What is Smouldering Myeloma?

It is nearly impossible to explain smouldering multiple myeloma (SMM) without first talking about its neighbours on the disease spectrum: multiple myeloma and MGUS (Monoclonal Gammopathy of Undetermined Significance).

Multiple myeloma is a cancer of plasma cells, a type of white blood cell, responsible for producing antibodies to protect us from invading pathogens. In myeloma, these plasma cells become abnormal, multiply uncontrollably, and produce a single clone of monoclonal paraprotein (or called M protein). A monoclonal paraprotein is an abnormal antibody made by a single clone of plasma cells. Your body normally makes many types of antibodies to fight off different germs. Sometimes, one group of plasma cells starts copying itself too much and makes large amounts of one single type of antibody. This extra antibody is not useful for fighting infections and is called a monoclonal paraprotein (also known as M protein or M-spike). This M protein can lead to various complications, including high Calcium level, Renal or kidney problems, Anaemia (low red blood cells), Bone damage. These complications are often referred to as the “CRAB” criteria.

MGUS is a condition that can be considered a precursor to myeloma. It is defined by the presence of an abnormal M protein in the blood at a level below 30 g/L, and less than 10% abnormal plasma cells in the bone marrow. Unlike multiple myeloma, MGUS does not cause damage to organs or show CRAB features. MGUS is quite common, and most people with MGUS will not progress to myeloma. However, it does carry a small risk of transformation to myeloma or other plasma cell disorders and lymphoma. Most patients with MGUS do not have any symptoms, so it often goes unnoticed. It is usually found by chance during blood tests done for other health issues.

SMM is an intermediate stage between MGUS and active multiple myeloma. Patients with SMM have higher levels of M protein or a greater percentage of plasma cells in their bone marrow than those with MGUS, but they still do not have the CRAB features of active myeloma. SMM is defined as either serum M protein ≥30 g/dL and/or 10% clonal plasma cells in the bone marrow. SMM has higher chance of transformation into myeloma compared to MGUS. The risk is even higher if they have high M protein of > 20 g/dL, bone marrow plasma cells of > 20%, light chain ratio of > 20, and certain high risk genetic mutations specifically seen in plasma cell disorder.

This diagram shows the spectrum of plasma cell disorders — MGUS, smouldering myeloma, and active myeloma — based on monoclonal protein levels, percentage of clonal plasma cells in the bone marrow, and the presence of end-organ damage or myeloma defining events, aka SLIM CRAB: hypercalcemia, renal (kidney) impairment, anaemia, bone lesions.

How common is SMM?

The exact prevalence of SMM in Singapore is not well-documented. However, data from the Asia–Pacific Myeloma and Related Diseases Registry (APAC MRDR) provide some insights. As of March 2024, among 1,513 patients enrolled from countries including Singapore, approximately 3% (46 patients) were diagnosed with SMM. This suggests that SMM accounts for a small proportion of plasma cell disorders in the region. Globally, a large population-based screening study reported a prevalence of 0.5% for SMM in individuals aged 40 years or older.

How does SMM affect patient?
Patients with SMM (smouldering multiple myeloma) typically do not experience any symptoms or notice changes in their body. Most people discover they have SMM by chance—often after routine blood tests performed for unrelated reasons. These tests may reveal abnormal plasma cells in the bone marrow and the presence of M protein in the blood. While these abnormal cells are detectable, they are not yet causing damage or symptoms. This is why SMM is considered a ‘quiet’ or asymptomatic phase of myeloma.

How does someone get diagnosed with SMM?

SMM is often picked up by chance. Many people are first flagged when routine blood tests show elevated total protein levels. This prompts doctors to do more specific tests to detect and measure the amount of M protein in the blood or urine. At the time of diagnosis, other baseline tests — such as haemoglobin levels, kidney function, and calcium levels — usually come back normal, since the disease has not yet caused organ damage.

A bone marrow biopsy may be needed in some cases. To check for early, silent signs of myeloma, the doctor may recommend advanced imaging like a whole-body CT scan or whole-body MRI scan. These scans can spot early bone changes that are not yet causing symptoms. Detecting these changes early is important because it can allow for an earlier diagnosis of active myeloma, ensuring that treatment is started promptly when needed.

How do we monitor patients with SMM?

For SMM, the risk of transformation to symptomatic myeloma is about 10% per year in the first 5 years after diagnosis. However, the risk then drops to around 3% per year in the next 5 years, and then to 1–2% per year after 10 years.

Since SMM is usually asymptomatic, regular monitoring is essential to detect any progression to active myeloma. This typically includes blood and urine tests to measure M protein, haemoglobin, calcium levels, and kidney function. In some cases, bone marrow biopsies may be needed and repeated to assess the change in the percentage of abnormal plasma cells. Imaging studies, such as MRI or CT scans as described above, may also be used during follow-ups. The frequency of monitoring depends on the individual patient’s risk of progression. Patients are regularly monitored for changes in test and scans, and for development of symptoms which could indicate that the myeloma is becoming active.

In general, patients with smouldering multiple myeloma may remain under active monitoring for several months—or even many years. Since each person’s situation is unique, it is difficult to predict exactly when, or if, SMM will progress to active disease. It is best to discuss individual risks and follow-up plans with the haematologist managing the case.

Do all patients with SMM need treatment?

Not all patients with SMM require treatment. In fact, most are monitored closely without the need for immediate therapy. However, in high-risk patients—those with a greater likelihood of progressing to active myeloma—early treatment with immunomodulatory agents such as lenalidomide may help delay or even prevent the onset of symptomatic disease compared to observation alone. These decisions are made based on a careful risk assessment and are typically guided by the haematologist after a thorough discussion of the potential benefits and risks of treatment.

What is the Emotional Impact of Active Monitoring?

Active monitoring, also known as ‘watch and wait,’ can be emotionally challenging for patients with SMM. Knowing they have a premalignant condition that could potentially progress to cancer may lead to anxiety and uncertainty. 

It is important for patients to maintain a positive outlook and continue living their lives as normally as possible. While it is natural to experience difficult days from time to time, ongoing worry should not be allowed to dominate their thoughts. Some individuals find that complementary approaches—such as mindfulness or relaxation techniques—can be helpful in managing anxiety.

Patients should also report any new or unusual symptoms, such as pain, unexplained fatigue, or weight loss, to their haematology team. While these symptoms do not necessarily indicate disease progression, it is important to have them evaluated as a precaution.

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– Contributed by Dr Lee Chun Tsu