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Multiple myeloma: From diagnosis to treatment

Article in Australian Family Physician · October 2013

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 Diagnostic challenges

Multiple myeloma: from

Renee Eslick
Dipti Talaulikar
diagnosis to treatment
Background Multiple myeloma (MM), also known as symptomatic
Multiple myeloma is characterised by the proliferation of plasma cell myeloma, is a plasma cell malignancy. It is
malignant plasma cells within the bone marrow, which characterised by a clonal population of bone marrow
produce an abnormal monoclonal paraprotein and evidence of plasma cells which secrete a monoclonal paraprotein or an
end organ damage. immunoglobulin free light chain (FLC) (Figure 1A, B). It may
Objective present with myriad complications including anaemia,
Multiple myeloma can pose a diagnostic challenge and this hypercalcaemia, renal failure, recurrent infections or
article highlights issues in diagnosis and provides an overview bony lytic lesions and can therefore present a diagnostic
of management. challenge for the general practitioner. Distinguishing
Discussion symptomatic myeloma, which typically requires treatment,
Multiple myeloma can present with a wide constellation from precursor lesions such as monoclonal gammopathy
of symptoms including hypercalcaemia, anaemia, renal of undetermined significance (MGUS) or smouldering
impairment and/or bony pain. A combination of these myeloma can also be difficult.
symptoms, particularly if unexpected or unexplained, should
prompt diagnostic evaluation for myeloma. Work up of MGUS and smouldering myeloma are asymptomatic with no evidence
plasma cell disorders involves establishing the presence of of end organ damage. Monoclonal gammopathy of undetermined
a monoclonal paraprotein, baseline bloods and radiological significance is defined as a serum paraprotein of <30 g/L with a
investigations. Haematology referral is required for bone
marrow plasma cell infiltrate of less than 10%. Smouldering multiple
marrow biopsy and ongoing management. Newer treatments
myeloma is typified by a serum paraprotein of >30 g/L or a bone
such as the immunomodulators thalidomide or lenalidomide,
marrow plasmacytosis of >10% (Table 1).
or the proteasome inhibitor bortezomib, administered
in combination with steroids and occasionally cytotoxic
agents have improved outcomes in patients with myeloma.
Autologous stem cell transplant is offered to younger
patients with few comorbidities. Some patients are offered
maintenance therapy with thalidomide or lenalidomide.

Keywords
multiple myeloma; diagnosis, differential; monoclonal
gammopathy of undetermined significance
Figure 1A. Bone marrow aspirate showing increased
numbers of plasma cells, including large and immature
forms (arrows)

Figure 1B. Trephine showing infiltration with malignant

plasma cells

684 REPRINTED FROM AUSTRALIAN FAMILY PHYSICIAN VOL. 42, NO. 10, OCTOBER 2013
 PTH related peptide assays to exclude paraneoplastic hypercalcaemia.
Table 1. When should a diagnosis of myeloma
If PTH levels are appropriately suppressed, an alternative explanation
be considered?
such as myeloma must be considered.
Finding When to consider myeloma Renal impairment occurs in 20–40% of newly diagnosed patients with
Anaemia Vitamin B12, folate and iron studies myeloma, and is typically due to light chain deposition within the distal
(normocytic or normal
macrocytic) and collecting renal tubules or hypercalcaemia.4 It is most commonly
No history of blood loss
No haemolysis detected as an asymptomatic elevation in serum creatinine, but patients
No clear alternative explanation such may rarely present with oliguria or uraemia.
as renal impairment or anaemia of Bony pain is a relatively common symptom, particularly back pain,
chronic disease occurring in up to 58% of patients. Lytic lesions are detectable in almost
Hypercalcaemia Parathyroid hormone appropriately 80% of patients at diagnosis.5 Those with more advanced disease may
suppressed
present with a pathological fracture from minimal trauma (Figure 2).
Vitamin D normal
No history of malignancy, sarcoidosis A skeletal survey, or whole body X-ray survey, is typically employed to
or use of medications such as detect osteolytic lesions. Magnetic resonance imaging (MRI) short-tau
thiazides inversion recovery (STIR) is a more sensitive investigation, and may be
Renal No clear explanation including pre- used to identify lytic lesions in suspicious cases when the skeletal survey
impairment renal causes, primary renal disorders fails to yield a diagnosis.6 In regions where MRI is unavailable, computed
or obstructive conditions
tomography (CT) may have a role in further investigating suspicious, but
Bony pain/ Evidence of bony lesions on imaging
fractures non-diagnostic, bony lesions seen on plain film.
Crush fractures in a young patient
Pathological fractures in unusual sites Less conventional presentations with myeloma include recurrent
bacterial infections (defined as >2 episodes in 12 months), often due to an
Monoclonal Usually required to confirm a
paraprotein diagnosis of multiple myeloma associated hypogammaglobulinaemia, or symptomatic hyperviscosity with
A small proportion of cases may be confusion, visual changes, headaches and vertigo.
non-secretory with undetectable
paraprotein Smouldering myeloma and MGUS
By definition, patients with MGUS and smouldering multiple myeloma
How can multiple myeloma and MGUS
are asymptomatic. The condition may become apparent when
present?
routine blood tests reveal an elevated total protein and globulin,
Multiple myeloma and subsequent serum electrophoresis demonstrates a monoclonal
The clinical presentation of multiple myeloma can be extremely varied. paraprotein. These patients may ultimately progress to symptomatic
The classical complications are often abbreviated into the acronym myeloma and require careful monitoring.
‘CRAB’: consisting of hypercalcaemia, renal impairment, anaemia Smouldering multiple myeloma requires closer follow up because of a
and bony lesions. A combination of these symptoms should heighten higher risk of progression (10% per year compared to 1% per year).7
diagnostic suspicion for myeloma.
Anaemia is found in approximately 70% of those with newly What investigations are performed to
diagnosed myeloma.1 Patients with significant anaemia may present with make a diagnosis of multiple myeloma?
fatigue, dyspnoea on exertion or angina. Alternatively, an asymptomatic, Evaluating a patient with suspected multiple myeloma involves
but persistent, anaemia may be detected on routine bloods. The anaemia establishing evidence of a monoclonal paraprotein with serum
of multiple myeloma is typically normochromic and normocytic, but mild
macrocytosis can also be seen. Routine haematinics are normal and
rouleaux may be noted on the blood film.
Hypercalcaemia is a less frequent manifestation of myeloma at
diagnosis, occurring in approximately 13% of patients.2 The serum
calcium level should always be interpreted after correction for albumin.
Symptomatic hypercalcaemia may present in a dramatic fashion with
confusion, disorientation, muscle weakness, constipation, anorexia,
polyuria and polydipsia. Profound elevations in serum calcium can
rarely lead to coma or cardiac arrhythmia.3 Alternative aetiologies
should be excluded with a laboratory assay for intact parathyroid Figure 2. Thoracic spine x-ray demonstrating multiple
wedge compression insufficiency fractures typical of
hormone (PTH), which should be suppressed in response to the
myeloma
hypercalcaemia, and vitamin D levels. Some laboratories also offer

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 FOCUS Multiple myeloma: from diagnosis to treatment

electrophoresis (EPG) and immunofixation, together with an FLC analysis. What are the management options in
Serum EPG establishes the presence of a monoclonal band, while myeloma?
immunofixation increases diagnostic sensitivity to 93% and determines
the precise nature of the paraprotein, for example, if it belongs to the IgA
Symptomatic myeloma
or IgG class and whether it involves the kappa or lambda light chains. Symptomatic myeloma usually requires immediate treatment (Figure 3).
IgM multiple myeloma is a very rare entity and the presence of an IgM For those younger than 65 years of age, or those aged 65–70 with few
paraprotein should raise suspicion of the related disease Waldenström’s comorbidities, autologous stem cell transplantation is the standard
macroglobulinaemia/lymphoplasmacytic lymphoma. A serum FLC analysis
Table 2. Relevant investigations in myeloma12
must always be requested, as a small percentage of patients do not have
measurable disease on serum EPG and immunofixation and would be Baseline investigations by Investigations by
otherwise missed. The combination of these three tests has a diagnostic GP haematologist
sensitivity of 97–98%.8 Two percent of patients have true non-secretory Haematology • Bone marrow aspirate
disease that is undetectable by any of these methods.9 The International • Full blood count and blood and trephine, including
film cytogenetic analysis/
Myeloma Working Group suggests the FLC assay can replace the FISH for common
Biochemistry
traditional 24-hour urine protein electrophoresis and immunofixation as translocations,
• Creatinine, urea and
part of a diagnostic screen10; but these tests are still recommended once immunohistochemistry
electrolytes
and flow cytometry
the diagnosis of multiple myeloma has been established. • Liver function tests,
• Viral serology
Full blood count and film, electrolytes including urea and creatinine, calcium, magnesium,
phosphate, urate ß2 • Transthoracic
calcium, magnesium and phosphate analysis should always be performed microglobulin echocardiography or
to detect evidence of end-organ disease. For prognostication purposes, gated heart pool scan
• Lactate dehydrogenase
(if indicated)
serum β2-microglobulin and albumin should also be assessed, in addition (LDH)
• MRI STIR (if indicated)
to serum LDH. Imaging to detect bony lesions, typically in the form of a • Serum electrophoresis and
immunofixation
skeletal survey, is mandatory. A referral to a haematologist should be
• Serum free light chain
made in order to obtain a bone marrow aspirate and trephine, and to analysis
guide further management (Table 2). • 24-hour urine protein and
electrophoresis studies
Diagnostic criteria Imaging
Diagnosis of multiple myeloma is based on the International Myeloma • Skeletal survey (whole
body X-rays)
Working Group guidelines (Table 3).10 The diagnosis rests on the presence
of a monoclonal paraprotein together with marrow plasmacytosis and
myeloma-related end-organ damage. These are typically the ‘CRAB’
Table 3. Diagnostic criteria for multiple
symptoms described, but recurrent bacterial infections (>2 a year), myeloma10
hyperviscosity symptoms and features of amyloidosis also qualify.10
Monoclonal Smouldering Multiple
Are there features that help determine gammopathy myeloma myeloma
of uncertain
prognosis? significance
Prognosis is commonly evaluated using the International Prognostic Serum monoclonal Serum Monoclonal
Index, which divides patients into three stages. Stage I disease, protein <30g/L monoclonal protein in
with a median survival of 62 months, is defined as those with a protein ≥30g/L serum and/or
urine
β2-microglobulin of <3.5mg/L and a serum albumin above 35g/L.
Stage III disease, median survival 29 months, includes those with a Bone marrow Bone marrow Bone marrow
clonal plasma cells monoclonal clonal plasma
β2-microglobulin above 5.5mg/L. Stage II disease, for patients who <10% plasma cells cells or
do not fulfil the criteria for the other stages, has a median survival ≥10% biopsy proven
of 44 months.11 There are a number of additional prognostic markers plasmacytoma
used by haematologists, including cytogenetics/fluorescence in situ No evidence No myeloma- Myeloma-
of other B cell related organ related organ
hybridisation (FISH) and the plasma cell labelling index, some of which
lymphoproliferative or tissue or tissue
are used more commonly than others. disorders impairment impairment
In MGUS, the type and quantity of paraprotein and the presence of No myeloma-
abnormal serum FLCs can determine the risk of transformation to overt related organ or
multiple myeloma. These parameters are used to help determine the tissue impairment
frequency of monitoring.

686 REPRINTED FROM AUSTRALIAN FAMILY PHYSICIAN VOL. 42, NO. 10, OCTOBER 2013
 Multiple myeloma: from diagnosis to treatment FOCUS

of care. Patients typically receive 3–6 cycles of induction treatment, presented to the emergency department four weeks later
aiming to achieve a complete or near complete response, prior to with ongoing back pain, and was prescribed additional
analgesia and discharged. He re-presented to the
receiving their transplant. There have been significant advances in
emergency department within a week due to uncontrolled
the choice of induction agents and several new agents that have
pain, and blood tests were taken for the first time. These
improved responses in multiple myeloma are now available. The best
revealed anaemia with a haemoglobin of 92 g/L (135–180),
results appear to be achieved with a combination of steroids, cytotoxic a corrected calcium of 3.17 mmol/L (2.1–2.55), a creatinine
chemotherapy (such as cyclophosphamide or doxorubicin), and a of 256 µmol/L (60–110) and an eGFR of 24 ml/min/1.73 m2.
novel immunomodulatory agent (eg. thalidomide or lenalidomide) or PTH was appropriately suppressed at <0.5 pmol/L (1.6–7.2).
proteasome inhibitor (eg. bortezomib).12 In addition, he had a raised total protein of 122 g/L (60–80)
The choice of novel agent is often determined by comorbidities with globulins of 88 g/L (10–42). A serum electrophoresis
and side effect profile; bortezomib is preferred in the setting of renal was subsequently requested, showing an IgAK monoclonal
impairment or advanced disease, while lenalidomide is preferred band, and bone marrow biopsy confirmed a diagnosis of
in the setting of peripheral neuropathy. Following transplant, myeloma.
patients are often offered maintenance thalidomide, with or
without prednisone, for approximately 12 months. Despite a clear Conclusion
improvement in progression-free survival, this strategy may be poorly Multiple myeloma can present a difficult diagnostic issue, as there
tolerated due to medication side effects and adversely impact on are a wide variety of presenting symptoms. Suspicion for myeloma
patient quality of life.13 Lenalidomide maintenance also appears
to prolong progression-free and event-free survival14 at a cost of
increased toxicity and second malignancies,15 but is not subsidised New
diagnosis
under the Pharmaceutical Benefits Scheme (PBS) unless patients are
multiple
intolerant to, or have disease progression on, thalidomide. myeloma
Those ineligible for transplant may be treated with a combination of
steroids, a cytotoxic agent (such as cyclophosphamide) and thalidomide
or bortezomib. The role of maintenance therapy following induction Transplant
eligible?
treatment remains unclear in this group.12
Bisphosphonates are a critical adjunctive therapy employed in YES NO
symptomatic myeloma, and offer a clear reduction in pathological
vertebral fractures, pain and other skeletal events. Intravenous monthly Induction regimen, Combination
zoledronic acid has also been reported to improve overall survival.16 typically using therapy with
Potential side effects include hypocalcemia, renal dysfunction and combination therapy choice of novel
osteonecrosis of the jaw (ONJ), which may present with localised pain, or traditional
swelling or exposed bone. Patients should have all necessary dental agents
Disease assessment:
work completed prior to commencing bisphosphonates to minimise the
at least partial
risk of ONJ. response achieved
Smouldering myeloma and MGUS
YES NO
Treatment for those with MGUS and smouldering myeloma consists
of watchful waiting, with serial monitoring of the paraprotein and Autologous Salvage
No response
frequent assessment for the development of myeloma-related organ transplant induction
achieved
or tissue impairment. Australian guidelines suggest monitoring of regimen,
MGUS occur 3–12 monthly, depending on the individual patient including
novel agents
risk.12

Case study Salvage

Consider
At least therapy
Matt, 44 years of age, presented to his general practitioner maintenance
partial with new/
with a two-week history of sudden onset lower back therapy with
response alternative
pain. X-ray revealed a thoracic vertebral crush fracture, novel agent
achieved agents
and he was prescribed analgesia. He was previously well
with no significant medical history, including no history Figure 3. Treatment flow chart for newly diagnosed
of corticosteroid use, and denied a history of trauma. He multiple myeloma

REPRINTED FROM AUSTRALIAN FAMILY PHYSICIAN VOL. 42, NO. 10, OCTOBER 2013 687
 FOCUS Multiple myeloma: from diagnosis to treatment

should be raised when a patient presents with a constellation of Cancer Institute of Canada Clinical Trials Group Myeloma 10 Trial. Blood
2013;121:1517–23.
unexplained symptoms, such as an ‘osteoporotic’ crush fracture or bony 14. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance
pain in a young person, hypercalcaemia with a normal PTH, anaemia after stem-cell transplantation for multiple myeloma. N Eng J Med
2012;366:1782–91.
with normal haematinics, and/or renal impairment without a history
15. McCarthy PL, Owzar K, Hofmeister CC. Lenalidomide after stem-cell trans-
of diabetes or autoimmune disease. Establishing the diagnosis rests plantation for multiple myeloma. N Engl J Med 2012;366:1770–81.
on identifying a monoclonal paraprotein in the serum and confirming 16. Mhaskar R, Redzepovic J, Wheatley K, et al. Bisphosphonates in mul-
tiple myeloma: a network meta-analysis. Cochrane DatabaseSyst Rev
the presence of myeloma-related organ or tissue injury, followed 2012;5:CD003188
by haematology referral to establish evidence of bone marrow
plasmacytosis, and for future management. With the introduction of
novel immunomodulatory agents and proteasome inhibitors, newly
diagnosed patients are enjoying a longer life expectancy than their
historical peers. However, the role of the general practitioner is still
crucial in helping to make an early diagnosis, allowing patients to be
identified and treated without potentially harmful delays.

Authors
Renee Eslick BMed, Haematology Advanced Trainee, Department of
Haematology, Canberra Hospital, Canberra, Australian Capital Territory.
[email protected]
Dipti Talaulikar MBBS, PhD, FRACP, FRACPA, Grad Cert HE,
Haematology Department of Haematology Staff Specialist, Canberra
Hospital, Canberra, ACT. [email protected]
Competing interests: None.
Provenance and peer review: Commissioned; externally peer reviewed.

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