Post on 14-Aug-2020
UCL CANCER INSTITUTE
www.ucl.ac.uk/cancer@uclcancer
Prognosis of patients relapsing after frontline ASCT
Kwee Yong
17 May 2019
Disclosures
• Honoraria: Takeda, Amgen, Sanofi, Janssen, Roche, Adaptive
• Research funding: Amgen, Sanofi, Celgene, Takeda, Autolus
• Consultancy: Autolus
What is the pathway for patients relapsing from frontline ASCT?
•Figure adapted from Durie BGM.1 Values for duration and response data from Yong K et al.3
•TTP, time to progression; CR/VGPR, complete response/very good partial response.1. Durie BGM. Concise review of the disease and treatment options. Multiple myeloma, cancer of the bone marrow. International Myeloma Foundation, 2017. Available at: www.myeloma.org/sites/default/files/images/publications/UnderstandingPDF/concisereview.pdf (accessed September 2017); 2. Moreau P, Touzeau C. Am Soc Clin Oncol Educ Book 2015:e504–e511; 3. Yong K et al. Br J Haematol 2016;175:252–264.
Relapse is usually associated with diminishing duration and depth of response over time1–3
Multiple myeloma disease course
Active disease
Remission
Diagnosis
Dis
ea
se
acti
vit
y(M
pro
tein
le
ve
l)
Relapse 1 Relapse 2 Relapse 3
Time
95% 61% 38%
Proportion of patients reaching each line of
therapy
TTP 18 months;74% CR/VGPR
TTP 13 months;58% CR/VGPR
TTP 7 months;43% CR/VGPR
First-line treatment Second-line treatment Third-line treatment Fourth-line treatment15%
21 Months12 Months
8 Months
Focus Form: Patient Pathway from 2L to 3L
5
Information from Census Form
Information from Focus Form
SCT in 1L31% (31%)
Ineligible for SCT in 1L 62% (62%)
SCT in 2L4% (13%)
Ineligible for SCT in 2L62% (100%)
Eligible for SCT in 1L but NO SCT 7% (7%)
NO SCT in 2L27% (87%)
SCT in 2L1% (20%)
NO SCT in 2L6% (80%)
SCT 2L 5%
Receive a 3L anti-tumor drug treatment
62%
No further anti-tumor drug treatment (SC, death…)
38%
Symptomatic MM Patients with a confirmed diagnosis, seem by a Hemato-Oncologists who are treated in 2L 100%*
NO SCT 68%SCT 1L only 27%
(27%)
Do not receive 2L maintenance
4% (83%)
Receive 2L maintenance
1% (17%)
Do not receive 2L maintenance
62% (91%)
Receive 2L maintenance
6% (9%)
Do not receive 2L maintenance
23% (87%)
Receive 2L maintenance
4% (13%)
Bortezomib-based induction therapy followed by second ASCT – Myeloma X
Median TTP (ITT) for ASCT is 19 mo. (95% CI 16, 25) vs 11 mo. (95% CI 9, 12) for C-weekly (HR 0.36 [95% CI 0.25, 0.53]; P<0.0001)
Stem cell remobilisation
Off study
Melphalan 200 mg/m2 IV & ASCT
Cyclophosphamide 400 mg/m2 PO/week x12
n=292
n=110
n=174
n=89 n=85
PD or <2x106/kg CD34+ cells
Bortezomib, doxorubicin & dexamethasone (PAD)
x2–4
Randomisation
Cook G, et al. Lancet Oncol 2014;15:874–85; Cook G, et al. Blood 2015;126: ASH abstract 394
C-weekly, cyclophosphamide weekly; CI, confidence interval; ITT, intent-to-treat; NTC, non-transplant consolidation; PD, progressive disease
TTP
NTC
ASCT2
1.0
0.9
Pro
po
rtio
n p
rogr
essi
on
-fre
e
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Log-RankΧ2
1 = 29.1830P < 0.0001
C-weeklyHDM & ASCT
0 3 6 9 12151821 242730333639424548Months since randomisation
Number at RiskC-weekly
HDM & ASCT8589
7181
6078
4566
2554
1346
1039
828
523
318
213
110
08
Cook,et al, BJHaem, 2019
PFS2 OS
Myeloma X: Second ASCT or chemotherapy at first relapse from ASCT
What factors influence outcomes of patients relapsing from frontline ASCT?
UCLH Retrospective study
Diagnosis RelapseSex M 180 (65%)Median age 57 years (28-70) 60 years (range 30-73)
MM IsotypeIgGIgALight chain only
158 (57%)63 (22.7%)44 (15.9%)
ISS Stage 1Stage 2Stage 3Unknown
88 (31.7%)63 (22.7%)45 (16.2%)81 (29.2%)
113 (40.8%)36 (13%)29 (10.5%)99 (35.7%)
FISHStandard riskHigh riskUnknown
117 (42.2%) 40 (14.4%)120 (43.3%)
61 (22%)72 (26%)144 (52.0%)
Best response post ASCTsCR/CRVGPRPR
40 (14.4%)144 (52%)79 (28.5%)13 (4.7%)
➢ 474 patients received ASCT 2000 – 2012
➢ 269 relapsed at 20 months (95% CI: 18-23)
➢Median follow up 52 months
➢ 171 died at 67 months from ASCT
Chavda SJ, et al. Br J Haematol. 2018; doi: 10.1111/bjh.15487.
Factors influencing survival of relapsed patients
Significant factor HR (95% CI) p-value Non-significantfactors
Early relapse ≤12months
2.64 (1.92 – 3.64 p<0.001 Response pre-ASCT
ISS 2/3 at relapse* 2.52 (1.74 - 3.66 ) p<0.001 Response post-ASCT
Adverse FISH* 2.44 (1.50 - 3.97 ) p<0.001 Response to salvage therapy
Anaemia (Hb≤110g/L ) p<0.001 Renal impairment, hypercalcaemia
* ISS and adverse FISH at diagnosis were also prognostic
Chavda SJ, et al. Br J Haematol. 2018; doi: 10.1111/bjh.15487.
Influence of early relapse on post-relapse and overall survival
Time from relapse (months)
Perc
en
t su
rviv
al
0 50 100 150
0
20
40
60
80
100
relapse <12/12post ASCT
relapse >12/12 post ASCT
Events/n Median (months) 107/196 49
61/73 18
HR 2.64, 95% CI: 1.92- 3.64, p<0.001
OS for relapse ≤12 months and >12 months post ASCT
>12 months 196 129 40 8 0≤12 months 73 13 2 2 0
Time since ASCT (months)
Perc
en
t su
rviv
al
0 50 100 150 200
0
20
40
60
80
100
relapse <12 months post
ASCT
relapse >12 months post
ASCT
Events/n Median (months) 107/196 85
61/73 27
HR 4.47, 95% CI: 3.22- 6.20, p<0.001
Post-relapse survival
Prognostic impact of early relapse on OS
Early385000
Late141932750
0 50 100 150 200
0
20
40
60
80
100
Time from ASCT (months)
Perc
en
t su
rviv
al
Early relapse
Late relapse
27 vs 81 monthsHR 6.15 95% CI 3.90- 9.68p<0.001
CR/VGPR post ASCT
Prognostic impact of early relapse from ASCT
Majithia et al, Leukemia (2016) 30, 2208–2213Ong et al, Bone Marrow Transplantation (2016) 51, 933–937Lee et al, Clinical Lymphoma, Myeloma & Leukemia, Vol. 18, No. 1, e69-75
Features associated with early relapse
Characteristics at relapse 12 months post ASCT
> 12 months post ASCT
p value (chi squared)
Number of patients 73 196
Sex M 48 (66%)F 25 (34%)
M 129 (66%)F 67 (34%)
p=0.99
Median age at relapse 57 (30-71) 61 (38-73) p=0.13
Haemoglobin levels<110g/l>110g/LUnknown
34 (46.6%)30 (41.1%)9 (12.3%)
64 (32.7%)116 (59.2%)16 (8.1%)
p=0.03
ISS stageISS stage 1ISS stage 2/3Unknown
24 (32.9%)23 (31.5%)26 (35.6%)
89 (45.4%)42 (21.4%)65 (33.2%)
p=0.13
FISH at relapse Standard riskHigh riskUnknown
12 (16.4%)23 (31.5%)38 (52.1%)
49 (25.0%)49 (25.0%)98 (50.0%)
p=0.27
Chavda SJ, et al. Br J Haematol. 2018; doi: 10.1111/bjh.15487.
15Myeloma XI – trial outline
CTD
CRD
CVD
No CVD
ASCT (if TE)
Lenalidomide
Observation
Induction 1 Induction 2 Maintenance
R1:1
R1:1
R1:1
Max.
response
VGPR
CR
MR
PR
PD
SD
Patients were ineligible for the CVD randomisation if they had achieved a CR or VGPR to induction (went straight to ASCT if eligible or
maintenance if not) or had PD or SD to induction (all primary refractory received CVD). Patients were ineligible for the maintenance randomisation
if they failed to respond to lenalidomide as their induction IMiD or failed to respond to all trial induction treatment, had PD or had previous or
concurrent active malignancies. Dose adjustments for renal impairment and following AEs were permitted.
• Primary endpoints: PFS and OS for each randomisation
• Phase III, multi-center, open label, parallel group, randomized controlled trial.
• 4420 newly diagnosed, symptomatic, myeloma patients of all ages - with TE and TNE
pathways.
16Patient characteristics of early relapse
• ANAEMIC, HEAVILY INFILTRATED, LAMBDA LC RESTRICTED PATIENT
WITH ISS-3 DISEASE
👤👤👤👤➢ 178 (14%) of 1274 patients relapsed within 12 months of ASCT
➢ These patients had received CTD or CRD induction and, in some by VCD
A: Griepp et al, JCO, 2005, other images courtesy of Ceri Bygrave, ASH 2018
17Landmark Analysis of Myeloma XI
• 1274 patients received ASCT, 14% relapsed within 12m
Characteristic PFS1<12m
n=178
PFS1>12m
n=1096
Lambda LC ↑
% of patients 43.3% 33.6% p=0.0145
Hb ↓
Mean (SD) 104.6g/l (19.2) 111.9g/l (20.1) p<0.0001
PC % ↑
Mean (SD) 45.9% (26.9) 36.7% (25.3) p<0.0001
ISS-3 ↑
% of patients 28.7% 20.3% p=0.0068
No statistically significant difference detected by:
age, gender, paraprotein subtype/concentration or induction therapy
What is the contribution of genetic risk?
Influence of genetic risk and ISS
Time from ASCT (months)
Perc
en
t su
rviv
al
0 50 100 150 200
0
20
40
60
80
100
ISS 2/3
ISS 1
OSforpatientswithISSstage2/3atrelapsecomparedtostage1
ISS111372236 0
ISS2/3652361 0
Time from ASCT (months)
Perc
en
t su
rviv
al
0 50 100 150
0
20
40
60
80
100
Adverse FISH
Standard risk FISH
Events/nMedian(months)
28/6197
48/7259HR2.44,95%CI:1.50-3.97,p<0.001
D OSforpatientswithadverseriskcytogeneticsat
relapsecomparedtostandardriskdisease
Std risk6137154
Highrisk72345 1
UCLH Retrospective study
Chavda SJ, et al. Br J Haematol. 2018; doi: 10.1111/bjh.15487.
Clonal evolution • 71 patients with FISH at diagnosis
and relapse
• Clonal evolution in 20 (28%)
• 95% of patients with adverse FISH at diagnosis had same at relapse
• Patients with adverse FISH had inferior PRS, OS
• OS of patients acquired adverse FISH at relapse = 57 mo vs 69 moin patients with adverse FISH at diagnosis, HR 1.82, 95%CI (0.97-3.49), p=0.08
At Diagnosis New at relapse Additional abnormalities
NIL abnormalities(14)
del (17p) = 6 del(13q) = 1del(13q), 1p loss = 11q gain = 2
1q gain, 1p loss = 2t(4;14) = 21q gain = 31p loss = 1
t(11;14)(2)
1p lossdel(17p)
Hyperdiploidy(1)
1q gain
Del (13q)(2)
del(17p)del(17p), 1q gain
1q gain(1)
del(17p)
21Molecular features of early relapsing patients
Feature,
number (%)
PFS1 <12m
n=87
PFS1 >12m
n=446
p-value
High Risk* 29 (33) 137 (31) 0.00001
Ultra-high Risk* 27 (31) 42 (9) 0.00001
t(4;14) 28 (32) 49 (11) 0.00001
del(17p) 14 (16) 29 (7) 0.0027
gain(1q) 41 (47) 133 (30) 0.0016
• 33% of PFS1<12m patients had one high-risk lesion (HR)
• 31% had two or more (UHiR) – treble rate in PFS1>12m
• Each risk lesion was more common in the PFS1<12m group
*In MXI HR = any one of t(4;14), t(14;16), t(14;20), del(17p), gain (1q), UHR = more than one of above
ISS-MUT
I = ISS 1 and 2 withnoCNA/structural abnormality or mutationII = One CNA/structural abnormality, or ISS 3 with noneIII = 2 or more CNA/structural abnormalities
E. The adverse features thatmake up the hazard ratio (HR) group in the ISS-MUT score
Progression Free survival Overall survival
Identifies 81% of patients relapsing early
Identifies 90% of patients early death
Walker et al, JCO 2014
Immune function in the bone marrow may also influence disease free survival
Marrow infiltrating regulatory T cells in newly diagnosed multiple myeloma associate with greater
frequency of dysfunctional PD-1 expressing CD4 cells and inferior progression free survival
Alrasheed et alEHA 2019, PF563, Submitted for publication
➢ 78 ND MM➢ 59 years (35-86)➢ ISS2/3 43.5%➢ Adverse risk 19%➢ PI treatment 88%➢ CR/VGPR 53.8%
Has early relapse from ASCT changed over time?
Trends in PFS and OS from ASCT
Kumar et al, Leukemia 2018
Proportion of early relapse patients remains unchanged
Kumar et al, Leukemia 2018
Poor outcomes of early relapse
Kumar et al, Leukemia 2018
Some improvement in last 15 years
Chavda SJ, et al. Br J Haematol. 2018; doi: 10.1111/bjh.15487.
A new prognostic model for patients relapsing from upfront ASCT: PFS1 and ISS are independent factors (UCL retrospective study)
0 89 34 7 0
1 66 8 3 1
2 23 2 0 0
0 50 100 150
0
20
40
60
80
100
Time from relapse (months)
Perc
en
t su
rviv
al
0 RF
1 RF
2 RF
Risk score Events/n Median (months) 44/89 65
48/66 34
22/23 10
p<0.001
A
PRS
Risk score
Timing of relapse
ISS stage
0 >12 months 1
1
Either≤12 months
or>12 months
1
2 or 3
2 ≤12 months 2 or 3
OS
0 89 65 21 4 0
1 66 27 8 3 0
2 23 3 0 0 0
0 50 100 150 200
0
20
40
60
80
100
Time from ASCT (months)
Perc
en
t su
rviv
al
0 RF
1 RF
2 RF
Events/n Median (months)
44/89 89
48/65 50
22/23 19
p<0.001
B Risk score
ASCT: autologous stem cell transplant; OS: overall survival; PFS: progression-free survival; PRS: post-relapse survival.
% s
urv
ival
% s
urv
ival
Time from ASCT (months)Time from relapse (months)
Summary
• Strong negative impact of early relapse on post-relapse outcomes and overall survival
• This group of patients may be partly identified at baseline by clinical and genetic features
• New model based on ISS and timing of relapse
• Tumour extrinsic features may also influence timing of relapse
• Influence of genetic risk appears less important when considering
• Proportion of early relapse patients has not changed over time
Acknowledgements
• Selina Chavda
• UCH Clinical Myeloma team
• Nouf Alrasheed
• Sergio Quezada
• Gordon Cook
• Ceri Bygrave, Graham Jackson
• All Myeloma X, XI investigators