Comorbidities in Multiple Myeloma Michel Delforge, MD, PhD University Hospital Leuven Leuven, Belgium COMy, Bangkok 12 may 2014 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 Efficacy Toxicity Risk of undertreatment: early relapse Risk of overtreatment: early treatment discontinuation
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. between 65 and 80y: one third has at least one comorbidity 80 y: up to 70% of the population has at least one comorbidity men women Fried et al, J Gerontol 2004;59:255
Type of comorbidities Chronic diseases 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 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
Impact of cardiac, infective and gastrointestinal AEs on survival All patients Treatment subgroups HR (95% CI ) P value n = 1435 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 without cardiac, infective or GI AEs Higher mortality in patients with cardiac, infective or GI AEs Bringhen et al. Haematologica 2013;98:980
Aiming too high in the very elderly MPR a MP Discontinuation rate b 65-75 years of age 17% 10% > 75 years of age 34% 16% Cumulative dose intensity c 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.
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)
Scores for overall health evaluation ECOG/0WHO/Zubrod performance score 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 Karnofsky 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
Specific comorbidity scores for myeloma n = 466 MM patients comorbidities measured: Karnofsky Performance Scale kidney function (egfr) respiratory function (FEV1/FVC) Kleber et al. Clin Myeloma, Lymphoma & Leukemia 2013;13:541
Specific comorbidity scores for myeloma combination with ISS and age Kleber et al. Clin Myeloma, Lymphoma & Leukemia 2013;13:541
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 speed 1 Kaplan Meier probability of survival over 12 years, according to baseline health status, for persons 70 years or older (D). 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
Overlap between comorbidity, frailty, disability Disability Comorbidity 21% 5.7% 46% 27% Frailty 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 (n = 85 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
Multiple myeloma is primarily a disease of the elderly patient patiens (%)
An intuitive approach for vulnerable MM patiens 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 Palumbo et al, Blood 2011;118(17):4519-29
Dose and regimen adjustment according to vulnerability 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/m 2 d 1,8,15,22 / 5 wks 1.0 mg/m 2 d 1,8,15,22 / 5 wks 1.3 mg/m 2 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
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 progressionfree 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