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Myeloma
Haematological Pathway
for
South Wales Cancer Network
Document Control Sheet
Organisation
Specialty/Project
Document Title
Document Number
South Wales Cancer Network
Haematological Site Specific Group
Myeloma Haematological Pathway
05/011
Version
2.0
Approved by
South Wales Haematology
Cancer Network Group
Author/s
Dr H Sati
Dr H Jackson
Dr C Marrin
Miss C Bloodworth
Approval date
Ratified by
19/03/15
19/03/16
Dr C Fegan
Dr W Ingram
Date of next review
Diagnosis
•
Multiple Myeloma
NSAG Patient Care Pathway
The revised IMWG diagnostic criteria (2014) should be used, see appendix 1
Investigations required at diagnosis
 FBC, renal, liver and bone profile, 2 microglobulin
 Serum immunoglobulin levels and paraprotein level by immunofixation, serum free
light chains (sFLC) assay in all patients at presentation.
 Urine Bence Jone protein level in light Chain Myeloma (may be replaced by sFLC
assay)
 Bone marrow aspiration and trephine biopsy; with flow cytometry, IHC and FISH
 Skeletal survey see appendix 2
 CT/PET scan in patients with Non-Secretory MM
 Patients with smouldering MM should be offered one of the following (to exclude
bone lesions not picked up on skeletal survey)
Whole body or spine and pelvis MRI
OR low dose whole body CT scan
OR CT/PET scan
Staging and Prognostication
 The international staging system (ISS) should be used, see appendix 3
 The Durie and Salmon staging system required for transplant-eligible patients
 Cytogenetics and FISH should be done when available
Information Required at MDT
 All new and relapsed patients need to be discussed at the MDT
 ICD10 v 4 and morphology codes: usually C90.0 and M9732/3.
 The ISS should be recorded.
 Treatment plan should be documented.
Indications to Treat
 According to the revised IMWG criteria (2014), the The term multiple myeloma
refers to multiple myeloma requiring therapy, see appendix 1.
Patient Information
 All Patients should have information on their diagnosis and treatment (including
trial options). These could be in the form of Macmillan information sheets
(available online) or via specific trial information sheets or Drug company
brochures.
 Patients to be made aware of Myeloma UK and their local support groups.
 Informed consent should be taken in writing before each new line of treatment.
Supportive Care
Pain management
● Pain is still a common symptom at presentation and relapse, that needs accurate
assessment and control. Pain should be measured using a 0-10 scale.
 Patients who repeatedly score pain as ≥ 5/10 or develop neuropathic pain should
be referred to the palliative care team.
 NSAIDs should generally be avoided. All patients on opioids should be prescribed
laxatives and regularly screened for other opioid-related toxicity.
 Consider other pain control measures such as:
o Local radiotherapy
o Vertbroplasty, kyphoplasty
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Bone Disease
 Bisphosphonate (BP) therapy is recommended for all patients with MM (revised
IMWG definition, 2014) with or without bone disease.
 Zoledronic acid is the BP of first choice. Pamidronate is the alternative BP in
patients who are allergic to zoledronic acid or have renal failure.
 Sodium clodronate can be used in patients who decline the intravenous
preparations.
 Dental evaluation should be carried out before starting intravenous BP therapy.
 Patients should be informed about possible side effects (including ONJ) to BP
therapy.
 If ONJ is suspected stop BP therapy and refer to dental hospital/maxillofacial
department for advice and management.
 Renal function should be carefully monitored and the dose of zoledronic acid (and
pamidronate if eGFR <30ml/min) reduced in line with the current manufacturer
(SPC) guidance.
 Oral calcium and Vit D supplementation is recommended in patients on zoledronic
acid.
 There is no consensus regarding the duration of BP therapy. However in view of
the serious complication of ONJ, the following has been adapted from the IMWG
(2013, J Clin Oncol 31:2347-2357.)
o BP therapy should be continued until disease progression in patients not
achieving CR or VGPR.
o Discontinuation of intravenous BP therapy may be considered after 1-2
years in patients who achieved CR or VGPR.
Anaemia
● A therapeutic trial of Erythropoiesis stimulating agent (ESA) should be considered
in a patient with persistent symptomatic anaemia (typically haemoglobin
concentration <100 g/l) in whom haematinic deficiency has been excluded.
 Patients with anaemia attributed to renal failure should have a trial of treatment
with ESA.
 Blood transfusions should be considered for symptomatic patients only, give with
caution if the paraprotein level is high.
Infection
 Patients should be warned about the high risk of infections (highest in the first 3
months following diagnosis) and is a major contributor to the high early death rate.
 Vaccination against influenza, Streptococcus pneumonae and Haemophilus
influenzae B is recommended but efficacy is not guaranteed.
 Prophylactic immunoglobulin may be useful in a small sub-set of patients with
severe, recurrent bacterial infections and hypogammaglobulinaemia.
 Prophylactic antibiotics may be considered in the first two months of treatment in
high risk patients and those with renal failure.
 Prophylactic aciclovir is recommended for patients receiving bortezomib therapy,
following autologous stem cell transplantation or patients with recurrent herpetic
infections.
Thromboprophylaxis
 All patients who are due to start thalidomide or lenalidomide containing therapy
should undergo a risk assessment for VTE and prospectively receive appropriate
thromboprophylaxis see appendix 4
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Management of peripheral neuropathy (PN)
 Symptoms and signs of PN should be actively sought and graded, at diagnosis and
while on treatment, using a validated tool such as NCRI grading score.
 Any significant (>NCI grade 2) or progressive PN at diagnosis should be
investigated to identify treatable causes and consider a referral to a neurologist.
 Potentially neurotoxic drugs should be used with caution in a patient with a preexisting PN.
 Any patient who develop >NCI grade 2 or progressive PN should be managed with
graded dose reduction or withdrawal of the neurotoxic drug.
Management of other complications
 Use local guidelines for the management of febrile neutropenia, cord compression,
and hypercalcaemia
 Consider plasmapheresis in symptomatic hyperviscosity.
 Renal failure, see below.
Assessment of Response and Monitoring
 For patients with smouldering MM, monitor 6-12 weekly with blood markers (do
both SPE and sFLC assays) and symptoms/signs of disease progression.
 For patients with MM, assess response after each cycle of treatment using the
IMWG response criteria, appendix 5.
 In true non-secretory multiple myeloma, a repeat bone marrow examination and
PET/CT OR MRI scan should be used to assess response.
 During remission monitor patients with MM, 6-12 weekly for blood markers (do
both SPE and sFLC assays) and symptoms/signs of disease relapse. Use the IMWG
relapse criteria, appendix 6.
 Patients with myeloma should not be discharged to primary care.
Specific Chemotherapy
Newly diagnosed patients eligible for high dose chemotherapy (HDT)
 Patients who are 65 years old or less and have no major co-morbidities.
 Older fit patients may also be considered for HDT, discuss with the SWBMT team.
 Offer Myeloma XI+ or any equivalent clinical trial if available.
 The aim of induction therapy is to achieve the greatest depth of response using a
stem cell-sparing regimen prior to consolidation with HDT and ASCT.
 If no clinical trial was available, Bortezomib based combination regimens, such as
VTD, PAD or VCD, are the recommended 1st line induction therapy.
 3 weekly CTD is the alternative option for patients who prefer an oral based
induction therapy.
 Assess response following 4 cycles (unless PD or intolerance) and decide about the
next step of management, see flowchart-1
 Inform the SWBMT program at the start of induction therapy. Complete
appropriate SWBMT referral forms in responding patients (preferably, no later than
the start of the 4th cycle of induction therapy)
 2nd line induction chemotherapy should be considered for patients with less than a
PR prior to stem cell mobilisation and in patients who develop PD or intolerance to
1st line induction therapy.
 Use Thalidomide based combination if Bortezomib based combination was used as
1st line induction and vice versa.
 For patients who received VTD as 1st line induction and failed to achieve PR,
consider RCD or DT/PACE as 2nd line induction OR discuss at the regional myeloma
MDT.
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Newly diagnosed patients ineligible for HDT
The choice of therapy should take into account patient preference, co-morbidities
and toxicity profile. Offer Myeloma XI+, non-intensive arm or any similar trial if
appropriate.
If no clinical trial was available, Bortezomib based combination such as VMP or
VCD are the recommended 1st line induction therapy.
MPT or CTDa are alternative options for patients who prefer oral based therapy.
Assess response after 4 cycles of treatment and consider further management
decisions as in flowchart -2
In less fit/frail patients, gradual build up of treatment is generally preferable over
full dose treatment from day one. Treatment toxicities must be managed proactively.
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Patients with relapsed myeloma
Therapy should be determined on an individual basis depending on the timing of
relapse, age, prior therapy, bone marrow function and co-morbidities, and patient
preference.
First Relapse
 Clinical trial if available (eg MUK five at UHW)
 If no trial available, use Bortezomib or Thalidomide based combination therapy
depending on the treatment regimen used at the initial diagnosis and the duration
of the 1st PFS.
 3 drug combination is recommended (VCD, PAD, VMP, CTD) in more fit patients.
 Consider Lenalidomide if patient has persistent PN >grade2 from previous
thalidomide or Bortezomib based therapy.
 Consider a second HDT/ASCT in fit patients with chemosensitive disease if the first
remission was > 18 months.
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Second Relapse and Beyond
 Clinical trial if available
 If no trial, consider Lenalidomide based treatment, preferably in a 3 drug
combinations (eg RCD or MPR) until plateau, then lenalidomide +/dexamethasone Therapy.
 Options for those who relapse beyond this stage are limited and may include,
1. Bendamustine based therapy eg BTD (Benda/Thal/Dex), BBD
(Benda/Bortez/Dex)
2. Pomalidamide based therapy
3. Re-using any of the previous therapy, if the initial response was ≥ the expected
PFS.
All the above options will need funding approval
Patients with renal failure at presentation
 These patients should be managed in liaison with the renal team, initiate
hydration, treat hypercalcaemia (pamidronate) and consider a pulse of
dexamethasone
 The IMWG recommended Bortezomib (at a standard dose) +dexamethasone as the
induction therapy of choice.
 Thalidomide pharmacokinetics are not affected by renal failure and can still be
used in combination with dexamethasone as an alternative option.

HDT/ASCT can still be an option in patients with persistent renal failure but this
should be restricted to <60 years of age with chemosensitive disease and good
performance status (IMWG, 2010, J Clin Oncol 28:4976-4984).
Patients with high risk cytogenetics (FISH) at diagnosis
 Risk stratification by FISH and Gene Expression Profiling has an established impact
on prognosis in patients with multiple myeloma.
 However, there is not enough evidence to support a risk-adapted therapy from
randomised controlled trials.
 The adverse effect of t(4;14) was partially improved with short term induction with
Bortezomib/dexamethasone in the IFM 2005 (J Clin Oncol , 2010, 28:4630-4634).
 Treat as per recommendations above, monitor closely for disease progression.
Primary Plasma cell leukaemia
 This is a rare form of aggressive plasma cell malignancy with a median survival of
6-11 months
 High proliferation index and poor risk cytogenetics are common and may explain
the poor prognosis
 No prospective trials to support strong recommendations
 In younger patients, intensive induction chemotherapy such as DT-PACE (with or
without Bortezomib) could be used followed by HDT/ASCT.
 Consider VCD for less fit patients.
References
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Rajkumar et al, 2014, International Myeloma Working Group updated criteria for
the diagnosis of multiple myeloma. Lancet Oncol 2014; 15: e538–48
Bird, J. et al, 2014, Guidelines for the diagnosis and management of multiple
myeloma.
Snowden, J. et al, 2011, Guidelines for supportive care in multiple myeloma. Br J
Haematol; 154, 76–103
Cancer. 2013 Dec 1;119(23):4119-28.doi:10.1002/cncr.28325. Epub 2013 Sep 4.
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Nooka, A. et al, 2013, Bortezomib-containing induction regimens in transplanteligible myeloma patients: a meta-analysis of phase 3 randomized clinical trials.
Cancer;119(23):4119-28
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Cavo, M., 2011, International MyelomaWorking Group consensus approach to the
treatment of multiple myeloma patients who are candidates for autologous stem
cell transplantation. Blood; 117, 6063-6073
Dimopoulos, MA et al, 2010, Renal Impairment in Patients With Multiple Myeloma:
A Consensus Statement on Behalf of the International Myeloma Working Group. J
Clin Oncol 28:4976-4984
Terpos et al, 2013, International Myeloma Working Group Recommendations
for the Treatment of Multiple Myeloma–Related Bone Disease. J Clin Oncol
31:2347-2357
Herve´ Avet-Loiseau, et al, 2010, Bortezomib Plus Dexamethasone Induction
Improves Outcome of Patients With t(4;14) Myeloma but Not Outcome of Patients
With del(17p). J Clin Oncol 28:4630-4634.
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APPENDIX 1
The Revised IMWG diagnostic criteria for MM and Smouldering MM (2014)
Definition of Smouldering MM
Both criteria must be met:
● M-protein in serum≥ 30 g/L (IgG of IgA) or urinary monoclonal protein
≥500mg/24 h and/or clonal bone marrow plasma cells 10-60%
● Absence of myeloma defining events or amyloidosis
Definition of Multiple Myeloma
Clonal bone marrow plasma cells ≥10% OR biopsy-proven bony or extramedullary
plasmacytoma AND any one or more of the following myeloma defining events:
Myeloma defining events:
●Evidence of end organ damage that can be attributed to the underlying Plasma Cell
Proliferative disorder, specifically
● Hypercalcaemia: s. calcium >0.25 mmol/L higher than the upper limit of normal
OR >2.75 mmol/L
● Renal Insufficiency: Creatinine Cl. <40ml/min OR serum creatinine >177 mol/L.
● Anaemia: haemoglobin value of >20 g/L below the lower limit of normal or a
haemoglobin value <100g/L
● Bone lesions: ≥1 osteolytic lesion on skeletal radiography, CT, or PET-CT scan.
●Any one or more of the following biomarkers of malignancy
● Clonal bone marrow plasma cell percentage ≥60% (preferably from a core
biopsy)
● Involved:Uninvolved sFLC ratio of ≥100 (the involved light chain level must be
≥100mg/l)
● >1 focal lesion on MRI studies (must be ≥5 mm in size). Consider a repeat
examination in 3-6 months in patients with a solitary focal lesion.
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APPENDIX 2
AXIAL SKELETAL SURVEY
The following axial skeletal survey images should be taken at presentation (adapted
from Royal College Guidelines):
Skull
LATERAL view
Shoulders
Cervical spine
Dorsal spine
Lumbar spine
Pelvis
Chest
Both AP views, include clavicles and humeri
AP, LATERAL and OPEN MOUTH view
AP and LATERAL
AP and LATERAL
AP to include upper femora
PA Chest X-ray
NB, In addition, any part that is affected by pain should also be examined.
For all skeletal surveys, it is essential to have good quality films with
fine bone detail.
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APPENDIX 3
INTERNATIONAL STAGING SYSTEM (ISS) FOR MULTIPLE MYELOMA ( Journal of
Clinical Oncololgy 2005; 23: 3412-3420)
Stage
I
Criteria
Median Survival in months
Serum ß2 microglobulin < 3.5 mg/l
62 months
and serum albumin > 35g/l
II
Neither I or III*
45 months
III
Serum ß2 microglobulin > 5.5 mg/
29 months
*Includes two categories, Serum ß2 microglobulin <3.5 mg/l and serum albumin <35 g/l OR
Serum ß2 microglobulin 3.5 to <5.5 mg/l irrespective of the serum albumin level.
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APPENDIX 4
Risk assessment model for the prevention of venous thromboembolism in multiple
myeloma patients treated with thalidomide or lenalidomide (IMWG)
Individual
o
o
o
o
o
o
o
Obesity (defined as body mass index > 30kg/m2)
Previous venous thromboembolism
Central venous catheter or pacemaker
Associated disease
 Cardiac disease
• Chronic renal disease • Diabetes
 Acute infection
• Immobilization
Surgery
 General surgery
• Any anesthesia
• Trauma
Medications
 Erythropoietin
Blood clotting disorders
Myeloma-related risk factors
o Diagnosis per se
o Hyperviscosity
Myeloma therapy (all are to be considered high-risk factors)
o High-dose dexamethasone
o Doxorubicin
o Multiagent chemotherapy
If one risk factor, consider aspirin (75-150 mg/d), (ie all patients with no other risk
factors should receive aspirin unless contraindicated)
If ≥ 2 risk factors consider LMWH (e.g. enoxaparin 40 mg od). This should be the
consideration in most patients with active disease who start combination chemotherapy.
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APPENDIX 5
IMWG Uniform Response criteria
(Blade et al, 1998; Durie et al, 2006 ; Rajkumar et al, 2011)
Complete Response (CR) requires all the following:
1) Absence of the original monoclonal paraprotein in serum/ urine by immunofixation.
( The presence of oligoclonal bands due to immune reconstitution does not exclude CR)
2) < 5% plasma cells in bone marrow
3) Disappearance of soft tissue plasmacytomas.
4) For patients with light chain myeloma (the serum and urine M-protein
are unmeasurable), a normal sFLC ratio, in addition to the CR criteria above.
Very Good Partial Response (VGPR)
1) Serum and urine M-protein detectable by immunofixation but not on
electrophoresis,
OR
2) ≥90% reduction in the serum monoclonal paraprotein level plus urinary light
chain
excretion < 100 mg/24 hours.
3) For patients with light chain myeloma (the serum and urine M-protein
are unmeasurable), >90% decrease in the difference between involved and
uninvolved FLC levels
Partial Response (PR)
1) ≥ 50% reduction in the serum monoclonal paraprotein level, and.
2) Reduction in 24-hour urinary light chain excretion either by ≥90% or to < 200
mg/24 hours, if measured.
3) For patients with light chain myeloma ≥ 50% reduction in the difference between
involved and uninvolved serum FLC levels.
4) For patients with non-secretory myeloma only, ≥ 50% reduction in plasma cells in
bone marrow, provided baseline percentage was ≥ 30% .
5) In addition, ≥ 50% reduction in the size of soft tissue plasmacytoma, if present at
baseline.
Minimal Response (MR) requires all the following
1) 25-49% reduction in the serum monoclonal paraprotein level.
2) 50-89% reduction in 24-hour urinary light chain excretion, which still exceeds
200 mg/24 hours.
3) For patients with non-secretory myeloma only, 25-49% reduction in plasma cells
in bone marrow.
4) 25-49% reduction in the size of soft tissue plasmacytomas.
5) No increase in size or number of lytic bone lesions on radiological investigations.
.
No Change (NC)
Not meeting the criteria of either minimal response or progressive disease.
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APPENDIX 6
IMWG uniform response criteria- Disease Progression and Relapse *
Durie et al, Leukemia 2006;20:1467-73
Progressive
Disease (PD)
Clinical relapse
Relapse from
CR
Requires at least one of the following
• ≥25% increase in serum M-protein(absolute increase must be ≥5 g/l)
• ≥25% increase in urine M-protein (absolute increase must be
≥200 mg/24 h)
• ≥25% increase in the difference between involved and uninvolved
sFLC levels (applicable only to patients without measurable serum/urin
M-protein, absolute increase must be >100 mg/l)
• ≥25% increase in bone marrow plasma cell percentage (absolute
percentage must be ≥10%)
• Development of new bone lesions or soft tissue plasmacytoma
• Development of hypercalcaemia
Requires at least one of the following
• Development of new bone lesions or soft tissue plasmacytoma
• Increase in size of existing plasmacytomas or bone lesions
• Any of the following attributable to myeloma:
Development of hypercalcaemia
Development of anaemia (drop in Hb ≥20 g/l)
Rise in serum creatinine
Requires at least one of the following
• Reappearance of serum or urine M-protein by immunofixation or
electrophoresis
• Development of >5% plasma cells in the bone marrow
• Appearance of any other sign of progression (e.g. new plasmacytoma,
new lytic bone lesion or hypercalcaemia)
*Requires two consecutive assessments prior classification as relapse, disease progression
or before the start of any new therapy.
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