Multiple myeloma is mostly a disease of the elderly. It is a form of haematological cancers that affects the Lymphocytes, and causes abnormal proliferation of plasma cells within the bone marrow, thus replacing the marrow, and is associated with multiple organ dysfunction. This presentation is an introduction to the disease. It however leaves out the specific haematological treatment, because by that point, patient should have been referred to haematology.

1. MULTIPLE MYELOMA
BY DR KD DELE [] DEPT OF INTERNAL MEDICINE

2. INTRODUCTION
• Multiple myeloma is a malignant disease of the plasma cells of
bone marrow that is characterized by
• Clonal expansion of abnormal, proliferating plasma cells in the
bone marrow microenvironment – replacing the marrow,
• Production of monoclonal paraproteinemia [i.e. abnormal Ig,
mainly IgG (60%) or IgA (20%) and rarely IgM and IgD, IgE]
• and/or excretion of the monoclonal paraprotein in the urine
(20% cases)
• and associated organ dysfunction
Plasma cells: a fully differentiated b lymphocyte cell

3. EPIDEMIOLOGY
• Myeloma is a disease of older adults;
• median age at presentation: 65 years.
• <65 years: 37% patients; 65 – 74 years: 26% patients; >75 years:
37% patients
• It is rare under 40 years of age.
• 1% of all malignant disease and 13% of hematologic cancers.
• Commoner in males and in black Africans, less common in Asians.
• In patients presenting at an age under 60 years, 10-year survival is
approximately 30%

4. PATHOPHYSIOLOGY
• Myeloma arises from an asymptomatic premalignant proliferation
of monoclonal plasma cells that are derived from post–germinal-
center B lymphocyte cells.
• Myeloma is thought to evolve most commonly from a monoclonal
gammopathy of undetermined clinical significance (MGUS) that
progresses to smouldering myeloma and, finally, to symptomatic
myeloma
• Several genetic abnormalities that occur in tumour plasma cells
play major roles in the pathogenesis of myeloma

5. OTHER TYPES OF MM
• 1. Light Chain Myeloma: incomplete Ig, i.e light chains antibodies. They collect in
the kidneys
• 2. Non-secretory Myeloma: Tests are negative for paraproteins. More agrresive
myeloma. Need BMAT for diagnosis
• 3. Solitary Plasmacytoma: Cancerous plasma cells forming tumours
• 4. Extramedullary Plasmacytoma: In soft tissues outside the bone marrows eg
throat sinuses, nose & larynx
• 5. Monoclonal Gammopathy of Undetermined Significance (MGUS): precancerous
• 6. Smoldering Multiple Myeloma (SMM): precancerous
• 7. Immunoglobulin D (IgD) Myeloma: 1-2%
• 8. Immunoglobulin E (IgE) Myeloma: rarest

6. PATHOLOGICAL FEATURES
• 1. Bone disease:
• There is dysregulation of bone remodelling which leads to the
typical lesions, usually seen in the spine, skull, long bones and
ribs.
• There is increased osteoclastic activity with no increased
osteoblast formation of bone.

7. PATHOLOGICAL FEATURES
• 2. Bone destruction:
• This often cause
• fractures of long bones or
• vertebral collapse (which can cause spinal cord compression) and
• hypercalcaemia.
• 3.Soft tissue plasmacytomas (tumours)
• This is the usual cause of spinal cord compression in myeloma.

8. PATHOLOGICAL FEATURES
• 4. Bone marrow infiltration with plasma cells:
• This results in
• anaemia,
• neutropenia,
• thrombocytopenia,
• 5. Hyperviscosity
• Very high paraprotein levels (either IgG or IgA) may rarely result in
symptoms of hyperviscosity (it is commoner with IgM)

9. PATHOLOGICAL FEATURES
• 6. Renal impairment:
• owing to a combination of factors –
• deposition of light chains in the renal tubules,
• hypercalcaemia,
• hyperuricaemia,
• use of NSAIDs, and
• deposition of amyloid.

10. PATHOLOGICAL FEATURES
• 7. Recurrent infection
• This is also due to a combination of factors:
• Reduction in the production of normal immunoglobulin (immuneparesis)
• Neutropenia
• Immunosuppressive effects of chemotherapy
• Patients are especially prone to infections from organisms such as
Streptococcus pneumoniae and Haemophilus influenzae. & thus
recurrent respiratory tract/urinary tract.

11. DIFFERENTIAL DIAGNOSES
• Hodgkin’s and non-Hodgkin’s lymphoma
• Acute leukaemia
• Metastatic carcinomas; Myelofibrosis
• Systemic lupus erythematosus
• Disseminated tuberculosis
• Myelodysplastic syndromes
• HIV
• Other causes of pancytopenia

12. CLINICAL SYMPTOMS AND SIGNS
• Patients can be asymptomatic, the diagnosis being suspected by ‘routine’
abnormal blood tests.
• The most common presenting complaints are those related to
• Bony lesion (80%) & Bone pain (58%)
• symptoms of anaemia (73%)
• recurrent infections
• symptoms of renal failure (20–40%) e.g. oliguric or anuric renal failure
• symptoms of hypercalcaemia
• rarely, symptoms of hyperviscosity and
• bleeding due to thrombocytopenia

13. CLINICAL SYMPTOMS AND SIGNS
• Bony Involvement:
• Bone pain is most common in the back, hips, or ribs
• Most commonly backache owing to vertebral involvement (60%)
• May present as a pathologic fracture, especially of the femoral
neck or vertebrae.
• Features of spinal cord compression, with neurological signs, with
peripheral neuropathy, or radiculopathy
• hyperviscosity syndrome:
• mucosal bleeding, vertigo, nausea, visual disturbances,
alterations in mental status.

14. CLINICAL SYMPTOMS AND SIGNS
• Examination findings may include:
• pallor, bone tenderness, and soft tissue masses.
• Patients may have neurologic signs related to neuropathy or spinal
cord compression.
• Others include:
• enlarged tongue (1 amyloidosis), peripheral or autonomic
neuropathy, congestive heart failure, or hepatomegaly.
• Fever occurs mainly with infection.

15. LIFE-THREATENING COMPLICATIONS
• Renal impairment: requires urgent attention and patients may need to
be considered for long-term peritoneal or haemodialysis.
• Hypercalcaemia: treat by rehydration and use of bisphosphonates such
as pamidronate.
• Spinal cord compression due to myeloma: treat with dexamethasone,
followed by radiotherapy to the lesion delineated by a magnetic
resonance imaging (MRI) scan.
• Hyperviscosity due to high circulating levels of paraprotein: may be
corrected by plasmapheresis

16. INVESTIGATIONS: HAEMATOLOGY
• Full blood count.
• Hb: Anaemia is nearly unversal
• WCC: Usually normal, raised in infection. May be low.
• Platelet count: Usually normal. May be low.
• ESR: almost always high to vey high.
• Blood film.
• rouleaux formation: usually marked – as as a consequence of the
paraprotein.(absent rouleaux formation does not exclude MM)
• Plasma cells: rarely seen, if seen, consider leukaemia.

17. INVESTIGATIONS: BLOOD CHEMISTRY
• C-reactive protein: almost always raised.
• Urea and electrolytes: There may be evidence of renal failure
• Calcium: is normal or raised.
• Total protein: is normal or raised.
• Serum albumin: is normal or low. Useful in prognosis.
• Alkaline phosphatase: is usually normal.
• LDH: raised. Useful in prognosis.
• Uric acid: normal or raised.
• Serum β2-microglobulin > 2.5 mg/L – useful in prognosis.

18. PROGNOSIS (MEDIAN SURVIVAL MONTHS)
• Stage 1 – β2M < 3.5 mg/L and s albumin ≥ 35 g/L: 62 months
• Stage 2 – i.e. not stage 1 or 3: 44 months
• Stage 3 – β2M ≥ 5.5 mg/L: 29 months
• ~
• Monoclonal gammopathy of unknown significance (MGUS).
• MGUS describes an isolated finding of a monoclonal paraprotein in
the serum, usually in the elderly;
• 20–30% go on to develop multiple myeloma over a 25-year period.

19. INVESTIGATIONS: IMMUNOLOGY
• Serum protein electrophoresis (PEP): detects paraprotein in
serum. It characteristically shows a monoclonal band.
• Immunofixation electrophoresis (IEE): detects paraprotein in
serum. reveals it to be a monoclonal immunoglobulin.
• Serum free light chain assay: 15% of patients will have no
demonstrable paraprotein in the serum because their myeloma
cells produce only light chains and not intact immunoglobulin
• Urine PEP/IEE: [excretion of light chains paraprotein i.e. Bence
Jones protein – either kappa or lambda].

20. INVESTIGATIONS: IMMUNOLOGY
• 24-hour urine electrophoresis and immunofixation is used for
assessment of light-chain excretion.
• Urine PEP/IEE:
• excretion of light chains paraprotein i.e. Bence Jones protein –
either kappa or lambda].

21. INVESTIGATIONS: BMAT
• Bone marrow aspirate or trephine:
• Shows characteristic infiltration by plasma cells. There is
replacement of the medullary cavity by abnormal plasma cells
• Amyloid may be found.

22. INVESTIGATIONS: IMAGING
• Bone radiographs are important in establishing the diagnosis of myeloma
• Skeletal survey:
• this may show characteristic lytic lesions, most easily seen the axial
skeleton: skull, spine, proximal long bones, and ribs
• Generalized osteoporosis
• CT, MRI and PET scan: better quality than plain radiographs
• are used in plasmacytomas (bone or soft tissue deposits).
• MRI spine is useful if there is back pain:
• may show imminent compression/collapse.

23. • Pathologival
fracture
• Osteoporosis
• Lytic lesion

24. • Multiple “punched-out”
lytic lesions are seen
throughout theskull/
calvarium.
• A large lytic lesion at
the vertex disrupts
both the inner and
outer table.

25. • Spinal cord
compression.
• This patient with
multiple myeloma
presented with rapidly
deteriorating lower
limb weakness.
• An MRI whole spine was
performed.

26. • BMAT
• an increase in bone
marrow plasma
cells.

27. DIAGNOSIS
• The Hallmark of Diagnosis
• Two out of three diagnostic features should be present:
• paraproteinemia (serum) or Bence Jones protein (urine)
• radiological evidence of lytic bone lesions
• an increase in bone marrow plasma cells.
• For symptomatic myeloma, evidence of end organ failure should also
be present, i.e. anaemia, lytic lesions, renal impairment,
hypercalcaemia, recurrent infections.

28. TREATMENT
• Myeloma remains incurable.
• Therapy is aimed at treatment of specific complications,
prevention of these and prolongation of overall survival.
• Complete remissions are rare.
• 2 components of treatment:
• good supportive and symptomatic care and
• chemotherapy

29. SUPPORTIVE THERAPY
• Anaemia
• Should be corrected;
• Blood transfusion may be required.
• Erythropoietin often helps.
• Transfusion should be undertaken cautiously in patients with
hyperviscosity.
• Infection
• Shouldd be treated promptly with antibiotics.
• Give yearly flu vaccinations.

30. SUPPORTIVE THERAPY
• Bone pain
• can be helped most quickly by radiotherapy and systemic
chemotherapy or high-dose dexamethasone.
• NSAIDs are usually avoided because of the risk of renal failure.
• Bisphosphonates, e.g. zoledronate, which inhibit osteoclast
activity, reduce progression of bone disease.

31. SUPPORTIVE THERAPY
• Pathological fractures
• may also be prevented
• by prompt orthopaedic surgery (kyphoplasty) with pinning of
lytic bone lesions seen on the skeletal survey.
• Kyphoplasty and vertebroplasty may be useful in treating
vertebral fractures.

32. CHEMOTHERAPY
• Refer haematology

33. FURTHER MGT
• When to Refer
• All patients with multiple myeloma should be referred to a
hematologist or an oncologist.
• When to Admit
• Hospitalization is indicated for
• treatment of acute kidney failure, hypercalcemia, infections
etc
• suspicion of spinal cord compression,
• chemotherapy regimens,
• for hematopoietic stem cell transplantation.

34. REFERENCES
• Damon E et al, (2013). Blood Disorders. Ch 13, Current Medical
Diagnosis & Treatment 52nd Ed, MCGraw Hill: New York.
• Kumar P. & Clark M. (Ed). 2009. Ch 9, Malignant disease. Clinical
Medicine. 7th ed, Elsevier Limited: Edinburg
• Palumbo A, & Anderson K., 2011. Multiple Myeloma. N Engl J Med
364;11 March 17, 2011