Initial treatment for myeloma
Myeloma UK Patient and Family Infoday, Leeds
16th March 2013
Dr Andrew Chantry
Senior Clinical Lecturer in Haematology, Dept of Oncology, University of Sheffield/
Honorary Consultant in Haematology, Sheffield Teaching Hospitals NHS
Foundation Trust
Multiple myeloma – 10% of all haem cancers;
second commonest haematological cancer
Cancer of white blood cells, known as plasma cells,
• Progressive bone marrow failure
• Monoclonal gammopathy
• Renal failiure
• Osteolytic bone disease – osteoporosis
c vertebral wedge
fractures, spinal cord compression, lytic lesions, pathological
fractures, hypercalcaemia, pain and grossly reduced mobility
‘Mollities Ossium’ (Dr Samuel Solly 1846)
• In May 1840, Sarah Newbury experienced severe back
pain while stooping and a strange sensation in her right leg.
• She was given an infusion of orange peel and a rhubarb
pill.
• Sections of the bones revealed ‘a red grumous matter’; the
red matter was examined by Dr Solly and Mr Birkett of
Guy’s Hospital; the majority of the nucleated cells had a
clear, oval outline and one or rarely two bright central
nucleoli
Calico Hills Burial #2 (AD 2900)
Dr Henry Bence Jones, renowned chemical
pathologist at St George’s Hospital, was
consulted on a second notable case
• Thomas McBean , ‘a grocer of temperate habits
and exemplary conduct’ presented with fatigue
and a stooped gait
• While vaulting out of an underground cavern on
his country vacation, he suddenly felt as if
something had snapped or given way within his
chest and for some minutes he lay, unable to stir
because of severe pain.
• Treated with acetate of ammonia, camphor julap
and compound tincture of camphor.
• Died in 1846 – cause of death ‘atrophy by
albuminuria’.
Henry Bence
Jones
‘Dear Dr Jones,
The tube contains urine of very high specific gravity. When boiled it becomes slightly opaque.
On the addition of nitric acid, it effervesces, assumes a reddish hue, and becomes quite
clear; but as it cools, assumes the consistence and appearance which you see. Heat reliquifies
it. What is it?’
(Dr Thomas
Watson
, GP,
Calico
Hills Burial
#2 (AD
2-to Dr Henry Bence Jones, 1847)
900)
Prehistoric multiple myeloma – Red Indian artefacts
Calico Hills Burial #1 (AD 2-900)
Calico Hills Burial #2 (AD 2900)
Calico Hills Burial #2 (AD 2-900)
Sowell Mound Skull (approx AD
610)
Morse, D et al, NY Acad Med, 1974
Approximately 60% of pts with myeloma present with
evidence of bone disease; 8080-90% pts with myeloma
bone disease at some stage of their disease (Coleman
1997; Kariyawasan et al. 2007)
Norma
l
Myeloma
‘pepper
pot skull’
If it wasn’t fractured before…
Fracture risk 16x higher than expected (Melton et al 2005)
Spinal cord compression – up to 5% of all patients
with myeloma at some stage (Kyle et al 2003)
Mechanisms of myeloma bone disease
CFU-GM
+
Mesenchymal
Stem Cells
Plasma cells
Pre-osteoclast
+
• RANKL
• MIP 1-α
• Il-3
-
+
Osteoclast
activating factors
Osteoprogenitor
Osteoblast
inhibitory factors
Osteoclasts
Osteoblasts
Bone
• Dkk-1
• sFRP-3
• HGF
• TGF-β1
These targets validated in our studies; working towards personalised therapy
The result – bones is destroyed
CFU-GM
+
Pre-osteoclast
Mesenchymal
stem cells
Plasma cells
+
+
Normal
Osteoclasts
Bone
Myeloma
Myeloma
– close up
At presentation
• 15% patients have no symptoms
• 38% emergency presentation
- Kidney failure
- Spinal cord compression/loss of movement
- Fracture
• Remainder have symptoms
- Backache or bone pain
- Tiredness/anaemia
Decision to treat
• Is the myeloma causing symptoms?
- unwell, tiredness, pain, frequent infections
• Is the myeloma causing organ damage?
- kidneys, bone marrow, bone, hypercalcemia
• Are there other medical problems or
individual issues to consider?
Asymptomatic myeloma
• Diagnosis does not automatically mean that
treatment must start
• Good reason to wait until symptoms develop
- regular monitoring of paraprotein, blood counts,
kidney function etc
• No symptoms but blood tests show
progression
- judgment when to start treatment
- joint decision
Aims of treatment
Anti-myeloma treatment:
Reduce myeloma activity
and related damage
Supportive treatment:
Relieve symptoms and
complications
Reduce symptoms and complications
Improve quality of life
Prevent further bone and other organ damage
Prolong survival
Successful treatment should…
• Reduce tumour burden and induce longest
possible remission/plateau
• Achieve maximum response with the
minimum of side-effects
• Relieve pain and address other symptoms
• Prevent further damage to the body
• Improve and preserve quality of life for
as long as possible
Treatment approach
Diagnosis
Asymptomatic
myeloma
Symptomatic
myeloma
Regular monitoring
Are you a candidate for
stem cell transplant
Yes
Induction treatment,
stem cell transplant
Clinical
study
No
Non-intensive
drug treatment
Treatment decisions:
Doctor’s perspective
Patient
needs &
priorities
Disease
Features
Treatment
recommendation
Evidence &
Guidelines
Patient
Features
Prior
Treatment
&
Response
Treatment decisions:
• What are my
options?
• What are the
side-effects
• What should I
expect?
• How long does
treatment last?
Practicalities
• How does the
myeloma affect
me?
• What’s my goal,
what do I want?
• How will I
expect to feel?
Treatment Options
Disease & Prognosis
Patient’s perspective
• Do I have to
stay in
hospital?
• Can I still
work?
• How far do I
have to travel &
what time?
• Can you help
with money?
Your consent to treatment should be an
informed one
Drugs used to treat myeloma
1950s - 60s
• Melphalan (+ prednisolone)
• High-dose dexamethasone
1970s - 80s
• Combination chemotherapy
- VAD (vincristine, adriamycin, dex)
• High-dose chemotherapy
• Bone marrow/stem cell transplantation
1990s - 2000s
• Thalidomide
• Velcade
• Revlimid
2010s -
• Carfilzomib, pomalidomide?
‘Novel agents’
Which combination?
Idarubicin
Be
nd
am
ust
ine
lo n e
de
Chemotherapy drug
e
mi d
lido
a
Th
Doxorubicin
Revlimid
Carm
niso
Novel agent
Velca
de
i
pham
phos
lo
c
y
C
P re d
Steroid
ustin
e
lp
Me
la
ha
Vincris
tine
n
Dexameth
asone
Randomise
CTD
RCD
• Is Revlimid superior
to thalidomide?
Assess response
SD + PD
CR + VGPR
PR + MR
Randomise
Myeloma XI
Nothing
study
VCD
• For patients achieving
sub-optimal response,
can VCD improve
response rates?
VCD
Assess
response
Assess response
TRANSPLANT IF APPROPRIATE
Randomise
No
maintenance
Revlimid
maintenance
Rev + vorinostat
maintenance
• Does Revlimid or
Rev + vorinostat
maintenance improve
survival
Treatment options:
Non-transplant patients
Thalidomide-based
• CTD
Velcade-based
• VMP
Cyclophosphamide
Thalidomide
Dexamethasone
• MPT
Velcade
Melphalan
Prednisolone
Max 8 cycles
Melphalan
Prednisolone
Thalidomide
Max 8 cycles
As per NICE guidance
Supportive
• Bisphosphonates
Zometa, pamidronate,
Bonefos
• Blood
transfusions/EPO
• Pain-killers
• Anti-thrombotic
Treatment options:
Transplant patients:
Step 1: Induction treatment
Step 2: High-dose therapy and stem cell transplant
- Autologous (own stem cells) – vast majority
- Allogeneic (donor stem cells) – very small minority
Step 1: Induction treatment
Thalidomide-based
• CTD
Cyclophosphamide
Thalidomide
Dexamethasone
Max 8 cycles –
must have partial
response or better
Velcade-based
• PAD
Velcade
Adriamycin
Dexamethasone
Max 6 cycles
Supportive
• Bisphosphonates
Zometa, pamidronate,
Bonefos
• Blood
transfusions/EPO
• Pain-killers
• Anti-thrombotic
Step 2: High-dose therapy
and stem cell transplant
1. Stem cell mobilisation
2. Stem cell collection
4. Stem cell
transplant
3. High-dose melphalan
Maintenance treatment?
• Continuous treatment after initial treatment
• Role of maintenance treatment still under debate
• Interferon – prolongs remission by ~6 months but
difficult to tolerate
• Thalidomide – may benefit some patients
• Revlimid – promising data, increasing length of
remission and overall survival, however, increased
risk of second cancers
Remission – current practice
•
•
•
•
No treatment, most drugs stopped
Maintenance treatment – not standard
Bisphosphonates for at least 2 years
Minimal effective pain management
100
50
20
1st
REMISSION
Summary
• Myeloma is an individual cancer - requires a
personalised approach
• Patients should have a role in their treatment plan important to discuss goals and perceptions
• Various treatment combinations are effective and
generally well tolerated
• But, it remains a difficult and challenging disease
• More research required to understand and develop
better treatments and better ways of using existing
treatments
Healthy Mouse Bone
Mouse bone with myeloma
Mouse bone with myeloma plus Anti Dkk-1
Chantry et al, JBMR 2009
For information:
www.myeloma.org.uk
0800 980 3332