Smouldering myeloma

Smouldering myeloma
Smouldering myeloma
Other names	Smoldering myeloma, Smoldering multiple myeloma, Indolent myeloma or Asymptomatic myeloma
Specialty	Hematology/oncology

Last updated September 02, 2024

Smouldering myeloma is a disease classified as intermediate in a spectrum of step-wise progressive diseases termed plasma cell dyscrasias. In this spectrum of diseases, a clone of plasma cells secreting monoclonal paraprotein (also termed myeloma protein or M protein) causes the relatively benign disease of monoclonal gammopathy of undetermined significance. This clone proliferates and may slowly evolve into more aggressive sub-clones that cause smouldering multiple myeloma. Further and more rapid evolution causes the overtly malignant stage of multiple myeloma and can subsequently lead to the extremely malignant stage of secondary plasma cell leukemia.^[1]^[2]^[3] Thus, some patients with smouldering myeloma progress to multiple myeloma and plasma cell leukemia. Smouldering myeloma, however, is not a malignant disease. It is characterised as a pre-malignant disease that lacks symptoms but is associated with bone marrow biopsy showing the presence of an abnormal number of clonal myeloma cells, blood and/or urine containing a myeloma protein, and a significant risk of developing into a malignant disease.^[2]

Diagnosis

Smouldering myeloma is characterised by:^[4]

Serum paraprotein >30 g/L or urinary monoclonal protein ≥500 mg per 24 h AND/OR
Clonal plasma cells >10% and <60% on bone marrow biopsy AND
No evidence of end organ damage that can be attributed to plasma cell disorder AND
No myeloma-defining event (>60% plasma cells in bone marrow OR Involved/Uninvolved light chain ratio>100)

Treatment

Treatment for multiple myeloma is focused on therapies that decrease the clonal plasma cell population and consequently decrease the signs and symptoms of disease. If the disease is completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow population but no end-organ damage), as in smouldering myeloma, treatment is typically deferred, or restricted to clinical trials.^[5]

They are generally responsive to IL-1β neutralisation.^[6]

Treatment for smoldering multiple myeloma (SMM) has changed significantly in the recent years. The current treatment of SMM depends on whether or not the patient has high or low risk of SMM.

The method to distinguish between high risk and low risk patients come from the MAYO 2008, PETHEMA, and SWOG models. The PETHEMA group characterizes between risk categories using immunoparesis and aberrant plasma cell percentages with high risk patients exhibiting short time to progression towards symptomatic multiple myeloma. The MAYO 2008 model also incorporates parameters such as bone marrow and plasma cell percentage, M-protein levels, and sFLC ratios.

In 2019, the 20/2/20 model emerged from the International Myeloma Foundation (IMF). This model states that if all three of the following are true: the percentage of plasma cells in the bone marrow is 20% or more, M-Protein level is 2g/dL or greater, or the sFLC ratio is greater than 20, then the patient is classified as high risk.^[7]

Patients classified as low risk SMM are cared for by being given active surveillance. Doctors would closely monitor the serum M protein, serum free light chain (FLC) levels, complete blood count, serum calcium, and serum creatinine of the patient every 3 to 4 months for 5 years. If any changes indicative of disease progression is detected, then the patient would be classified as a high risk and will be diagnosed as such. If the patient does not show any signs of change, additional visits after the initial 5 years will separated by 6 months instead.

High risk patients require early intervention to prevent or delay the progression towards symptomatic multiple myeloma and other complications. Lenalidomide or lenalidomide plus dexamethasone (Rd) is a common treatment for high risk SMM. Many clinical trials have shown that a lenalidomide based therapy can significantly lengthen the time before the patient progresses to symptomatic multiple myeloma. The duration and intensity of lenalidomide based therapy may vary based on factors of the patient as well as the response to the treatment. Other treatments include bisphosphonates or monoclonal antibodies. These may be used in selecting high risk patients, specifically, bisphosphonates may be used to reduce the risk of skeletal related events in high risk patients with osteopenia or osteoporosis.

The purpose of using lenalidomide based therapy instead of myeloma like therapy for high risk SMM is based on randomized trials that ultimately show that lenalidomide based therapy has a clear increase in survival rate. The reason as to not immediately go straight to myeloma like therapy is due to the high amount of regulation required. Tests must be made to check if using a certain drug is actually beneficial to the patient before it may be administered, however lenalidomide based therapy can be administered regularly.^[8]

Prognosis

Smouldering myeloma with an increasingly abnormal serum free light chain (FLC) ratio is associated with a higher risk for progression to active multiple myeloma.^[9]

Related Research Articles

<span class="mw-page-title-main">Serum protein electrophoresis</span> Laboratory test

Serum protein electrophoresis is a laboratory test that examines specific proteins in the blood called globulins. The most common indications for a serum protein electrophoresis test are to diagnose or monitor multiple myeloma, a monoclonal gammopathy of uncertain significance (MGUS), or further investigate a discrepancy between a low albumin and a relatively high total protein. Unexplained bone pain, anemia, proteinuria, chronic kidney disease, and hypercalcemia are also signs of multiple myeloma, and indications for SPE. Blood must first be collected, usually into an airtight vial or syringe. Electrophoresis is a laboratory technique in which the blood serum is applied to either an acetate membrane soaked in a liquid buffer, or to a buffered agarose gel matrix, or into liquid in a capillary tube, and exposed to an electric current to separate the serum protein components into five major fractions by size and electrical charge: serum albumin, alpha-1 globulins, alpha-2 globulins, beta 1 and 2 globulins, and gamma globulins.

Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, anemia, renal insufficiency, and infections may occur. Complications may include hypercalcemia and amyloidosis.

POEMS syndrome is a rare paraneoplastic syndrome caused by a clone of aberrant plasma cells. The name POEMS is an acronym for some of the disease's major signs and symptoms, as is PEP.

<span class="mw-page-title-main">Cryoglobulinemia</span> Presence of cold-sensitive antibodies in the blood

Cryoglobulinemia is a medical condition in which the blood contains large amounts of pathological cold sensitive antibodies called cryoglobulins – proteins that become insoluble at reduced temperatures. This should be contrasted with cold agglutinins, which cause agglutination of red blood cells.

Lenalidomide, sold under the brand name Revlimid among others, is a medication used to treat multiple myeloma, smoldering myeloma, and myelodysplastic syndromes (MDS). For multiple myeloma, it is a first line treatment, and is given with dexamethasone. It is taken by mouth.

A precancerous condition is a condition, tumor or lesion involving abnormal cells which are associated with an increased risk of developing into cancer. Clinically, precancerous conditions encompass a variety of abnormal tissues with an increased risk of developing into cancer. Some of the most common precancerous conditions include certain colon polyps, which can progress into colon cancer, monoclonal gammopathy of undetermined significance, which can progress into multiple myeloma or myelodysplastic syndrome. and cervical dysplasia, which can progress into cervical cancer. Bronchial premalignant lesions can progress to squamous cell carcinoma of the lung.

<span class="mw-page-title-main">Monoclonal gammopathy of undetermined significance</span> Medical condition

Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell dyscrasia in which plasma cells or other types of antibody-producing cells secrete a myeloma protein, i.e. an abnormal antibody, into the blood; this abnormal protein is usually found during standard laboratory blood or urine tests. MGUS resembles multiple myeloma and similar diseases, but the levels of antibodies are lower, the number of plasma cells in the bone marrow is lower, and it rarely has symptoms or major problems. However, since MGUS can lead to multiple myeloma, which develops at the rate of about 1.5% a year, or other symptomatic conditions, yearly monitoring is recommended.

Waldenström macroglobulinemia is a type of cancer affecting two types of B cells: lymphoplasmacytoid cells and plasma cells. Both cell types are white blood cells. It is characterized by having high levels of a circulating antibody, immunoglobulin M (IgM), which is made and secreted by the cells involved in the disease. Waldenström macroglobulinemia is an "indolent lymphoma" and a type of lymphoproliferative disease which shares clinical characteristics with the indolent non-Hodgkin lymphomas. It is commonly classified as a form of plasma cell dyscrasia, similar to other plasma cell dyscrasias that, for example, lead to multiple myeloma. Waldenström macroglobulinemia is commonly preceded by two clinically asymptomatic but progressively more pre-malignant phases, IgM monoclonal gammopathy of undetermined significance and smoldering Waldenström macroglobulinemia. The Waldenström macroglobulinemia spectrum of dysplasias differs from other spectrums of plasma cell dyscrasias in that it involves not only aberrant plasma cells but also aberrant lymphoplasmacytoid cells and that it involves IgM while other plasma dyscrasias involve other antibody isoforms.

Plasmacytoma is a plasma cell dyscrasia in which a plasma cell tumour grows within soft tissue or within the axial skeleton.

Monoclonal gammopathy, also known as paraproteinemia, is the presence of excessive amounts of myeloma protein or monoclonal gamma globulin in the blood. It is usually due to an underlying immunoproliferative disorder or hematologic neoplasms, especially multiple myeloma. It is sometimes considered equivalent to plasma cell dyscrasia. The most common form of the disease is monoclonal gammopathy of undetermined significance.

A myeloma protein is an abnormal antibody (immunoglobulin) or a fragment thereof, such as an immunoglobulin light chain, that is produced in excess by an abnormal monoclonal proliferation of plasma cells, typically in multiple myeloma or Monoclonal gammopathy of undetermined significance. Other terms for such a protein are monoclonal protein, M protein, M component, M spike, spike protein, or paraprotein. This proliferation of the myeloma protein has several deleterious effects on the body, including impaired immune function, abnormally high blood viscosity, and kidney damage.

In hematology, plasma cell dyscrasias are a spectrum of progressively more severe monoclonal gammopathies in which a clone or multiple clones of pre-malignant or malignant plasma cells over-produce and secrete into the blood stream a myeloma protein, i.e. an abnormal monoclonal antibody or portion thereof. The exception to this rule is the disorder termed non-secretory multiple myeloma; this disorder is a form of plasma cell dyscrasia in which no myeloma protein is detected in serum or urine of individuals who have clear evidence of an increase in clonal bone marrow plasma cells and/or evidence of clonal plasma cell-mediated tissue injury. Here, a clone of plasma cells refers to group of plasma cells that are abnormal in that they have an identical genetic identity and therefore are descendants of a single genetically distinct ancestor cell.

Plasma cell leukemia (PCL) is a plasma cell dyscrasia, i.e. a disease involving the malignant degeneration of a subtype of white blood cells called plasma cells. It is the terminal stage and most aggressive form of these dyscrasias, constituting 2% to 4% of all cases of plasma cell malignancies. PCL may present as primary plasma cell leukemia, i.e. in patients without prior history of a plasma cell dyscrasia or as secondary plasma cell dyscrasia, i.e. in patients previously diagnosed with a history of its predecessor dyscrasia, multiple myeloma. The two forms of PCL appear to be at least partially distinct from each other. In all cases, however, PCL is an extremely serious, life-threatening, and therapeutically challenging disease.

Free light chains (FLCs) are immunoglobulin light chains that are found in the serum (blood) in an unbound (free) state. In recent decades, measuring the amount of free light chains (FLCs) in the blood has become a practical clinical test. FLC tests can be used to diagnose and monitor diseases like multiple myeloma and amyloidosis.

MDX-1097 is a monoclonal antibody therapy that in 2023 has been assessed in a Phase IIb clinical trial in conjunction with lenalidomide and dexamethasone as a treatment for multiple myeloma, a type of white blood cell cancer. MDX-1097 was originally developed by scientists at Immune System Therapeutics Ltd. In 2015, Haemalogix Ltd acquired the rights to MDX-1097 and are taking it through clinical testing.

<span class="mw-page-title-main">Ixazomib</span> Chemical compound

Ixazomib is a drug for the treatment of multiple myeloma, a type of white blood cell cancer, in combination with other drugs. It is taken by mouth in the form of capsules.

Serum B-cell maturation antigen (sBCMA) is the cleaved form of B-cell maturation antigen (BCMA), found at low levels in the serum of normal patients and generally elevated in patients with multiple myeloma (MM). Changes in sBCMA levels have been found to correlate with a MM patient’s clinical status in response to treatment.

Monoclonal immunoglobulin deposition disease, or MIDD, is a disease characterised by the deposition of monoclonal immunoglobulins on the basement membrane of the kidney. Monoclonal immunoglobulins are produced by monoclonal plasma cells, which are found in a variety of plasma cell dyscrasias. The deposition of monoclonal immunoglobulins on the basement membrane of the kidney causes renal impairment. As well as the kidney, MIDD may also affect the liver, heart, peripheral nerves, lung and skin.

Monoclonal gammopathy of renal significance (MGRS) are a group of kidney disorders that present with kidney damage due to nephrotoxic monoclonal immunoglobulins secreted by clonal plasma cells or B cells. By definition, people with MGRS do not meet criteria for multiple myeloma or other hematologic malignancies. The term MGRS was introduced in 2012 by the International Kidney and Monoclonal Gammopathy Research Group (IKMG). MGRS is associated with monoclonal gammopathy of undetermined significance (MGUS). People with MGUS have a monoclonal gammopathy but does not meet the criteria for the clonal burden nor the presence of end organ damage seen in hematologic malignancies. In a population based study based on the NHANES III health survey; 6% of patients with MGUS were subsequently classified as having MGRS. The prevalence and incidence of MGRS in the general population or in specific populations is not known but it is more prevalent in those over the age of 50 as there is a monoclonal protein (M-protein) present in 3% of those 50 and years older and 5% of those 70 years and older, placing those 50 and older at increased risk of MGRS.

Irene Ghobrial is an American-Egyptian physician who is a professor at the Dana–Farber Cancer Institute and Harvard Medical School, where her research investigates early detection, mechanisms of disease progression and early interception of multiple myeloma. She is interested in why certain patients with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) develop multiple myeloma.

References

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