A tumour of neoplastic type consisting of plasma cells - plasmacytes. When solitary, it is denoted a plasmacytoma, multiple lesions being termed multiple myeloma. It is a tumour of bone marrow origin.
Multiple myeloma is quite lethal, depending on the tumour burden the median survival from diagnosis was classically from 1 to 5 years.
In laboratory research and the biotechnology industry, myeloma cells can be exploited to produce monoclonal antibodies. This is achieved by fusion of a myeloma cell with an immune cell from an animal previously exposed to an antigen. The cell resulting from the fusion is called a hybridoma, which due to its transformed nature is able to replicate beyond the normal lifespan of a plasma cell.
A multiple clonal malignancy. Unknown induction events but it often (50-60%) seems to arise from a B-cell line in a normal germinal centre as a result of a chromosomal translocation that places an oncogene under the control of immunoglobulin enhancers. There is an increased risk in Gaucher disease, petroleum workers and obesity.
The relationship with age-specific incidence is marked and up to >40/100,000 for persons >80 years of age. The median age at diagnosis is 71 years. Median survival after diagnosis doubled from 3 to 6 years between 1995 and 2015. The association with Gaucher disease may be related to lysolipids such as lyso-glucosylceramide or lysophosphatidylcholine stimulating the monoclonal clone.
A known early event in 50% is the inappropriate translocation of oncogenes from partner chromosomes into the immunoglobulin heavy chain switch region (IgH) locus on chromosome 14q32. The five recurring translocation partner oncogenes are:
- Cyclin D1 (11q13)
- Cyclin D3 (6p21)
- Fibroblast growth factor receptor 3 (FGFR3, 4p16)
- c-maf (6q23)
- mafB (20q11)
The remaining 50% lack translocations but have chromosomal duplication (hyperdiploidy). This results in up-regulation of cyclins D1, D2 and D3
The other early event is the loss of part of chromosome 13 at 13q14.3, which presumably codes for a tumour suppressor gene.
These events are often present during the asymptomatic and stable form of the disease presenting as monoclonal gammopathy of unknown significance (MGUS). Active disease might well therefore require subsequent genetic events such as mutation/deletion of p53 or Ras mutations.
Can be detected all but incidentally when a patient presents with vague symptoms. Up to 25% of patients are effectively asymptomatic at time of biochemical/radiological diagnosis. Presentations include pathological fracture, bone pain, renal failure and hypercalcaemia (see Diagnosis section).
- X-ray of bone shows radiolucent appearances - classic pepperpot skull.
- Cause of high ESR
- Renal failure
- High total protein in blood
The exact definition of myeloma depends on the choice of criteria, but most are based on identifying a clonal plasma cell population and determining organ damage or the potential for organ damage based on clinical and biochemical parameters.
The classic Bence Jones demonstration of protein in urine has been superseded by protein electrophoresis, either of serum or urine is used to identify a monoclonal band. Oligoclonal bands can be seen where there is more than one distinct clones. A monoclonal band may be absent, especially with light chain disease, or in non-secretory myeloma.
Skeletal survey and bone marrow examination are also key investigations.
Monoclonal gammopathy of undetermined significance is distinguished from multiple myeloma by the by the level of the paraprotein (depends on choice of criteria) and the presence of clinical/biochemical parameters abbreviated to CRAB:
- Renal failure
- Bone lesions
The IMWG guidelines were updated in 2014 to reflect biomarkers that better predict prognosis and progression, particularly in the heterogenous smouldering myeloma group.
Consensus classification has recently been attempted but there is no accurate predictive classification at this time.
|Classification||Proportion of patients||Features|
|Hyperdiploid||45%||More favorable, IgG-κ, older patients.|
|Non-hyperdiploid||40%||Aggressive, IgA-λ, younger patients|
|Cyclin D translocation||18%|
|t(11;14)(q13;q32)||16%||Upregulation of CCND1, favourable prognosis, bone lesions|
|t(6;14q)(p21;32)||2%||? same as CCND1|
|t(4;14)(p16;q32)||15%||Upregulation of MMSET & FGFR3, unfavourable prognosis with conventional therapy, bone lesions rarer|
|Unclassified (other)||15%||Includes the 7% with plasma cell leukaemia, IgD, IgE, IgM and non-secretory myeloma|
Smouldering multiple myeloma is defined as multiple myeloma with no end organ damage.
Smouldering multiple myeloma does not warrant treatment and has a risk of progession of 10% in the first 5 years after initial diagnosis. 3% a year for the next 5 years and 1% a year there after. The genetic myeloma division into hyperdiploid and non-hyperdiploid subtypes is useful as the later tends to worse prognosis. Age, symptoms at presentation and myeloma genetics (determined by fluorescence in situ hybridization - FISH) are important. Before the latest genetic markers the ISS (International staging system) was the best of many systems. This was based on the associations with prognosis of:
A recent major improvement of long-term survival had been achieved in younger patients but not nearly to this extent in the more common elderly presentation. The advent of novel agents such as thalidomide, has significantly improved the quality of life of the diagnosed elderly.
Has been fairly unsatisfactory until recently. 5-year relative survival increased from 28.8% to 34.7% and 10-year relative survival increased from 11.1% to 17.4% in the decade from 1992 with the major improvement being in younger patients. High-dose melphalan with autologous stem cell transplantation (ASCT) is now the standard of care for patients younger than 65 years. More recently thalidomide has been found to improve outcome in the elderly. Increasingly combination induction regimes like:
containing classic agents combined with one of:
are being used. As of 2010 a MPV regime (melphalan , prednisone and bortezomib) is the most efficacious with however a high incidence of side effects so melphalan, prednisone and thalidomide (MPT) is a very acceptable alternative. However the first phase 3 studies of lenalidomide in combination with dexamethasone suggest this may no longer be the case, with low dose dexamethasone regimes appearing to have greatest over all efficacy.
- Autologous stem cell transplant is also effective.
- Pomalidomide is in development and appears useful in those refractory to lenalidomide.
- The classic induction regimes that tend no longer to be used are:
Useful to treat solitary osseous or extraosseous plasmacytomas.
- BCSH guidelines on tmultiple myeloma -diagnosis & management
- BCSH guidelines on multiple myeloma -symptomatic and supportive care
Rare with poor prognosis. Only 5% of myelomas spread outside bone and most are such with an aggressive course. Spread is reported to be most common to upper airways but can be almost anywhere.
A single isolated plasma cell tumour. See myeloma for treatment.
Plasma cell leukaemia
Plasma cell leukaemia (PCL) is characterised by the presence of >20% circulating plasma cells and/or an absolute level of > 2.0x109/l. It may be primary or secondary to multiple myeloma. See myeloma for treatment.
- ↑ Dib A, Gabrea A, Glebov OK, Bergsagel PL, Kuehl WM. Characterization of MYC translocations in multiple myeloma cell lines. Journal of the National Cancer Institute. Monographs. 2008; (39):25-31.(Link to article – subscription may be required.)
- ↑ Takimoto M, Ogawa K, Kato Y, Saito T, Suzuki T, Irei M, Shibuya Y, Suzuki Y, Kato M, Inoue Y, Takahashi M, Sugimori H, Miura I. Close relation between 14q32/IGH translocations and chromosome 13 abnormalities in multiple myeloma: a high incidence of 11q13/CCND1 and 16q23/MAF. International journal of hematology. 2008 Apr; 87(3):260-5.(Link to article – subscription may be required.)
- ↑ Kirkeleit J, Riise T, Bråtveit M, Moen BE. Increased risk of acute myelogenous leukemia and multiple myeloma in a historical cohort of upstream petroleum workers exposed to crude oil. . 2007 Sep 29.(Epub ahead of print) (Link to article – subscription may be required.)
- ↑ Birmann BM, Giovannucci E, Rosner B, Anderson KC, Colditz GA. Body mass index, physical activity, and risk of multiple myeloma. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2007 Jul; 16(7):1474-8.(Link to article – subscription may be required.)
- ↑ a b Röllig C, Knop S, Bornhäuser M. Multiple myeloma. Lancet. 2014 Dec 22.(Epub ahead of print) (Link to article – subscription may be required.)
- ↑ Nair S, Branagan AR, Liu J, Boddupalli CS, Mistry PK, Dhodapkar MV. Clonal Immunoglobulin against Lysolipids in the Origin of Myeloma. The New England journal of medicine. 2016 Feb 11; 374(6):555-61.(Link to article – subscription may be required.)
- ↑ Micallef J, Dharsee M, Chen J, Ackloo S, Evans K, Qiu L, Chang H. Applying mass spectrometry based proteomic technology to advance the understanding of multiple myeloma. Journal of hematology & oncology. 2010; 3:13.(Epub) (Link to article – subscription may be required.)
- ↑ Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM, Larson DR, Plevak MF, Jelinek DF, Fonseca R, Melton LJ, Rajkumar SV. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. The New England journal of medicine. 2007 Jun 21; 356(25):2582-90.(Link to article – subscription may be required.)
- ↑ Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. British journal of haematology. 2003 Jun; 121(5):749-57.
- ↑ Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV. International uniform response criteria for multiple myeloma. Leukemia. 2006 Sep; 20(9):1467-73.(Link to article – subscription may be required.)
- ↑ Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. The Lancet. Oncology. 2014 Nov; 15(12):e538-48.(Link to article – subscription may be required.)
- ↑ a b c Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart AK, Morgan G, Van Ness B, Chesi M, Minvielle S, Neri A, Barlogie B, Kuehl WM, Liebisch P, Davies F, Chen-Kiang S, Durie BG, Carrasco R, Sezer O, Reiman T, Pilarski L, Avet-Loiseau H. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2009 Dec; 23(12):2210-21.(Link to article – subscription may be required.)
- ↑ Steward AK, Fonseca R. Review of molecular diagnostics in multiple myeloma. Expert review of molecular diagnostics. 2007 Jul; 7(4):453-9.(Link to article – subscription may be required.)
- ↑ Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, Boccadoro M, Child JA, Avet-Loiseau H, Harousseau JL, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J. International staging system for multiple myeloma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005 May 20; 23(15):3412-20.(Link to article – subscription may be required.)
- ↑ Dimopoulos MA, Kastritis E, Christoulas D, Migkou M, Gavriatopoulou M, Gkotzamanidou M, Iakovaki M, Matsouka C, Mparmparoussi D, Roussou M, Efstathiou E, Terpos E. Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities and of previous therapies. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2010 Oct; 24(10):1769-78.(Link to article – subscription may be required.)
- ↑ Brenner H, Gondos A, Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. . 2007 Sep 27.(Epub ahead of print) (Link to article – subscription may be required.)
- ↑ Facon T, Mary JY, Hulin C et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial The Lancet 2007; 370:1209-1218
- ↑ Richardson P, Mitsiades C, Laubach J, Schlossman R, Ghobrial I, Hideshima T, Munshi N, Anderson K. Lenalidomide in multiple myeloma: an evidence-based review of its role in therapy. Core evidence. 2010; 4:215-45.(Epub)