the most common (known) premalignant condition incidence increases with age up to 1% - 3.5% in elderly population average risk for progression : 1% annually IgG or IgA MGUS→myeloma IgM→lymphoma MGUS:higher incidence of osteoporosis, thrombosis and bacterial infection compared to general population

Multiple Myeloma and related plasma cell disorders Flashcards by Raunak Chandiramani

Define Multiple Myeloma

Malignancy of bone marrow plasma cells, the terminally differentiated and immunoglobulin (Ig) secreting B cells

Myeloma plasma cells:

home and infiltrate the bonemarrow
may form bone expansile or soft tissue tumours : plasmacytomas

• produce a serum monoclonal IgG or IgA: paraprotein or M-spike

produce excess of monoclonal (κ or λ) serum free light chains
Bence Jones protein :urine monoclonal free light chains

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Describe the epidemiology of myeloma.

The second most common haematological malignancy, 19th in all cancers
Median age 67 years
Incidence increases with age
Only 1% of patients are younger than 40 years
Men > women
Black > Caucasian and Asians
>17,600 people with myeloma live today in the UK
Prevalence of myeloma in the community is increasing

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What is the aetiology of myeloma? What are the risk factors?

Aetiology is unknown …

Risk factors
• Obesity increases the risk for myeloma (SIGNIFICANT)

Age
Genetics
Incidence in black population
Sporadic cases of familiar myelom

… but, myeloma is always preceded by a premalignant condition:

Monoclonal Gammopathy of Uncertain Significance (MGUS)

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What is MGUS?

the most common (known) premalignant condition
incidence increases with age
up to 1% - 3.5% in elderly population
average risk for progression : 1% annually
- IgG or IgA MGUS→myeloma
- IgM→lymphoma

MGUS:higher incidence of osteoporosis, thrombosis and bacterial infection compared to general population

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What is the diagnostic criteria for MGUS?

Serum M-protein <30g/L
Bone marrow clonal plasma cells <10%
No lytic bone lesions
No myeloma-related organ or tissue impairment
No evidence of other B-cell proliferative disorder

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How do we calculate the chance of progression from MGUs to myeloma

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Define smouldering myeloma.

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What is the progression of myeloma?

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Describe the primary and secondary genetic events of myeloma?

Primary events
- Hyperdiploidy (60%)
- ❑additional odd number Chr
IGH rearrangements (Chr 14q32)
- ❑t(11;14) IGH/CCND1
- ❑t(4;14) IGH/FGFR3
- ❑t(14;16) IGH/MAF

Common secondary events

KRAS, NRAS
t(8;14) IGH/MYC
1qgain/1pdel
del 17p (TP53)
13- / del 13q

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Describe the patterns of the driver genetic events in myeloma.

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How do myeloma cells interact with bone marrow microenvironment?

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What is the diagnostic criteria of multiple myeloma?

MDE - new criteria

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How does myeloma present?

80% of myeloma patients present with bone disease

Proximal skeleton
Back (spine), chest wall and pelvic pain
Osteolytic lesions, never osteoblastic
Osteopenia
Pathological fractures
Hypercalcaemia

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How do we use imaging in myeloma?

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What is the most COMMON cytogenetic abnormality is myeloma?

Hyperdiploid karyotype

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Which of the following is NOT a typical clinical myeloma characteristic?

Anameia
Lytic bone disease
Splenomegaly

Splenomegaly

What are the emergencies in myeloma?

Cord compression

Diagnosis & treatment within 24hrs
MRI scan
Ig and FLC studies +/- biopsy
Dexamethasone
Radiotherapy
Neurosurgery: rarely required
Stabilise unstable spine
MDT meeting

Hypercalcaemia

Presents with drowsiness, constipation, fatigue, muscle weakness, AKI
Fluids, steroids, zolendronic acid

Define myeloma kidney disease

– Serum creatinine >177μmol/L (>2mg/dL ) or eGFR <40ml/min (CDK-EPI)

– Acute kidney injury and result of myeloma

20-50% acute kidney injury at diagnosis
2-4% of newly diagnosed patients will require dialysis
25% develop renal insufficiency at relapse

What causes myeloma kidney disease?

Cast nephropathy is caused by high serum free light chains (FLC) levels and Bence Jone proteinuria
Hypercalcaemia, loop diuretics, infection, dehydration, nephrotoxics

How does myeloma kidney diases develop?

Cells in PCT take up light chains
This becomes overwhelming
Cells go into stress and inflamed
Form a gelantinous material –> cast
Leads to acute kidney injury

Why is kidney disease a determinant of prognosis?

Patients with severe kidney disease (eGFR <30ml/min) have a much worse outcome
Early mortality in severe kidney disease is an area on unmet clinical need
- 12% early death (<2 months)
- Prolonged hospital stay, lethal infections
- Nephrotoxic or renal excreted myeloma drugs: eg zoledronic acid, lenalidomide

How do you treat myeloma kidney disease?

Myeloma kidney disease should be treated as an emergency

Bortezomib-based therapy is the cornerstone of myeloma kidney disease treatment

What is the relation between infections and myeloma?

Complex humoral and cellular immunodeficiency

Immunoparesis: low serum normal Igs
Myeloid, T cells and NK cells impairment
Chemotherapy impairs immune response
Myeloma immune evasion

What are the investigations for myeloma?

Immunoglobulin studies

Serum protein electrophoresis
Serum free light chain levels - screening
24h Bence Jones protein

Bone marrow aspirate and biopsy

IHC for CD138

FISH analysis

Should include at least high risk abnormalities

Flow cytometry immunophenotyping

Diagnosis
MRD

Which of the following is a key histological myeloma marker? * CD19 * CD138 * Surface Ig * CD20

CD138

What is the international staging system for myeloma?

What causes Amyloidosis? How do we detect it? What light chains are involved?

* Misfolded free light chains aggregate into amyloid fibrils in target organs * The amyloidogenic potential of light chains is more important than their amount * Amyloid fibrils stain with **Congo Red**, are solid, non- branching and randomly arranged with a diameter of 7 – 12 nm * Lambda light chain is involved in 60% * - IGLV6-57 in kidney * - IGLV1-44 in cardiac

What is the clinical presentation of amyloidosis?

Common target organs: kidney, heart, liver, neuropathy Clinical presentation: * Nephrotic syndrome (70%) * – Proteinuria (not BJP!), peripheral oedema * Unexplained heart failure → determinant of prognosis * – Raised NT-proBNP * – Abnormal echocardiography and cardiac MRI * Sensory neuropathy * Abnormal liver function tests * Macroglossia

Define Monoclonal Gammopathy of Renal Significance (MGRS)

Definition “...MGRS applies specifically to any B-cell clonal lymphoproliferation where there are: 1. one or more kidney lesions caused by mechanisms related to the produced monoclonal immunoglobulin (Ig) and 2. the underlying B cell clone does not cause tumor complications or meet current hematological criteria for immediate specific therapy”

Describe MGRS pathology?

* Rare disease, several subtypes * Demonstration of the involved monoclonal Ig or light chain is possible in most cases * Work up similar to myeloma * Many patients will require myeloma-type treatment aiming to renal survival

How has myeloma been treated in the past? How about now?

Melphalan * Nitrogenmustardderivate,inusesincethe1960’s * Backboneofmyelomatherapyuntillate1990’s * High-dosemelphalan200mg/m2stillinuseinAutologousSCT Cyclophosphamide * Widelyusedincombinationwithsteroidsand/orotherdrugs * Immunomodulationandmicroenvironment Dexamethasone and Prednisolone * Induceapoptosisinmyelomacells * Strongsynergy,partofalmostallcombinationregimens **Thalidomide** in combination with cyclophosphamide and dexamethasone was established in the treatment of relapsed myeloma It was later replaced older therapies as a front line treatment prior to autologous SCT Thalidomide lead the way for the development of a new class of anti-myeloma drugs **Immunomodulatory drugs (IMiD)** **Lenalidomide - 2005:** more potent, different toxicity profile, better tolerated **Pomalidomide – 2013** : even more potent than Lenalidomide **Iberdomide–awaits approval**

How does lenalimdomide work

Cereblon Binding Molecules -A new mechanism of action Selective degradation of IKZF1 and IKZF3

Describe the use of proteasome inhibitors in myeloma

Myeloma cells are protein production factories Proteasome is crucial in removing misfolded protein **Accumulation of misfolded protein→endoplasmic reticulum stress and unfolded protein response → apoptosis**

Describe the use of moABs in multiple myeloma-

Daratumumab monotherapy in relapsed/refractory myeloma 36% of patients with multiple previous treatments and refractory disease to standard myeloma therapies responded to daratumumab

How do we treat multiple myeloma?

What is the treatment algorithm in new diagnosis of myeloma?

What is the objective of myeloma therapy?

MRD negativity may be required at least in high-risk disease

What are the emerging treatment in myeloma?

Monoclonal antibodies * Belantamab mafodotin - Anti-BCMA toxin conjugate * CAR-BCMA T cell therapy BCMA: B cell maturing antigen, specific for plasma cells (normal and malignant)