1. CPC vignettes – challenging cases in the elderly
Dr Neil Rabin
Consultant Haematologist
University College London Hospital
& North Middlesex University Hospital

2. Case 1: William 70 year old retired biomedical scientist
June 2007: weight loss and fatigue
IgG lambda pp 44g/L, BJP negative
Hypercalcaemia with normal renal function
BM 80-90% plasma cells
SS: multiple lytic lesions
Cytogenetic – FISH - normal
ISS stage: 2
PMHx – Asthma, investigated for SVTs
PHx - Ex smoker. PS = 0. Active lifestyle.

3. Case 1: William Diagnosed with symptomatic myeloma (age 70)
Treated with Cyclophosphamide Dexamethasone Thalidomide (CTD) for 4 months at local hospital
PP falls from 44g/L to 13 g/L (partial response)
Echocardiogram – normal
Creatinine clearance – normal
How would you treat him ?

4. Case 1: William Decision – what treatment now?
Continue CTD to maximal response
Switch to salvage treatment (Velcade based)
Proceed to ASCT
Other

5. Case 1: William CDT M200 THALIDOMIDE CVD Retro-orbital Plasmacytoma
Serum paraprotein (g/L)
Time (months)

6. Stratification of treatment by age40 50 60 70 80 90 30
120
150
AGE
NUMBER OF PATIENTS
Myeloma IX: AGE DISTRIBUTION BY PATHWAY
INTENSIVE
NON-INTENSIVE
ASCT-eligible
Not eligible ?
67.4% of patients entered into Intensive arm proceeded to ASCT

7. How do we decide if a patient is for intensive therapy (ASCT eligible) ?
Age
Performance status
Organ Function
Disease biology
Adequate stem cells
Patient choice

8. Transplantation in the elderly
ASCT performed at UCLH from 1993 →2010
338 patients
Median age 57 years (range 34-71)
40 patients >65 years
Maciocioa P, unpublished data

9. Improvement in PFS/OS with MPT vs MP/M100
IFM trial
MPT vs MP vs M100
Age 65-75
Improvement in PFS/OS with MPT vs MP/M100
Facon T. et al. Lancet; 370: , 2007

10. Case 2: Jennifer 69 year old retired elderly care nurse
Anaemia last 2 years
PMHx -↑BP
Fall going down the
stairs at home
PHx – previously active,
current PS = 2

11. Case 2: Jennifer
CT fracture through lytic lesion with extraosseous tumour
Biopsy lytic lesion = plasma cell neoplasm
MRI: multiple lytic lesions vertebrae, sacrum, femora, fractures T6, L1, L5, small paravertebral mass at T6
Haemoglobin 9 g/dL, Creatinine 107 umol/L, Calcium normal
IgD lambda PP 12 g/L + Lambda LC
Urinary BJP 2.72 g/L
BM 80-90% plasma cells
ISS stage 3 (beta-2 m 7.7mg/L)
Cytogenetic – FISH failed

12. Case 2: Jennifer Decision – what initial treatment?
Aim for induction treatment prior to ASCT
MPV
CTDa or MPT
Clinical trial

13. Case 2: Jennifer Decision for non-intensive treatment
Declined clinical trial entry
Treated with MPV November 2012
Intra-medullary nail inserted November 2012
Single fraction radiotherapy to humerus
Completed 8 cycles – achieving CR
Lambda LC
15,571 mg/l pre-cycle 1
3,274 mg/l pre-cycle 2
SFLC normal from cycle 4 onward
“Velcade eyes” cycle 6

14. VISTA study: VMP vs MP R A N D O M I Z E
Cycles 1-4
Bortezomib 1.3 mg/m2 IV: days 1,4,8,11,22,25,29,32
Melphalan 9 mg/m2 and Prednisone 60 mg/m2 days 1-4
Cycles 5-9
Bortezomib 1.3 mg/m2 IV: days 1,8,22,29 R A N D O M I Z E
9 x 6-week cycles (54 weeks) in both arms MP
Cycles 1-9
Melphalan 9 mg/m2 and Prednisone 60 mg/m2 days 1-4
Primary Endpoint: TTP
Secondary Endpoints: CR rate, ORR, TTR, DOR, PFS, TNT, OS, QoL (PRO)
San Miguel et al. N Engl J Med 2008;359:906–17

15. VISTA: Updated Survival
13.3 months OS benefit
San Miguel J F et al. JCO 2013

16. Case 3: Ruth 68 year old retired secretary
PMHx – 2005: invasive ductal breast ca – treated with lumpectomy, RT, tamoxifem / arimidex
2008: Anaemia, Back pain, Epistaxis
IgG lambda PP 82 g/L, BJP 0.74g/L
BM 80% plasma cells
SS: multiple lytic lesions
Cytogenetic – FISH – t(4:14)
ISS stage: 2

17. Treatment Options Intensive: not fit Non-Intensive
Clinical Trial: ineligible
NICE approved:
CTDa
MPT
VMP (if unable to receive thalidomide based regimen)
Others:
M&P
Cyclo Dex
Case 3

18. Case 3: Ruth MPT x 3 Bowel disturbance, neutropaenia
MR (PP 82 → 56 g/L)
VMP x 8
Biweekly to weekly bortezomib
Weekly bortezomib at 1.3 mg/m2→ 1mg/m2 (progressive PN)
VGPR (PP 56 → 4 g/L)
Relapsed 2 years later (2010):
Lenalidomide and Dex x 4
PD on treatment (pp 36 → 65 g/L)

19. Case 3: Ruth Decision – what treatment now?
Velcade re-treatment
Bendamustine
Clinical trial
Other

21. Overview: Case [t(4;14)] 2008 - 2012
MPT
VMP RD
Velcade & Panobinostat
MUK 1
ADMYRE
FOCUS
NICE approved
Clinical Trials
1st Line
3rd Line
4th Line
5th Line
2nd Line
6th Line

22. Case 4: John 76 year old Afro-Caribbean retired builder
6 month history of exertional dyspnoea and marked peripheral oedema
Repeat admissions to hospital
PMHx – Diabetes / ↑BP / ↑Cholesterol / Atrial fibrillation
Echocardiogram – 30% LVEF, severe concentric LVH
Lambda LC noted in serum and urine
Kappa FLC 11 mg/L, lambda FLC 864 mg/L
Haemoglobin / Creatinine / Calcium - normal
Bone marrow – 75% plasma cells
Skeletal survey normal

23. Case 4: John Decision – what is the likely diagnosis?
Symptomatic myeloma
AL cardiac amyloidosis
Cardiac failure (unrelated)
Other

24. Case 4: John Referred to National Amyloidosis Centre
Echocardiogram characteristic of amyloid
IVSd 1.9 cm, moderate to severely impaired LV systolic function, grade 2 diastolic dysfunction.
ECG showed atrial flutter, variable AV block,↓ QRS
Troponin-t 0.1 ng/mL (normal), NT pro BNP 430 pmol/L
No visceral amyloid detected on SAP scintography
Differential diagnosis of
AL amyloid
Senile cardiac amyloid with co-existent myeloma
Hereditary cardiac amyloid with co-existent myeloma

25. Case 4: John Endocardial biopsy Endocardial biopsy
stained with Congo Red
Endocardial biopsy
showing apple-green birefringence
in polarised light
Lydia Lee et al, BJHM, Nov 2011
Positive immunohistochemical
staining for transthyretin

26. Case 4: John Hereditary cardiac amyloid (TTR variant)
Reviewed regularly at the NAC and local cardiologist
Cardiac medication (Enalapril, Digoxin and Furosemide) adjusted. Anti-coagulated for mural thrombus
Cardiac function remained stable for 2 years (NYHA II)
Treatment – low salt diet, fluid management, diuretics
Myeloma
Declined chemotherapy (? initial treatment needed)
Inappropriate to treat for AL cardiac amyloid
Died 2 years later

27. Cardiac amyloid
Deposition of amyloid fibrils (cardiac and other tissues)
Common findings
Low amplitude QRS complexes (<1mV in pre-cordial leads or <0.5mV in all limb leads)
Pseudoinfarction pattern (Q waves in consecutive leads)
Conduction delays + arrhythmias (commonly AF)
LV wall thickening in the absence of hypertension
AL amyloid (associated with a plasma cell clone)
Senile systemic amyloid (wild type transthyretin)
Hereditary cardiac amyloid (ATTR)

28. Hereditary cardiac amyloid (TTR)
4 % Afro-Caribbeans Val122Ile
Variable penetrance
Presents in the 7th decade
Cardiac failure / arrythmia
Resistant to diuretics / ACE i
Diagnosis based on
-Finding of cardiac amyloid
-Mutation in TTR gene
Occasionally cardiac biopsy
Gilmore et al, Heart 1999

29. Case 5: Joan 86 year old artist
Referred to general haematology clinic with normocytic anaemia (Hb 9.8 g/dL) developed previous 2 years
Symptom - fatigue, and exertional chest pain
IgG kappa PP 16 g/L, no BJP, normal SFLC ratio
Creatinine, Calcium - normal
BM 20% plasma cells
SS: no lytic lesions
Cytogenetic – FISH – 1q gain
ISS stage: 1
PMHx - ↑BP, Hiatus hernia, previous Cystitis
PHx - Lives alone, independent with ADL

30. Case 5: Joan Decision – how would you treat?
Observation only
Treatment for anaemia alone
Systemic chemotherapy
Other

31. Case 5: Joan Adopted watchful waiting
Reviewed by cardiologist – normal myocardial perfusion scan
Erythropoetin, rise in haemaglobin → 11 g/L
Bisphosphonates (absence of bone disease)
Observed for 9 months
Asymptomatic
Presented with acute lower back pain
Lower back pain whilst gardening
Plain x-rays showed fractures T12, L4 and L5
Paraprotein increase from 16g/L → 24 g/L

32. Case 5: Joan
How would you treat her ?

33. Case 5: Joan Decision – how would you treat her?
Systemic chemotherapy + Analgesia
Systemic chemotherapy + Radiotherapy
Systemic chemotherapy + Vertebral augmentation
Other

34. Case 5:Joan Admitted for pain control
Treated with long acting and short acting opiate analgesia
Received palliative RT to lumbar spine (8Gy)
Started on Cyclophosphamide po weekly, and Dexamethasone 20mg daily for 4 days / month
Discharged when mobility improved
Ongoing problems with pain
Multiple level kyphoplasty at Royal National Orthopaedic Hospital (Sean Molloy)
Very good symptomatic benefit
Support from palliative care team, and liaison with primary care

35. Case 5: Joan Weekly sc, Velcade Dose reduced to 1 mg/m2 from cycle 3
Cyclo Dex
Velcade Dex
Weekly sc, Velcade
Dose reduced to 1 mg/m2
from cycle 3
Completed 8 cycles
No sig. Rx toxicity
Progressed within 3 months
completing Velcade RT
K’plasty

36. 36

37. Case 6: Arthur 97 year old Known diagnosis of Alzheimer’s disease
Mobile with a Zimmer Frame
Lives at home with carers – washing/cooking/cleaning
Memantadine.
PMHx - ↑BP, GORD, BPH
2012: 6 week history
Confusion
Lower back pain
Bed bound

38. Case 6: Arthur IgG kappa pp 14g/L, BJP – faint band
Haemoglobin 11 g/dL
Hypercalcaemia
Creatinine 120 umol/L (eGFR 50 ml/min)
BM 40% plasma cells
SS: Fracture L4/L5, lytic lesion pelvis/femur
Cytogenetic – FISH – 17p del
ISS stage: 2
Diagnosed with symptomatic myeloma

39. Case 6: Arthur Decision – how would you treat?
Analgesia + Bisphosphonate treatment
+ Radiotherapy
+ Dexamethasone
+ Systemic chemotherapy

40. Case 6: Arthur Pain control Palliative care input Opiate analgesia
Treatment
Dexamethasone (low dose). Decision not systemic RX
Bisphophonate
Radiotherapy to lumbar spine and left ilium
Discharged home, returned to previous baseline
Re-instituted package of care
Community palliative care input
Haematology day unit

41. Case 6: Arthur Well for 3 months Decline mobility
Pain weight bearing right leg. Unable to mobilise
Re-assessed
Radiotherapy – right femur + sacrum (symptom better)
Systemic chemotherapy
? Imid based (need for anticoagulation)
? Proteosome inhibitor (able to visit hospital)
Velcade sc weekly at 1mg/m2, with Dex (10mg 2/7)
PP 14 → < 3g/L (VGPR). Received 4 cycles, stop.
No treatment emergent problems
Stable for 9 months → RIP

42. Frail elderly patient
Dependent on co-morbidities – more likely > 75 yrs.
Assessments of frailty / co-morbidities
Comprehensive geriatric assessment (CGA)
Cumulative illness rating scale (CIRS-G)
Important to note the impact of disease on performance status
Ability to benefit from novel agents
Modification of treatment dose and schedule
Balance goal of depth of response with minimising toxicities

43. PALUMBO ET AL< BLOOD, 27 OCTOBER 2011 VOLUME 118, NUMBER 1743

44. 44

45. Summary Fit elderly should be treated as any other patient
Dependent on co-morbidities – more likely > 75 yrs.
Assessments of frailty / co-morbidities
Important to note the impact of disease on performance status
Ability to benefit from novel agents
Modification of treatment dose and schedule
Balance goal of depth of response with minimising toxicities
Consider other causes for co-existent medical problems

46. UCLH
Clinical team
Kwee Yong / Shirley D’Sa / Ali Rismani / Rakesh Popat
Jaimal Kothari / Dean Smith / Laura Percy / Lydia Lee
Clinical Nurse Specialists
Aviva Cerner / Samantha Darby
Jude Dorman
Clinical Trials
Janet Lyons – Lewis / Diane Gowers
North Middlesex
Clinical Nurse Specialist
Millicent Blake – McCoy
Christy Griffin-Pritchard