Haematology JC046: An Old Man With Bone Pain And Anaemia: Multiple Myeloma, Monoclonal Gammopathy Flashcards
Multiple myeloma
Prototypical **plasma cell neoplasm
- Abnormal proliferation of **plasma cells + Presence of ***end-organ damage
- disease of elderly (very rare <30)
Epidemiology of Myeloma
- Age-standardised incidence: ~5 per 100,000
- Median age: ***66-70
- Extremely rare <30 yo
- M > F
- more common in black
- exposure to radiation / pesticide (e.g. agent orange in agriculture)
- ***runs in family
Case: 74 male
- Reduced exercise tolerance
- Low back pain
CBP:
- **Anaemia (Normochromic Normocytic)
- **Thrombocytopenia
- **High creatinine + Low eGFR (AKI)
- **High adjusted Ca (Osteolytic)
- Normal ALP
- ***High Globulin
- Low Albumin
Serum protein electrophoresis:
- High IgG: Monoclonal IgGκ —> explain high globulin, anaemia, AKI
- Low IgA
X-ray:
- Collapsed + Fractured lumbar + thoracic spine
- Osteolytic lesions in skull
BM exam:
- **Pleomorphic plasma cells (multi-lobed nucleus + clock face chromatin + abundant blue cytoplasm with perinuclear halo)
—> 64% of nucleated cells in BM
- **Trilineage haematopoiesis markedly reduced —> explain anaemia, thrombocytopenia
Renal biopsy:
- Mild tubular atrophy + Interstitial fibrosis
- **Angulated, “Fracture” appearance casts in lumen of renal tubules —> pathognomonic of **Myeloma kidneys (light chain filtered into renal tubules and block them) —> ***Cast nephropathy
- No deposits of immunoglobulin
- Congo red stain negative
Diagnosis:
- Multiple myeloma with complications of anaemia, multiple bone fractures, acute renal failure
Diagnosis of Multiple myeloma
2 requirements:
1. Presence of **Clonal plasma cells (i.e. likely derived from single tumour cell)
- same gene rearrangement —> producing Ig of **same specificity
- Presence of **End-organ damage
- **CRAB: Ca, Renal impairment, Anaemia, Bone system
Plasma cell dyscrasia
Plasma cell dyscrasia: consists of a spectrum of plasma cell disorders
- spectrum: Asymptomatic —> Highly aggressive
- ranging from MGUS —> Smouldering myeloma —> Symptomatic Multiple myeloma
MGUS (Monoclonal gammopathy of unknown significance):
- Presence of ***small quantity of paraprotein (<30 g/L) + % of plasma cell within BM <10%
- patient asymptomatic from paraprotein
- can be considered as “pre-cancerous” condition before myeloma with risk of progression 1% per year
Smouldering myeloma:
- intermediate between MGUS and Symptomatic Multiple myeloma
- markedly ↑ level of paraprotein (>30 g/L) + ↑ % of abnormal plasma cells in BM (>10%, <60%)
- **but fall short of criteria for myeloma (i.e. **without end organ damage)
- patient ***asymptomatic from paraprotein
- risk of progression ~10% per year
Multiple myeloma:
- could be considered as an ”end-of-spectrum”
2 steps events in Plasma cell dyscrasia
Normal B cell
—> Abnormal response to antigenic stimulation (Primary cytogenetic abnormalities) (Cumulative damage)
—> MGUS
—> Progressive events (Random 2nd hit dependent conversion)
—> MM
Translocation of Ig **heavy chain gene during class switching cause MGUS development
—> ∴ **Chronic antigenic stimulation predispose development of MGUS
—> Observed in some patients that Paraprotein disappear when inflammation / infection resolved
—> ∴ in some patients is reversible
1st step (necessary but not sufficient):
Cytogenetic abnormalities in MGUS patients:
- 50%: exposed to antigens —> IgH translocation at **14q32 (irreversible) —> partner with oncogenes (e.g. cyclin D1, D3) —> upregulation of oncogenes —> development of MGUS
- 50%: **Hyperdiploidy —> odd no. of chromosomes —> upregulation of oncogenes —> development of MGUS
2nd step (2nd hit):
- Random events (1% per year): Secondary translocations / Mutation of tumour suppression (worst prognosis: ***Del 17p) or oncogenes / Change in BM environment
—> Accumulation of 2nd hit events
—> development of MM
Concept of Clonal burden
MGUS:
- least clonal burden
- no end organ damage
- only presence of paraprotein and small no. of plasma cells not fulfilling criteria
Smouldering:
- much larger clonal burden
—> BM plasma cells (**10-60%)
—> paraprotein IgG / A **>30 g/L
—> urine paraprotein ***>500 mg per 24 hours
- absence of myeloma defining events (end-organ damage CRAB)
MM:
- CRAB
Paraproteins
Serum immunoglobulin:
- combined output from millions of different plasma cells
- polyclonal (different specificities)
Paraproteinaemia:
- **monoclonal immunoglobulin band in the blood
- secreted by **single clone of neoplastic cells (usually plasma cells) (i.e. myeloma cells)
- this abnormal protein called Paraprotein —> detected by serum / urine protein electrophoresis
NOT all paraproteinaemia are due to MM / MGUS:
- paraproteinaemia NOT always equivalent to MM
- some other haematological conditions could be associated with Paraprotein presence:
—> **Amyloid light-chain (AL) amyloidosis (systemic manifestations: disposition of amyloid proteins in numerous organs e.g. nerves, GI)
—> **Marginal zone lymphoma
—> ***CLL / Small lymphocytic lymphoma
—> Lymphoplasmacytic lymphoma (typically IgM) —> Waldenstrom macroglobulinemia
Serum protein electrophoresis
- Densitometry or Gel electrophoresis
2 types of proteins in blood:
1. Albumin (usually highest)
2. Globulin (usually polyclonal)
- α1: α1-antitrypsin, α1-acid glycoprotein
- α2: Haptoglobin, Ceruloplasmin, α2-macroglobulin, α2-antiplasmin
- β: Transferrin, LDL, Complement
- γ: Immunoglobulin (M protein i.e. Ig fragments usually appear in this band)
if serum has Paraprotein (e.g. IgG paraprotein):
- peak in γ globulin (~ to albumin peak)
- other globulin peaks suppressed (***Immunoparesis)
Diagnosis of Myeloma
International Myeloma Working Group (IMWG) 2014 diagnostic criteria:
1. Clonal BM plasma cells ***>=10% / Biopsy-proven bony or extramedullary plasmacytoma (a solid tumour consisting of plasma cells)
- ***>=1 myeloma-defining events
- Evidence of end organ damage (attributed to underlying plasma cell proliferative disorder):
—> Hypercalcaemia (C): serum Ca >0.25 higher than ULN / **>2.75
—> Renal insufficiency (R): creatinine **>177 / creatinine clearance <40
—> Anaemia (A): Hb **<10 / Hb >2 below LLN
—> Bone lesions (B): **>=1 osteolytic bone lesions - Any >=1 of following biomarkers of malignancy:
—> Clonal BM plasma cells ***>=60%
—> Involved: Uninvolved serum free light chain ratio >=100 with involved free light chain >=100 mg/L
—> >=1 (>=5 mm) focal lesions on whole body MRI scans
Myeloma related complications
- Anaemia
- Bone / Ca
- Kidney
- Anaemia
Causes:
1. Marrow replacement by plasma cells (**suppressing normal haematopoiesis)
2. **Reduced erythropoietin (∵ renal impairment)
3. **Haemodilution by paraprotein
4. **Rouleax formation of red cells (∵ ↑ globulin)
- Bone / Ca
Pathophysiology:
- quite different from metastasis of other malignancies
- **markedly ↑ bone resorption secondary to ↑ osteoclastic activity —> caused by secretion of potent cytokines including **RANKL (significant imbalance with OPG), macrophage inflammatory factor (MIP), TNF, IL-1, IL-6, PTH-rP
- myeloma cells **suppress OPG secretion —> osteoblastic activity is NOT ↑ —> ∴ ALP is **not ↑ in typical myeloma bone disease
Vicious cycle:
- Bone resorption release cytokines (e.g. IL-6) into BM microenvironment —> ***nurturing myeloma cells —> release more RANKL into circulation —> more bone resorption
**Direct myeloma deposit:
- causing radiological appearance of **punch-out lesion on skull
Clinical features:
1. **Hypercalcaemia (bone resorption + leakage of Ca into circulation)
2. **Bone lesions (widespread ↓ in bone density, punch-out lesions on skull, vertebral fractures, bone pain, propensity to pathological fracture)
3. ***Acute spinal cord compression (Potential medical emergencies)
- Extramedullary plasmacytoma / Fracture of vertebral body —> Acute spinal cord compression (neurological emergency) —> immediate RT / decompression surgery
Management:
- **Bisphosphonate (shown to improve BMD in myeloma + **help overall disease control ∵ action on osteoclast activity)
Screening modalities for Bone complications
- ***Whole body low dose CT (reasonable + low cost)
- ***PET-CT (best to pick up extramedullary disease, expensive)
- ***Whole body MRI (best + most sensitive but most expensive + long time)
- Skeletal survey (used in past, not sensitive enough)
- cannot pick up abnormality since it is ***lytic lesion rather than blastic lesion (SpC Revision))
- Kidney
- > =50% of patients with newly diagnosed myeloma have various degree of renal involvement
- **Cast nephropathy (aka **Myeloma kidney): predominant cause of kidney injury
- Other mechanisms of kidney injury:
—> **Hypercalcaemia
—> **Dehydration
—> ***Hyperuricaemia
—> Amyloidosis (deposition of amyloid protein in kidney: significant proteinuria) (rare)
—> Direct myeloma deposition (rare)
Acute renal failure (medical emergency)
—> ***Emergency dialysis + Myeloma treatment to salvage kidney
