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

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

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

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

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), e019758 (2018)

Patient pathway

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

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.

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)

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)

Blood test trajectories over time

Investigations Sensitivity (%) Specificity (%) LR- Individual   ESR 85 (82-87) 54 (51-57) 0.28 (0.24-0.33) PV 81 (74-86) 59 (52-64) 0.32 (0.24-0.44) Hb 68 (65-70) 78 (76-79) 0.42 (0.39-0.45) CAL 22 (19-24) 97 (97-98) 0.81 (0.78-0.83) Creatinine 35 (33-37) 82 (81-83) 0.80 (0.77-0.83) CRP 46 (42-50) 63 (59-67) 0.87 (0.78-0.94)

Sensitivity (%) Specificity (%) LR- Combinations (2 tests) Hb + PV 95 (90-97) 44 (37-50) 0.12 (0.07-0.23) Hb + ESR 93 (91-94) 46 (43-49) 0.16 (0.13-0.21) Hb + CRP 84 (80-86) 47 (43-52) 0.39 (0.32-0.47) Combinations (3 tests)   Hb + CREAT + PV 97 (93-99) 40 (33-47) 0.09 (0.04-0.20) Hb + CAL + PV 98 (94-100) 40 (30-52) 0.06(0.02-0.18) Hb + CREAT + ESR 94 (92-95) 39 (36-42) 0.16 (0.12-0.21) Hb + CAL + ESR 93 (91-95) 44 (40-49) 0.16 (0.12-0.22) Hb + CREAT + CRP 88 (85-90) 37 (33-41) 0.33 (0.26-0.42) Hb + CAL + CRP 85 (81-88) 46 (40-52) 0.33 (0.25-0.42)

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)

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.

Current/Future research Development and validation of clinical prediction rules for the diagnosis of multiple myeloma Developed on a population of 836 056 patients who received multiple blood tests within a year and validated at a population of 446 986 patients Validated the results of the case-control study Published within the next months

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

Questions?