1. The challenges of managing myeloma in the elderly Stella Bowcock November 2013

2. The UK population is aging

3. 80+ are currently 3 million Predicted to be nearly 6 million by 2030

4. Definition of Elderly? 1.Age ≤ 65 Eligible for asct (autologous stem cell transplant) 2.Age 65-75 May or may not be eligible for asct 3.Age ≥ 75 Not eligible for asct Talk today mostly about category 3

5. Epidemiology of Myeloma Myeloma is a disease of the elderly Incidence according to age In UK median age at diagnosis 73 (1990s) Latest USA SEER registry data: 55% are ≥ age 75 (1975- 2010) Incidence and prevalence of myeloma expected to rise – Aging population predicted increased incidence of 57% between 2010-2030 – Improved survival with novel therapies therefore increased prevalence

6. NCIN. Haematological malignancies in England 2001-2008 Age-specific incidence rates by age group for myeloma in males and females between 2006-2008 in England

7. Myeloma survival in England according to age NCIN. Courtesy Hamish Ross

8. Why such a high early death rate? Early deaths age >75: (Rodon et al, 2001 and Bang et al, 2013) Infection rate high Not treated -(comorbidity, poor PS, very old age, patient refusal) Drop out from treatment (mostly toxicity) Delayed diagnosis? Rodon et al. Multiple myeloma in elderly patients: presenting features and outcome. Eur J Haematol. 2001:66:11-17 Bang et al. Treatment patterns and outcomes in elderly patient with multiple myeloma. Luekemia. 2013:27:971-974

9. Is the disease more aggressive in older patients? No Disease presentation at a later stage?Yes

10. Can we improve early mortality? Infection – TEAMM trial (Tackling EArly Mortality and Morbidity in Myeloma) – Important question in elderly

11. Eligibility Newly diagnosed symptomatic myeloma Intention to give anti-myeloma therapy Want to include the elderly and frail Levofloxacin for 12 weeks (n=400) Placebo for 12 weeks (n=400) Benefits Assess number of febrile episodes plus Deaths <12 wks Days in hospital <12 wks Myeloma response Survival and QOL TEAMM Risks Healthcare associated infections 4 weekly nasal swabs & stools Invasive infections

12. Do elderly patients want treatment? Majority do Emphasis on quality of life (QoL) vs increased survival Dependent upon the attitude of the physician

13. How does treatment affect QoL? Haematologists slow to include QoL in trials 1990s solid tumour trials included QoL – Less chemoresponsive than Haematological malignancies Results consistently showed that, provided the tumour is responding, QoL is better on chemotherapy than no treatment

14. QoL studies in myeloma QoL is worse when disease activity is high QoL improves as the disease comes under control – Physical aspects of QoL especially pain and fatigue If the aim is QoL, trial of treatment is likely to be beneficial

15. Summary so far Dreadful early mortality in the elderly – Need to try to improve on it Majority of elderly patients do want treatment Responses to treatment are associated with improved QoL Myeloma is a highly treatable cancer We need very good reasons NOT to offer treatment to elderly patients

16. Questions when faced with a newly diagnosed elderly patient – Are they likely to benefit from treatment? – How can I assess the patient? – How much is reversible due to myeloma and how much pre existing? – How can I predict toxicity? – How can I modify treatment and supportive care to gain maximum efficacy without toxicity?

17. Normal aging Progressive decline in all physiological systems with age After ~age 75 our systems are less able to compensate for insult Frailty –minor insult may lead to disproportionate deterioration in health

18. Figure 1 Vulnerability of frail elderly people to a sudden change in health status after a minor illness Andrew Clegg, John Young, Steve Iliffe, Marcel Olde Rikkert, Kenneth Rockwood Frailty in elderly people The Lancet Volume 381, Issue 9868 2013 752 - 762 http://dx.doi.org/10.1016/S0140-6736(12)62167-9

19. Measures of Frailty Phenotype model (Fried et al) – ≥3 of weakness, poor endurance, weight loss, low physical activity, slow gait speed Cumulative deficit model (frailty index Rockwood et al ) – 92 variables symptoms, signs, lab values, disease states, disability Fried et al, Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146-156 Rockwood et al, A global clinical measure of fitness and frailty in elderly people. CMAJ 2005;173:489-495

20. Assessment ComorbidityFunctional assessment Tools Charlson comorbidity index (CCI) Cumulative index rating scale- geriatric(CIRS-G) Tools Multiple different assessment tools Comprehensive geriatric assessment -gold standard

21. Which patients do not benefit from treatment? Comorbidity Unlikely to benefit if severe life threatening comorbidity eg CIRS-G score 4 – Extremely severe/ end organ failure Patients with score 1, 2 and probably 3 should be offered treatment – Exceptions eg dementia – Need to tailor treatment according to comorbidity

22. Which patients do not benefit from treatment? (2) Frailty Overall QOL improves as disease comes under control BUT some severely frail patients may not benefit

23. Pragmatic patient assessment Frailty gradeDescription Fit/ moderately fit Active Vulnerable Limited activity but independent Mildly frail Need help for household tasks eg shopping, finances (IADL) Moderately frail Partial help for personal care eg dressing, bathing, toileting (ADL) Severely frail (NOT poor PS due to myeloma) Completely dependent for personal care (ADL)

24. Is the poor performance status reversible? Very dependent on the patient and carer history In QoL studies physical and fatigue aspects may be reversible Psychosocial issues may be more important than physical ones for prognosis

25. How can I predict toxicity? Older age Full dose chemotherapy Abnormal laboratory values eg Hb, albumin, creatinine – Mostly due to high disease activity/burden Geriatric assessment – Inability to walk one block – Falls – Requires support with taking medication – Decreased social activity Hurria et al, J Clin Oncol.2011;29(25):3457-6. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study Extermann M et al, Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer.2012;118(13):3377-86

26. How can I modify treatment to avoid toxicity? Dose reduce, especially in first 1-2 cycles – Complication and toxicity rate highest when disease burden/activity is highest – Retrospective analyses shows some patients drop out early due to toxicity – Treatment interruptions associated with poorer outcome

27. How much to dose reduce? Risk factors 1.Age >75 2.Mild, moderate or severe frailty 3.Comorbidities; cardiac, pulmonary, hepatic, renal Standard dose Dose level -1 ~75% Dose level -2 ~50% dose* noneone ≥2* Modified from Palumbo et al, Personalised therapy in multiple myeloma according to patient age and vulnerability. Blood 2011;118:4519-1529 *Peyrade et al, Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B cell lymphoma. Lancet Oncol 2011;12:460-468

28. Avoiding toxicity Dose reduction Patients want QoL rather than survival Increase the dose if well tolerated Toxicity assessment after each cycle

29. Supportive care Most important in elderly – Medical aspects eg. High infection rate, higher rate herpes zoster, thromboembolism Psychosocial support Need the help of the geriatricians

30. Future Research Improve on early mortality Improve on QoL data Which patients are unlikely to benefit from treatment Appropriate dose reductions Supportive care

31. Summary Myeloma in the frail elderly is becoming commoner High early mortality in the elderly Most elderly patients want treatment provided they have good QoL Functional assessment in oncology is still evolving Toxicity can be reduced with dose reduction Meticulous supportive care is probably important

32. Conclusion Elderly patients live on the borderline of a precariously balanced physiological state. Attention to detail in ALL aspects of the patient’s care is likely to produce the best outcome