Myeloma
Epidemiology § Incidence variable with race 1/100,000 for Asians; 4/100,000 Caucasians and 8/100,000 for Afrocaribeans
Aetiology § 3-5% occur in families § Radiation / chemical such as doxins § Viruses HHV8, EBV, HIV, Hepatitis but studies inconclusive
Pathogenesis § Clonal proliferation of plasma cells which have undergone VDJ gene rearrangement and have homed to the bone marrow (plasma cells generally only appear in the peripheral blood in end stage disease). § Precise stage of the malignant change unclear – some evidence that circulating blood lymphocytes have the same VDJ rearrangement as in myeloma § Proliferate slowly <1% actively synthesising DNA
Immunophenotype CD38 +, CD138 +, CD79a+, CD45 – CD19 – or CD19+/CD56+ (cf normal plasma cells which are consistently CD19+/CD56-). CD56 marker of neoplastic plasma cells.
Cytogenetics § Karyotypes of myeloma are complex and more closely related to epithelial tumours and blast phase CML than other haemopoietic malignancies § Multiple deletions and hyperdiploidy are common particularly - Monosomy 13 or deletions in 13q § Chromosone 14 (IgH) genes involving a large array of chromosomal partners are detected in over 80% § Particularly cyclin D1 – t(11;14) § Also Cyclin D3, FGFR3, MUM1 (see table below) § Deletion 17p13 (P53) – poor outcome (25%) § Hyperdiploidy with chromosome counts >50 has been reported in over 30% § Hypodipoloidy also common
§ Monosomy 13 detected in 50% by FISH (also up to 40% of MGUS) § Increases during course of disease (70% in plasma cell leukaemia) § Uncertain whether it has prognostic significance
Bone marrow microenvironment § Extracellular matrix § Five types of stromal cells § Fibroblasts § Osteoblasts § Osteoclasts § Vascular endothelial cells § Lymphocytes § Interact with cytokines § Stromal cell activation of NFkB pathway leads to the production of IL6 which then stimulates plasma cells (dex, thalidomide and bortezomib all inhibit this pathway).
Biology of bone disease § Increased osteoclastic activity without a concomittent increase in osteoblastic activity § Cytokines produced by either myeloma or stem cells stimulate osteoclast activity (IL6, TNF alpha and beta, IL1beta, IL11). § More recently RANKL on stem cells activates its receptor RANK which interacts with a cellular activator of the NF-kB pathway leading to increased osteoclast survival. § Osteoproteogerin (OPG) binds RANKL competitively inhibiting its interaction with RANK – OPG levels fall in myeloma. § Blocking RANKL activity reduces bone destruction and tumour burden. § Denosumab is a monoclonal antibody to RANKL; in trial
Diagnositic criteria
New BCSH Guidelines 2005
§ If there is uncertainty as to whether end organ damage is attributable to myeloma or not, the percentage of plasma cells should be >30% § SS and BM not mandatory to make a diagnosis of MGUS in absence of relevant clinical symptoms, anaemia, hypercalcaemia or renal impairment § Risk of progression from MGUS to active disease is about 1% per year § Rate of progression dependant on PP level/ type of PP (A & M >G)/ abnormal SFLC ratio § Median time to progression from asymptomatic to symptomatic is 12-32 months
Clinical features 1. Asymptomatic 2. Bone disease – 90% at some point 3. Marrow infiltration (anaemia / neutropenia / thrombocytopenia) 4. Hypercalcaemia; increased osteoclasts with reduced osteoblasts but also PTHrP form plasma cells 5. Renal failure 6. Plasmacytomas 7. Hyperviscosity 8. Cord compression 9. Amyloidosis eg. Nephritic syndrome, cardiac failure
Bone disease § 80% will have bone pain; typically chest or back, worse with movement and better at night. § 60% develop pathological fractures § Vertebral fractures and wedging from collapsed vertebral bodies common § Advanced disease – fractures of ribs, sternum and long bones § Skull lesions rarely painful
Bone marrow infiltration § Normochromic anaemia common initial finding § EPO levels with be raised or reduced depending on renal function
Hypercalcaemia § 25% at presentation § Polydypsia, polyuria, constipation, renal stones, depression
Renal failure Pathophysiology § Light chain casts and interstitial nephritis due to exhaustion of renal tubular capacity to reabsorb light chains. § Hypercalcaemia § AL amyloidosis § Sepsis § Hyperuricaemia § Anti-inflammatory drugs § Hyperviscosity § Infiltration by plasma cells (rare)
Neurological complications § Plasmacytomas causing spinal cord or peripheral nerve compression § Peripheral neuropathy – amyloid or treatment § POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) § Hyperviscosity § Meningitis by plasma cells occasionally seen in plasma cell leukaemia § Intracerebral masses – very rare
Hyperviscosity § <10% usually due to IgM paraproteins § IgA > IgG (IgG3 the most common of Ig subclasses) § Measure plasma viscosity (centipoles (1=water) NR 1.4-1.6 rare to get symptoms when <4) § Cerebral, pulmonary and renal dysfunction § Haemorrhagic tendency § Visual disturbances / sudden onset blindness § Fundoscopy – retinal vein distension, increased vessel tortuosity, A-V nipping, beading of veins / retinopathy with haemorrhages and exudates
Coagulopathy § Rare § Bleeding due to interference by the paraprotien with fibrin aggregation / VIII / X § Thrombosis due to antiphospholipid antibodies or acquired protein C deficiency or hyperviscosity
Amyloid – see separate notes
Investigations § FBC + film (plasma cell leukaemia) § U&E / Ca / LFT / LDH / Coag § Protein electrophoresis and paraprotein estimation § 60% IgG § 20% IgA § 20% Light chain § <1% IgD or IgE § Immunofixation more sensitive § Immunoglobulins § 90% have immunoparesis § Serum free light chains § Normal and neoplastic cells produce FLCs, therefore the kappa: lamda ratio is a surrogate marker for monoclonal FLCs. § Ratio may be abnormal even when renal resorption not exceeded (ie. When no detectable FLCs in urine) § Therefore, non secretory and some cases of AL amyloidosis may only be detected by SFLCs § Abnormal ratios can also occur in immune dysregulation eg. HIV, SLE, post BMT § Beta 2 microgobulin § 24h urine for total protein and light chain excretion
Bone marrow aspirate and trephine § Immunophenotyping (CD138, CD79a, kappa/lambda, CD20) § Myeloma cytogenetics
Imaging § Skeletal survey § CT / MRI if signs or symptoms of spinal cord compression
Other investigations § Fat / rectal / renal biopsy for amyloid +/- SAP scan § DEXA scan for bone density § PET rarely useful as small tumour with low metabolic activity
Staging Salmon-Durie classification
New International Prognostic Index (IPI) § Based on data from 8500 patients
§ Age < 60 good prognositic factor § Low platelet count bad prognositic factor § Cytogenetics also influence outcome but ch 13 deletion and complex chromosomal abnormalities don’t seem to add to age, albumin and B2M
Assessing response to treatment § Complete remission § No M-protein in serum or urine by immunofixation for a minimum of 6 weeks and <5% PCs § Very good partial response § Normal EP but positive immunofixation or a 90% reduction in PP § Partial response § >50% reduction in M-protein &/or 90% reduction in BJP or reduction to <200mg/24hrs for 6 weeks § Minimal response § 25-49% reduction M-protein &/or 50-89% reduction in urine § No change § Plateau § No evidence of continuing end organ damage § <25% change in M-protein and BJP for 3 months § Progressive disease § End organ damage continuing despite therapy or its reappearance in plateau phase § >25% increase in M-protein § >25% increase in BJP (>200mg/24hours) § >25% increase in PCs § Relapse § Reappearance of disease in patients previously in CR
§ SFLCs may be helpful in assessing response in patients with an intact Ig PP, because they have a shorter life and are therefore a more sensitive indicator of change
Treatment Analgesia § WHO analgesic ladder § Use NSAIDs with caution § Neuropathic pain § Dex esp for palliative pain control
Radiotherapy § 8 Gy single fraction § May also promote healing of fracture sites § Use judiciously, as effect on bone marrow may effect ability to harvest stem cells for auto.
Orthopaedic bone fixation § Vertebroplasty § Injection of polymethacrylate § Several vertebrae can be treated simultaneously § Pain relief and bone strengthening, but no effect on vertebral height § Kyphoplasty § Insertion of small inflatable balloon § Restores vertebral height § Balloon then removed and cavity filled with cement
Hypercalcaemia § C.Ca 2.6-2.9 § Rehydrate with oral fluids § C.Ca >2.9 § Iv fluids +/- frusemide § Bisphosphonate § ZA better than pamidronate § Alternatives include steroids, IM calcitonin for refractory hypercalcaemia
Bone disease § Bisphosphonates recommended for all requiring chemotherapy § Reduce bone pain, fractures and progression of lytic lesions § Should be continued for a minimum of 2 years if in remission at that stage, although often continued long-term § Oral clodronate or pamidronate or ZA § Pamidronate and ZA are equal in efficacy § P = 90mg once monthly; 2 hour infusion § ZA = 4mg once monthly; 15 minute infusion § Check renal function § ZA should not be used if Cr > 265 § Risk of osteonecrosis of the jaw increases with; § Duration of bisphosphonate use § Active myeloma § Dental extractions/ surgery
Renal failure § Iv fluids to achieve UO of >3l/ 24hrs § Correct hypercalcaemia § Treat infection § Nephrology within 48 hours if no improvement § Renal biopsy § ATN / cast nephropathy / amyloid § Plasma exchange of potential benefit in cast nepropathy – MERIT trial § New filters produced by Gambro which have small enough pores to allow removal of SFLCs
Anaemia § Often improves with chemotherapy § Try epo if symptomatic whilst on chemo § Poor indicators for response § Epo >200 § High transfusion requirement (>3 in 3months) § Low platelet count § If no effect after 4-6 weeks, double dose § Probability of effect is low if Hb not risen by 1-2 after 6-8 weeks, and epo should be stopped § Stop epo when Hb >12 § Can be considered if symptomatic and not on chemo § Monitor iron status
Infection § PCP for 1st 2 months in patients starting alkylating agents § Influenza, pneumococcal, HIB recommended but efficacy not guaranteed § IVIG may be helpful
Cord compression § Dex 8-16mg/ day § Local radiotherapy within 24 hours § Surgery only implicated if spinal instability
Chemotherapy recommended for symptomatic or asymptomatic with end-organ damage § Decision 1 = autograft candidate or not § If candidate for autograft need to avoid melphalan as may be difficult to harvest
HDT planned § Cytoreduction without compromising harvest § 1st line in UK is CTD +/- thromboprophylaxis § Higher CR rates than VAD (20% v. 12%) § New alternatives include vel/ dex (similar CR rates, and better harvests but not NICE approved in UK) or PAD (velcade, adriamycin and dex) § Some work combining novel agents eg. Vel/ thal/ dex with good responses but concerns re peripheral neuropathy, these may be overcome with lenalidomide that doesn’t cause neuropathy § Older alternatives include § VAD (vincristine, doxo and dex) § VAMP ( vincristine, adriamycin, methotreaxte and pred) § C-VAMP (cyclophosphamide) § CR in 10-25% § Requires central access § Z-dex (idarubicin and dex) § Oral equivalent § VAD may have better response and survival rates § Much of the effect is steroid mediated § Most treat to 4-6 months before auto § Although CR is a good prognostic factor, delaying HDT in hope of reaching CR does not improve outcome
High dose therapy § HDT with ASCT should be part of primary treatment strategy in newly diagnosed patients up to 65 years § May be considered over 65 yrs if good PS § Conditioning with single agent melphalan 200mg/m2 § Dose reduce if older/ renal failure (140mg/m2), even if on dialysis § TRM is higher in renal failure, but reversibility of ESRF was observed § Mobilizing regime is commonly cyclophosphamide and GCSF § Purging of collected cells with eg MAB has not demonstrated clinical benefit § Planned double transplants not recommended, but it is recommended that enough stem cells are collected to permit 2 procedures § Allogeneic SCT § Up to 50 years with at least partial remission after initial therapy may be considered for sib allo § DLI if persistent or progressive disease § 50% respond § 17% CR § RIC allos may be considered up to 70 years with a sib allo § VUDs may be considered
HDT not planned § Aim to achieve response with minimal toxicity § Oral regimes preferred § 1st line regimens include CTD or MPT § MPV, MPR, VRD are all under trial § No of cycles not clear, ? fixed number, ?treat until progression or side effects § Older regimens ; § Melphalan or cyclophosphamide + prednisolone § Cyclo cause less cytopenia § Treatment should be continued to maximum response + 3 months § Renal failure § Either VAD or dex alone § Don’t require dose reduction § Melphalan with dose reduction can be used § Thalidomide can be used without dose reduction
§ Maintenance therapy § Follows achievement of plateau phase § Role of novel agents as maintenance not clear yet § Interferon § May have some activity as maintenance following chemo or HDT § Bad side effects § Unfavourable cost per QALY
Relapsed/ progressive disease § Bortezomib is now NICE approved for use in first relapse after one therapy who have undergone or are unsuitable for auto. § Usually combined with dex. § Lenalidomide expected to be NICE approved for subsequent relapses. § If stable plateau achieved with MP, 50% will have further response
Thalidomide § 30% response as single agent, 60% if combined with dex § Side effects § Teratogenecity § Thrombosis (increased when used with steroid) § Neuropathy § Somnolence § Constipation
Bortezomib § Proteosome inhibitor § Can be used as single agent or in combination with dex § 30% response in relapsed disease § Iv administration § Side effects § Thrombocytopenia § Neuropathy (less than thalidomide) § APEX trial § Dex v. bortezomib at first or subsequent relapse § 669 patients § Response rate 38 v 18% § NICE guidelines 2007 § Bortezomib monotherapy at first relapse after one therapy who have undergone or are unuitable for transplant § Measure response after 4 cycles § Continue treatment if PR or CR § Company refunds for those with less than a partial response § Can also be used as induction – PAD (bortezomib, adriamycin and dex) § Appears to be effective and doesn’t impair harvest § 2nd SCT § Single agent dexamethasone § C weekly
Guidelines on radiology § Screening § Skeletal survey § Standard method for screening § Clear association between no of lytic lesions and tumour load § Not useful for routine follow-up § 80% have radiological evidence of skeletal involvement § Vertebra 66% § Ribs 45% § Skull 40% § Shoulder 40% § Pelvis 30% § Long bones 25% § Can assess risk of pathological fracture § Low sensitivity § Demonstrates lucency when >30% of trabecular bone is lost § Should include all of the above areas as well as any symptomatic areas
MR imaging § Myeloma lesions have a low signal intensity on T1 and high signal intensity on T2 weighted images § Procedure of choice for suspected cord compression § MR imaging of the whole spine and pelvis in addition to skeletal survey, if an apparently solitary plasmacytoma irrespective of index lesion § MR to clarify ambiguous CT findings § Can be considered as a base line assessment in non-secretory myeloma
CT imaging § May be used in suspected cord compression in patients where MR is contraindicated § May confirm areas of bone destruction suspected clinically, but in whom MR is negative § Clarify ambiguous areas on plain radiography § More sensitive than Xray, therefore can be considered in symptomatic patients negative on Xray, but not routine due to high radiation dose § To delineate soft tissue disease, and can be used to guide biopsy
Bone scintigraphy § Technetium 99 phosphorus compound § Incorporated into areas of increased bone mineralization § Lack of osteoblastic activity in myeloma, therefore has low sensitivity § No place in routine staging
DEXA scanning § Routine assessment of bone mineral density not recommended § All symptomatic patients should have bisphosphonate regardless
PET and MIBI screening § Neither recommended for routine imaging § Pet rarely useful as tumour with low metabolic activity § PET-CT appears to be more sensitive for small lytic lesions, but not routine due to high false positive rate § PET may be useful in extramedullary disease § Best to avoid within 4 weeks of chemo or 3 months of radiotherapy
SAP scanning § Should be requested if AL amyloid suspected, along with a tissue biopsy § Follow-up SAP scans every 6-12 months
Management of vertebral collapse § NICE recommends percutaneous vertebroplasty when pain is not relieved by conventional analgesia § Prior to PV, AP and lateral views of cervical, thoracic and lumbar spine and CT or MR of target area to exclude cord compression
Response to therapy § Skeletal survey § No role for routine follow-up SS in asymptomatic patients with no signs of disease progression § If disease progression, should be done as part of restaging. If progression within 3 months of previous SS and no new skeletal symptoms, unlikely to provide additional information § MR imaging § May be used for follow-up of non-secretory instead of BMs § Investigation of choice for AVN § CT imaging § Can be used to monitor response to therapy of soft tissue masses § PET / MIBI § Can be used to monitor those with extramedllary non-secretory disease
Solitary bone/ extramedullary plasmacytoma § SBP has high risk of progression to MM (the majority will progress) § 25% with an apparently solitary lesion have evidence of disease elsewhere on MRI scanning
§ SBP § Mainly affects axial skeleton, esp vertebrae § M protein in 24-72% § Levels generally low § Median time to MM 2-4 years § Adverse prognostic features for progression to MM § Immunoparesis § Axial disease § Older age § > 5cm § Persistence of M protein after treatment § Abnormal SFLC ratio § Recent report from MD Anderson reported that the only independent RF was persistence of M protein 1 year after radiotherapy § Diagnosis § Tissue biopsy - Single area of bone destruction due to clonal plasma cells (FNA not adequate) § Normal marrow (<5%) § Normal SS § No end organ damage § Absent or low M protein (>20g/l suspicious of MM) § Nil additional on MRI § No established role yet for B2M § Treatment § Radiotherapy § Radical with at least 2cm margin § 40Gy in 20 fractions § >5cm, 50Gy in 25 fractions § No response to radiotherapy, should be treated with chemotherapy § Surgery § Contra-indicated in absence of structural instability or neurological compromise § If surgery is required, it should ideally be done before radiotherapy (renders surgery more difficult) ¨ But metal supports may make radiation less effective § Vertebroplasty ¨ Contraindicated if neurology involvement ¨ Degree of destruction often renders it unsuitable § Adjuvant chemotherapy § Not clearly defined § Should be considered in those at higher risk of treatment failure (>5cm) § Bisphosphonates § No evidence § Thalidomide § No evidence § SBP with positive MRI § Should be considered as having MM § If plasmacytoma is the only cause of symptoms, can treat as above and delay chemo until signs of progression
Solitary extramedullary plasmacytoma § Less common than SBP § Better prognosis as most can be cured by local radiotherapy § Usually remain localised and progression to MM is uncommon § 90% arise in the head and neck § M protein detected <25% § Local recurrence rates <5% after radiotherapy § Distant relapse rates <30% § Within 2-3 years of diagnosis § MM, SBP or SEP § >2/3 survive for >10 years
§ Diagnosis § As above but single extramedullary mass of clonal plasma cells § CT or MRI is required to delineate the extent of the lesion, § Not necessary to MRI spine § Treatment § Radiotherapy § Margin of at least 2cm § Cervical nodes should be included if involved or if high risk eg. Waldeyer’s ring ¨ Otherwise not because of high freq of side effects esp. xerostomia § 40Gy in 20 fractions § 50Gy in 25 fractions if > 5cm § Surgery § Most occur in head and neck and given that they are highly radiosensitive and surgery very disfiguring, radiotherapy alone is treatment of choice § For SEP at other sites, complete surgical removal should be considered § Involved surgical margins, should receive adjuvant radiotherapy § Adjuvant chemotherapy § Considered in tumours >5cm § Indicated for relapsed/ refractory disease
Prognosis for solitary plasmacytomas
Bortezomib
NICE guidance October 2007
1. Bortezomib monotherapy recommended as an option for progressive MM at first relapse having received 1 prior therapy and have undergone or are unsuitable for bone marrow transplantation a. Response is measured with serum M-protein after a maximum of 4 cycles, and continued only if CR or PR i. M protein reduced by 50% or undetectable b. Manufacturer rebates full cost for people with less than a PR 2. People currently receiving bortezomib who do not meet the criteria should have the option to continue until their clinician deems it appropriate to stop
Technology § Proteasome inhibitor – reversible § Proteasome is central to the breakdown of ubiquinated proteins and consequently for normal cellular homeostasis § Induces apotosis in myeloma cell lines, particularly those resistant to conventional chemotherapy § Different mechanism , not affected by the drug resistance leading to alkylator and steroid resistance § Inhibits break down of inhibitory kappa B with consequent stabalisation of NFKB § NFKB can’t translocate to nucleus so there is inactivation of multiple downstream pathways § P53 is also stabalised § Doesn’t cross the blood-brain barrier § Metabolised by cytochrome p450 in the liver
§ Administration § Iv 1.3mg/m2 § Out patient § Days 1, 4, 8, 11 of a 21 day cycle § Side effects § Peripheral neuropathy § Mainly sensory § Dose withdrawal or reduction may be required § Usually resolves, but there can be persistent damage § Patients with previous peripheral neuropathy are at greatest risk § Mildly emetegenic § Renal § Small proportion is excreted by kidneys, needs to be used with care if CrCL <30 § Thrombocytopenia § Blocks megakaryocyte budding § Nadir at day 14 § Doesn’t damage stem cells or impair ability to harvest Cost § £3000/ cycle § Incremental cost effectiveness ratio of £31 000 at first relapse, £77 000 at 2nd relapse and £107 000 at 3rd relapse § Not cost effective when used at 2nd or subsequent relapse
Evidence § APEX trial (Assessment of Proteasome inhibition for Extending Remissions) § Phase III RCT comparing high dose dex (also effective monotherapy) with bortezomib at first or subsequent relapse § Interim analysis (median follow-up 8.3 months), bortezomib had a significantly § Longer median time to disease progression (6.2 v 3.5months) § Improved overall survival § Higher overall response rate (38% v. 18%) § As a result of the interim analysis, all patients were switched to bortezomib § At 22 months, median overall length of survival 29.8 months v. 23.7 months § Observational studies showed improved Hb, reduced transfusion requirements and improved QOL in patients who responded to therapy
Combinations § In development § Some evidence of an additive effect with dexamethasone § Not been approved by NICE
Induction therapy § PAD (adriamycin, bortezomib and dex) § Has been used successfully as auto induction
§ Recommendations – diagnosis § Screening normal populations for M proteins is not recommended. § Serum and urine EP is indicated in § Persistent ESR >30 § Anaemia § Renal failure § hypercalcaemia § Serum and urine EP should be requested if clinical suspicion of a plasma cell dyscarsia or B-cell malignancy. § If M protein not detectable by EP, immunofixation should be performed. § SFLC measurement required to detect non-secretory myeloma and some cases of AL amyloidosis and light chain only myeloma when urine not available. § Lab should perform EP if there are abnormally high or low serum levels of total Igs or an individual Ig class. § If low Igs and no serum M protein, the lab should measure SFLCs or request urine § Associated with RA, SLE, scleroderma, polymyositis, ank spond, HCV, HIV, autologous SCT
Differential diagnosis of M proteins § MGUS § Multiple myeloma § Solitary plasmacytoma § AL amyloidosis § Wladenstroms macroglobulinaemia § Low grade B NHL § Other M protein related disorders
M-protein related disorders § M-protein aggregation § Light chain cast nephropathy § AL amyloidosis § Light chain deposition disease § Crystal storing histiocytosis – adult Fanconi syndrome § Cryglobulinaemia type 1 § M-protein antibody activity § Mixed cryoglobulinaemia type 2 § Monoclonal cold agglutinins § Polyneuropathies
Recommendations – disease associations § M-protein in a patient with polyneuropathy, vasculitis or cardiac/ renal/ hepatic abnormalities with no other explanation should raise the possibility of an M protein related disorder § No evidence that an M protein in patients with rheumatoid arthritis, other connective tissue disorders, dermatological disorders, infections, primary hyperparathyroidism or following transplant should be managed differently to patients with isolated MGUS.
Risk factors for malignant transformation of MGUS § Type of M protein § IgA and IgM have higher risk § Level of M protein § Level of bone marrow plasmacytosis § Abnormal SFLC ratio
§ Factors not associated include BJ protein, age, sex, immunosupression
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