23rd July 2024

Paraproteinaemias

A heterogenous group of conditions caused by clonal proliferation of plasma cells or B-cells associated with production of a monoclonal immunoglobulin (also called a paraprotein or M-protein), found in serum or urine.

Multiple myeloma (MM)

Background of MM

Multiple myeloma is the second most common haematological malignancy and accounts for 1-2% of all diagnosed malignancies. Diagnosis is most frequent between the ages of 65 and 74. It has a slight male predominance. MM is more common in Afro-Caribbeans and less common in Asians.

No clear aetiological factors have been identified. There may be a genetic component.

Common chromosomal aberrations are seen across MM. Hyperdiploidy or translocations involving the immunoglobulin heavy chain (IgH) region at 14q32 are seen in the majority of cases.

Myeloma is classified according to the combination of immunoglobulin (Ig) heavy chain (G, A, D, E or M) and light chain (kappa or lambda) secreted by the malignant cells.

IgG kappa myeloma is the most common subtype. Around 15% of patients exhibit light chain myeloma (Bence-Jones myeloma) where only light chains are secreted. IgM myeloma can occur in MM but is very rare; IgM production is more commonly seen in Waldenström’s macroglobulinaemia.

Diagnostic criteria for MM

Diagnosis is made using the International Myeloma Working Group diagnostic criteria. These criteria serve to differentiate active MM from monoclonal gammopathy of undetermined/unknown significance (MGUS) and smouldering myeloma.

MGUS is an asymptomatic premalignant stage that almost always precedes the development of MM. IgM MGUS is more likely to progress to Waldenström’s macroglobulinaemia, but all other types, if they progress, are likely to progress to MM.

Smouldering myeloma is an intermediate, asymptomatic stage between MGUS and MM, which has a higher chance of progression to MM than MGUS.

Myeloma-defining events (MDE) form part of the diagnostic criteria, and their presence differentiates smouldering myeloma from MM. MDEs include the well-known CRAB criteria, which are evidence of end-organ damage that can be attributed to a plasma cell proliferative disorder:

• C – hyperCalcaemia: 0.25 mmol/L above the normal upper limit or serum calcium >2.75 mmol/L
• R – Renal impairment: serum creatinine >177 µmol/L or creatinine clearance < 40 mL/min
• A – Anaemia: Hb 20 g/L below the lower limit of normal or Hb < 100 g/L
• B – Bony lesions: ≥1 osteolytic lesions on imaging

These are the diagnostic criteria:

* A plasmacytoma is a mass of malignant plasma cells that can occur in bone or soft tissue

Presentation and investigations in MM

MM may be picked up incidentally. It may also present with signs and symptoms from the CRAB criteria.

Symptoms of anaemia are the most common presenting complaint. Anaemia can be from bone marrow failure or from erythropoietin deficiency. Bony pain is also very common. In MM there is osteoclast activation and osteoblast inhibition, leading to osteolytic bone lesions and hypercalcaemia. The lytic lesions may also result in pathological fractures. Renal failure may cause fatigue and generalised weakness. Renal failure can occur in MM due to light chain cast nephropathy (‘myeloma kidney’) or hypercalcaemia. If patients do not secrete light chains, then they are not at risk of developing myeloma kidney. Other signs of renal failure and hypercalcaemia may be present.

Investigations for diagnosis may include:

• Bloods: full blood count, urea and electrolytes, bone profile, serum protein electrophoresis, serum immunoglobulins, serum free light chains
• Blood film: may show rouleaux formation (stacking of red blood cells)
• Urine: urinalysis, urine Bence-Jones protein
• Bone marrow aspirate
• Imaging: whole-body low-dose CT (preferred over skeletal survey to identify lytic lesions), FDG-PET, MRI

Image Source: Wikimedia Commons (2012). Rouleaux, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Rouleaux.jpg#/media/File:Rouleaux.jpg (Accessed: 16 January 2024)

Image Source: Wikimedia Commons (2023). Raindrop skull, Licensed under a creative commons licence. Available for free at: https://radiopaedia.org/articles/raindrop-skull?lang=gb (Accessed: 16 January 2024)

Management and prognosis of MM

MGUS and smouldering myeloma do not require treatment; they are managed with surveillance.

Treatment of MM depends on eligibility for autologous stem cell transplant (SCT). Generally, patients <65 years old with no significant comorbidities are eligible for SCT in MM.

• If SCT eligible, treatment is with induction therapy, which can be chemotherapy based (e.g. vincristine, doxorubicin, dexamethasone) or non-chemotherapy based (e.g. thalidomide and dexamethasone), followed by autologous SCT and maintenance therapy.
• If SCT ineligible, treatment is with induction therapy followed by maintenance therapy.

MM is incurable. Even following remission, relapse normally occurs after 2-5 years.

Prognosis is predicted using a combination of serum beta-2 microglobulin level, serum LDH and presence of high-risk chromosomal abnormalities.

Waldenström’s macroglobulinaemia (WM)

Background of WM

WM is an indolent B-cell lymphoma characterised by bone marrow infiltration of lymphoplasmacytic cells which secrete a monoclonal IgM into blood.

The median age of diagnosis is 70 years, with a higher incidence in males and Caucasians.

The specific aetiology of WM is unknown. A history of IgM MGUS or a first-degree relative with a B-cell lymphoproliferative disorder are the only known risk factors.

Presentation and diagnosis of WM

Some patients may be asymptomatic at presentation. Others may present with the following symptoms:

• Constitutional symptoms: fatigue, weakness, weight loss
• IgM paraproteinaemia: hyperviscosity syndrome (visual disturbance, headache, vertigo, tinnitus, bleeding), peripheral neuropathy (usually sensorimotor, distal, symmetric, slowly progressive, legs>arms), infections (reduced production of other Ig types)
• Tissue infiltration: anaemia, lymphadenopathy, hepatosplenomegaly
• Cryoglobulinaemia (discussed later)

Bone pain and bone lesions are rare in WM compared to MM.

Diagnosis requires blood tests, urine electrophoresis, bone marrow biopsy (with immunophenotyping) and imaging for disease staging. Blood tests include full blood count (anaemia), erythrocyte sedimentation rate (usually very high), serum immunoglobulins, serum protein electrophoresis and serum free light chains.

Management and prognosis of WM

Asymptomatic patients are considered to have smouldering WM and do not require treatment; they should be followed up every 3-6 months.

Symptomatic patients should be treated. WM is incurable, so treatment aims are to reduce symptoms and increase quality of life and survival. There is no standardised first-line therapy. Chemoimmunotherapy is normally used (e.g. bendamustine and rituximab).

Symptomatic hyperviscosity is a medical emergency that requires treatment with plasmapheresis.

Median survival is >10 years with many patients dying of causes unrelated to WM.

Cryoglobulinaemia

Cryoglobulins are Igs that precipitate out at temperatures below 37°C. Cryoglobulinaemia refers to the presence of cryoglobulins in serum.

There are three types:

• Type I: monoclonal Ig production (usually IgM, sometimes IgG). Associated with monoclonal gammopathies.
• Type II: mixed cryoglobulinaemia; monoclonal Ig (usually IgM) forms a complex with polyclonal Igs (usually IgG). Associated with chronic viral infections, especially hepatitis C, autoimmune disorders and lymphoproliferative disorders.
• Type III: mixed cryoglobulinaemia; polyclonal IgM forms a complex with polyclonal IgG. Associated with autoimmune conditions and sometimes chronic viral infections, mainly hepatitis C.

Type I presents with hyperviscosity syndrome and signs of small vessel obstruction (e.g. acrocyanosis, digital ischaemia, skin necrosis).

Mixed cryoglobulinaemia often presents with Meltzer’s triad of purpura, arthralgia and weakness. It can also cause glomerulonephritis and peripheral neuropathy.

Diagnosis is by identification of cryoglobulins in the blood with investigation for underlying precipitants.

Treatment requires management of any underlying conditions. Symptomatic mixed cryoglobulinaemia may be treated with steroids ± cyclophosphamide, depending on severity. Hyperviscosity syndrome requires urgent plasmapheresis.

References

• Laubach JP. Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis [Internet]. Rajkumar SV, Connor RF, editors. UpToDate. 2021 [cited 2021 Dec 22]. Available from: https://www.uptodate.com/contents/multiple-myeloma-clinical-features-laboratory-manifestations-and-diagnosis
• Santo L, Lei MM, Raje N. Multiple myeloma [Internet]. BMJ Best Practice. 2021 [cited 2021 Dec 22]. Available from: https://bestpractice.bmj.com/topics/en-gb/179
• Provan D, Baglin T, Dokal I, de Vos J. Oxford Handbook of Clinical Haematology. 4th ed. Oxford: Oxford University Press; 2015
• International Myeloma Foundation. Types of Myeloma [Internet]. International Myeloma Foundation. 2021 [cited 2021 Dec 23]. Available from: https://www.myeloma.org/types-of-myeloma
• Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV et al. International Myeloma Working Group updated the criteria for the diagnosis of multiple myeloma. The Lancet Oncology. 2014;15(12):e538-548. Available from: doi: 10.1016/S1470-2045(14)70442-5
• Sive J, Cuthill K, Hunter H, Kazmi M, Pratt G, Smith D. Guidelines on the diagnosis, investigation and initial treatment of myeloma: a British Society for Haematology/UK Myeloma Forum Guideline. British Journal of Haematology. 2021;193(2):245-268. Available from: doi: 10.1111/bjh.17410
• Rajkumar SV. Multiple myeloma: Overview of management [Internet]. Kyle RA, Connor RF, editors. UpToDate. 2021 [cited 2021 Dec 22]. Available from: https://www.uptodate.com/contents/multiple-myeloma-overview-of-management
• Palumbo A, Avet-Loiseau H, Olivia S, Lokhorst HM, Goldschmidt H, Rosinol L et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. Journal of Clinical Oncology. 2015;33(26):2863-2869. Available from: doi: 10.1200/JCO.2015.61.2267
• Ansell SM. Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia [Internet]. Rajkumar SV, Connor RF, editors. UpToDate. 2020 [cited 2021 Dec 27]. Available from: https://www.uptodate.com/contents/epidemiology-pathogenesis-clinical-manifestations-and-diagnosis-of-waldenstrom-macroglobulinemia
• Pratt G. Waldenström’s macroglobulinemia [Internet]. BMJ Best Practice. 2021 [cited 2021 Dec 27]. Available from: https://bestpractice.bmj.com/topics/en-gb/897
• Ansell SM. Treatment and prognosis of Waldenström macroglobulinemia [Internet]. Rajkumar SV, Connor RF, editors. UpToDate. 2021 [cited 2021 Dec 27]. Available from: https://www.uptodate.com/contents/treatment-and-prognosis-of-waldenstrom-macroglobulinemia
• Cacoub P. Overview of cryoglobulins and cryoglobulinemia [Internet]. Wener MH, Curtis MR, editors. UpToDate. 2021 [cited 2021 Dec 27]. Available from: https://www.uptodate.com/contents/overview-of-cryoglobulins-and-cryoglobulinemia
• Kaeley GS. Cryoglobulinaemia [Internet]. BMJ Best Practice. 2019 [cited 2021 Dec 27]. Available from: https://bestpractice.bmj.com/topics/en-gb/870