Myeloma (Multiple Myeloma)

Question 1

History of Myeloma

Answer 1

• Egytpian mummy found in Qubbet el Hawa: showed Multiple Myeloma lesion using special CT scans
• Adult male skull with multiple lesions of vault likely due to multiple myeloma

Question 2

What is Myeloma
What is Multiple Myeloma

Answer 2

• Part of a spectrum of disorders known as plasma cell Neoplasms.
• also called plasma cell meloma
• Characterised by : Accumulation of plasma cells in the bone marrow, presence of monoclonal protein in the serum and/or urine, tissue damage.
• Disease of elderly: peak onset of 65-70 years
• some asymtpomatic cases ( smouldering myeloma)

Multiple myeloma: characterized by the proliferation of malignant plasma cells in the bone marrow that produce excessive amounts of a single type of antibody(monoclonal protein/ M-protien)

Myeloma: refers to any type of cancer involving plasma cells. can manifest in different forms: multiple myeloma, solitary plasmacytoma, and extramedullary plasmacytoma.

Multiple Myeloma: “Multiple myeloma” specifically refers to a type of myeloma characterized by the presence of multiple malignant plasma cell tumors within the bone marrow. In multiple myeloma, these abnormal plasma cells proliferate uncontrollably, crowding out normal blood cells and interfering with the production of normal antibodies

Question 3

Features- What is a paraprotein?

Answer 3

Monoclonal immunoglobulin (M-protein) produced by lone of plasma cells.

Question 4

Causes/ Risk factors

Answer 4

Cause unknown, some association with radiation, farmers, benzene and inflammatory disorders.

• The disease is characterised by an Accumulation of genetic abnormalities e.g. aneuploidy, increased expression of cyclin D genes through translocations etc.

Question 5

Pathogenesis

Answer 5

• Most cases develop from monoclonal gammopathy of undetermined significance (MGUS).
  MGUS -> Smouldering MM -> MM

Question 6

Pathogenesis - What triggers signalling of pathogenic mechanisms?

Answer 6

• Complex interaction between plasma cells with microenvironment is key to disease development:

-Plasma cells home in on the bone marrow.
Bone marrow endothelial and stromal cells produce chemo-attractants for myeloma cells e.g. SDF-1.

• MM cells adhere to extracellular matrix proteins and bone marrow stromal cells via adhesion molecules e.g. β1 integrin family, VCAM-1 and ICAM-1.

-Binding of myeloma cells induces production of cytokines e.g. IL-6, TNF-α by plasma cells and stromal cells.

• This triggers signalling pathways and promotes cell proliferation, inhibits apoptosis and modulates production of more adhesion molecules.

Question 7

What causes Bone Lesions/ bone loss?

Answer 7

Interaction of MM and stromal cells responsible for osteolytic lesions:
- Increased cytokines
- Increased osteoclast activity due to secretion of osteoclast activating factors e.g. RANKL and MIP-1α (cytokines).
-Decreased osteoblast activity.
-Increased bone loss.
- Hypercalcaemia.

RANKL: Receptor activator of nuclear factor κB ligand.
MIP: Macrophage Inflammatory Protein
OPG: Osteoproteregrin

Question 8

Effects of paraprotein and free light chains

Answer 8

Wide spectrum of abnormalities:
Abnormal platelet function/ coagulation
Amyloidosis
Dilutional anaemia
Hyperviscosity

Renal failure: Obstruction of the tubules due to light chains. The imbalance between bone formation and destruction also causes hypercalcaemia - can cause cause life-threatening dehydration and renal failure.

Question 9

Clinical Features

Answer 9

Bone Pain, especially back (due to lesions etc.) – most frequent complication.
Renal Failure.
Anaemia – due to marrow infiltration, Epo def etc.
Recurrent infections (reduced normal Igs).
Bleeding.
Amyloidosis.
Hyper viscosity syndrome (purpura, haemorrhages, visual failure, CNS symptoms etc.).

Question 10

Symptomatic MM

Answer 10

Clonal proliferation of plasma cells in the bone marrow or plasmacytoma.

Demonstration of Monoclonal protein in serum and/or urine.

Related organ and tissue impairment – e.g CRAB (hyperCalcaemia, Renal impairment, Anaemia, Bone disease)

Question 11

Lab Investigations

Answer 11

Immunoglobulin electrophoresis of serum and urine e.g. gel or capillary electrophoresis - 60% of cases are IgG, 20% are IgA, others usually light chain only.

Reduced normal immunoglobulins.

Light chain assays show elevated serum immunoglobulin‐free light chains - Either the κ or λ serum free light chain.

Urine may contain free light chains (Bence Jones Protein) - 2/3rds usually show BJP in urine

Bone Marrow (≥ 10% plasma cells).

Peripheral blood film may also show plasma cells.

Raised ESR and viscosity.
N/N anaemia.

Rouleaux and background stain (due to protein).

Neutropenia and thrombocytopenia in advanced disease.

Question 12

Lab investigations - Immunotype, cytogenetics, chemistry

Answer 12

Immunophenotype shows high expression of CD38 and CD138.

Cytogenetics / molecular studies e.g. aneuploidy, 14q32 translocations.

Chemistry: Raised serum calcium, Raised creatinine, Low serum albumin (advanced cases)

Question 13

Investigations for patients with suspected myeloma - screening tests

Answer 13

FBC
Urea & creatinine
Calcium
Immunoglobulins & serum electrophoresis
Serum free light chains

Question 14

tests to establish diagnosis of myeloma

Answer 14

Bone marrow aspirate & trephine biopsy with plasma cell phenotyping*

Immunofixation of serum

Imaging – PET-CT, WB-MRI (diffusion weighted preferably) or low dose WB-CT.

Question 15

tests to estimate tumour burden and prognosis of myeloma

Answer 15

FISH Analysis for t(4;14), t(14;16), t(11;14), 17p−, 1q+, 1p−

Consider testing for t(14;20) and hyperdiploidy
β2 microglobulin,

LDH

Albumin

Question 16

Diagnosis and investigations of MM

Answer 16

Bone marrow biopsy - in patients where there is clinical concern for end organ damage nd/or patients with significatntly elevated monoclonal proteins (M-proteins)

• Monoclonal protein qualified by densitometry of monoclonal peak.

Quantification of monoclonal immunoglobulin (Ig) A by electrophoresis can be complicated by migration into the beta region.
International Myeloma Working Group (IMWG) guidance recommends that for IgA and IgD myelomas, quantitative immunoglobulin measurements are preferred.
NICE guidance recommends the use of serum free light chains (SFLC) rather than urinary Bence Jones protein (BJP).
Urine albumin:creatinine ratio along with troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) : useful screening tool for detecting amyloid.

Skeletal survey replaced by cross-sectional imaging, including low-dose, whole-body computed tomography (CT), or ideally functional imaging such as computed tomography-positron emission tomography (CT-PET) or diffusion weighted whole body magnetic resonance imaging (MRI).

Focal imaging (e.g., dedicated MRI scan of the spine and pelvis, or plain films of long bones) should be performed to look at specific sites in more detail if required.

Diagnoses should be reviewed at a multidisciplinary team (MDT) meeting `

Question 17

Criteria to diagnose Myeloma

Answer 17

1. Clonal bone marrow plasma cells > or equal to 10 or biopsy proven plasmacytoma. (. Kappa:Lambda ratio ≥100 or ≤0·01. † Creatinine clearance measured or estimated by validated equations. ‡ If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement)
2. One or more myeloma defining events:
   [S] ≥60% plasma cells in marrow
   [LI] Involved: uninvolved light chain ratio ≥100* (provided the involved light chain is >100 mg/l)
   [M] 2 or more focal lesions on MRI (>5 mm in size)
   [C] Hypercalcaemia: (>2·75 mmol/l or >0·25 mmol/l higher than upper limit of normal)
   [R] Renal insufficiency: (serum creatinine >177 µmol/l or creatinine clearance <40 ml/min†)
   [A] Anaemia: Hb <100 g/l or 20 g/l below lower limit of normal
   [B] 1 or more lytic bone lesion on X-ray, CT or PET/CT‡ (>5 mm in size)

Question 18

Diagnostic criteria for smouldering myeloma

Answer 18

Both critera must be met:

1. Serum M-protein (IgG/ IGA > or equal to 30 g/l
   Urinary M-protein > 500 mg/24 h and/ or clonal bone marrow plasma cells 10-60%.
2. Absence of myeloma- defining events or amyloidosis

Question 19

Diagnostic criteria for Non-IgM MGUS+

Answer 19

All three criteria must be met:
1. Serum M-protein (non-IgM) <30g/l
2. Clonal bone marrow plasma cells <10%
3. Absence of end organ damage that can be attributed to the plasma cell proliferative disorder (e.g. CRAB features, amyloidosis

Question 20

Diagnostic Criteria updates

Answer 20

End organ damage no longer requried to diagnose myeloma
Biomarkers added to myeloma defining events (each assocaited with -80% probability of the development of CRAB features) :(≥60% clonal plasma cells in the bone marrow, involved:uninvolved light chain ratio ≥100 and ≥2 focal lesions on MRI) - reffered to as SLiM criteria
- Studies showing rate of progresesion of myeloma within 2 years in approx 95, 80, 70 % respectively

Question 21

Diagnostic criteria updates

Answer 21

Current guidance confirms 10% clonal plasma cells or biopsy-proven plasmacytoma is required.

also clarifies that presence of osteolytic bone lesions >5 mm seen on CT or PET-CT (and not on skeletal radiography) is consistent with a myeloma-defining event.

Increased uptake on PET-CT alone, without a corresponding lytic lesion, is insufficient to be a myeloma-defining event, but is associated with an increased risk of progression to myeloma.

If there is doubt regarding equivocal or small lucencies (<5 mm), repeat imaging should be performed.

Bone lesions should be biopsied if there are concerns they may represent bony metastases from concurrent malignancies.

Osteoporosis with compression fractures is no longer a myeloma-defining event.

Question 22

ISS and R- ISS

Answer 22

ISS ( international Staging System) for MM is outdates
Revised - ISS combines traditional ISS with presence of : high risk cytogenetics ((del(17p), t(4;14) or t(14;16)) or evelated serum lactate dehydrogenase (LDH)

used data from 4445 pateints with newly diagnosed myeloma that were enrolled onto 11 international mutlicentre trials, 95% treated with novel agents.

Question 23

Treatment

Answer 23

Proteasome Inhibitors: (act by altering the degradation of proteins essential for cell cycle and growth)
The first in class, bortezomib,
Carfilzomib is a second-generation PI

Immunomodulatory Drugs(IMiDs): - oral agents that cause myeloma cell apoptosis primarily by interaction with cereblon. Mechanisms of action include degradation of the transcription factors IKZF1 and IKZF3,
The first drug in class, thalidomide,….lenalidomide and pomalidomide,

Corticosteroids:
dexamethasone and prednisolone

Alkylating Agents: e.g. melphalan, cyclophosphamide

Monoclonal Antibodies:
anti-CD38 antibody daratumumab,
isatuximab (anti-CD38) and elotuzumab (anti-SLAMF7),

Myeloma drugs can also be combined (lecture ntoes)

Question 24

Treatment - Stem Cell Transplantation

Answer 24

Autologous Stem Cell Transplantation (ASCT):

• ASCT following high dose chemotherapy: standard of care for consolidation following induction treatment in those considered fit enough. first demonstrated to prolong PFS and OS with acceptable low levels of transplant-related mortality (TRM).
• Mobilisation with Cyclo-G or G-CSF alone or with plerixafor is recommended, aiming for enough stem cells for two procedures if possible in those considered of an age to undergo a second procedure.
• Conditioning with HDM at 200 mg/m2 is the standard dose, with a dose reduction to 140 mg/m2 recommended in those with GFR <30 ml/min or >65 years of age.

Post -ASCT:
post-ASCT
- Maintenance therapy with thalidomide is not recommended post-ASCT.
- Maintenance therapy with lenalidomide is recommended post-ASCT.
- Maintenance therapy with bortezomib is not routinely recommended post-ACST, but can be considered in patients with high-risk cytogenetics.

Allogeneic stem cell transplantation:
- Role of allogeneic stem cell transplantation in myeloma remains controversial, although a graft-versus-myeloma (GvM) effect is well recognised.