Types of Multiple Myeloma

How Many Types of Multiple Myeloma are There?

Multiple myeloma is not a single disease. There are wide variations of myeloma subtypes including inactive and active types of myeloma, and in active myeloma, non-aggresive and aggressive types of myeloma.

Using specific tests like the FISH analysis, cytogenetics testing and gene expression profiling (through bone marrow aspirates), your type of myeloma can be determined. This information will tell you about the chromosomes and the genes that have gone awry and have allowed the myeloma to grow.

As a patient, we may wonder if having this detailed information really matters. Will it change the way we are treated? Yes. Currently, myeloma specialists typically adjust their treatment based on the specific types. Once a patient better understands their specific myeloma, they can achieve more personalized care.

What are the Different Types of Multiple Myeloma?

Inactive Myeloma Types

Monoclonal Gammopathy of Undetermined Significance (MGUS)

MGUS (monoclonal gammopathy of undetermined significance) is when abnormal plasma cells make an M protein but there are no symptoms. However, the abnormal plasma cells in the bone marrow already have the typical genetic features by FISH analysis and gene expression profiling of active, but non-aggressive myeloma. The risk of progressing to active myeloma is approximately 1% per year. After 20 years of having been diagnosed with MGUS, only 20% will have progressed to myeloma. Because of the “benign” nature of MGUS, these patients are not typically treated unless the myeloma protein causes problems, such as neuropathy, bleeding or heart or kidney problems. Because these patients may progress to myeloma, regular lab tests (every 3 to 6 months) to check for a further increase in the level of M protein or evidence of organ damage typically seen in active myeloma.

Smoldering Myeloma (SMM)

Smoldering myeloma is also asymptomatic and, when compared to MGUS, has a larger M protein in the blood or presence of more myeloma plasma cells in the bone marrow. The levels of these markers are lower than those in active multiple myeloma. Smoldering myeloma also progresses slowly, but in contrast to MGUS, after 5 years 50% of these patients will have progressed to active myeloma. The recommended treatment is watchful observation, patients should be followed very closely. PET-CT scan and MRI are important to exclude the presence of bone disease. Skeletal surveys by regular X-rays are not sufficiently sensitive. Researchers are studying genes from these patients to help define who is most likely to progress to active myeloma and therefore might benefit from early treatment.

High risk smoldering myeloma is classified by the following: 

The new criteria for high-risk smoldering myeloma, as presented at the International Myeloma Society (IMS) 21st Annual Meeting, are centered on specific cytogenetic and clinical markers. These criteria, part of the IMS-International Myeloma Working Group's definition, aim to identify patients at higher risk of poor outcomes. Here are the key points:

1. Del(17p) in ≥ 20% of sorted plasma cells and/or TP53 mutation.
2. Monoallelic del(1p32) along with +1q, or biallelic del(1p32).
3. Translocations such as t(4;14) or t(14;16) that co-occur with +1q and/or del(1p32).
4. High Beta-2 microglobulin (> 5.5 mg/dL) with normal creatinine (< 1.2 mg/dL).

High-risk smoldering myeloma is more likely to progress within a 2-year period, so patients should consider early treatment in the context of a clinical trial.

Active Myeloma Types

Solitary Plasmacytoma

Unlike multiple myeloma, solitary plasmacytoma is only one tumor, usually in a bone. This type of myeloma responds well to treatment, usually radiation and/or surgery. Because patients with solitary plasmacytomas have a higher risk for multiple myeloma, they must be monitored closely with regular checkups. Again, it is critical that these patients have a baseline PET-CT scan and/or MRI to confirm that it is indeed a solitary plasmacytoma. Skeletal surveys by regular X-rays are not sufficiently sensitive.

Multiple Myeloma

Multiple myeloma comes in a variety of forms and is not a single disease. Understanding and properly classifying myeloma is not easy, and requires information about the genetic make-up of the myeloma cells by FISH analysis, cytogenetics and if possible gene expression profiling. In terms of classifying the disease, these are the various “types” of myeloma.

Hyperdiploid vs. Hypodiploid

In general terms, there are two types of myeloma:

• Hyperdiploid- Myeloma cells have more chromosomes than normal. This occurs in about 45% of myeloma patients and is less aggressive.
• Hypodiploid– Myeloma cells have fewer chromosomes than normal. This occurs in about 40% of myeloma patients and is more aggressive.

Healthy plasma cells produce antibodies (also called immunoglobulins [Ig]) that fight infection. These immunoglobulins are made up of heavy and light chains. There are two types of the light chains – kappa or lambda. The heavy chain is defined by five types A, G, M, D and E. In total, there are 10 variations of these immunoglobulins: IgA kappa, IgG kappa, IgM kappa, IgD kappa, IgE kappa, IgA lambda, IgG lambda, IgM lambda, IgD lambda, and IgE lambda.

When myeloma progresses, the myeloma cells start to produce more light chains than heavy chains. This can be measured by the Free Light Chain Assay test on a blood specimen. In general, the higher the free light chains, the more aggressive the disease is. Therefore, the serum free light chain test is a better predictor of outcome than the amount of M-protein in the serum.

What is Light Chain Only Myeloma (LCMM)? 

Light-chain multiple myeloma (LCMM) or light-chain-only multiple myeloma is a specific subtype of multiple myeloma, making up around 15% of all multiple myeloma cases. In light-chain-only myeloma, abnormal plasma cells only produce light-chain proteins (kappa or lambda) instead of both heavy and light chains, leading to unique clinical challenges and manifestations. 

Genetics and Chromosomes

As research has progressed, the detail of the abnormal genes and chromosomes has been studied and 7 disease sub-types have been identified. Approximately 60% of myeloma patients will fall into one of these classifications. In addition to cells having more or fewer chromosomes than a healthy cell, FISH testing and gene array testing can show chromosomal abnormalities, like a deletion of a chromosome or chromosomes that have moved from their proper position (called a translocation.) For example, you will see something like t(14;16), which means that chromosome 14 and 16 have exchanged material of their chromosomes. If a gene or chromosome has been deleted, it will be described as something like this: del(17p13), which is the deletion of the tumor-suppressor gene and is associated with myeloma that responds poorly to treatment.

Genetic information can help patients decide on which treatment protocol to select and whether to be more or less aggressive in their treatment approach.

Research Articles:

• Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, Epstein J, Yaccoby S, Sawyer J, Burington B, Anaissie E, Hollmig K, Pineda-Roman M, Tricot G,van Rhee F, Walker R, Zangari M, Crowley J, Barlogie B, Shaughnessy JD Jr. The molecular classification of Multiple Myeloma. Blood. 2006 Sep 15;108(6):2020-8. Epub 2006 May 25.
• R Fonseca, PL Bergsagel,J Drach,J. Shaughnessy, N Gutierrez,AK Stewart,G Morgan,B Van Ness, M Chesi, S Minvielle, A Neri, B Barlogie, WM Kuehl, P Liebisch, F Davies, S Chen-Kiang, BGM Durie, R Carrasco, Orhan Sezer, Tony Reiman, Linda Pilarski, and H Avet-Loiseau. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review, Leukemia 2009.Leukemia 23, 2210-2221 (December 2009) | doi:10.1038/leu.2009.174.
• Fonseca R, Debes-Marun CS, Picken EB, Dewald G, Bryant S, Winler J, Blood E, Oken M, Santana-Davila R, Gonzales-Paz N, Kyle R, Gertz M, Dispenzieri A, Lacy M, Greipp P. The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma. Blood October 1, 2003 vol. 102 no. 7 2562-2567.
• Smadja NV, Bastard C, Brigaudeau C, Leroux D, Fruchart C. Hypodiploidy is a major prognostic factor in multiple myeloma. Blood October 1, 2001 vol. 98 no. 7 2229-2238.