Prognosis of patients relapsing after frontline ASCTcme-utilities.com/mailshotcme/Material for Websites/COMy... · 2019-05-18 · Eligible for SCT in L but NO SCT 7% (NO SCT in 2

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



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%)


62% (91%)


6% (9%)


23% (87%)


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


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


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

http://jco.ascopubs.org/content/23/15/3412/F5.large.jpg

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


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


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


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


Poor outcomes of early relapse


Some improvement in last 15 years


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


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

Documents

Prognosis of patients relapsing after frontline ASCTcme-utilities.com/mailshotcme/Material for Websites/COMy... · 2019-05-18 · Eligible for SCT in L but NO SCT 7% (NO SCT in 2