ Percentage of bone marrow plasmocytosis(median 7%)
◼ t(11;14) more frequent than in myeloma 50% vs < 16 %
unfavourable with bortezomib + dexamethasone, favourable with M-Dex
Bone marrow studies:
◼ Percentage of bone marrow plasmocytosis(median 7%)
◼ t(11;14) more frequent than in myeloma 50% vs < 16 %
favourable with M-Dex, unfavourable with bortezomib + dexamethasone
Why so many t(11;14) in AL: Database IFM: Jill Core/Hervé Avet-Loiseau
◼ 320 myeloma pts with t(11;14)
– Isotype Lambda : 34%vs 35%
– Light chain myeloma: 36% vs 16%
– MGUS ?
◼ Gain of 1q21, Del 17: unfavourable prognosis
Other parameters outside cardiac involvement
◼ Renal failure, especially if rapidly progressing
◼ Liver amyloidosis with high bilirubin
◼ Peripheral Neuropathy
◼ Young age
How can we progress in 2019 ?
1) Response criteria
2) Other parameters outside cardiac involvement
3) Clinical studies
◼ A high FLC burden (dFLC >180 mg/L) was associated with poorer survival in stage II patients treated with MDex (38% vs. 68% at 3 years, P<0.001) and CyBorD (50% vs. 70% at 3 years, P=0.033), but not in subjects treated with BMDex (67% vs. 70% at 3 years, P=0.401).
BMDex > Mdex or VCD
A Randomized Phase III Trial of Melphalan and Dexamethasone (MDex) versus Bortezomib, Melphalan and Dexamethasone
(BMDex) for Untreated Patients with AL Amyloidosis
Kastritis, E. et al. Blood 128, 646 (2016).
ASH 2016
Response and Survival• 28 patients died, 18 (32%) in the MDex arm and 10 (19%) in the BMDex arm
• The median follow-up of living patients is 33 months
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72
Time (months)
Su
rviv
al p
rob
ab
ility (
%)
P=0.137
MDex
BMDex
Overall survival
P = 0,3545
P = 0.0062
MDEX (39 patients)Median survival 36 months
BMDEX (37 patients)Median survival not reached
Mayo stage II
Mayo stage I Mayo stage III
P = 0,7656
G Palladini
Survival
Treatment in 2019 ? Non IgM
◼ Mdex for stage I with normal renal function
Without any bad prognosis factor
◼ Bone marrow infiltration < 10% (3 drugs if plasmocytosis > 10%)
◼ Not very low albumin
◼ No liver disease with high bilirubin
Add bortezomib if less than VGPR after 2 cycles
◼ Bortezomib-Mdex or VCD for Mayo stage II and IIIA
Bmdex if dFLC > 180 mg/l or t(11;14)
VCD if renal failure or young patients
◼ If severe neuropathy without other bad prognosis factor: Mdex or Lenalidomide Dex
Treatment in 2019 ? Non IgM
◼ Treatment goal:
VGPR + organ response or CR (or dFLC < 10 mg/l)
Rapid modification if bortezomib used and no rapid response
The median time to initial hematological response in these patients was 1month(range, 1–15), while the median time to best hematological response was2 months (range, 1–27). Sixty-one (68.5%) patients achieved PR-dFLC after thefirst cycle of treatment, with dFLC decreasing from a median level of 212.0 mg/L(range, 14.0–2664.4) at baseline to 15.0 mg/L (range, 2.0– 464.0). PR-dFLC afterthe first cycle of treatment was a predictive factor (odds ratio = 39.750; 95% CI
= 10.904– 144.907; p < 0.001) for further VGPR/CR.
81 VCD8 VD
Treatment in 2019 ? Non IgM
◼ Stade IIIB:
Support:
◼Hospi and monitoring +++
◼Hydratation optimization
◼Pacemaker or ICD or cordarone if necessary
VCD or VMDex (if normal renal function)
◼VCD:
– D1 bortezomib D2 cyclophosphamide and Dex 10 mg
– D8 FLC and Dexamethasone dose depending on response
◼ Rapid modification for stage IIIB if no response with VCD:
FLC once a week and decision before C2
Wechalekar AD, et al.. Blood. 2013;121(17):3420-7.Lilleness B et al. Blood. 2019 Jan 17;133(3):215-223
High troponin and NT-proBNP > 8500 ng/l (or BNP > 700 ng/l)
Italian recommendations
1069 AL patients. ASCT first line 21 (2%)Milani P et al. Blood. 2017 Aug 3;130(5):625-631
◊
Survival according to European Mayo staging
1, n=38
2, n=52
3a, n=18
3b, n=37
Cardiac transplantationUnmet medical need
Relapse and refractory patients
1965 1995 2000 2003 2006 2012 2016
MP ASCT MDEX Thalidomide Bortezomib PomalidomideCTD CyborD 70%
30% 65% 65% 65% 80/94% CarfilzomibLenalidomide Ixazomib
60% Bendamustine
And all myeloma regimens: VRD, BVD …..
Dispenzieri, A. et al. Blood 109, 465–470 (2007). Palladini G et al. Blood 129, 2120–2123 (2017).
Sanchorawal V et al. Blood 130, 597–605 (2017). CohenAD et al Blood 128, 645–645 (2016).Milani P et al. 132: 1988-1991. (2018)
But 80% of death for MAYO IIIB
Kastritis E. et al.- ASH® 2018 – Abs.#3248
85% VGPR or CR
AL amyloidosis and relapse
Retrospective study, 104 patients non IgM
Median time for second treatment 23.5 months, median OS after relapse 51 mois,
Villesuzanne C. et al.- ASH® 2018 – Abs.#3297
36%
73%
17%
34%
Hematologic response >= VGPR
Organ response
2 drugs 3 drugs first line second linePI containing regimens
same PFS
88% 87%
50%
25%
Relapse and refractory patients
1965 1995 2000 2003 2006 2012 2016
MP ASCT MDEX Thalidomide Bortezomib PomalidomideCTD CyborD 70%
30% 65% 65% 65% 80/94% IxazomibLenalidomide 60% Carlfizomib
Daratumumab
Kaufman, G. P. et al. Daratumumab yields rapid and deephematologic responses in patients with heavily pretreatedAL amyloidosis. Blood 130, 900–902 (2017).
A Prospective Phase II of Daratumumab in
Previously Treated Systemic Light Chain (AL)
Amyloidosis
Arnaud Jaccard, Anne Marie Stoppa, Aurore Perrot, Lionel Karlin, Bertrand
Arnulf, Margaret Macro, Antoine Huart, Laurent Frenzel, Pierre Morel, Eileen
Boyle, Veronique Dorvaux, Giampaolo Merlini, Giovanni Palladini, David
Lavergne, Frank Bridoux and Murielle Roussel
Amyloidosis Research and Treatment Center
University of Pavia, Italy
Study design:◼ 40 patients,
median 3 lines of treatment
dFLC > 50 mg/l, NT-proBNP < 8500 ng/l
◼ 21 centers in France and 1center in Italy
◼ Once a week during 2 months then twice a month for 4 months
◼ Central lab for immunochemistry and NT-proBNP
FLC: day 1 and 8 cycle 1, day 1 cycle 2 to 6, end of treatment and every 3 months for 1 year
Daratumumab. 6 x 28-day cycles, 16 mg/kg IV ,
Safety and Dosing summary:
◼ 40 patients have been included between September 2016 and April 2018
◼ 34 patients have completed the planned 6 cycles.
◼ Survival
◼ Three patients died during the treatment period Median follow-up: 21.7 [1.5-29] months
◼ Cardiac progression despite a partial response
◼ Cardiac arrest at home (disease progression)
◼ Lung cancer diagnosed after 5 injections
◼ Three patients died of progression after end of treatment
◼ Three patients discontinued study treatment
due to disease progression
◼ No patients stopped study treatment due to side effect
61
Hematological responses at 6 months or at last evaluation in 40 patients (at least 1 cycle of 4 injections)
40 patientsCR 7.5%VGPR 40%PR 7.5%
55%
Best response N (%)
VGPR or better 22 (55%)
PR 4 (10%)
NR 14 (35%)
Global response rate: 65%
-80
-60
-40
-20
0
20
40
60
80
100
120
62
Hematological responses after 1 injection
VGPR = 13 (32,5%)PR = 7 (17,5%)NR = 17 (40,6%)
Missing data: 4
Global response rate: 50 %
For the 23 patients who finally responded, after a single injection of Dara: Median dFLC : 146 mg/l to 39 mg/LMedian decrease in dFLC: 67%Minimum decrease in dFLC: 32%
-20
0
20
40
60
80
100
120
Response over time (treated population)Hematological response by cycle
C1D8 C2D1 C3D1 C4D1 C5D1 C6D1 EOT M3 M6 M9 M12
NR NR NR NR
NR NR
NR NR NR NR NR NR
NR VGPR NR NR NR NR
NR NR NR NR NR
NR NR NR NR NR NR NR
NR NR NR NR NR NR NR
NR NR NR NR NR NR
NR NR NR NR NR NR
NR NR NR PR NR
NR NR NR NR NR
NR NR NR NR NR NR NR
NR NR NR NR NR NR NR
NR NR NR PR NR NR NR
NR NR NR NR
VGPR VGPR VGPR NR NR NR
VGPR VGPR VGPR VGPR NR NR NR
PR PR PR PR PR
NR PR
NR PR PR NR NR NR PR Relapsed
PR PR VGPR PR PR PR PR NR Relapsed
NR PR VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR
NR PR PR VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR
PR VGPR RC RC RC VGPR RC RC
VGPR VGPR RC RC VGPR RC RC RC VGPR RC
VGPR VGPR VGPR VGPR VGPR VGPR RC VGPR VGPR RC RC
Nr VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR
PR VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR
PR VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR
PR VGPR VGPR VGPR VGPR VGPR VGPR
RC VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR
RC VGPR VGPR VGPR VGPR VGPR VGPR VGPR
RC VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR
VGPR VGPR NR NR NR VGPR Relapsed
VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR
VGPR VGPR VGPR VGPR VGPR RC VGPR VGPR VGPR VGPR
VGPR VGPR VGPR VGPR VGPR VGPR VGPR NR VGPR NR NR
VGPR VGPR VGPR VGPR VGPR VGPR VGPR RC VGPR RC
VGPR VGPR VGPR VGPR VGPR VGPR VGPR VGPR
VGPR VGPR VGPR VGPR VGPR VGPR Relapsed
Monotherapy Association
DPomaDex 36%
DRevDex: 32%DBortDex 18%
Organ responses
Median follow-up: 21.7 [1.5-29] months
Cardiac n=24 8 responses (30% decrease in NT-proBNP if baseline >650 ng/L)
Renal n=28 15 responses
(30 % decrease in proteinuria without
25% decrease in creatinine clearance)
◼ 18 patients were in response at the end of treatment (6 cycles)
◼ With a median follow-up of 7,5 (1.4-14.2) months after end of treatment,
4 among these 18 patients have been retreated
Progression
Patient 65 year-old, cardiac, renal, liver and bone
involvement
VCDVRD Dara
Daratumumab in AL amyloidosis: Phase 3 study in newly diagnosed AL (stage 1–3A)
Primary Outcome: Overall Complete Hematologic Response
Secondary Outcomes : Major Organ Deterioration Progression-Free Survival (MOD-PFS); Progression-Free Survival (PFS); Organ Response Rate (OrRR); Overall Survival (OS); QOL measurements; Time to Next Treatment (TNT); Hematologic VGPR; Time to CR and time to hematologic VGPR or better; Duration of CR and duration of hematologic VGPR or better, Time to organ response, Duration of organ response
CyBorD: dexamethasone (40 mg PO or IV, followed by cyclophosphamide (300 mg/m2 PO or IV), then bortezomib (1.3 mg/m2 SC) weekly on Days 1, 8, 15, 22 in every 28-day cycle for a maximum of 6 cycles
CyBorD6 cycles
CyBorD + DARA6 cycles
(Cycles 1-2: DARA QW;Cycles 3-6: DARA Q2W)
RA
ND
OM
IZ
E
N = 370
Survival Follow-
Up
CyB
orD
+ D
AR
A (
10
pts
)
DARA Q4W until PD or start of subsequent therapy or max of 2 years
Previously untreated AL patients with measurable
disease
ClinicalTrials.gov Identifier: NCT03201965Raymond Comenzo (ASCO 2018); Giampaolo Merlini (EHA 2018)
Inclusions should be completed in July
T(11;14) : 50% des patients
Venetoclax-Dex
VCD DaratumumabVRD/VPomaDex VBendaDex
allergy70 year-oldPatient witht(11;14)
Follow-up after treatment
◼ Free light chains and all organ markers
62 year-old woman , severe cardiac amyloidosis in 2006
7 cycles of MDex
NT-proBNP
Lambda light chain detectable in the urine with IF
CR with second line treatment : VCD
VCD
57 year-old man with bone, liver and renal involvement
FLC Kappa
Alcaline Ph
When to retreat?
Depending on initial severity (before NT-proBNP rise )
If dFLC > 50% initial dFLC
If worsening of organ function but beware
◼ Aggravation not due to amyloidosis progression
– Renal failure due to initial nephronic reduction
– Conduction or rhythm disorders
No NT-proBNP progression (40 patients, median survival 62 months)
NT-proBNP progression (20 patients, median survival 17 months).
BAV 1 (PR: 321 ms), bradycardia 54/mn
French Consensus : patients with IgM amyloidosis
But
New strategies : to accelerate deposits elimination
◼ 3 antibodies tested in 2018
2 anticonformartionnal antibodies
1) NEOD001 (2A4)
2) 11-1F4 (Phase I)
1) Anti-SAP antibody after treatment with CPHPC (in vivo SAP KO)
Potential NEOD001 MOA: Neutralizes Soluble Toxic
Aggregates and Clears AL Amyloid Deposits
116 patients 236 patients
Futility study negativeNo difference with
placebo
15 patients
very rapid clearance of
liver deposits :
Heart and kidney ?
July 15, 2015
January 2018
Vascularitis in one patient
No evidence of efficacy outside liver
Third antibody: 11-1F4
Buthani D. et al.- ASH® 2018 – Abs.#958
Treatments
Mel-Dex, BMDex, VCD, ASCTOther anti myeloma regimensAnti-CD38 antibodiesVenetoclax
LC knockdown Si RNA
Randomized trials in progress
Conclusions
◼ Diagnostic before severe heart involvement +++
◼ Amyloidosis typing +++
◼ Severity (Mayo staging) and response taylored treatment +++ (Free light
chain assay and NT-proBNP)
◼ Innovative treatments for severe Mayo stage III
◼ New era is open with anti-plasma cells antibodies and treatments aimed to eliminate deposits (??)
ACKNOWLEDGMENTS
◼ All members of the French network for AL amyloidosis
87
http//www.cr.amylose-al.fr
http//www.unilim.fr/cr-amylose-al.fr
