Michel Delforge, MD, PhD

University Hospital Leuven

Leuven, Belgium

COMy, Bangkok 12 may 2014

Comorbidities in Multiple Myeloma

Comy Meeting, Bangkok, 12 may 2014

Disclosures

• Advisory board: Janssen, Celgene

• Speaker’s honoraria: Janssen, Celgene,

Novartis

3

• Male patient, 76 y

• Medical history:

• arterial hypertension

• total knee replacement

• Medication: amlodipine 5 mg/d

• Current problem: newly diagnosed MM, IgG kappa

• CRAB: anemia, pathological rib fracture

• Patient is active and independent

• Which treatment would you prefer:

1. VMP twice weekly

2. VMP weekly

3. VMPT

4. MPT

5. Lenalidomide-dexamethasone

• Male patient, 72 y

• Medical history:

• coronary bypass

• COPD GOLD II

• chronic atrial fibrillation

• Medication: dabigatran, atenolol, perindopril

• Current problem: newly diagnosed MM, IgG kappa

• CRAB: anemia, pathological vertebral fracture

• Patient has mild/moderate dyspnea

• Which treatment would you prefer:

1. VMP twice weekly

2. VMP weekly

3. VMPT

4. MPT

5. Lenalidomide-dexamethasone

Treatment optimization

Aim: to deliver effective treatment without excessive

toxicity

Risk of undertreatment: early relapse

Risk of overtreatment: early treatment discontinuation

Toxicity Efficacy

• between 65 and 80y:

one third has at least

one comorbidity

• ≥ 80 y: up to 70% of the

population has at least

one comorbidity

Comorbidities

“It is the concurrent presence of two or more medically

diagnosed diseases in the same individual, with the

diagnosis of each contributing disease based on

established, widely recognized criteria.”

men women

Fried et al, J Gerontol 2004;59:255

Type of comorbidities

• mental illness

• cardiac disease (e.g. cardiac

failure, arhytmia)

• chronic respiratory disease (e,g,

COPD)

• hepatic disease

• kidney disorders (e.g. renal

insufficiency)

• diabetes

• vascular disease

• musculoskeletal disorders

• peripheral nerve disorders

Chronic diseases

acute intercurrent

diseases

another invasive

malignancy

* examples for multiple myeloma

disease-related adverse events as

comorbidities

• pathological fracture,

spinal cord compression,

hypercalcemia

• renal failure

• infection

Treatment-related adverse events

More treatment

discontinuation in

patients > 75y

Palumbo et al, Blood 2011;118:4519

All patients Treatment subgroups

HR (95% CI ) P value

All 2.53 (1.75 to 3.64) <0.001

MP 1.46 (0.59 to 3.63) 0.41

MPT 2.96 (1.71 to 5.15) <0.001

VMP 2.73 (1.03 to 7.24) 0.04

VMPT/VTP 2.77 (1.18 to 6.51) 0.02

0,1 1 10

Higher mortality in patients with cardiac, infective or GI AEs

Higher mortality in patients without cardiac, infective or GI AEs

n = 1435

Impact of cardiac, infective and gastro-

intestinal AEs on survival

Bringhen et al. Haematologica 2013;98:980

MPRa MP

Discontinuation rateb

65 - 75 years of age 17% 10%

> 75 years of age 34% 16%

Cumulative dose intensityc

65 - 75 years of age 88% 97%

> 75 years of age 56% 97%

a MPR includes MPR-R and MPR for the initial 9 cycles. b Discontinuation due to AEs or withdrawal of consent c Cumulative dose intensity of melphalan and lenalidomide/placebo

Palumbo A, et al. Blood. 2010;116: Abstract 622.

Aiming too high in the very elderly

How to assess comorbidities ?

• Clinical judgement

• driven by clinical experience

• Pro: fast

• Con: measurement can be time- and circumstance-dependent

• Global scores for health assessment:

• Karnofsky Performance Status

• ECOG/WHO score

• Specific scores:

• for transplant candidates: HCT-CI (Charlson, Sorror)

• for non-transplant candidates: comprehensive geriatric

assessment (cGA)

Score Description

0 asymptomatic (Fully active, able to carry on all predisease activities without restriction)

1 Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and

able to carry out work of a light or sedentary nature. For example, light housework, office work)

2 Symptomatic, <50% in bed during the day (Ambulatory and capable of all self care but unable to carry out

any work activities. Up and about more than 50% of waking hours)

3 Symptomatic, >50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair

50% or more of waking hours)

4 Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair)

5 death

Scores for overall health evaluation ECOG/0WHO/Zubrod performance score

Score Description

100% normal, no complaints or signs of disease

90% normal activity, few symptoms or signs

80% normal activity with some difficulty, symptoms or signs

70% caring for self, not capable of normal activity or work

60% requires some help, can take care of most personal requirements

50% requires help often, requires frequent medical care

40% disabled, requires special care and help

30% severely disabled, hospital admission indicated but no risk of death

20% very ill, urgently requiring admission, requires supportive measurements or treatment

10% moribund, rapidly progressive fatal disease process

0% death

Karnofsky DA et al. 1949

Scores for overall health evaluation Karnofsky Performance Score

Kleber et al. Clin Myeloma, Lymphoma & Leukemia 2013;13:541

• n = 466 MM patients

• comorbidities measured:

• Karnofsky Performance Scale

• kidney function (eGFR)

• respiratory function (FEV1/FVC)

Specific comorbidity scores for myeloma

Kleber et al. Clin Myeloma, Lymphoma & Leukemia 2013;13:541

Specific comorbidity scores for myeloma combination with ISS and age

Disability

“Disability is defined as difficulty or dependency in

carrying out activities essential to independent living,

including essential roles, tasks needed for self-care and

living independently in a home, and desired activities

important to one’s quality of life”

Disability can be measured with:

-ADL*: e.g. dressing, eating,

bathing,…

-IADL**: e.g. using a phone,

preparing a meal,…

*ADL: activities of daily living

**IADL: instrumental activities of daily living

Fried et al, J Gerontol 2004;59:255

Frailty

“Frailty can be defined as a physiologic state of increased

vulnerability to stressors that results from decreased

physiologic reserves, and even dysregulation, of multiple

physiologic systems.” Clinical symptoms are: weakness, low

physical activity, weight loss, poor endurance, slow gait speed1

1.Fried et al, J Gerontol 2004;59:255 Rockwood et al. CMAJ 2011.

DOI:10.1503 /cmaj.101271

2. Palumbo et al, Blood 2011;118(17):4519-29

Kaplan–Meier probability of survival over 12

years, according to baseline health status, for

persons 70 years or older (D).

Comorbidity Disability

Frailty

5.7% 46%

21%

27%

Overlap between comorbidity, frailty,

disability

Data from the Cardiovascular Health

Study (n = 2762 participants > 65y)

Fried et al, J Gerontol Med Sci 2001;56A: M146

Frail patients with comorbidities are

underrepresented in clinical trials

“The main finding from our study

is that older patients are still

commonly excluded from clinical

trials on hematologic

malignancies,,,,”

Cherubini et al. Haematologica 2013;98:997

(n = 85 clinical trials)

pa

tie

ns (

%)

Multiple myeloma is primarily a disease of

the elderly patient

An intuitive approach for ‘vulnerable’ MM patiens

Palumbo et al, Blood 2011;118(17):4519-29

Risk factors

• age over 75 y

• mild, moderate or severe frailty

• comorbidities: cardiac/pulmonary/hepatic/renal

dysfunction

GO-GO MODERATE-GO SLOW-GO

no risk factors at least one risk factor at least one risk

factor plus

occurence of

grade 3-4 non-hematol. AE

Dose level 0

Dose level - 1 Dose level - 2

DOSE LEVEL 0 DOSE LEVEL −1 DOSE LEVEL −2

Lenalidomide 25 mg/d

d 1-21 / 4 wks

15 mg/d

d 1-21 / 4 wks

10 mg/d

d 1-21 / 4 wks

Thalidomide 100 mg/d 50 mg/d 50 mg/every other day

Bortezomib 1.3 mg/m2

d 1,8,15,22 / 5 wks

1.0 mg/m2

d 1,8,15,22 / 5 wks

1.3 mg/m2

d 1,15 / 4 wks

Melphalan 0.2 mg/kg/d

d 1-4 / 5 wks

0.15 mg/kg

d 1-4 / 5 wks

0.10 mg/kg

d 1-4 / 5 wks

Prednisone 2 mg/kg/d

d 1-4 / 5 wks

1.5 mg/kg/d

d 1-4 / 5 wks

1 mg/kg/d

d 1-4 / 5 wks

Palumbo et al N Engl J Med. 2011;364:1046

Dose and regimen adjustment according to

vulnerability

Comprehensive geriatric assessment • Functionality:

• ADL

• IADL

• Falls

• Fatigue:

• MOB-T

• Pain:

• VAS score

• Mental health:

• MMSE

• GDS-4

• Nutritional status:

• MNA-SF

• Social Status

ADL: Activities of Daily Living; IADL: Instrumental Activities of Daily Living, MOB-T: Mobility-Tiredness Test: MMSE: Mini-Mental Status

Examination; GDS: Geriatric Depression Score; MNA: Mini-Nutritional Assessment Short Form; VAS: Visual Analogue Scale

Kenis et al. Ann Oncol 2013;24:1307

• n = 1967 cancer patients

• 70% had a geriatric risk profile (G8 score)

• in 62% physicians were aware of the geriatric

assessment

• In 52% GA detected unknown geriatric problems

• In 26% this resulted in a specific geriatric

intervention

• In 25% GA influenced anti-tumoral treatment

decision

Kenis et al. Ann Oncol 2013;24:1307

Larocca et al. ASH 2013 (Abstract 687), oral presentation

Larocca et al. ASH 2013 (Abstract 687), oral presentation

Larocca et al. ASH 2013 (Abstract 687), oral presentation

Larocca et al. ASH 2013 (Abstract 687), oral presentation

Larocca et al. ASH 2013 (Abstract 687), oral presentation

Larocca et al. ASH 2013 (Abstract 687), oral presentation

Larocca et al. ASH 2013 (Abstract 687), oral presentation

Overall conclusions

• Patient-specific characteristics (comorbidities,

disability, frailty) should be included in

treatment decision

• A comprehensive geriatric assessment is

recommended in the (very) elderly MM patients

• Patient vulnerability affects treatment adverse

events, treatment duration and progression-

free and overall survival

• ‘Risk-adapted’ treatment can improve the

outcome of the vulnerable MM patient

Future: specific biomarkers for aging ?

Pallis et al. J Geriat Oncol 2014;5:84