assessing response in multiple myeloma cfz-deu-amg-1697-2014-november-np note: carfilzomib is an...

Assessing response in multiple myeloma

CFZ-DEU-AMG-1697-2014-November-NP

Note: Carfilzomib is an investigational product and is not licensed in the EU

Section

Multiple myeloma: burden of disease and evolving treatment paradigmsWhy is the assessment of response important?

What is the clinical value of response assessment?

What is beyond complete response?

Clinical value of detecting minimal residual disease

Assessing response in multiple myeloma

Multiple myeloma: burden of disease and evolving treatment paradigms

• Multiple myeloma (MM) is a B-cell malignancy derived from antibody-producing plasma cells in bone marrow (BM)

• Myeloma cells crowd out and interfere with development and function of normal cells in BM

• Abnormal accumulation of myeloma cells in BM and production of monoclonal (M)-protein have direct and indirect effects on the blood, skeleton and kidneys

International Myeloma Foundation. Multiple myeloma. Available at: http://myeloma.org/pdfs/CR2011-Eng_b1.pdf [Accessed September 2014].Multiple Myeloma Research Foundation. Multiple myeloma disease overview. Available at: http://www.themmrf.org/assets/mmrf-disease-overview.pdf [Accessed September 2014].

Multiple myeloma is a neoplastic, plasma cell malignancy

• Globally, almost 230,000* individuals living with MM1

– Highest prevalence in USA, Europe, Australia and New Zealand• 2nd most common haematological malignancy2

1. International Agency for Research on Cancer. GLOBOCAN 2012 database. Available at: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx [Accessed September 2014]; 2. Dimopoulous MA, et al. Eur J Haematol 2011;86:1–15.

*5-year prevalence; †1-year incidence

Epidemiology and mortality burden of MM

Estimated new cases annually

% of all new cancer cases

Estimated deaths annually

% of all cancer deaths

114,251† 0.8 80,015 1.0

GLOBOCAN 2012: estimated incidence and mortality1

Classification Criteria1–4

Monoclonal gammopathy of unknown significance (MGUS)

• M-protein in serum (< 30 g/L)• No active plasma cell disorder (BM clonal plasma

cells < 10%)• Asymptomatic with no signs of end-organ damage

Smouldering (asymptomatic) MM

• M-protein in serum ≥ 30 g/L and/or BM clonal plasma cells ≥ 10%

• Asymptomatic with no signs of end-organ damage

Symptomatic,active MM

• Presence of M-protein in serum and/or urine• BM clonal plasma cells ≥ 10% or biopsy proven plasmacytoma• End-organ damage determined by the presence of one or more

‘CRAB’ features as defined on the following slide

1. International Myeloma Working Group. Br J Haematol 2003;121:749–757; 2. Kyle RA, Rajkumar SV. Leukemia 2009;23:3–9;3. Moreau P, et al. Ann Oncol 2013;24(Suppl 6):vi133–vi137; 4. Bird JM, et al. Br J Haematol 2011;154:32–75.

CRAB, hyperCalcaemia, Renal impairment, Anaemia, Bone disease;

IMWG, International Myeloma Working Group

Diagnosis and classification should be made using IMWG criteria

• HyperCalcaemia (corrected serum calcium > 0.25 mmol/L above ULN or > 2.75 mmol/L)

• Renal impairment attributable to MM (creatinine > 173 mmol/L)

• Anaemia (haemoglobin 2 g/dL below LLN or < 10 g/dL)

• Bone disease (lytic lesions or osteoporosis with compression fractures [MRI or CT scan may clarify])

Bird JM, et al. Br J Haematol 2011;154:32–75.

CT, computed tomography; LLN, lower limit of normal;

MRI, magnetic resonance imaging; ULN, upper limit of normal

The presence of CRAB features indicates a need for intervention

Kyle RA, Rajkumar SV. Leukemia 2009;23:3–9;American Cancer Society. Multiple myeloma. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003121-pdf.pdf [Accessed September 2014].

CBC, complete blood count; FLCs, free light chain;

PET, positron emission tomography; SPEP, serum protein electrophoresis;

UPEP, urine protein electrophoresis

Several diagnostic techniques should be used to confirm a case of suspected MM

• Immunophenotyping e.g. flow cytometry• Conventional cytogenetics• Fluorescence in situ hybridisation (FISH)• BM plasma cell labelling (prognostic value)

BM aspirate

• X-ray (bone destruction)• CT, MRI and/or PET scans

Imaging techniques

MM diagnosis

• FLCs when no M-protein detected by SPEP• Quantitative immunoglobulins in blood• β2-microglobulin (prognostic indicator)

• Identification of M-protein in serum (SPEP)• Identification of M-protein fragments in

urine (Bence-Jones protein; UPEP)

• Red and white blood cells, and platelets• Blood urea nitrogen and creatinine• Albumin, Ca and other electrolytes

Other

SPEP and UPEP

CBC and blood

chemistry

Laboratory tests

Mehrotra R, et al. Cytojournal 2007;4:9.

BM clonal plasma cells in MM

BM clonal plasma cells

Best Practice New Zealand. Making sense of serum protein bands. Available at: http://www.bpac.org.nz/BT/2011/July/serum-protein.aspx [Accessed September 2014].

Measuring proteins in serum and urine permits diagnosis and monitoring of MM

M-proteinspike

Example of densitometry following SPEP

Albumin α2α1 β γ

Normal

MM

• Skeletal survey by X-ray permits evaluation of bone lesions and diagnosis

GPonline. Haematology – Multiple myeloma. Available at: http://www.gponline.com/haematology-multiple-myeloma/haematology/article/1058325 [Accessed September 2014];Healy CF, et al. Bone Marrow Res 2011;2011:583439.

X-ray imaging is useful in the evaluation of bone lesions in suspected MM

Bonelesions

CT1 MRI2

1. Talamo G. Bone lesions. Available at: http://www.myelomapennstate.net/Contents/04a-ClinManifest.htm [Accessed September 2014]; 2. Terada T. Cases J 2009;2:9110.

CT imaging and MRI are also useful in the evaluation of lesions in suspected MM

Bone lesion Plasmacytoma

• PET provides a whole body image and shows only active MM lesions

• PET is especially useful in determining response to treatment– Superior to MRI• Inactive lesions identified on

MRI can lead to a false-positive result

Talamo G. Evaluation of bone disease. Available at: http://www.myelomapennstate.net/Contents/10a-BoneDis-PET.htm [Accessed September 2014]

PET is useful in determining response to treatment

Bone lesions with activemetabolic uptake

Adapted from O'Connor, C. Fluorescence in situ hybridization. Available at: http://www.nature.com/scitable/topicpage/fluorescence-in-situ-hybridization-fish-327 [Accessed September 2014].

FISH; fluorescence in situ hybridisation

The assessment of genetic abnormalities has prognostic value

Detection of chromosomal deletion by FISH

Deletion of one copy of chromosome 13

detected

BMsample

Smear ofcells

Chromosome 13-specific fluorescent probe

Analyse under fluorescence microscope

Hybridise

Chromosome 10-specific fluorescent probe

Adapted from Andres. Springer ebook, 2009.

cDNA, complementary deoxyribonucleic acid; RNA, ribonucleic acid

Gene express profiling may be useful in the stratification of risks

Malignant cells harvested from patient

Purified RNA

Application of fluorescent probes

Reverse transcription

Synthesised cDNA

Microarray chip with hybridised

cDNA probe

OS from diagnosis between 1971 and 2006 (N = 2,981)1

OS from diagnosis between 2001 and 2010 (N = 1,038)2

Kumar SJ, et al. Blood 2008;111:2516–2520; Kumar SK, et al. Leukemia 2014;28:1122–1128.

*Trend in improvement in this time period thought to be due to high-dose

therapy (HDT) and supportive care

Overall survival (OS) in MM continues to improve vs. historical estimates

Patie

nts

aliv

e (%

)

20 40 60 80 100 1200

Time (mo.)

2001–20061994–2000*1989–19941983–19881977–19821971–1976

0

20

40

60

80

100 1.0

0.8

0.2

0.6

0.4

0.00 1 2 3 4 5 6

Follow up from diagnosis (years)

Prop

ortio

n su

rviv

ing

2006–20102001–2005

Kumar SK, et al. Leukemia 2014;28:1122–1128.

Improvements in survival have been attributed to the use of novel agents

0.8

0.6

0.4

0.2

0.0 0 1 2 3 4 5 6

Prop

ortio

n su

rviv

ing

Follow up from diagnosis (years)

1.0

P < 0.001

Received novel agents* (n = 621)No novel agents (n = 417)

*Bortezomib (BTZ), lenalidomide (LEN) or thalidomide (THAL)

as part of initial therapy

Note: Carfilzomib is an investigational product and is not licensed in the EU

ASCT, autologous stem cell transplant; CFZ, carfilzomib;

POM, pomalidomide

Several novel therapies have been approved for treatment of MM

Approval dates of novel agents

2013POM (USA, EU)

1980s 1990s 2000s

1999THAL(USA)

2002BTZ(US)LEN(USA)

2004BTZ

(EU)

2007LEN(EU)

2010s

1983ASCT

2008THAL(EU)

2012CFZ(USA)

Comparative OS in patients receiving/not receiving novel agents after first relapse* (N = 387)

Kumar SK, et al. Blood 2008;111:2516–2520.

*BTZ, LEN or THAL as part of therapy following relapse after ASCT

Prognosis after relapse is always poor

The vast majority of relapsed MM patients treated with current therapies do not achieve optimal responses

0.8

0.6

0.4

0.2

0.00 20 40 60 80 100

Prop

ortio

n su

rviv

ing

Exposed to new drugs (n = 161) No exposure to new drugs (n = 226)

1.0

Time from after ASCT relapse (mo.)

P < 0.001

• MM is associated with a significant clinical burden that affects almost 230,000 individuals worldwide

• Diagnosis of symptomatic MM requires observation of:– M-protein in serum and/or urine– BM clonal plasma cells or biopsy-proven plasmacytoma– Hypercalcaemia, renal impairment attributable to MM, anaemia and/or bone

disease (CRAB criteria)• The availability of novel therapies has led to improvements in survival vs.

historical estimates• The vast majority of relapsed MM patients treated with current therapies

do not achieve optimal responses

Summary

Why is the assessment of response important?

Martinez-Lopez J, et al. Blood 2011;118:529–534;Harousseau JL, et al. Haematologica 2010;95:1738–1744.

Evidence shows deeper responses correlate with improved symptom control and survival

1 × 1012

Stringent CR(sCR)

Immunophenotypic CRMolecular CR

Cure?

Diseaseburden

Newly diagnosed

1 × 108

1 × 104

0.0?

Complete response (CR)

1 × 106

Median response duration OS

Kumar SK, et al. Mayo Clin Proc 2004;79:867–874.

578 patients were seen between 1 January 1985 and 31 December 1998

With subsequent lines of therapy, the duration of response decreases

Treatment line

Med

ian

resp

onse

du

ratio

n (m

o)

12

10

8

6

4

2

0First Second Third Fourth Fifth Sixth

Treatment line

1.0

0.8

0.2

0.6

0.4

0.0

Years from initiation of regimenCu

mul

ative

pro

babi

lity

0 2 4 6 8 10

FirstSecondThirdFourthFifthSixth

Bladé J, Rosiñol L. Haematologica 2009;94:163–166;Martinez-Lopez J, et al. Blood 2011;118:529–534;International Myeloma Foundation. About BSRI®. Available at: http://myeloma.org/ArticlePage.action?tabId=0&articleId=3982 [Accessed September 2014].

The availability of novel treatments has led to more ambitious treatment goals

Disease stabilisation

Achievement of deeper, more durable responses

Cure?

Continuing treatment even after response to further deepen response and improve outcomes?

1. Ballester OF, et al. Br J Haematol 1997;96:746–748; 2. Bladé J. Br J Haematol 1998;102:1115–1123; 3. Richardson PG, et al. Oncology (Williston Park) 2005;19:1781–1792; 4. Durie BG, et al. Leukemia 2006;20:1467–1473; 5. Kyle RA, Rajkumar SV. Leukemia 2009;23:3–9; 6. Rajkumar SV, et al. Blood 2011;117:4691–4695.

nCR, near complete response; sCR, stringent complete response; VGPR, very good partial response

More ambitious treatment goals demand increasingly rigorous response criteria

Years

Incr

easi

ng s

trin

genc

y

1990 2000 2010

1998CR defined, but modified to include nCR2,3

2003VGPR defined3

2006nCR and VGPR combined, sCR introduced4,5

2011Immunophenotypic

and molecular CRintroduced6

1997nCR introduced1

Durie BG, et al. Leukemia 2006;20:1467–1473.

The use of more rigorous response criteria improves patient evaluation

• Better comparisons between different treatment strategies in specific patient types

• More accurate means to compare the efficacy of different treatment approaches

• More reliable assessment of quality/depth of response

• Improved detection accuracy and easier monitoring/predication of relapse

Tailored therapy

Comparisons of efficacy

Improved reliability

Better monitoring

• The use of consistent and increasingly rigorous response criteria is anticipated to facilitate:

Category Criteria

Complete response (CR) • Negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, < 5% plasma cells in BM

Near complete response (nCR) • Absence of M-protein on electrophoresis, stable bone disease and normal serum calcium

Partial response (PR)• ≥ 50% reduction of serum M-protein, ≥ 90% reduction in 24-hr urinary M-protein

(or to < 200 mg/24 hrs)• ≥ 50% reduction in size of plasmacytomas

Minimal response (MR) • 25–49% reduction of serum M-protein, 50–89% reduction in 24-hr urine M-protein• 25–49% reduction in size of soft tissue plasmacytomas

No change(Stable disease [SD]) • Not meeting criteria for CR, nCR, PR, MR or PD

Progressive disease (PD)

• > 25% increase from lowest response value in serum M-protein (absolute increase ≥ 5 g/L) or in 24-hr urinary M-protein (absolute increase ≥ 200 mg/24 hrs)

• > 25% increase in plasma cells in BM• Development of new bone lesions or soft tissue plasmacytomas• Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or

2.8 mmol/L) not attributable to any other cause

Bladé J, et al. Br J Haematol 1998;102:1115–1123; Richardson PG, et al. N Engl J Med 2003;348:2609–2617.

EBMT, European Group for Blood and Marrow Transplantation

Evolution in definitions of response:modified EBMT criteria (2003)

• nCR, while used in many trials, is no longer recommended

Category Criteria

Molecular CR • CR plus negative allele-specific oligonucleotide polymerase chain reaction (ASO-PCR); sensitivity 10−5

Immunophenotypic CR • Absence of phenotypically aberrant clonal plasma cells in BM with minimum of 1 million BM cells analysed by ≥ 4-colour multiparametric flow cytometry (MFC)

Stringent complete response (sCR)

• CR as defined below plus normal FLC ratio and absence of clonal plasma cells by immunohistochemistry or 2- to 4-colour flow cytometry


Very good partial response (VGPR)

• Serum and urine M-protein detectable by immunofixation but not electrophoresis, or, ≥ 90% reduction in serum M-protein with urine M-protein < 100 mg/24 hrs

Partial response (PR)

• ≥ 50% reduction of serum M-protein, ≥ 90% reduction in 24-hr urinary M-protein (or to < 200 mg/24 hrs), ≥ 50% reduction in size of soft tissue plasmacytomas if present at baseline

• If M-protein immeasurable: ≥ 50% reduction in difference between involved and uninvolved FLC levels or, if FLC also not measurable, ≥ 50% reduction in BM plasma cells provided baseline BM plasma cell percentage was ≥ 30%

Minimal response (MR) • 25–49% reduction of serum M-protein, 50–89% reduction in 24-hr urine M-protein• 25–49% reduction in size of soft tissue plasmacytomas if present at baseline

Stable disease (SD) • Not meeting criteria for sCR, CR, VGPR, PR, MR or PD

Progressive disease (PD) • 25% increase from lowest response value in serum M-protein (absolute increase ≥ 0.5 g/dL) and/or urine M-protein (absolute increase ≥ 200 mg/24 hrs)

Rajkumar SV, et al. Blood 2011;117:4691–4695.

Evolution in definitions of response: IMWG consensus recommendation (2011)

Category Criteria

Molecular CR • CR plus negative ASO-PCR; sensitivity 10−5

Immunophenotypic CR • sCR with absence of phenotypically aberrant clonal plasma cells in BM with minimum of 1 million total BM cells analysed by MFC (≥ 4 colours)

Stringent complete response (sCR)

• CR as defined below plus normal FLC ratio and absence of clonal plasma cells by immunohistochemistry or 2- to 4-colour flow cytometry


Very good partial response (VGPR)

• Serum and urine M-protein detectable by immunofixation but not electrophoresis, or, ≥ 90% reduction in serum M-protein with urine M-protein < 100 mg/24 hrs

Partial response (PR)

• ≥ 50% reduction of serum M-protein, ≥ 90% reduction in 24-hr urine M-protein (or to < 200 mg/24 hrs), ≥ 50% reduction in size of soft tissue plasmacytomas if present at baseline

• If M-protein immeasurable: ≥ 50% reduction in difference between involved and uninvolved FLC levels or, if FLC also not measurable, ≥ 50% reduction in BM plasma cells provided baseline BM plasma cell percentage was ≥ 30%

Moreau P, et al. Ann Oncol 2013;24(Suppl 6):vi133–vi137.

ESMO, European Society for Medical Oncology

Evolution in definitions of response: ESMO clinical practice guidelines (2013)

• Evidence shows deeper responses correlate with improved symptom control and survival

• With subsequent lines of therapy, durations of response decrease• The availability of novel treatments has led to more ambitious

treatment goals• More ambitious treatment goals demand increasingly rigorous

response criteria• More rigorous response criteria improve patient evaluation• Consensus definitions of response have evolved in line with improved

outcomes and improved techniques for the detection of residual disease

Summary

What is the clinical value of response assessment?

Publication Regimen CR (%)

Patients ineligible for transplant and HDT

Palumbo A, et al. 20101 BTZ, MEL, PRED (VMP) 24

Facon T, et al. 20072 MEL, PRED, THAL (MPT) 13

Palumbo A, et al. 20123 MEL, PRED, LEN (MPR)* 31

Patients eligible for transplant

Sonneveld P, et al. 20124 BTZ, DOX, DEX (PAD) 36

Rosiñol L, et al. 20125 BTZ, THAL, DEX (VTD) 35

Kumar S, et al. 20126 BTZ, CYCLO, DEX (VCD) 22

Roussel M, et al. 20147 LEN, BTZ, DEX (RVD) 58

1. Palumbo A, et al. J Clin Oncol 2010;28:5101–5109; 2. Facon T, et al. Lancet 2007;370:1209–1218; 3. Palumbo A, et al. N Engl J Med 2012;366:1759–1769; 4. Sonneveld P, et al. J Clin Oncol 2012;30:2946–2955; 5. Rosiñol L, et al. Blood 2012;120:1589–1596; 6. Kumar S, et al. Blood 2012;119:4375–4382; 7. Roussel M, et al. J Clin Oncol 2014;32:2712–2717.

*Note: not currently approved in the EUCYCLO, cyclophosphamide;

DOX, doxorubicin; MEL, melphalan; PRED, prednisone

Responses to current therapies in newly diagnosed patients, based on approval status

Publication Prior therapies (median) Regimen CR

(%)TTP

(mo.)

Dimopoulos MA, et al. 20091 ≥ 1 (2)2 LEN, DEX (RD) 15 13.4

Richardson PG, et al. 20073 1–3 (2)4 BTZ (V; single agent) 9 6.2

Orlowski RZ, et al. 20075 ≥ 1 (NR) BTZ plus pegylated liposomal DOX 4 9.3

Siegel DS, et al. 20126 Placeholder for 003-a1 data (due to approval status in EU)

Richardson PG, et al. 20147 > 2 (5) POM, low-dose DEX (Pd) 3 4.2

Placeholder for ASPIRE data (due to approval status in EU)

1. Dimopoulos MA, et al. Leukemia 2009;23:2147–2152; 2. Dimopoulos MA, et al. N Engl J Med 2007;357:2123–2132; 3. Richardson PG, et al. Blood 2007;110:3557–3560; 4. Richardson PG, et al. N Engl J Med 2005;352:2487–2498; 5. Orlowski RZ, et al. J Clin Oncol 2007;25:3892–3901; 6. Siegel DS, et al. Blood 2012;120:2817–2825; 7. Richardson PG, et al. Blood 2014;123:1826–1832; 8. Moreau P, et al. Ann Oncol 2013;24(Suppl 6):vi133–vi137.

TTP, time to progression

Treatment responses in relapsed or relapsed/refractory MM

• The choice of therapy in the relapsed setting depends on:8

— Patient factors e.g. age, performance status, co-morbidities— Treatment considerations e.g. type, efficacy and tolerance of previous treatment; number of prior

lines; available remaining options; interval since last intervention

Observed survival by landmark analysis of 1 year according to response attained following induction

Tan D, et al. Bone Marrow Transplant 2010;45:1625–1630.

For induction, transplant-eligible patients received vincristine, adriamycin and DEX, or THAL/DEX. BTZ induction was used in patients with high-risk disease. Transplant-ineligible patients received vincristine, adriamycin and DEX or MEL/PRED combination, and THAL/DEX or MPT.

Response measures correlate with survival post-induction in newly diagnosed patients

0 2 4 6 8 10

P = 0.001

Prop

ortio

n su

rviv

ing

Survival (years)

Induction response≥ VGPR (n = 67)PR (n = 49)No response (n = 32)

Median survival (years)8.14.62.3

0.0

1.0

0.8

0.6

0.4

0.2

≥ VGPR

PR

No response

Attainment of ≥ VGPR after induction is an important surrogate for improved survival

Martinez-Lopez J, et al. Blood 2011;118:529–534.

PFS, progression-free survival;Data from 344 patients treated with a single

previous chemotherapy combination and ≥ 1 ASCT

Response measures correlate with survival after transplant in newly diagnosed patients

201510500

20

40

60

80

100

PFS

(%)

Time since transplantation (years)

CR vs. nCR: P = 0.002CR vs. VGPR: P = 0.003CR vs. PR: P < 10−5

CR (n = 84) nCR (n = 66) VGPR (n = 54) PR (n = 114) SD (n = 12) PD (n = 14)

201510500

20

40

60

80

100

OS

(%)


CR vs. nCR: P = 0.01CR vs. VGPR: P = 0.0001CR vs. PR: P = 0.003

Prognostic influence of 6 response categories on survival

CR associated with significantly improved PFS and OS vs. other response categories

sCR(n = 109)

CR(n = 37)

nCR(n = 91)

Median OS post-ASCT, mo. NR 81 60

5-year OS, % 80 53 47

Median TTP from ASCT, mo. 50 20 19

Kapoor P, et al. J Clin Oncol 2013;31:4529–4535.

Data from 445 patients treated with ASCT following various induction

regimens

sCR associated with improved long-term post-ASCT outcomes in newly diagnosed patients

• On multivariable analysis, achievement of sCR post-ASCT was an independent prognostic factor for survival

– Hazard ratio 0.44 (95% CI: 0.25, 0.80)

Duration of response in patients achieving CR or PR

CR CR or PR0

5

10

15

20

25

30

24.0

19.9

12.8 13.1

VMP MP

Me

dia

n r

es

po

ns

ed

ura

tio

n (

mo

.)

San Miguel JF, et al. N Engl J Med 2008;359:906–917.

MP, melphalan+prednisone; VMP, bortezomib+melphalan+prednisone. Data from symptomatic patients who were not candidates for HDT/ASCT because of age or co-existing conditions; quality of response was assessed against criteria of the EBMT

Durability of response is important in newly diagnosed patients ineligible for HDT/ASCT

• Addition of novel agents can improve duration of CR

n = 102 n = 12 n = 238 n = 115

• Total therapy (TT) is the concept of applying all available, active agents up-front e.g.1,2

– TT1 (tandem transplant)– TT2 (addition of THAL)– TT3 (addition of BTZ)

• CR duration is longer with TT31

1. Usmani SZ, et al. Leukemia 2013;27:226–232; 2. University of Arkansas for Medical Sciences. Total Therapy Approach. Available at: http://myeloma.uams.edu/treating-myeloma/total-therapy-approach/ [Accessed September 2014].

Choice of therapy influences response duration in newly diagnosed patients in CR

Patie

nts

with

CR

(%)

Time after CR attainment (years)

80

60

40

20

0

100

0 5 10 15 20

Events/N5 year

estimate

37/18998/20186/14672/87

TT3 79% (73.3, 85.5)TT2 + ThalTT2 − ThalTT1

59% (52.3, 66.1)52% (43.4, 59.7)35% (24.6, 44.8)

P < 0.0001

Durations of CR in TT trials1

Achievement of VGPR or CR

(n = 114)

Achievement of PR

(n = 100)Hazard ratio (95%

CI) P-value

Duration of median response (mo.) 24.0 8.3 0.45

(0.31, 0.64) < 0.001

Median TTP (mo.) 27.7 12.0 0.45(0.31, 0.64) < 0.001

OS (%) NR 44.2 0.64(0.43, 0.94) 0.021

Harousseau JL, et al. Haematologica 2010;95:1738–1744.

Data from 353 patients with progressive MM following one or more previous

regimens

Improved quality responses associated with better outcomes in relapsed/refractory MM

Treating to deeper response is essential to optimise clinical outcomes for relapsed/refractory MM patients

• Certain patients with low-risk MM who do not achieve CR may still exhibit good long-term survival1

• The prognostic value of achieving CR might not be as significant as that for achieving and sustaining CR2

• In older patients, substantial treatment-related toxicity may overshadow the benefits of achieving CR3

1. Haessler J, et al. Clin Cancer Res 2007;13:7073–7079; 2. Barlogie B, et al. Cancer 2008;113:355–359; 3. Mehta J, et al. Blood 2010;116:2215–2223.

The clinical value of achieving CR is not identical for all patients

• There is growing evidence that deeper responses correlate with symptom control and longer survival

• Treating to deeper response is essential to optimise clinical outcomes in both newly diagnosed and relapsed/refractory patients

• Durations of CR can differ depending on treatment– Improved regimens and novel therapies have been associated with more

durable CR• Therapies that provide deep and durable responses while minimising

toxicity should be prioritised

Summary

What is beyond complete response?

Time since transplantation (years)20151050

0

20

40

60

80

100

OS

(%)

CR (n = 84)

Martinez-Lopez J, et al. Blood 2011;118:529–534.

Data from 344 patients treated with a single previous chemotherapy

combination and ≥ 1 ASCT

MM is incurable and all patients relapse and die despite achievement of CR

Median and 12-year OS: 91 mo. and 35%Median and 12-year PFS: 47 mo. and 28%

201510500

20

40

60

80

100


CR (n = 84)

PFS

(%)

Prognostic influence of CR obtained after HDT/ASCT on PFS and OS

• The true depth of response, and risk of relapse, can only be detected if sufficiently sensitive techniques are used

Suzuki K. Clin Exp Nephrol 2012;16:659–671; Paiva B, et al. Blood 2008;112:4017–4023.

A critical goal of treatment is achievement of a deep and durable response

CR

nCR

VGPR

PR

MR

Time to disease progression

Diagnosis

Molecular/immunophenotypic CR

Dep

th o

f res

pons

e

sCR

Multiparameter flow cytometry (MFC) can be used to quantify myeloma cells

Cells ‘focused’ into single stream

Laser light source

Different fluorescence signals from different fluorophores measured

Light from all cells detected

BM aspirate labelled with fluorophore-conjugated antibodies that bind epitopes characteristic of MM

• MFC can assess abnormal expression of antigens on the surface of plasma cells, which indicate an MM phenotype, such as:

—Essential: CD19, CD56—Recommended: CD117, CD20, CD27, CD28—Suggested: CD81, CD200

• Patient with low-level residual disease at Day 100 following HDT

• Patient in continuedremission several years after HDT

Rawstron AC, et al. Haematologica 2008;93:431–438.

MFC can be used to measure immunophenotypic CR

Example of the results of MFC

*Corresponding to the rearranged variable region of immunoglobulin

heavy-chain genes

ASO-PCR amplifies genetic material specific to residual myeloma cells

Patient-specificprimers*

Target sequence: rearranged variable region of immunoglobulin heavy-chain gene

DNA

(1) Heat denaturation of DNA

DNA polymerase

(2) Primer annealing

(3) Primer extension

PCR cycle

Patient-specificprimers*

• Detects the presence or absence of residual myeloma cells1

• Patient-specific primers are constructed from the rearranged variable region of immunoglobulin heavy-chain genes1

– These cannot always be identified in every patient

1. Corradini P, et al. J Clin Oncol 1999;17:208–215; 2. Corradini P, et al. Blood 2003;102:1927–1929.

ASO-PCR can be used to measure molecular CR

Molecular follow up of patients by ASO-PCR2

PCR-negative patients

PCR-mixed patients

PCR-positive patients

Time following ASCT (years)0 1 2 3 4 5 6 7 8 9 10

✠RR

RR

✠✠✠R

R

RR

RR

R✠

RR

R

R

✠

✠✠

Patie

nt n

umbe

r

484746454443424140393837363534333231302928272625242322212019181716151413121110987654321

PCR negative PCR positive R: relapse

: death✠

• More difficult to perform• Less widely applicable than MFC

(75% of MM patients)• More time-consuming than MFC

– Patient-specific primers needed• More sensitive and specific

than MFC– Can detect 1 clonal plasma cell in

105 normal cells

• Straightforward to perform• Applicable in 90% of MM patients• Shorter turnaround time than

ASO-PCR and less expensive• Less sensitive and specific

than ASO-PCR– Can detect 1 clonal plasma cell in

104 normal cells• Sophisticated analysis needed to

obtain objective results– Automation possible to facilitate

and expedite analysis

MFC ASO-PCR

Munshi NC, Anderson KC. J Clin Oncol 2013;31:2523–2526.

MFC and ASO-PCR have advantages and limitations in quantifying responses

Current treatment goals

1. Harousseau JL, et al. Blood 2009;114:3139–3146; 2. Ludwig H, et al. Oncologist 2014;19:829–844.

Treatment goals beyond CR and the impact of consolidation and maintenance

Achievement of CR1

Achievement of deeper, more durable responses1

How best to measure ‘depth’ of response?2

Role of minimal residual disease (MRD)?2

• Deep and durable responses are a critical goal of treatment• In the current era of novel therapies, achieving CR should not be

the only objective• It may be possible to prolong CR further by improving the depth and

duration of response• Highly sensitive and specific measures are needed to quantify depths

of response• MFC can measure immunophenotypic CR• ASO-PCR can measure molecular CR• MFC and ASO-PCR each have advantages and limitations in measuring

depth of response• The use of highly sensitive imaging techniques to measure depth of

response may reduce the risk of sampling error

Summary

Clinical value of detecting minimal residual disease

What is MRD?

The persistence in patients of small numbers of residual MM cells during or following treatment

Such clinically relevant levels of MM cells can lead to relapse, irrespective of achievement of CR or VGPR

Identification of MRD is an accurate way of determining if a patient has remaining (residual) signs of disease

Patients without signs of residual disease are described as being MRD-negative

PFS OS

Rawstron AC, et al. J Clin Oncol 2013;31:2540–2547.

Data from 397 patients with/without MRD at Day 100 after ASCT

Presence of MRD associated with inferior post-ASCT outcomes in newly diagnosed patients

Patients without MRD exhibited a significant OS advantage vs. MRD-positive patients

20

MRD− (n = 247); median OS: 80.6 mo.MRD+ (n = 150); median OS: 59.0 mo.

MRD− (n = 247); median OS: 28.6 mo.MRD+ (n = 150); median OS: 15.5 mo.

100

80

60

40

20

12 24 36 48 60 72 84 96

100

80

60

40

12 24 36 48 60 72 84 960

PFS

(%)

Time since MRD assessment (mo.) Time since MRD assessment (mo.)

OS

(%)

Χ21 = 24.0

P < 0.001

No. at risk MRD−MRD+

200 87

145 59

107 42

7324

4114

20 7

20

00

No. at risk MRD−MRD+

237132

220124

197105

157 83

9246

4325

91

00

Χ21 = 5.566

P = 0.018300

0

Duration of response by presence of MRD*

Ferrero S, et al. Leukemia 2014; doi: 10.1038/leu.2014.219.

*MRD assessed by ASO-PCR at diagnosis, study entry, after two VTD courses, at end of treatment and every 6 mo. until relapse; Data from 39 patients with ≥ VGPR after ASCT receiving VTD consolidation therapy; Median follow-up 93 mo; VTD, bortezomib, thalidomide, dexamethasone

Ongoing monitoring of MRD has prognostic value

Ongoing absence of MRD(Median: not reached)

Reappearance of MRD(Median: 38 mo.)

Persistence of MRD(Median: 9 mo.)

72604836241200.0

0.2

0.4

0.6

0.8

1.0

Time (mo.)

Resp

onse

dur

ation

(pro

babi

lity)

84 96

P < 0.001

Different patterns of MRD kinetics have different risks of relapse

PFS according to presence of sCR and MRD1*

PFS according to presence of CR and MRD2†

Paiva B, et al. J Clin Oncol 2011;29:1627–1633; Rawstron AC, et al. J Clin Oncol 2013;31:2540–2547.

MRD determined by MFC; *Data from 102 elderly patients after 6 cycles of VMP or VTP induction followed by BTZ+THAL or BTZ+PRED maintenance; †Data from 378 patients following 4–6 cycles of CTD or CVAD, followed by high-dose MEL and ASCT.

Achievement of sCR/CR is not always associated with MRD negativity

Patients who achieve CR and are MRD negative have the most favourable outcomes

MRD− and sCR (n = 20); median, NR MRD+ and sCR (n = 11); median, 35 mo.MRD− but not sCR (n = 11); median, NR MRD+ but not sCR (n = 60); median, 28 mo.

MRD− and CRMRD− but not CRMRD+ and CRMRD+ but not CR

Χ2 = 27.4757P < 0.001

Time (mo.)

100

80

60

40

20

0

PFS

(%)

P = 0.001

10 20 30 40 50 600 0

100

80

12 24 36 48 72

60

40

20

084 9660

PFS

(%)

Time (mo.)

ASO-PCR

Sarasquete ME, et al. Haematologica 2005;90:1365–1372.

Data from 53 patients who achieved CR or nCR following a first ASCT transplant after 4 cycles of VBCMP/VBAD and high-dose MEL

Results of MRD assessment using MFC and ASO-PCR show a high degree of correlation

432100

20

40

60

80

100


P = 0.042

432100

20

40

60

80

100


P = 0.059

≤ 1 × 10−4 byASO-PCR, n = 11

> 1 × 10−4 byASO-PCR, n = 13

Negative flow cytometry, n = 13

Positiveflow cytometry, n = 11

The correlation between MFC and ASO-PCR is very high (R = 0.861)

PFS

(%)

PFS

(%)

MFC

TTP according to CR achievement and MRD status

Ashcroft J, et al. Blood (ASH Annual Meeting Abstracts) 2013;122:3378.

Data from 297 patients a first relapse after ASCT.

MRD assessment is a sensitive predictor of outcome in the first relapse setting

72604836241200.0

0.2

0.4

0.6

0.8

1.0

Time since randomisation (mo.)

Prop

ortio

n w

ithou

t pro

gres

sion

84 96

P < 0.0001

CR, MRD− (median TTP: 25 mo. [95% CI: 15, 41])< CR, MRD− (median TTP: 16 mo. [95% CI: 4, 29])

< CR, MRD+ (median TTP: 11 mo. [95% CI: 9, 12])CR, MRD+ (median TTP: 10 mo. [95% CI: 7, 24])

Treating to deeper response is essential to optimise clinical outcomes for relapsed MM patients

• MRD assessment in clinical trials is now recommended by international consensus1

• Historically, the complexity of MRD data meant that expertise in its interpretation was needed to minimise subjectivity2

• Recent initiatives enable reliable, standardised MFC assessment

1. Rajkumar SV, et al. Blood 2011;117:4691–4695; 2. Kalina T, et al. Leukemia 2012;26:1986–2010;3. EuroFlow-ESLHO. Aims of EuroFlow consortium. Available at: http://www.euroflow.org/usr/pub/pub.php [Accessed August 2014]; 4. International Myeloma Foundation. Press release, 18 March 2014. Available at: http://myeloma.org/ArticlePage.action?tabId=0&menuId=0&articleId=4323&aTab=-1 [Accessed September 2014].

Future prospects with MRD development

• The EuroFlow Consortium provides protocols, software and antibody panels for standardised approaches3

• The International Myeloma Foundation, in association with EuroFlow, have launched a fully automated flow cytometry test, sensitive to 1 clonal plasma cell in 106 normal cells4

• High-throughput sequencing of variable, diversity, and joining (VDJ) gene segment rearrangements in a myeloma clone1,2

– Sensitivity to 1 clonal plasma cell in 106 normal cells in blood3

– Can distinguish high, intermediate and low MRD levels with significantly different TTP: 27, 48, and 80 mo., respectively2

– No need for patient-specific reagents4

• Sequencing the coding exome of purified tumour cells5

– Allows comprehensive analysis of recurrent mutated genes– Higher numbers of mutations associated with worse prognosis

1. Mailankody S, et al. Blood (ASH Annual Meeting Abstracts) 2013;122:1902; 2. Martinez-Lopez J, et al. Blood 2014;123:3073–3079; 3. Faham M, et al. Blood 2012;120:5173–5180; 4. Ladetto M, et al. Leukemia 2014;28:1299–1307; 5. Bolli N, et al. Nat Commun 2014;5:2997.

Future prospects with MRD development: next-generation sequencing

• Which is the optimum technique for ascertainment of MRD?• What is the comparative value of different methodologies and role of MRD

in different treatment settings (e.g. relapsed/refractory MM)?• What does a loss of MRD negativity mean?

– How should a loss of MRD negativity influence treatment strategies?– Can all clonal MM populations lead to a full-blown relapse?

• How many years might it be before MRD assessment can be incorporated into routine clinical practice?

• Can MRD testing be made sufficiently straightforward for widespread use in non-specialist centres?

Unanswered questions

• Deep and durable responses are a critical goal of treatment• MRD may supplement traditional response criteria enabling ‘depth’ of

responses to be more accurately gauged• MRD is a sensitive predictor of outcome following transplantation and first

relapse, with MRD monitoring also having prognostic value• ASO-PCR or MFC can detect MRD, with results from both techniques

showing a high degree of correlation• MRD assessment in clinical trials is now recommended following

international consensus• Future incorporation of MRD into routine practice would require:

– Continued evaluation of prognostic role in different treatment settings– Standardisation and simplification of measurement and analysis

Summary

assessing response in multiple myeloma cfz-deu-amg-1697-2014-november-np note: carfilzomib is an...

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