myeloma update - sobell house education · 2019. 12. 4. · myeloma at diagnosis cytogenetic...
TRANSCRIPT
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Myeloma update Sobell House
November 2019
Topic
• Myeloma diagnosis & risk stratification
• Bone and Renal issues
• Treatment outcomes Newly diagnosed MM
• Treatment outcomes relapsed MM
• Double refractory MM
• QoL
• Living with myeloma
• Smouldering myeloma/precursor conditions
• Improving outcomes……………………………
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Themes
• Impact of disease-physical/emotional/economic.
• Interventions and outcomes-when to intervene/when not to.
• measuring outcomes…OS/PFS/MRD?
• Survival vs living well.
• Cure?
What is myeloma?
• Incurable plasma cell malignancy
• 2% of all cancers in the UK
• Average age at diagnosis 69 years
• Has a premalignant and early asymptomatic stage
• Remitting relapsing course
• Affects multiple body systems – bone, renal, immunity, bone marrow function
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Myeloma Incidence
• Myeloma is the 19th most common cancer in the UK, accounting for 2% of all new cancer cases (2016).
• In females in the UK it is the 18th most common cancer (1% of all new female cancer cases). In males in the UK, myeloma is the 16th most common cancer (2% of all new male cancer cases).
• 43% of myeloma cases in the UK are in females, and 57% are in males.
Incidence according to age
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Incidence according to age groups over time
Myeloma (C90): 1971-2011 Age-Standardised Five-Year Net Survival, England and Wales
Please include the citation provided in our Frequently Asked Questions when reproducing this chart: http://info.cancerresearchuk.org/cancerstats/faqs/#How Prepared by Cancer Research UK Original data sources: Survival estimates were provided on request by the Cancer Research UK Cancer Survival Group at the London School of Hygiene and Tropical Medicine. http://www.lshtm.ac.uk/eph/ncde/cancersurvival/http://www.lshtm.ac.uk/eph/ncde/cancersurvival/
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Clinical presentation
• Bone disease
• Anaemia
• Impaired kidney function
• Hypercalcaemia
• Recurrent/persistent infections
• Incidental finding?.....
At presentation
• 15% patients have no symptoms
• 38% emergency presentation - Kidney failure
- Spinal cord compression/loss of movement
- Fracture
- High calcium
• Remainder have symptoms, commonly - Backache or bone pain
- Tiredness / anaemia / increased infections
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The normal bone marrow
Plasma Cells in health-protein producing factory
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Ag
Pre-B cell
Naive B cell
Follicular B blast
Centroblast
Centrocyte
Marginal Zone
Memory B-cells
Plasma cell
Extrafollicular B-Immunoblast
Interfollicular area
Immature B-cell
Progenitor B-cell
What are plasma cells?
Follicular area
FDC
Ag
Lymph Node
Germinal Centre
SHM +
class switching
Germs
IgM IgG IgA
B-cell affinity maturation
Normally up to 3% in BM Also present in respiratory and GI tissues
Malignant transformation
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Diagnosing Disease
Too many proteins
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What is an M-protein? SPEP
Polyclonal
smear
M-spike
Normal antibody repertoire
Myeloma antibodies
Serum protein electrophoresis
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Immunofixation
1 normal 2 high level IgG + monoclonal free light chains + immune paresis (pt with MM and renal failure) 3 low level IgA M-protein 4 moderate IgM M-protein
Freelite - serum free light chain immunoassay
Exposed surface Lambda
Kappa
Hidden surface
Light chain
Heavy chain
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FLC (mg/L)
F
LC (
mg
/L)
Blood.2001: 97: 2900-02
Immunoglobulin FLC levels in myeloma
Immunohistochemistry CD138 staining of marrow or biopsy and light chain restriction
CD138
Kappa LC
Images provided by Sue Brown Senior BMS , Royal Berkshire Hospital, UK
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Myeloma(‘pepper(pot(skull’(
i. ii. iii. iv. v.
vi. vii. viii. ix.
Devastating consequences of myeloma bone disease
A 60 year old male with Durie-Salmon IIIA, presenting a multi-focal MRI pattern on saggital T2 sequence with mildly increased signal intensity of FL throughout the vertebral column (A), more intense STIR signal (B). Corresponding PET/CT image shows a high degree of FDG avidity with a multi-focal uptake pattern (C).
Mesguich C, et al. State of the art imaging of multiple myeloma: Comparative review of FDG PET/CT imaging in various clinical settings. Eur J Radiol (2014),
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Increased sensitivity over skeletal survey in detecting lytic lesions.
Finding on WBLDCT not identified on SS. a. Conventional lateral radiograph of the thoracic spine – no focal lytic lesion identifiable. b. WBLDCT sagittal view of the spine showing a focal lytic lesion eroding through the cortex of the anterior wall of the spinal canal at T10 c. WBLDCT axial image showing extension into the canal at high risk of cord compression. The patient was referred for emergency radiotherapy. (Gleeson, T.G. et al 2009 ‘Accuracy of whole-body low-dose multidetector CT (WBLDCT) versus skeletal survey in the detection of myelomatous lesions and correlation of disease with whole body MRI (WBMRI)’
Whole body computerised tomography (WBCT)
Renal complications
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Myeloma Renal Disease
• “Myeloma kidney” • Normal glomerular function
• Concentrated light chains precipitate in tubules
• Monoclonal light chains seen in UPEP with immunofixation
• Glomerular lesions
• Deposits of amyloid or light chain deposition disease
• Nonselective leakage of all serum proteins
• UPEP preponderance of albumin
Cast nephropathy
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Renal Manifestations
Amyloidosis
Light chain Deposition
Pierre Ronco JNEPHROL 2000; 13 (suppl. 3):
Myeloma Kidney Cast Formation
‘Umbrella’ term
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P. Leif Bergsagel et al. Blood 2013;121:884-892
©2013 by American Society of Hematology
15 15
5 10
35
10
40
0
10
20
30
40
50
t(11;14) t(4;14) t(14;16) 17p- 1q+ 1p- 13q-
%
CYTOGENETIC ABNORMALITY
FREQUENCY OF CYTOGENETIC ABNORMALITIES IN MYELOMA AT DIAGNOSIS
Cytogenetic Abnormalities In Myeloma
5 recurrent chromosomal translocations – lead to over expression of an
oncogene
Genomic imbalances – alteration in the number of copies of
chromosomes, or parts of chromosomes (short arm = p arm,
long arm = q arm)
Other Plasma Cell Diagnoses
• MGUS
• Smouldering Myeloma
• IgM Waldenstrom’s Macroglogulinaemia
• AL amyloidosis
• POEMS
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Intact immunoglobulin
Light chain Nonsecretory
AL amyloidosis
MGUS SMM
Multiple myeloma
Monoclonal gammopathies
80% 15 – 20% 1 – 2%
Myeloma vs MGUS vs Smouldering Myeloma
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Diagnosis
CRAB HyperCalcaemia Renal
insufficiency
Anaemia Bone
pain/fractures/osteoporosis
When to Suspect Myeloma?
Unexplained, one or multiple of:
Request a Myeloma Screen (Freelite + SPE)
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Time to MM diagnosis is prolonged
0
30
60
90
120
150
180
Acute myeloidleukemia
Diffuse large B-celllymphoma
Myeloma
Median Time (days)
Adapted from Howell BMC Hematol 2013;13:9
Haematological Malignancy Research Network (2004 to 2011)
Shortest 84
Howell BMC Hematol 2013;13:9
0 300 100 200
Median 163
Longest 306
Time to MM diagnosis is prolonged
Time (days)
Median of 3 or more appointments required for a MM
diagnosis
Lyratzopoulos Lancet 2012;13:353-65
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0 300 100 200
Time (days)
Lyratzopoulos Lancet 2012;13:353-65
SPE No
urine/urine insensitive
Biopsy
63% with co-morbidities 100% with co-morbidities
Kariyawasan Q J Med 2007;100:635-40 Howell BMC Hematol 2013;13:9
Increasing time to diagnosis = increasing comorbidity development (eg renal impairment)
Median of 3 or more appointments required for a MM
diagnosis
Miss – symptoms not spotted MM Diagnosis Miss – lab investigation negative/incomplete
T=0
SPE = -ve No urine
Development of Comorbidities
SPE = -ve FLC = +ve
Biopsy
Tumour Burden Disease Stage Co-morbidities
Due to delay in seeking help
Due to delay in seeking lab investigation
Due to lab investigation
negative/incomplete
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Delays in Diagnosis
When to Suspect Myeloma?
Myeloma Warning Signs/Symptoms Back Pain
(1st Episode)
Back Pain (2nd
Episode)
Rib Pain Other Bone Pain
Joint Pain Chest Pain
Nose-bleeds
Shortness of Breath
Weight Loss
Nausea Chest Infection
Fracture
As a single symptom
Back pain
HyperCa
Raised Creatinine
Raised MCV
Raised Inflammatory
Markers
Low Platelets
Low Hb
Leukopenia
Suspected Myeloma?: Request SPE+sFLC → Either or both abnormal → Possible Myeloma → Refer to Haematologist → Both normal → Myeloma Unlikely
Positive Predictive Value
for Myeloma
Not Calculated <1% 1-2% 2-3% 3-4%* 4% and above*
Colour key
* NICE recommends all warning signs/symptom (combinations) with a positive predictive value (PPV) >3% should be investigated, those <3% should at least be considered for investigation.
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Too little, too late…..
How many doctors
• Not being heard….
• Multiple presentations
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Psychological impact
• Depression
• Social interaction
Economic impact
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QoL
Assessment of a myeloma patient
• Confirmation of multiple myeloma
• Assessing co morbidities
• Bone disease?
• Renal Impairment?
• Neuropathy?
• Performance status?
• What does the patient want ?
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Natural History
Achieving and Maintaining Disease Control
Symptomatic myeloma
Asymptomatic
1
10
100
Refractory relapse
MGUS or smouldering
myeloma Plateau
remission
Symptomatic
Relapse
M p
rote
in (
g/d
L)
Time
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Treatment
When does treatment start?
• Many patients do not start treatment as soon as they are diagnosed
• No evidence that treating asymptomatic disease will increase survival
• Symptoms or evidence of progression
• Joint decision by doctor and patient
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Aims of treatment
Anti-myeloma treatment
Improve quality of
life and survival
Prevent and treat bone and
tissue damage
Salvage kidney
function
Approach to Treatment of Myeloma
Nontransplant Candidate (based on age, performance status,
and comorbidities)
Induction treatment
Transplant Candidate
Induction treatment (4-6 cycles)
Stem cell harvest
Stem cell transplantation
Relapsed disease – salvage treatment
Monitor disease
Monitor disease
Relapsed disease – salvage treatment
Further relapse – salvage treatment
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Remission – current practice • No treatment, most drugs stopped
• Maintenance treatment – not standard
• Bisphosphonates for at least 2 years
• Minimal effective pain management
20
50
100
1st REMISSION
When do you treat at relapse?
Options
1. Wait till u have a level of paraprotein or light chain load (presentation level)
2. Wait till onset of CRAB
3. At first onset of biochemical relapse
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Aims of treatment at relapse
• Prevent CRAB
• Achieve response
• A response which translates into improved overall survival
• A response that you can maintain?
• Treatment choice that is well tolerated - QoL
Geriatric assessment of MM patients
Blood. 2015 Mar 26;125(13):2068-74
Survival stats for 3 yrs
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Assess fraility
Fit Unfit Frail
Full
go
Slow
go
Very
slow go
2 or 3 drug
regimen
reduce dose
2 (3) drug
regimen
further dose
reduction
MP, CTX-P
VD, Ld
Treatment of patients with multiple myeloma not eligible for transplantation
An approach to treatment
1st Line 2nd Line 3rd Line 4th LineSubsequent
line
Subsequent relapse
3rd Relapse2nd Relapse1st RelapsePresentation
1st Line 2nd Line 3rd Line 4th LineSubsequent
line
Thalidomide Velcade RevlimidClinical
Trials
Clinical
Trials
Clinical
Trials
Disease assessments
“Treatment Palette”
Typical UK approach to treatment
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Immunomodulatory Management
IMiD Structures
Potency Side effects Potency
Renal excretion 80% Renal excretion 20%
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0
10
20
30
40
50
60
70
80
90
100
VAD TD RD PAD VTD RVD CVRD CyBorD CarRD*
Pe
rce
nt
Res
po
nse
Induction Regimen
ORR
VGPR
CR/nCR
Improved Response rates - Its the combinations…..
It’s not just the combinations its also the duration – even in elderly
0
10
20
30
40
50
60
70
80
90
MP TD CTD MPR MPT Rd MPR-R MPV MPVT-VT MPV-VT
PFS
3 Year OS
Mo
nth
s
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RA
ND
OM
ISA
TIO
N 1
:1:1
Arm B
Ld18
Arm C
MPT
LEN + LoDEX: 18 Cycles (72 wks) LENALIDOMIDE 25 mg D1-21/28
LoDEX 40 mg D1,8,15, & 22/28
MEL + PRED + THAL 12 Cycles (72 wks) MELPHALAN 0.25 mg/kg D1-4/42
PREDNISONE 2 mg/kg D1-4/42
THALIDOMIDE 200 mg D1-42/42
PD
, O
S, an
d
Su
bs
eq
ue
nt
an
ti-M
M T
x
PD
or
Un
accep
tab
le T
ox
icit
y
Active Treatment + PFS Follow-up Phase Screening LT Follow-Up
Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL (100 mg D1-42/42); MEL 0.2 mg/kg D1–4
• Stratification: age (≤ 75 y vs. > 75 y), country, and ISS stage (I or II vs. III)
• Thromboprophylaxis was mandatory
FIRST Trial: Study Design
LEN + LoDEX: Continuously LENALIDOMIDE 25 mg D1-21/28
LoDEX 40 mg D1,8,15, & 22/28
Arm A
Continuous Ld
FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; ISS, International Staging
System; Ld, lenalidomide plus low-dose dexamethasone; Ld18, lenalidomide plus low-dose dexamethasone for 18 cycles;
LEN, lenalidomide; LoDEX, low-dose dexamethasone; LT, long-term; MEL, melphalan; MM, multiple myeloma; MPT,
melphalan, prednisone, thalidomide; OS, overall survival; PD, progressive disease; PFS, progression-free survival; Pred,
prednisone; pt, patient; THAL, thalidomide; Tx, treatment. Benboubker L, et al. NEJM. 2014;371:906-17
Median PFS
Ld (n=535) 25.5 mos
Ld18 (n=541) 20.7 mos
MPT (n=547) 21.2 mos
Ld 535 400 319 265 218 168 105 55 19 2 0
Ld18 541 391 319 265 167 108 56 30 7 2 0
MPT 547 380 304 244 170 116 58 28 6 1 0
Hazard ratio
Ld vs. MPT: 0.72 (CI: 0.61-0.85); P < 0.001
Ld vs. Ld18: 0.70 (CI: 0.60-0.82) ; P < 0.001
Ld18 vs. MPT: 1.03 (CI: 0.89-1.20); P = 0.70
Time (months)
Pati
en
ts (
%)
100
80
60
40
20
0 0 6 12 18 24 30 36 42 48 54 60
FIRST Trial: Final Progression-free Survival
23% (Ld18)
23% (MPT)
42% (Ld)
CI, confidence interval; mos, months; FIRST, Frontline Investigation of Revlimid and Dexamethasone
versus Standard Thalidomide; Ld, lenalidomide plus low-dose dexamethasone; Ld18, lenalidomide plus
low-dose dexamethasone for 18 cycles; MPT, melphalan, prednisolone, thalidomide; mos, months; PFS,
progression-free survival; wks, weeks
Benboubker L, et al. NEJM. 2014;371:906-17
Facon T, et al: EHA 2014; Oral Presentation and Abstract S643
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FIRST Trial: Overall Survival Interim Analysis
574 deaths (35% of ITT)
FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; Ld, lenalidomide plus low-dose dexamethasone; Ld18, lenalidomide plus low-dose dexamethasone for 18 cycles; MPT, melphalan, prednisone, thalidomide; OS, overall survival
Pa
tie
nts
(%
)
Ld
Ld18
MPT
535
541
547
488
505
484
457
465
448
433
425
418
403
393
375
338
324
312
224
209
205
121
124
106
43
44
30
5
6
3
0
0
0
4-year OS
Ld (n= 535) 59%
Ld18 (n= 541) 56%
MPT (n= 547) 51%
Overall survival (months)
100
80
60
40
20
0 0 6 12 18 24 30 36 42 48 54 60
Hazard ratio
Ld vs. MPT: 0.78 (CI: 0.64-0.96); P = 0.02
Ld vs. Ld18: 0.90; P = 0.31
Ld18 vs. MPT: 0.88; P = 0.18
Benboubker L, et al. NEJM. 2014;371:906-17
Monoclonal antibodies in Myeloma
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Daratumumab: Mechanism of Action
• Human CD38 IgGκ monoclonal antibody
• Direct and indirect anti-myeloma activity1-5
• Depletes CD38+ immunosuppressive regulatory cells5
• Promotes T-cell expansion and activation5
1. Lammerts van Bueren J, et al. Blood. 2014;124:Abstract 3474.
2. Jansen JMH, et al. Blood. 2012;120:Abstract 2974.
3. de Weers M, et al. J Immunol. 2011;186:1840-8.
4. Overdijk MB, et al. MAbs. 2015;7:311-21.
5. Krejcik J, et al. Blood. 2016. Epub ahead of print. 72
Progression-free Survival
73
Pro
port
ion s
urv
ivin
g w
ithout p
rog
ressio
n
0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21
283
286
249
266
206
248
179
232
139
189
36
55
5
8
0
0
Rd
DRd
No. at risk Months
73
Rd
DRd
63% reduction in the risk of disease progression or death for DRd vs Rd
12-month PFS*
*KM estimate; HR, hazard ratio.
83%
60%
18-month PFS*
78%
52%
HR: 0.37 (95% CI, 0.27-0.52; P <0.0001)
Median PFS: 18.4 months
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CAR-T
Crossroads
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Continuous treatment
Consolidation/maintenance
Remission induction Initial treatment to kill myeloma cells
Consolidation
Short period of treatment aimed at maximising response from
previous treatment
Maintenance
Longer term treatment aimed at
long term disease control
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Patient journey and the value of extended remission
Hulin C, et al. Leukaemia Research 2016. Manuscript under review.
Hulin C, et al. EHA 2014:abstract P635. Poster presentation.
Emotional journey. Illustration from a UK patient diagnosed with MM 9 years ago,
who had experienced 2 relapses (according to physician records). Note: this
diagram was re-drawn by the interviewer during the discussion. Illustration
reproduced using computer software.
Effects of relapsed disease on the patient
Hulin C, et al. Leukaemia Research 2016. Manuscript under review.
Hulin C, et al. EHA 2014:abstract P635. Poster presentation.
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Patient perceptions at relapse
Patients were asked to indicate the extent of change, if any, since the most recent time
they felt their disease was stable, until their latest relapse/disease progression, based on
a 7-point scale where 1 = very much improved and 7 = very much worse. Mean score
does not include respondents who selected ‘not applicable’ or ‘don’t know’.
Hulin C, et al. Leukaemia Research 2016.
Manuscript under review.
Effect of relapse on the haematologist
Hulin C, et al. Leukaemia Research 2016. Manuscript under review.
Hansen T, et al. EHA 2014:abstract P633. Poster presentation.
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QoL instruments
CIPN, chemotherapy-induced peripheral neuropathy; FACT-G, FACT-General; MID, minimally
important difference; QoL, quality of life. Sonneveld P, et al Leukemia. 2013;27:1959-69.
Instrument Description Validation
QLQ-C30 30-item, self-administered HRQoL patient
questionnaire
Designed for use in cancer patients
QLQ-MY24
and
QLQ-MY20
QLQ-MY24 was developed as an addition to
QLQ-C30 for specific use in MM. The QLQ-MY24
was refined to 20 items (QLQ-MY20)
The psychometrics, including reliability and validity
of QLQ-MY20, in MM have been published
QLQ-CIPN20 20-item QLQ-CIPN20 instrument for patient-
reported CIPN
The reliability, validity and responsiveness of this
instrument is currently being investigated in a wide
range of oncology patient populations
FACT-Multiple
Myeloma
14-item disease-specific FACT-MM HRQoL
measure
Acceptable psychometric properties
FACIT-
Fatigue
Bolt-on module to the base FACT-G HRQoL
questionnaire; a 27-item instrument measuring
well being (Physical, Social/Family, Emotional
and Functional), with a recall period of 1 week
No reliability, validity or other psychometric
properties specific to MM have been described
FACT-NTx Another FACT-G bolt-on module with additional
neurotoxicity parameters
Good psychometric properties in women with ovarian
cancer; however, it has only been used in a limited
number of MM studies, similarly to FACIT-Fatigue
EQ-5D Standardised generic HRQoL questionnaire that
can be converted into a ‘health utility’ score
questionnaire used to measure health outcomes
The MID reported in MM patients
What concerns patients most?
• Is this chemotherapy?
• How is it given and what are the side effects?
• What are my chances on this?
• How long is the treatment given?
• Can I continue to do things as normal at home?
• Do I get admitted, how frequently do I have to come to hospital?
• When will you know that I am getting better?
• Am I getting better?
• Can I travel/work during treatment?
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Individualised treatment approach
• Listen to patient/patient preference
• Discuss treatment goals e.g. symptom relief, going on holiday, getting back to work
• Explain how side effects can be minimised
• Offer flexibility in appointments
• Communicate MM treatment updates
• Perform holistic needs assessment
• Be open to using web-based tools so that patient can take control
Long-term therapy requires considerable support
Agree clear treatment goals with patients and review
at appropriate intervals; keep your patient well informed.
Build a team
around the patients, e.g. nurse specialist,
pain team, psychologist
Ensure QoL is taken into account
Manage side effects expectantly and
encourage discussion with support group
Successful long-term treatment
delivery
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Cure?
Myeloma is clonally heterogenous
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Clonal tides….
Slide Courtesy of Dr Rafael Fonseca
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Treating Myeloma earlier?
• Treating smouldering/asymptomatic myeloma
• Targeting MGUS?
• Treating well patients with toxic treatments……
• Delaying progression vs toxicities
• Measurement of QoL imperative.
• No outcomes to change practice yet.
Themes
• Impact of disease-physical/emotional/economic.
• Survival vs living well.
• Interventions and outcomes-when to intervene/when not to/measuring outcomes…
• Cure?
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Thank you.
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Future
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Stem Cell Transplant
Coping with treament
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Future Treatments
New drugs on the way?....
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BCMA/BiTE
Improved Survival
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Toxicities/Patient Related Outcomes
Quality of Life?