1. Protein dynamics in early disease
Distinguishing myeloma from MGUS by m-protein and serum free light chain results alone
Professor Mark Drayson, University of Birmingham
13th March 2019

2. Myeloma 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

3. 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 patient
Major cost to the health service

4. MGUS 1% risk of progression to myeloma
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. Use of m-protein levels and serum FLC ratios
to distinguish myeloma from MGUS
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/l
10% 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.

6. M-protein types and levels in UK Myeloma trials 1980-2013
Old trials
(n = 2807)
MIX
(n = 1555)
MXI
(n = 1692)
To June 2013
Age, %
≥ 65 years 51
53.1
59.5
>65 years Intensive pathway –
12.8
18.9
M-protein type, %
IgG
57.5
61.7
58.2
IgA
24.0
21.5
25.8
Light chain only
13.3
12.5
13.4
IgD
1.6
1.9
1.5
Non-secretory
3.6
1.0
0.5
IgM
0.3
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

8. Combining high thresholds for serum FLC ratios and m-protein levels to facilitate appropriate and rapid referral for myeloma diagnosis
Methods: retrospective cohort study Measured 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.

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-protein
and 2717 patients with different m-protein concentrations

11. Light chain only (n= 418) oligosecretory
The percentage of myeloma patients missed through stratification according to different serum FLC κ:λ ratios and M-protein levels
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
κ:λ ratio
% (n)
M-protein
< 5g/L
(n = 122)
< 10g/L
(n = 226)
< 15g/L
(n = 336)
Normal ratio range
(0·26–1·65)
5·2%
(166)
0·8%
(24)
4·7%
(148)
0·4%
(12)
(23)
1·1%
(29)
Extended ratio range 1
(0·15–3·36)
10%
(318)
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)
(5)
16·5%
(449)
0·6%
1·5%
(40)
2·4%
(65)

12. 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
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
(646)
93%
(663)
1.5%
96%
(684)
2.4%
Percentage of secretory myeloma patients missed

13. MGUS risk of progression to myeloma
Mayo study (Blood 2005 Rajkumar)
1148 patients median 15 years follow up (8982 patient years follow up)
M-protein >15 g/l HR 2.4
Abnormal 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 3.6
Abnormal FLC ratio HR 3.0
Immunoparesis HR 2.8

14. MGUS precedes myeloma (m-protein dynamics)
American cancer screening study (Blood 2009 Landgren)
77,469 healthy adults; 71 developed myeloma.
Stored serum from 2 – 9.8 years available pre myeloma diagnosis
MGUS present in 100% 2 years prior; 82% 8 years prior
M-protein concentration (g/dL) levels
year by year prior to multiple
myeloma diagnosis
HALF RISING; HALF STABLE
SAME FOR FLC

15. MGUS precedes myeloma (m-protein dynamics)
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 diagnosis
MGUS present in 27/30
M-protein concentration (g/dL) levels
year by year prior to multiple
myeloma diagnosis
HALF RISING; HALF STABLE
SAME FOR FLC

16. for a complete response to become evident
Immunoglobulin half lives and response; can take several months
for a complete response to become evident
IgG 21 days
IgA 5 days
FLC 12 hours
Short half lives of serum FLC allow
real time evaluation of tumour kill

17. FLC response to 3 week cycles of myeloma therapy
Facilitates real time evaluation of tumour kill A B
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.

18. Half life of IgG during induction therapy reduced to 11 days
Early response in myeloma 11 and the importance of Ig half life % Reduction in M-protein/FLC post -cycle 1 - three weeks
Unpaired T-test
(N)
531
117
211
756
328 58
225
p=0.99
p=0.07
p= 5.1E-15
p= 0.005
p= 1.4E-07
FLC
Half life of IgG during induction therapy reduced to 11 days

19. Acknowledgements
Chief Investigators:
Professor Ian MacLennan
Professor Tony Child
Professor Gareth Morgan
Professor Gordon Cook
Professor Graham Jackson
Clinical Trials Research Units:
Leeds
Professor Walter Gregory
Professor David Cairns
Dr Sue Bell
Birmingham / Warwick
Professor Janet Dunn
Dr Gulnaz Begum
Clinical Immunology Service
Mr Tim Plant
Mrs Nicki Newnham
Mrs Karen Walker
Mrs Alison Adkins
Mr Zaheer Afzal
Mrs Jean Giles
Mr Mark Fellows
Mr Ramesh Ramnatsing
Mrs Tarana Ahm
Miss Claire Backhouse
R&D
Dr Margaret Goodall
Dr John Campbell
Dr Jennifer Heaney
Dr Ilaria Chicca
Dr Hannah Giles
MRD studies
Dr Roger Owen
Molecular/translational studies:
Professor Faith Davies
Dr Brian Walker
Dr Martin Kaiser
Cytogenetics
Dr Fiona Ross
All the patients and staff at over 100 centres throughout the UK
whose participation made these studies possible.
All principle investigators for their dedication and commitment to recruiting
patients to the studies.