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

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.

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 ?

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

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

Stratification of treatment by age 40 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

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

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65 years Maciocioa P, unpublished data

Improvement in PFS/OS with MPT vs MP/M100 IFM 99-06 trial MPT vs MP vs M100 Age 65-75 Improvement in PFS/OS with MPT vs MP/M100 Facon T. et al. Lancet; 370:1209-1218, 2007

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

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

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

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)

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

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

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

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

Case 5: Joan How would you treat her ?

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

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

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

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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

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

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

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

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

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

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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

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