Protein dynamics in early disease - PowerPoint Presentation

Slide1

Protein dynamics in early disease

Professor Mark Drayson, University of Birmingham13th March 2019

Distinguishing myeloma from MGUS by m-protein and serum free light chain results alone

M

yeloma is the worst cancer for delayed diagnosis because

it

is rare in primary care

and non-haem specialty consultations

the

symptoms

are common

, variable, and of low predictive

value

Of

32,236 newly diagnosed myeloma patients in England, 11,006 (34%) presented as emergencies; of these, 4,182 (38%) died within 6 months of diagnosis, accounting for 78% of all myeloma deaths within 6 months of diagnosis.

Myeloma could be detected earlier because 99% of all myeloma patients have a serum m-protein and or an abnormal serum free light chain ratio

that

can be easily detected in

blood

Inhibitions to laboratory testing:

Cost of tests needs to be considered

Testing also

reveals 100% of the

100x more common MGUS MGUS must then be distinguished from myeloma at Great cost to the patientMajor cost to the health service

3

MGUS 1% risk of progression to myeloma

4

Prevalence of MGUS 100 fold that of the incidence of myeloma

Are we testing for myeloma too little or too much

New

m-proteins

in a

hospital 15 years ago

Mayo

Malmo

St Helier

Diagnosis (1510) (930) (200)

MGUS

51

% 72% 74%

Myeloma 24% 19% 16%

WM 3% 2% 2%

AL 11% 1% 1%

Other 11% 6% 7%

5

m-proteins >30g/l are attributable to myeloma; this is the International guideline cut point for distinguishing myeloma from

MGUS.

40

% of myeloma patients have m-proteins <30g/l10% have m-proteins <10 g/l.Over 90% of myeloma patients have an abnormal SFLCR so do some 40% of patients with

MGUS.

So do many patients who do not have a monoclonal

gammopathy

(renal impairment present in 25% of the myeloma demography; autoimmune disease SLE

etc

; infection; inflammatory disease)

Accordingly neither m-protein nor SFLC ratio alone can provide good sensitivity and specificity for distinguishing myeloma from MGUS.

Use of m-protein levels and serum FLC ratios

to distinguish myeloma from MGUS

Old trials

(n = 2807)

MIX

(n = 1555)

MXI

(n = 1692)

1980-1997

2003-2008

To June 2013

Age, %

  ≥ 65 years5153.159.5>65 years Intensive pathway–12.818.9M-protein type, %    IgG57.561.758.2IgA24.021.525.8Light chain only 13.312.513.4IgD1.61.91.5Non-secretory3.61.00.5IgM –0.5 0.3

M-protein types and levels in UK Myeloma trials 1980-2013

Patients getting older

Treatment intensifying

Reduced % non-secretory

7

M-protein types and levels at diagnosis in UK Myeloma IX and XI

M-protein levels in 1894 patients with IgG and 757 patients with IgA m-proteins

32.7% < 30 g/L

42.3% < 30 g/L

Combining high thresholds for serum

FLC ratios and m-protein levels to facilitate appropriate and rapidreferral

for myeloma diagnosis

Methods: retrospective

cohort studyMeasured serum FLC ratio and m-protein concentrations in samples from 3177 newly diagnosed myeloma patients and 711 MGUS cases.Applied different thresholds for

SFLC ratio

range and

m-protein

levels

at 5

, 10 and 15

g/L to decide whether a patient should be considered at risk of myeloma and thus need further investigation.8

9

Using an M-protein at any level and/or a SFLC ratio outside the normal range

(0.26 – 1.65) then

3153/3177

(99%) of newly diagnosed myeloma patients were identified(0.8% were non-secretory).This strategy identified 100% of 771 MGUS cases for consideration of myeloma.

10

Inverse relationship between SFLC ratio and m-protein level

Involved/uninvolved

FLC ratio in

436 patients without an intact m-proteinand 2717 patients with different m-protein concentrations

11

All patients

(N = 3177)

Non-secretors

(n = 24)

Light chain only (n= 418) oligosecretory

(n = 18)

IgG/A/D/M

(n = 2717)

IgG/A/M/D

(n = 2717)

κ:λ ratio % (n)     M-protein< 5g/L(n = 122)M-protein< 10g/L(n = 226) M-protein< 15g/L(n = 336) Normal ratio range(0·26–1·65)5·2% (166)  0·8%(24)04·7% (148) 0·4%(12)0·8%(23)1·1%(29)Extended ratio range 1(0·15–3·36)10%(318)0·8%(24)0·5%(2)10·8% (293)0·60%(16)1·3%(35)1·8%(49)Extended ratio range 2(0·08–7·41) 15%(477)0·8%(24)1·1%(5)16·5%

(449)

0·6%

(16)

1·5%

(40)

2·4%

(65)

The percentage of myeloma

patients missed through

stratification according to different serum FLC κ:λ ratios and M-protein levels

12

M-protein cut-off

% (n)

Normal ratio range

(0·26–1·65)

Extended ratio range 1

(0·15–3·36)

Extended ratio range 2

(0·08–7·41)

M-protein ≥ 5g/L

66%

(468

)0.4%82% (581)0.8%91%(645)1.1%M-protein ≥ 10g/L 81% (577)0.6%89% (630)1.3%94%(670)1.8%M-protein ≥ 15g/L  91%(646)0.6%93%(663)1.5%

96%(684

)

2.4%

The percentage of 711 patients with MGUS that would

be excluded

from

further assessment for myeloma using the stated

cut-offs for

m-protein

level and reference ranges for serum free light chain κ:λ ratio

Percentage of secretory myeloma

patients missed

MGUS risk of progression to myeloma

13

Mayo study (Blood 2005

Rajkumar

)1148 patients median 15 years follow up (8982 patient years follow up)M-protein >15 g/l HR 2.4Abnormal FLC ratio HR 2.6

Non-IgG

type m-protein HR

2.6

39% MGUS patients

no factors abnormal absolute

risk of progression at 20 years accounting for death as a competing risk, 2%

37% MGUS patients one factor abnormal absolute risk of progression at 20 years accounting for death as a competing risk, 10%Swedish study (Blood 2014 Turesson)728 patients median 10 years follow up (7590 patient years follow up)

M-protein

>15 g/l HR 3.6Abnormal FLC ratio HR 3.0Immunoparesis HR 2.8

MGUS precedes myeloma (m-protein dynamics)

14

American cancer screening study (Blood 2009

Landgren

)77,469 healthy adults; 71 developed myeloma.Stored serum from 2 – 9.8 years available pre myeloma diagnosisMGUS present in 100% 2 years prior; 82% 8 years priorM-protein concentration (g/dL) levelsyear by year prior to multiplemyeloma diagnosisHALF RISING; HALF STABLE

SAME FOR FLC

MGUS precedes myeloma (m-protein dynamics)

15

American armed forces health study (Blood 2009 Weiss)

7 million army

personel; 90 received transplants for myeloma; 30 had Stored serum from 2.2 – 15.3 years available pre myeloma diagnosisMGUS present in 27/30M-protein concentration (g/dL) levelsyear by year prior to multiplemyeloma diagnosisHALF RISING; HALF STABLE

SAME FOR FLC

IgG 21 days

IgA 5 days

FLC 12 hours

Short half lives of serum FLC allow

real time evaluation of tumour kill

Immunoglobulin half lives and

response; c

an take several months

for a complete response to become evident

Changes in FLC (A) and IgG paraprotein (B) levels during the first four cycles of induction chemotherapy if a 60% kill was achieved in each cycle. The FLC reduction at the end of each cycle is representative of the percentage kill of MM cells. Due to the long half-life of IgG, the reduction in the level of the IgG paraprotein represents a combination of IgG half-life and the MM kill.

A

B

FLC response to 3 week cycles of myeloma

therapy

Facilitates real time evaluation of tumour kill

Unpaired T-test

(N)

531

117

211

211

756

328

58

531

225

p=0.99

p=0.07 p= 5.1E-15 p= 0.005 p= 1.4E-07FLCFLCFLCEarly response in myeloma 11 and the importance of Ig half life% Reduction in M-protein/FLC post -cycle 1 - three weeksHalf life of IgG during induction therapy reduced to 11 days

Acknowledgements

Clinical Immunology Service

Mr

Tim Plant

Mrs

Nicki Newnham

Mrs

Karen Walker

Mrs

Alison Adkins

Mr

Zaheer Afzal Mrs Jean GilesMr Mark Fellows Mr Ramesh RamnatsingMrs Tarana AhmMiss Claire BackhouseR&D Dr Margaret GoodallDr John CampbellDr Jennifer HeaneyDr Ilaria ChiccaDr Hannah GilesChief Investigators:Professor Ian MacLennanProfessor Tony ChildProfessor Gareth MorganProfessor Gordon CookProfessor Graham JacksonAll the patients and staff at over 100 centres throughout the UKwhose participation made these studies possible. All principle investigators for their dedication and commitment to recruitingpatients to the studies.

MRD studies

Dr Roger Owen

Molecular/translational

studies:

Professor Faith Davies

Dr

Brian Walker

Dr Martin

Kaiser

Cytogenetics

Dr Fiona Ross

Clinical Trials Research

Units

:

Leeds

Professor

Walter

Gregory

Professor David Cairns

Dr Sue Bell

Birmingham / Warwick

Professor Janet Dunn

Dr Gulnaz Begum