1. Delay in the diagnosis of MM – Methods for early diagnosis in primary care
Dr Constantinos Koshiaris
Nuffield Department of Primary Care Health Sciences
University of Oxford
13/03/2019

2. Outline
Quantifying intervals to diagnosis in myeloma: a systematic review and meta-analysis
Early detection of multiple myeloma in primary care using blood tests: a case-control study in primary care
Current/Future research

3. Number of consultations before referral
Least consultations: Breast cancer with 7.4% of patients experiencing more than 3 consultations before referral Most consultations: Myeloma with 50% of patients experiencing more than 3 consultations before referral
Lyratzopoulos G, Neal RD, Barbiere JM, et al. Variation in number of general practitioner consultations before hospital referral for cancer: findings from the 2010 National Cancer Patient Experience Survey in England. Lancet Oncol 2012; 13(4): 353–365

4. Difficulties of myeloma diagnosis in primary care
Rarity of the disease - The average full time GP will diagnose 1 myeloma case every 5 years. Non-specific nature of the symptoms – No single symptom has a positive predictive value greater than 0.2%* Presence of comorbidities that can mask myeloma symptoms**
*Shephard EA, Neal RD, Rose P, et al. Quantifying the risk of multiple myeloma from symptoms reported in primary care patients: a large case-control study using electronic records. Br J Gen Pract 2015
**Friese CR, Abel GA, Magazu LS, et al. Diagnostic delay and complications for older adults with multiple myeloma. Leuk Lymphoma 2009; 50(3): 392–400

5. Koshiaris C, Oke J, Abel L, Nicholson BD, Ramasamy K, Van den Bruel A
Koshiaris C, Oke J, Abel L, Nicholson BD, Ramasamy K, Van den Bruel A. Quantifying intervals to diagnosis in myeloma: a systematic review and meta-analysis. BMJ Open 8(6), e (2018)

6. Patient pathway

7. No papers reported this interval
Interval Length N
50th
IQR
Patient interval
465 (2 studies) 26
1-98 
Primary care interval
326 (2 studies) 22
5-56
Referral to diagnosis interval
No papers reported this interval
Diagnostic interval
5395 (7 studies)
109
33-242
Total time to diagnosis interval
341 (1 study)
163
84-306

8. Conclusions Most of the delays are observed in the healthcare system
Median diagnostic interval is longer than three months
Median primary care interval is approximately three weeks which is longer than any other cancer
Referral to diagnosis interval seems to be longer than the primary care interval.

9. Koshiaris C, Van den Bruel A, Oke JL, Nicholson BD, Shephard E, Braddick M, Hamilton W. Early detection of multiple myeloma in primary care using blood tests: a case-control study in primary care. Br.J.Gen.Pract.68(674), e586–e593 (2018)

10. Study design
Nested case-control study using CPRD (Clinical Practice Research Database)
12157 controls were matched to 2703 cases based on gender, age and practice
Trajectories of common blood tests that are used for myeloma were generated for up to 5 years before diagnosis
The rule out properties of blood tests were examined (individual and in combination)

11. Blood test trajectories over time

13. Investigations
Sensitivity (%)
Specificity (%)
LR-
Individual
ESR
85 (82-87)
54 (51-57)
0.28 ( ) PV
81 (74-86)
59 (52-64)
0.32 ( ) Hb
68 (65-70)
78 (76-79)
0.42 ( )
CAL
22 (19-24)
97 (97-98)
0.81 ( )
Creatinine
35 (33-37)
82 (81-83)
0.80 ( )
CRP
46 (42-50)
63 (59-67)
0.87 ( )

14. Sensitivity (%) Specificity (%) LR- Combinations (2 tests) Hb + PV
95 (90-97)
44 (37-50)
0.12 ( )
Hb + ESR
93 (91-94)
46 (43-49)
0.16 ( )
Hb + CRP
84 (80-86)
47 (43-52)
0.39 ( )
Combinations (3 tests)
Hb + CREAT + PV
97 (93-99)
40 (33-47)
0.09 ( )
Hb + CAL + PV
98 (94-100)
40 (30-52)
0.06( )
Hb + CREAT + ESR
94 (92-95)
39 (36-42)
0.16 ( )
Hb + CAL + ESR
93 (91-95)
44 (40-49)
0.16 ( )
Hb + CREAT + CRP
88 (85-90)
37 (33-41)
0.33 ( )
Hb + CAL + CRP
85 (81-88)
46 (40-52)
0.33 ( )

15. Example
Probability of myeloma in a patient with rib pain in primary care is 0.2% (1 in 500) Patient is tested with ESR and full blood count and both tests are normal (negative LR = 0.16) This reduces the myeloma probability from 0.2% to 0.03% (1 in 3333)

16. Conclusions
ESR and PV are better for diagnosis myeloma compared to CRP
Haemoglobin most sensitive component of the FBC and starts declining at 2-3 years before diagnosis
Calcium and creatinine rise a bit later and cannot rule out myeloma if normal
Normal ESR/PV and full blood count could work as a simple rule-out approach on patients that present with myeloma related symptoms.

17. Current/Future research
Development and validation of clinical prediction rules for the diagnosis of multiple myeloma Developed on a population of patients who received multiple blood tests within a year and validated at a population of patients Validated the results of the case-control study Published within the next months

18. Acknowledgements
Oxford-Primary Care Research Trust Graduate Scholarship NIHR CLAHRC Oxford University of Exeter

19. Questions?