3
MULTIPLE MYELOMA
Clinical features
Multiple myeloma (MM) is a disease with a peak incidence in the 6th and seventh decades of life, but can also occur in younger patients. It is characterised by infiltration of the bone marrow by malignant plasma cells. This may lead to single or multiple cytopenias, the most common being anaemia and thrombocytopenia. Patients with IgA, and occasionally IgG, myeloma may develop a hyperviscosity syndrome. The malignant plasma cells disturb the normal balance of bone resorption and bone formation resulting in the development of osteoporosis and/or lytic lesions. Approximately 70% of patients present with bone pain and 10% with hypercalcaemia. Renal impairment may be a presenting feature of multiple myeloma and may be reversible due to hypercalcaemia, dehydration and hyperviscosity, or may be more chronic due to light chain nephropathy caused by excessive production of light chains. This may occur in pure Bence Jones Myeloma or also in some cases with intact immunoglobulin production but which can also be associated with excessive light chain production. This may cause the formation of casts in the renal tubules.
Diagnostic and prognostic investigations
The following investigations are required at diagnosis, so that a disease category and stage can be assigned (see below).
A. Blood
Full blood count, blood film and ESR
Coagulation screen including fibrinogen and D-dimers. Serum B12, folate and TSH
Biochemistry profile (LFTs,Creatinine and electrolytes, bone profile and urate) β2 -microglobulin and CRP
Immunoglobulins and serum protein electrophoresis Serum free light chains: particularly useful in:
Patients with renal failure and light chain myeloma Patients with associated AL amyloid and myeloma Oligosecretory and non-secretory myeloma
Initially in MGUS as it may be of prognostic significance ABO blood group and alloantibody screen
Serology for hepatitis B & C, CMV & HIV1/2 (with consent), if proceeding to SCT HLA type patient and siblings (if appropriate)
15ml serum for biochemical markers of bone disease (contact Dr. Rahemtulla at HH)
(send 5ml of EDTA or heparinised blood to the haematology dept, West Middlesex Hospital)
B. Urine
Random sample for Bence-Jones protein analysis & 24-hour collection for urinary light chain quantitation
Creatinine clearance
20ml urine for biochemical markers of bone disease (contact Dr. Rahemtulla at HH)
C. Bone marrow
Aspirate for morphology, immunophenotyping
Please also send samples marked ‘Urgent’ for FISH analysis for abnormalities of
chromosomes 13 and 14 to
Dr Alistair Reid
Leukaemia Cytogenetics Unit (ext 32169) Department of Haematology
c/o CSU Specimen Reception
G Block
Hammersmith Hospital Du Cane Road London W12 0NN
Trephine biopsy with immunophenotyping for κ / λ, CD38 and CD138 Staining for amyloid (if there is clinical suspicion of amyloidosis)
D. Imaging
‘Limited’ radiographic skeletal survey (axial skeleton, pelvis, skull & chest, femora and humeri)
Consider MRI in the following situations:
- When treatment may be altered by the presence of lesions e.g. asymptomatic Myeloma)
- Young patients with MGUS who are considered for ‘rainy day’ PSC harvest)
- If neurological signs present - If cord compression suspected
Consider bone densitometry by DEXA scanning E. Amyloid
Amyloidosis should be excluded in the presence of the following features; Unusual bruising,
Malabsorption or macroglossia,
Peripheral neuropathy or carpal tunnel syndrome, Cardiomegaly or cardiac failure
Nephrotic syndrome or renal failure using ;
Rectal biopsy, abdominal fat biopsy
Echocardiogram and ultrasound scan of the kidneys may also be helpful National amyloid diagnostic and monitoring service at Royal Free Hospital.
Prognosis and Staging
The prognosis of myeloma is generally poor, with a median survival of 3-4 years. Poorer outcome is associated with:
more advanced stage (see below), low albumin,
high β2-microglobulin (> 4mg/l) or high CRP
renal dysfunction
abnormalities of chromosome 13q. and /or T(4:14) The staging of disease is as follows:
Monoclonal Gammopathy of Undetermined Significance (MGUS)
1. Monoclonal serum Ig: 4. Asymptomatic
IgG < 30g/l 5. Urine light chains: absent/trace only IgA < 20g/l 6. Normal polyclonal IgG, IgA, IgM 2. BM plasmacytosis < 10% 7. Normal Hb, serum albumin 3. No lytic lesions 8. β2-microglobulin usually < 2mg/l
Staging: Durie/Salmon Staging: Cuzick (MRC)
I All of: A All of:
• Hb > 10g/dl • Hb > 10g/dl
• Ca++ (corrected) <3.0mmol/l • Urea < 8mmol/l
• Normal bone x-rays, or 1 lytic lesion • Asymptomatic/minimal symptoms • Monoclonal IgG < 50 or IgA < 30g/l
• Urine light chains < 4g/24 hrs
II Not fitting either I or III B Not fitting either A or C III Any of:
• Hb < 8.5g/dl
• Ca++ (corrected) >3.0mmol/l C Either of: • Advanced lytic bone lesions • Hb < 7.5g/dl • Monoclonal IgG > 70 or IgA > 50g/l • Urea > 8mmol/l • Urine light chains > 12g/24 hrs
And
A if creatinine < 177µmol/l • Restricted activity/bedridden B if creatinine ≥ 177µmol/l
International Prognostic Index (Griepp et al, 2003)
I β2 microglobulin < 3.5 mg/L(296nmol/L) and
Albumin ≥ 35g/L (532 µmol/L) 62 months
II β2 microglobulin < 3.5 mg/L(296nmol/L) and
Albumin <35g/L (532 µmol/L) OR
β2 microglobulin 3.5 – 5.5 mg/L irrespective
of serum albumin level
45 months
III β2 microglobulin >5.5mg/L(465nmol/L) 29 months
General Management
Throughout the course of the disease supportive care is very important and includes: A large fluid intake, especially in cases with high urinary light chain excretion Encourage 3L / 24hours oral fluid intake.
Allopurinol 300mg (or 100mg if creatinine clearance <20mls/min) od po during the first two treatment cycles.
Management of hypercalcaemia (hydration and bisphosphonates)
Pain control: analgesics (NSAID [avoid in BJ myeloma], opiates etc) and radiotherapy
Surgical stabilisation of pathological fractures
Maintenance of bone mass/structure: keeping active, adopting a good posture, avoiding heavy lifting & use of bisphosphonates (see 11)
Blood transfusions if symptomatically anaemic
Treatment and prophylaxis of infections: antibiotics and consideration of immunoglobulin infusions
Renal dialysis
In case of sepsis please avoid the use of nephrotoxic antibiotics if possible especially in patients with BJ myeloma. If these have to be used, extra caution should be taken in monitoring level
Pre-treatment Evaluation
Document FBC (with film), plasma viscosity, U&E, creatinine, LFTs, calcium, glucose, serum protein electrophoresis and paraprotein quantitation, CRP, 2-microglobulin and immunoglobulin levels.
Urine for BJP (and formal evaluation of 24 hour urinary BJP excretion if light chain only myeloma).
Bone marrow aspirate ± trephine (and cytogenetics if part of local protocol).
Skeletal survey.
Document WHO performance status of patient. Document height and weight and surface area.
Consider ECG ± echocardiogram if clinical suspicion of cardiac dysfunction.
Patient will require a (tunnelled) central venous access catheter (or PICC line) only if VAD or similar regime is used.
Give adequate verbal and written information for patients and relatives concerning patient’s disease, treatment strategy and side effects. Obtain written consent from patient or guardian.
Discuss issues relating to contraception and potential risk of infertility with patient and relatives (if applicable).
Definitions of response to treatment
The international myeloma working group has published a consensus document defining response criteria as in the following tables (Durie et al Leukemia (2006) 20, 1467–1473).
Response subcategory
Response criteria
(International Myeloma Working Group) Response criteria BONE MARROW Response criteria SERUM / URINE M-PROTEINS Response criteria PLASMA CYTOMAS Response criteria SERUM / URINE FLC
sCR CR as defined below plus Normal FLC ratio and
Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence
None Negative Negative Normal
CR Negative immunofixation on the serum and urine and
Disappearance of any soft tissue plasmacytomas and
≤5% plasma cells in bone marrow
≤5% plasma cells
Negative Negative Normal
VGPR Serum and urine M-protein
detectable by immunofixation but not on electrophoresis or
≥90% reduction in serum M-protein plus
urine M-protein level <100mg per 24 hrs ≥90% reduction in serum + <100mg per 24hr urine sample ≥50% reduction in size PR ≥50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by ≥90% or <200mg per 24 hrs.
If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria if serum and urine M-protein are unmeasurable, and serum free light assay is also unmeasurable, ≥50% reduction in plasma cell is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is also required. ≥50% reduction of serum M-protein + <200mg per 24hr urine sample or ≥90% reduction Unmeasurable serum & urine
Unmeasurable ≥50% reduction in size ≥50% reduction in size ≥50% decrease in the difference between involved and uninvolved FLC levels Unmeasurable
≥50% reduction in plasma cell, only if baseline bone marrow plasma cell percentage was ≥30%. ≥50% reduction in size
SD Not meeting criteria for CR, VGPR, PR or progressive disease. (Not recommended for use as an indicator of response: stability of disease is best described by providing the time to progression estimates)
Plateau phase
Patient is asymptomatic or has minimal symptoms attributable to myeloma Haemoglobin stable without requirement for transfusion
Stable values of serum & urine paraprotein and serum β2-microglobulin, for at
least 3 months.
Strategy of initial management
Some patients with stage I MM are not initially treated. They are monitored closely and treated when there is clinical or biochemical evidence of progression. Recently, patients have been treated more aggressively to achieve rapid remissions. However, treatment must be appropriate for the patient’s age and general health. For the elderly (> 65 years) aggressive therapy may be inappropriate. The choice of treatment will depend on the performance status and co-morbidities. Until recently, the standard treatment was melphalan or cyclophosphamide, often given together with prednisolone (see 9). The response to this type of treatment is about 50-60% but patients rarely obtain complete remission (CR). More recently trials have shown
that better responses can be obtained in older patients if thalidomide is added to the initial treatment with MP (MPT) or attenuated CD (CTDa) see below. The major added morbidity from these regimens is an increased risk of thromboembolic disease and this together with the choice of, or contraindications to anticoagulation have to be considered in choice of treatment ( see sewction on risk of VTE in myeloma below). Younger/fitter patients may be considered for high dose therapy with auto-SCT, which induces CR in approximately 50% of cases and has been shown in large randomised trials to confer benefit in terms of overall and progression-free survival. Auto-SCT is not, however, a curative procedure, with most patients experiencing progression at 2-3 years post grafting. Attempts to ‘purge’ auto-SCT products by positive selection of stem cells have not been shown to improve outcome compared to unselected transplants. Allogeneic SCT using histocompatible sibling donors can be curative but is associated with high transplant related mortality, particularly in men. For this reason early allografting is rarely offered to patients over the age of 45. The outcome of allo-SCT is better if the transplant is performed early in the course of the disease in patients who are responsive to chemotherapy. There is a similar trend in recipients of auto-SCT, although refractory patients may also derive some benefit. For these reasons together with the need to stabilise patients prior to high dose therapy and the desirability of having a transplant product relatively free of tumour cells, cytoreductive chemotherapy is usually given for several months prior to transplant. The agents used have to be non-toxic to stem cells and may be one of the following:
CTD (Cyclophosphamide, thalidomide and dexamethasone) Consider
thromboprophylaxis
VAD (vincristine, adriamycin (doxorubicin) and dexamethasone),
C-VAMP (cyclophosphamide, vincristine, adriamycin (doxorubicin) and methyl
prednisolone),
Z-Dex (idarubicin and dexamethasone)
Followed by High dose melphalan (70-140mg/m2) with or without stem cell support.
These regimen do not confer any survival benefit over conventional oral alkylating therapy but temporary complete remissions can be achieved, and the speed of remission is more rapid than with oral regimens. Maximal response to VAD is seen after 2-3 cycles of treatment.
The role of -interferon in myeloma has been the subject of much discussion in recent years and a clearer pattern is now beginning to emerge. Patients who receive -interferon whilst in partial or complete remission after conventional chemotherapy or after transplant may experience a 6-12 month prolongation in progression free survival but there is no major difference in overall survival. Patients may be offered -interferon (3MU x3/week) at the time of achieving remission but a balance must be achieved between a short improvement in survival and the quality of life of the individual.
The risk of venous thromboembolism in patients with MM and effect of various treatment regimens on increasing this risk: (ref Palumbo et al Leukaemia 2008 ,22, 414-423)
The incidence of VTE in patients with MM is thought to be between 3-4% in patients treated with conventional M+P or Dexamethasone.
Thalidomide:
The risk of thrombosis is not thought to be increased in patients treated with
thalidomide monotherapy. However there is an increased risk in patients treated with a combination of Thalidomide and other agents as shown in the table below.
It should be noted that:
1. The risk of thrombosis is higher in newly diagnosed patients than in relapsed or refractory patients
2. Most episodes of VTE (veno-thrombotic event) occur within the first three months of initiating therapy.
Lenalidomide:
There is no increased incidence of VTE when lenalidomide is used as a single agent . There is an increased risk of VTE when Len Dex is used and the risk is higher with higher doses of Dex and also with concomitant use of erythropoietin as shown in the table below.
Other risk factors for increased incidence of VTE include: Age <40 years, obesity, past history of VTE, DM, infections, heart disease, limited mobility, surgery and certain other medical conditions.
Recommendations: based on published data
• Aim to use safest and least cumbersome therapy that reduces risk to <10% • Thal alone: no prophylaxis recommended
• Thal dex: reduced incidence with full dose Warfarin but not LDW (low dose warfarin), no data on LMWH (low molecular weight heparin) or aspirin • MPT LMWH effective but others not studied
• Dox and multiagent: LDA (low dose aspirin) and LDW ineffective • Lenalidomide no prophylaxis needed
• Lenalidomide + low dose dex or dox or Melph, aspirin effective • Len + High dose dex needs more aggressive prophylaxis
Pending further studies it is reasonable to assume that in patients with more than one risk factor thromboprophylaxis with LMW heparin or full dose warfarin should be given when thalidomide containing regimens are used.
Main reference for above is: Palumbo et al 2008. Leukaemia. Prevention of thalidomide- or lenalidomide-associated thrombosis in myeloma. 22,414-423
Useful guideline to refer to is the UK Nordic Myeloma Guideline: http://www.bcshguidelines.com/pdf/UKNordic_070705.pdf
3.01 VAD
3.03 Z-Dex
3.04 Melphalan +/- prednisolone
3.05 Cyclophosphamide weekly
3.06 Cyclophosphamide 3 weekly
3.07 Intermediate dose melphalan
3.08 C-Thal-Dex 3.09 Attenuated C-Thal-Dex 3.10 Thalidomide +/- dexamethasone 3.11 CIDEX 3.12 MPT 3.13 DT-PACE 3.14 Bortezomib
3.15 Lenalidomide
3.16 MDT
Written by: Dr Saad Abdalla, Pauline McCalla and Dr Amin Rahemtulla
Revised by: Dr Saad Abdalla, Stephanie Kirschke, Pauline McCalla and Dr Amin Rahemtulla Authorised by: WLCN Haematology TWG September 2009
