Myeloma: recognize active disease before damage

A 67-year-old seamstress comes to the primary care unit with low back pain for 4 months, which worsens at night and does not improve with common painkillers. She feels tired. The blood count shows hemoglobin of 10.8 g/dL, with the laboratory lower limit at 12; creatinine is 1.3 mg/dL and calcium is 10.2 mg/dL. Protein electrophoresis shows a monoclonal peak of 2.4 g/dL, IgG kappa. The spine X-ray was described as osteopenia with degenerative changes. The scene is fictional and was written for teaching.

This text uses the case as a clinical reasoning scenario for students and health professionals. The topic is recognizing active myeloma before it causes serious damage, using the criteria of the International Myeloma Working Group, the IMWG, revised in 2014. The focus is diagnosis: separating monoclonal gammopathy of undetermined significance, smoldering myeloma and myeloma that needs treatment. It does not discuss treatment or the integrated care of already diagnosed myeloma, topics of other texts in the series. If you play the case of the day on NEXO, you will recognize the challenge: the clues look common, and each one has a more frequent explanation.

Key points

• Persistent bone pain, anemia without a clear cause, kidney injury and high calcium call for thinking about myeloma.
• Smoldering myeloma has monoclonal protein of at least 3 g/dL or 10 to 59 percent clonal plasma cells in the marrow, without a myeloma-defining event.
• The 2014 revision added three biomarkers to the CRAB criteria: plasma cells of 60 percent or more, free light chain ratio of 100 or more and more than 1 focal lesion on MRI.
• Plain X-ray misses many lesions; low-dose whole-body CT, PET with CT or MRI are preferred.
• The 2/20/20 model estimates the risk of progression of smoldering myeloma at 2 years.

Why this is a reasoning scenario

Low back pain is one of the most common complaints in primary care, and mild anemia at the seamstress's age has many causes. A review on delayed diagnosis of myeloma recalls that bone or low back pain is often attributed to arthrosis or osteoporosis and not taken seriously, which delays diagnosis and increases morbidity and mortality (Zorlu et al., 2025). The post on signs, symptoms and history helps value the pain that worsens at night and does not go away.

The same review points out that monoclonal gammopathy affects about 3 percent of people over 50 and smoldering myeloma, 0.5 to 1 percent, while hypertension and diabetes are much more common in the same age range (Zorlu et al., 2025). Therefore, symptoms are often attributed to frequent diseases, and referral to the hematologist takes time (Zorlu et al., 2025). The post on clinical decision making helps decide when one more test is worth it.

What the scene teaches

The scene trains six habits. The first is to put together common clues that, added up, stop being common. The second is to know the criteria for organ damage. The third is to know that a normal X-ray does not rule out bone lesion. The fourth is to know the three biomarkers from the 2014 revision. The fifth is to estimate the risk of smoldering myeloma. The sixth is to refer without delay.

What is not at stake

The text does not discuss treatment regimens, transplant, cell therapy or kidney and bone care in already treated myeloma. The post on diagnostic uncertainty helps when tests sit at the limit of the criteria.

The clues that arrive before the diagnosis

The warning signs

The review on delayed diagnosis proposes signs that, together, should lead to investigation (Zorlu et al., 2025). They are in the list below.

• Persistent bone or low back pain, especially without response to painkillers.
• Normocytic normochromic anemia with hemoglobin below 10 g/dL and without a clear cause.
• Very high erythrocyte sedimentation rate, above 60 mm/h.
• Calcium above 11 mg/dL.
• Filtration rate below 60 mL/min without another cause, or unexplained tiredness and weight loss.

With 2 or more of these signs, the review suggests ordering serum protein electrophoresis, free light chains and immunofixation (Zorlu et al., 2025). The seamstress has persistent pain, anemia and a monoclonal spike; it remains to be seen whether there is organ damage caused by the clone.

Attributing it to the clone

Not every anemia or kidney injury in a patient with monoclonal protein comes from myeloma. In a series of smoldering myeloma, the few patients with hemoglobin below 10 g/dL had other causes, such as chronic kidney disease, myelodysplasia and nutritional deficiency, and those with high calcium had sarcoidosis or hyperparathyroidism (Lakshman et al., 2018). The criteria require that the damage be attributable to the proliferation of clonal plasma cells (Abdallah et al., 2024). The post on differential diagnosis helps avoid attributing everything to the most striking finding.

Monoclonal gammopathy, smoldering myeloma and active myeloma

Monoclonal gammopathy of undetermined significance

Almost every myeloma arises from a symptom-free phase called monoclonal gammopathy of undetermined significance (Zorlu et al., 2025). In a cohort of 1384 people followed for a median of 34.1 years, progression in IgM gammopathy was 2 percent per year in the first 10 years and 1 percent per year afterwards; in non-IgM gammopathy, the risk did not decrease with follow-up time (Kyle et al., 2018). The initial level of the monoclonal protein and the free light chain ratio were the most important risk factors (Kyle et al., 2018).

The IMWG consensus on gammopathy recommends repeating electrophoresis 3 to 6 months after the finding, to rule out myeloma or macroglobulinemia, because the monoclonal protein is usually found by chance (Kyle et al., 2010). In low-risk gammopathy, with protein below 15 g/L, IgG type and a normal light chain ratio, bone marrow biopsy and skeletal survey are not routine if the clinical assessment and basic tests are normal (Kyle et al., 2010).

Gammopathy is also not harmless for survival. In the same cohort, median survival was 8.1 years, against 12.4 years expected for people of the same age and sex, and most deaths came from cardiovascular and cerebrovascular diseases and other cancers (Kyle et al., 2018). This is a reminder that following gammopathy also means caring for the rest of the person's health.

Smoldering myeloma

Smoldering myeloma is defined by serum monoclonal protein of 3 g/dL or more, urinary monoclonal protein of 500 mg in 24 hours or more, or 10 percent or more clonal plasma cells in the marrow, without the SLiM-CRAB criteria (Abdallah et al., 2024). In Iceland, in a population screening with bone marrow biopsy, prevalence was 0.53 percent in people aged 40 or older and 1.59 percent above 80 (Thorsteinsdóttir et al., 2023). The average risk of progression is about 10 percent per year in the first 5 years (Thorsteinsdóttir et al., 2023). The 2/20/20 model then describes 3 percent per year in the following 5 years and 1 percent per year after 10 years (Mateos et al., 2020). Prevalence was higher in men, 0.67 percent, than in women, 0.39 percent (Thorsteinsdóttir et al., 2023).

Active myeloma

Active myeloma is the one with at least one myeloma-defining event, whether CRAB-type organ damage or one of the three biomarkers from the 2014 revision (Abdallah et al., 2024). This is the diagnosis that indicates treatment. The central question of the scene is whether the seamstress has gammopathy, smoldering myeloma or active myeloma.

The SLiM-CRAB criteria

Why the 2014 revision changed the criteria

Before 2014, the diagnosis of myeloma required organ damage: high calcium, kidney dysfunction, anemia or bone lesions (Lakshman et al., 2018). Studies showed that patients with 60 percent or more plasma cells, more than 1 focal lesion on MRI or a free light chain ratio of 100 or more had about an 80 percent risk of progression in 2 years (Lakshman et al., 2018). Since much of the morbidity of myeloma comes from organ damage, the 2014 revision began classifying these patients, about 10 percent of smoldering myeloma cases, as myeloma that needs treatment (Lakshman et al., 2018).

The criteria

The table summarizes the myeloma-defining events, with the thresholds described in the open publications that apply the criteria (Abdallah et al., 2024).

Criterion	Threshold	Source
S, clonal plasma cells in the marrow	60 percent or more	(Abdallah et al., 2024)
Li, free light chains	Involved to uninvolved ratio of 100 or more, with the involved chain above 100 mg/L	(Abdallah et al., 2024)
M, MRI	More than 1 focal lesion in bone or marrow, larger than 5 mm	(Abdallah et al., 2024)
C, calcium	Serum calcium above 11 mg/dL	(Abdallah et al., 2024)
R, kidney	Serum creatinine above 2 mg/dL	(Abdallah et al., 2024)
A, anemia	Hemoglobin below 10 g/dL or more than 2 g/dL below the lower limit of normal	(Abdallah et al., 2024)
B, bone	1 or more osteolytic lesions of 5 mm or more on radiography, MRI, CT or PET with CT	(Abdallah et al., 2024)

Applying the table, the seamstress still does not meet C, R or A: calcium is 10.2 mg/dL, creatinine is 1.3 mg/dL and hemoglobin is 1.2 g/dL below the lower limit. The marrow, the free light chains and an adequate image of the skeleton are missing. The post about diagnostic pause helps avoid closing the case as gammopathy just because the basic tests are borderline.

The image that defines the bone

Radiography is not enough

Osteolytic lesions are a hallmark of myeloma and appear in up to 80 percent of patients at diagnosis, especially in the spine and proximal long bones (Rasch et al., 2020). According to the 2014 revision, 1 or more lytic lesions of 5 mm or more on CT, low-dose CT or PET with CT meet the bone criterion, even if they do not appear on radiography (Rasch et al., 2020). Focal uptake on PET alone is not enough; bone destruction must be visible on the CT portion (Rasch et al., 2020).

A review of low-dose whole-body CT notes that skeletal radiography has low accuracy, with 30 to 70 percent false negatives, and should only be used if it is the only option (Pierro et al., 2021). The seamstress's radiography, described as osteopenia, does not rule out a lytic lesion.

The review of low-dose CT also points out its limits: the exam uses radiation, although low-dose protocols reduce it considerably, and it is not as efficient at detecting early marrow infiltration before frank bone destruction, especially in the spine and pelvis (Pierro et al., 2021). MRI is therefore suggested when CT shows suspicious lesions that do not meet the requirements (Pierro et al., 2021). For PET with CT, several studies reported sensitivity and specificity of 80 to 100 percent for bone lesions (Zamagni and Talarico, 2025).

MRI

On MRI, a focal lesion is a circumscribed area of 5 mm or more, with a typical signal on the sequences, outside the usual sites of degenerative change (Wennmann et al., 2020). More than 1 focal lesion is a myeloma-defining event (Zamagni and Talarico, 2025). In a study of smoldering myeloma, the MRI protocol and the body area examined influenced the detection of focal lesions and, with it, the staging (Wennmann et al., 2020). The post about interprofessional clinical reasoning notes that talking with radiology changes the diagnosis.

The outcome of the scene

In the scene, low-dose whole-body CT shows an 8 mm lytic lesion in the body of a lumbar vertebra. Marrow biopsy shows 25 percent clonal plasma cells. With the bone lesion, the seamstress has active myeloma by criterion B, even without high calcium, without kidney impairment by criterion and without anemia by criterion. Without the adequate image, she would have been classified as smoldering myeloma.

The risk of smoldering myeloma

The 2/20/20 model

For smoldering myeloma without a defining event, the IMWG model uses three factors: monoclonal protein above 2 g/dL, bone marrow plasma cells above 20 percent and free light chain ratio above 20 (Mateos et al., 2020). In 1363 patients with all three data points, the risk of progression in 2 years was 6 percent with no factor, 18 percent with 1 factor and 44 percent with 2 or 3 factors (Mateos et al., 2020). The thresholds came from a Mayo Clinic series that sought the best cutoffs after the 2014 revision (Lakshman et al., 2018).

In the Mayo Clinic series, progression was 18 percent in the first year, about 10 percent per year in the following 3 years and lower after that (Lakshman et al., 2018). In a study of 406 patients with smoldering myeloma, 72 percent of those who were only observed progressed during the study, and about half of those who progressed had clinically relevant organ damage (Abdallah et al., 2024). Bone lesions were the most common defining event, in more than a third (Abdallah et al., 2024).

In the same study, among patients who received early treatment, 11 percent progressed to myeloma, versus 72 percent of those who were only observed (Abdallah et al., 2024). The authors note that, despite clinical trial data suggesting a benefit of early intervention, most patients with smoldering myeloma were observed in practice (Abdallah et al., 2024). This study is retrospective and does not compare randomized groups, so it does not by itself define who should be treated early. It does show, however, that observing without a clear plan lets many patients reach organ damage.

For the seamstress, that is no longer the question, because the lytic lesion defines active myeloma. But the same reasoning applies to the next patient with a monoclonal spike and borderline tests: classify carefully, estimate the risk and agree on follow-up.

Follow closely

The same study showed highly variable follow-up intervals in practice, from 1 to 18 months, with a median of 3 months (Abdallah et al., 2024). The authors recommend shared decision-making about observing or treating high-risk smoldering myeloma early and follow-up that detects progression before damage (Abdallah et al., 2024). The post about clinical deterioration on the ward recalls that tracking the trend allows action before the crisis.

The investigation of a person with suspected myeloma starts with serum protein electrophoresis, immunofixation and free light chains, with a blood count, calcium, creatinine and urine protein. Then comes skeletal imaging, with low-dose computed tomography, PET with computed tomography or magnetic resonance, and referral to the hematologist for a bone marrow biopsy. With all of this, the person is classified as monoclonal gammopathy, smoldering myeloma or active myeloma by the criteria.

Imaging also changes the risk

A review of functional imaging cites a study in which the 2-year risk of progression of smoldering myeloma was 87 percent with osteolytic lesions on PET with computed tomography, 61 percent with abnormal uptake without a change in bone structure and 30 percent with a negative PET (Zamagni and Talarico, 2025). This finding shows that imaging is not only for meeting criterion B, but also for understanding the risk of those who do not yet meet it.

Cytogenetics also enters the risk discussion. In the cohort of the 2/20/20 model, among patients with this data, the most frequent alterations were trisomies and deletion of chromosome 13, and the t(4;14) translocation appeared in 10.2 percent (Mateos et al., 2020). The IMWG model uses these alterations to separate one more risk group (Abdallah et al., 2024).

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by searching for the ICD-10 code. Myeloma is a good exercise because the early clues look common and the diagnosis depends on putting together tests from different areas. The post about case-based learning explains why this format fixes knowledge.

Three case exercises

Change the imaging. Say how you would classify the seamstress if the computed tomography showed no lesion and the magnetic resonance showed 1 focal lesion of 7 mm.

Change the light chains. Say what changes if the free light chain ratio were 140, with an involved chain of 180 mg/L.

Change the creatinine. Say what you would investigate if the creatinine were 2.6 mg/dL in a diabetic patient.

The post about simulated consultations helps train the history taking that leads to thinking of myeloma.

The limits on using the game are described on the NEXO economy page. If you research the teaching of clinical reasoning, the page for researchers explains how to get in touch. Professionals who write or review cases find information under curation and creators, and institutions can learn about the proposal on the partnerships page.

Frequently asked questions

Is every monoclonal peak myeloma?

No. Most are monoclonal gammopathy of undetermined significance, with a low risk of progression (Kyle et al., 2018).

What is SLiM-CRAB?

These are the myeloma-defining events: three biomarkers and the four types of organ damage (Abdallah et al., 2024).

Does a normal X-ray rule out bone lesions?

No. X-rays have many false negatives; low-dose CT, PET with CT or MRI are preferred (Pierro et al., 2021).

Does smoldering myeloma need treatment?

It does not meet the criteria for active myeloma. Risk is estimated with the 2/20/20 model, and the decision on early treatment is shared (Mateos et al., 2020) (Abdallah et al., 2024).

Is myeloma curable?

The review on bone disease describes myeloma as incurable (Rasch et al., 2020). The goal of early diagnosis is to prevent organ damage.

Final checklist

• I took persistent bone pain with anemia seriously.
• I ordered electrophoresis, immunofixation and free light chains.
• I checked calcium, creatinine and hemoglobin against the criteria thresholds.
• I verified whether the damage is attributable to the clone.
• I ordered adequate imaging of the skeleton.
• I referred the patient for a bone marrow biopsy.
• I classified it as gammopathy, smoldering or active.
• I estimated the risk with the 2/20/20 model in smoldering myeloma.

Want to practice the reasoning with progressive clues? Play the case of the day.

References

1. Abdallah NH, Lakshman A, Kumar SK, et al. Mode of progression in smoldering multiple myeloma: a study of 406 patients. Blood Cancer J. 2024. PMID 38228628.
2. Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010. PMID 20410922.
3. Kyle RA, Larson DR, Therneau TM, et al. Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance. N Engl J Med. 2018. PMID 29342381.
4. Lakshman A, Rajkumar SV, Buadi FK, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J. 2018. PMID 29895887.
5. Mateos MV, Kumar S, Dimopoulos MA, et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J. 2020. PMID 33067414.
6. Pierro A, Posa A, Astore C, et al. Whole-Body Low-Dose Multidetector-Row CT in Multiple Myeloma: Guidance in Performing, Observing, and Interpreting the Imaging Findings. Life (Basel). 2021. PMID 34947851.
7. Rasch S, Lund T, Asmussen JT, et al. Multiple Myeloma Associated Bone Disease. Cancers (Basel). 2020. PMID 32751464.
8. Thorsteinsdóttir S, Gíslason GK, Aspelund T, et al. Prevalence of smoldering multiple myeloma based on nationwide screening. Nat Med. 2023. PMID 36747117.
9. Wennmann M, Hielscher T, Kintzelé L, et al. Spatial Distribution of Focal Lesions in Whole-Body MRI and Influence of MRI Protocol on Staging in Patients with Smoldering Multiple Myeloma According to the New SLiM-CRAB-Criteria. Cancers (Basel). 2020. PMID 32906608.
10. Zamagni E, Talarico M. Fifteen years of use of functional imaging in multiple myeloma: where we started and where we are going. Blood Adv. 2025. PMID 40875592.
11. Zorlu T, Kayer MA, Okumus N, et al. Challenges, Difficulties, and Delayed Diagnosis of Multiple Myeloma. Diagnostics (Basel). 2025. PMID 40647707.