CPC vignettes – challenging cases in the elderly

Consultant HaematologistUniversity College London Hospital& North Middlesex University Hospital

Dr Neil Rabin

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: WilliamDecision – what treatment now?

• Continue CTD to maximal response• Switch to salvage treatment (Velcade based)• Proceed to ASCT• Other

Case 1: WilliamM200 THALIDOMIDE CVDCDT

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Retro-orbitalPlasmacytoma

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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

Maciocioa P, unpublished data

• ASCT performed at UCLH from 1993 →2010• 338 patients• Median age 57 years (range 34-71)• 40 patients >65 years

Facon T. et al. Lancet; 370:1209-1218, 2007

• IFM 99-06 trial

• MPT vs MP vs M100• Age 65-75

• Improvement in PFS/OS with MPT vs MP/M100

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: JenniferDecision – 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 13,274 mg/l pre-cycle 2SFLC normal from cycle 4 onward“Velcade eyes” cycle 6

San Miguel et al. N Engl J Med 2008;359:906–17

VMPCycles 1-4Bortezomib 1.3 mg/m2 IV: days 1,4,8,11,22,25,29,32Melphalan 9 mg/m2 and Prednisone 60 mg/m2 days 1-4

Cycles 5-9Bortezomib 1.3 mg/m2 IV: days 1,8,22,29Melphalan 9 mg/m2 and Prednisone 60 mg/m2 days 1-4

MPCycles 1-9Melphalan 9 mg/m2 and Prednisone 60 mg/m2 days 1-4

RANDOMIZE

9 x 6-week cycles (54 weeks) in both arms

Primary Endpoint: TTP Secondary Endpoints: CR rate, ORR, TTR, DOR, PFS, TNT, OS, QoL

(PRO)

VISTA study: VMP vs MP

VISTA: Updated Survival

San Miguel J F et al. JCO 2013

13.3 months OS benefit

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

1. Intensive: not fit2. Non-Intensive

a) Clinical Trial: ineligibleb) NICE approved:

1. CTDa2. MPT3. VMP (if unable to receive thalidomide based regimen)

c) Others:1. M&P2. 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: RuthDecision – 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

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NICE approved Clinical Trials

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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: JohnDecision – 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 amyloidIVSd 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 biopsystained with Congo Red

Endocardial biopsyshowing apple-green birefringencein polarised light

Positive immunohistochemicalstaining for transthyretin

Lydia Lee et al, BJHM, Nov 2011

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 Val122IleVariable penetrancePresents in the 7th decadeCardiac failure / arrythmiaResistant to diuretics / ACE i

Diagnosis based on-Finding of cardiac amyloid-Mutation in TTR geneOccasionally 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: JoanDecision – 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 monthsAsymptomatic

• 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: JoanDecision – 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 Velcade Dex

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RT K’plastyWeekly sc, VelcadeDose reduced to 1 mg/m2 from cycle 3Completed 8 cyclesNo sig. Rx toxicity

Progressed within 3 monthscompleting Velcade

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: ArthurDecision – 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

PALUMBO ET AL< BLOOD, 27 OCTOBER 2011 VOLUME 118, NUMBER 17

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 PopatJaimal Kothari / Dean Smith / Laura Percy / Lydia Lee

• Clinical Nurse SpecialistsAviva Cerner / Samantha DarbyJude Dorman

• Clinical TrialsJanet Lyons – Lewis / Diane Gowers

North Middlesex• Clinical Nurse Specialist

Millicent Blake – McCoy• Clinical Trials

Christy Griffin-Pritchard