Multiple Myeloma Without Bone Damage: Understanding the Diagnosis and Criteria

When discussing multiple myeloma, many people assume that bone damage is a required symptom for diagnosis. However, this is not always the case. Multiple myeloma can indeed be diagnosed even in the absence of visible bone lesions. This article explores the diagnostic criteria, explains how patients can meet the definition of active myeloma without skeletal involvement, and sheds light on related precursor conditions such as smoldering myeloma.

The Three Pillars of Multiple Myeloma Diagnosis

According to widely accepted medical guidelines, including those from the International Myeloma Working Group (IMWG), the diagnosis of multiple myeloma rests on three primary criteria. Meeting just one of these, in addition to confirming the presence of clonal plasma cells, is sufficient to establish a diagnosis of active disease.

1. Clonal Plasma Cells in the Bone Marrow

A key diagnostic marker is the presence of 10% or more clonal plasma cells in the bone marrow aspirate or biopsy. These abnormal plasma cells are monoclonal, meaning they originate from a single mutated cell and proliferate uncontrollably. This clonality can be confirmed through flow cytometry or immunohistochemistry, which detect specific surface markers like CD138, CD38, and aberrant light chain expression (kappa or lambda restriction).

2. Detection of Monoclonal Protein in Blood or Urine

Another critical component is the identification of a monoclonal (M) protein in either serum or urine. This abnormal immunoglobulin—often IgG, IgA, or free light chains—is produced by the malignant plasma cell clone. Serum protein electrophoresis (SPEP) and immunofixation (IFE), along with urine tests (UPEP and urine immunofixation), are standard tools used to detect and characterize the M-protein. In some cases, only free light chains are present, a condition known as light-chain myeloma.

3. Evidence of Myeloma-Related End-Organ Damage (CRAB Criteria)

The third pillar involves signs of end-organ damage caused by the underlying plasma cell disorder. The acronym CRAB summarizes these manifestations:

C – Hypercalcemia: Elevated calcium levels in the blood, often leading to symptoms like fatigue, confusion, or kidney problems.
R – Renal insufficiency: Increased creatinine levels indicating impaired kidney function, commonly due to light chain deposition in the tubules.
A – Anemia: Low hemoglobin levels resulting from bone marrow infiltration that suppresses normal red blood cell production.
B – Bone lesions: Lytic bone lesions, osteoporosis, or fractures detected via imaging such as X-ray, CT, MRI, or PET-CT.

It's important to emphasize that only one of these CRAB features is necessary to confirm active multiple myeloma. Therefore, a patient may be diagnosed based on anemia, renal failure, or hypercalcemia—even if no bone destruction is present.

Beyond CRAB: Biomarkers of Early Active Disease

In recent years, the IMWG has expanded the diagnostic framework to include biomarkers that predict imminent organ damage, even in asymptomatic individuals. These biomarkers allow earlier intervention before full-blown CRAB symptoms develop.

Examples include:

Clonal bone marrow plasma cells ≥60%
Involved/uninvolved serum free light chain ratio ≥100 (with the involved FLC level at least 100 mg/L)
More than one focal lesion on MRI (≥5 mm in size)

Patients meeting any of these biomarker criteria are now classified as having active myeloma, regardless of whether traditional CRAB features are present. This shift underscores the importance of advanced diagnostics beyond skeletal imaging alone.

Smoldering Multiple Myeloma: A Precursor Without Organ Damage

Not all plasma cell disorders progress immediately to symptomatic disease. Smoldering multiple myeloma (SMM) refers to an intermediate stage where patients have elevated levels of clonal plasma cells and/or M-proteins but lack any signs of end-organ damage.

Typically, SMM is characterized by:

10–59% clonal plasma cells in the bone marrow
Or serum M-protein ≥3 g/dL plus urinary M-protein ≥500 mg/24h
No CRAB abnormalities or amyloidosis

While SMM does not require immediate treatment, it carries a significant risk of progression to active myeloma—approximately 10% per year during the first five years. Close monitoring and risk stratification using tools like the 20/2/20 model help guide clinical decisions.

Other Related Conditions That May Mimic or Coexist With Myeloma

In addition to classic myeloma and SMM, several other plasma cell disorders may present without bone involvement:

Monoclonal Gammopathy of Undetermined Significance (MGUS)

MGUS is a benign precursor condition with low levels of M-protein and fewer than 10% plasma cells in the marrow. It rarely causes symptoms and progresses to myeloma at a rate of about 1% per year. Importantly, MGUS does not involve organ damage and does not require therapy.

AL Amyloidosis and Hyperviscosity Syndrome

Sometimes, the monoclonal protein leads to complications such as AL amyloidosis—where misfolded light chains deposit in organs like the heart or kidneys—or hyperviscosity syndrome, typically seen in Waldenström macroglobulinemia. These are considered "myeloma-defining events" when occurring in the context of a clonal plasma cell disorder.

Conclusion: Bone Lesions Are Just One Piece of the Puzzle

In summary, bone damage is not mandatory for diagnosing multiple myeloma. While lytic lesions are common and clinically significant, the presence of clonal plasma cells, monoclonal proteins, and other organ dysfunctions are equally valid diagnostic pathways. Advances in laboratory testing and imaging have enabled earlier detection, allowing clinicians to identify high-risk patients before irreversible damage occurs. Understanding these nuances ensures timely and accurate diagnosis, improving long-term outcomes for patients worldwide.