Main diagnostic criteria for Multiple Myeloma
September 1, 2025 by adminIntroduction
Multiple myeloma is classified as a plasma cell dyscrasia comprising a malignant proliferation of the clonal plasma cells primarily involving the bone marrow. As third-year medical students preparing for board examinations, it is extremely important to have a thorough understanding of the clinical presentation and laboratory work-up for diagnosing this condition. The criteria for diagnosis have constantly evolved over the years, owing to insights gained from clinical studies and improvements in imaging and molecular technologies. This outline can be used as a comprehensive guide emphasizing the important features of multiple myeloma, both clinically and from the laboratory. It will serve as a concise, high-yield revision tool geared toward examination preparation.
For ease of explanation, these guidelines will refer to standard diagnostic criteria such as those established by the International Myeloma Working Group (IMWG). These criteria aid in the diagnosis of this disease with a focus on the symptoms and measurable laboratory abnormalities. Key features are emphasized concerning recall in the sections below so that students may easily pinpoint and remember the pathognomonic features of multiple myeloma.
I. Clinical Diagnostic Criteria
The clinical assessment of a patient suspected to have multiple myeloma goes hand in hand with the patient’s medical history and physical findings. The hallmark of multiple myeloma consists of the “CRAB” acronym that has been utilized as a handy summary of the major end-organ effects of the disease. This section will highlight the key clinical features, though one should not forget additional relevant findings.
A. CRAB Features
- Hypercalcemia:
Elevated serum calcium levels are seen in many patients with myeloma. This happens because of increased bone resorption resulting from osteolytic activity due to the presence of myeloma cells. Clinically, hypercalcemia will be present with several symptoms like polyuria, polydipsia, constipation, confusion, and in severe cases, cardiac arrhythmias. Typically what is considered an abnormal level in myeloma evaluation is the corrected serum calcium higher than the upper limit of normal.
- Renal insufficiency (renal failure):
Renal involvement is common and may be secondary to light chain deposition, hypercalcemia-induced nephropathy, and direct toxicity from the circulating free light chains. The so-called “myeloma kidney” may manifest as an elevation of creatinine or depression of estimated glomerular filtration rate (eGFR). The renal dysfunction may be acute or may progress slowly, becoming a major cause of morbidity in either case.
- Anemia:
In myeloma it is typically a normocytic and normochromic anemia due to marrow infiltration by plasma cells. Patients feel fatigued, develop pallor, and feel cramps on exertion. Anemia often happens to be one of the earliest laboratory abnormalities in myeloma.
- Bone Disease (Lytic Lesions):
Bony pains, especially in the lower back or ribs, are common complaints. Osteolytic lesions, fractures, or even generalized osteopenia are often evident on radiological scans. In examination settings, in an elderly patient with bone pains, lesions on imaging usually form a key clinical pointer for multiple myeloma. The “punched-out” lytic lesions seen on skeletal surveys are often deemed diagnostic.
B. Additional Clinical Presentations
- Soft Tissue Plasmacytomas:
In some cases, extramedullary manifestations occur, meaning that plasma cells exit the bone marrow and form masses called plasmacytomas. These may be incidental finding on an imaging study, or they may have localized effects that depend on their location (nasal obstruction if certain in the upper airway).
- Neuropathic Symptoms
Less commonly, peripheral neuropathy may be inflicted due to amyloid deposits or to plasmacytomas compressing neural structures. Recognizing unexplained neuropathies may be a clue integrated into the overall clinical picture.
- Recurrent Infections:
The abnormal immunoglobulin formed in multiple myeloma is often non-functional. This immunoparesis decreases host defenses against bacterial infections. Recurrent infections of the respiratory or urinary tracts may represent an important clinical hint worth additional investigation.
- Constitutional Symptoms:
Weight loss, fatigue, and night sweats may be present as well. These symptoms are very much non-specific, yet, in the correct clinical setting, they may add to the suspicion for multiple myeloma.
C. Physical Examination Findings
- Evidence of Bone Tenderness and Deformities:
Checking the patient shows tenderness along the axial skeleton, especially the spine and ribs. Advanced cases show pathological fracture; localized swellings are palpable, probably plasmacytomas.
- Lymphadenopathy and Hepatosplenomegaly:
Occasionally the lymph nodes or the liver and spleen may be mildly enlarged for advanced cases; this is not typical for multiple myeloma as compared against other lymphoproliferative disorders.
- Signs of Renal Dysfunction:
If renal failure is advanced, the patient may exhibit signs of fluid overload on physical examination, such as peripheral edema; however, patients with hypercalcemia might exhibit neurological abnormalities, for instance, confusion.
II. Laboratory Diagnostic Criteria
The laboratory workup for multiple myeloma is very complex and multi-dimensional; it incorporates serum and urine protein measures, quantitation of immunoglobulin production, and direct assessment of bone marrow plasma cell infiltration. A laboratory worker cannot earnestly confirm the diagnosis of multiple myeloma without the aid of these tests, therefore knowing them would also include determination of the disease burden and formation of treatment plans.
A. Serum Studies
- Complete Blood Count (CBC):
The CBC is one of the first investigations requested for. Some characteristic findings may include normocytic and normochromic anemia, which can be complicated by leukopenia or thrombocytopenia from marrow suppression. One must always correlate these laboratory findings with the symptoms of the patient.
- Serum Chemistry Panel:
These abnormalities in serum chemistry include hypercalcemia and deranged renal function tests such as increase in blood urea nitrogen (BUN) and serum creatinine. It is, therefore, important to monitor any electrolyte imbalance as these changes are directly related to the activity of the disease.
- Serum Protein Electrophoresis (SPEP):
SPEP is looked into by ECG to look for M spike usually found in the gamma region. Monoclonal protein is the hallmark of plasma cell dyscrasias. Students must remember that the mere presence of an M-protein often supports the diagnosis, but its degree and the pattern of presence must be interpreted alongside the clinical presentation.
- Serum Immunofixation Electrophoresis (SIFE):
During SIFE tests, carried out after SPEP has given an initial profile of the monoclonal protein, the exact nature of the Ig isotype (IgG, IgA, IgD, etc.) and the accompanying light chain (kappa or lambda) are established. This confirmation is essential since the type and amount of monoclonal protein may correlate with the behavior of the disease process.
- Quantitation of Immunoglobulin Levels:
The quantitative evaluation of serum immunoglobulins (IgG, IgA, IgM) also assists in further evaluation. Usually, in myeloma, one immunoglobulin class is elevated with corresponding suppression of others, known as immunoparesis. This relative deficiency of polyclonal immunoglobulins predisposes these patients to infections, signifying that its recognition can be an important diagnostic clue.
- Serum Free Light Chain Assay:
Free light chains have become an important diagnostic tool: they are small fragments, kappa or lambda, which are not bound to larger immunoglobulins. One of the myeloma-defining biomarkers is an abnormal involved-to-uninvolved serum free light chain ratio, which is usually present if the ratio is 100 or greater. Strict attention to this parameter could expedite the diagnosis.
B. Urine Studies
- Urine Protein Electrophoresis (UPEP):
UPEP is the procedure used to determine the presence of Bence Jones proteins, which are free light chains excreted in the urine. These proteins are precipitated with heat and are a sensitive but less specific marker for multiple myeloma.
- Urine Immunofixation Electrophoresis (UIFE):
In a manner similar to serum studies, UIFE is used to confirm and type the monoclonal protein detected in urine samples. Confirmation of light chains in urine becomes particularly important in instances where serum studies might be equivocal.
- 24-Hour Urine Collection:
Some patients are subjected to 24-hour urine collection to quantify the total amount of Bence Jones protein. This alone can provide additional prognostic information and sometimes may be included in staging multiple myeloma.
C. Bone Marrow Evaluation
The definitive diagnosis of multiple myeloma requires the histologic assessment of bone marrow.
- Bone Marrow Biopsy (BMB):
The bone marrow biopsy evaluates the percentage of plasma cells present. A diagnostic criterion is having 10 percent or more clonal plasma cells on bone marrow aspirate or biopsy. Sometimes, biomarkers dating the diagnosis can be relied upon if markers are present and overt end-organ damage (CRAB features) is absent.
- Cytogenetics and Molecular Studies:
Cytogenetics involving FISH analyses detect chromosomal aberrations such as translocations involving the IgH locus (i.e., t(4;14), t(11;14)) and deletions and amplifications (i.e., deletion 17p). They not only serve as diagnostic tools but also provide prognostic indicators concerning the probable course and aggressiveness of the disease.
D. Radiologic and Imaging Studies
Imaging plays a supportive role in detecting bone lesions and extramedullary disease.
- Skeletal Survey:
Radiographic modality involves conventional whole-body X-rays to detect typical “punched-out” lytic lesions. Although less sensitive compared to newer imaging modalities, skeletal survey remains crucial to bone involvement assessment.
- MRI:
MRI has an edge over other imaging studies in assessing marrow involvement and elucidating focal lesions either missed or occult on standard radiographs. One or more focal lesions on MRI constitute a myeloma-defining event without the presence of CRAB criteria.
- Computed Tomography and Positron Emission Tomography-CT and PET scan:
Contemporary imaging techniques comprising low-dose CT and PET scans have improved the sensitivity toward detecting both bone and soft tissue lesions. In conjunction with tumor markers, the scans reveal the full extent of the disease and are useful in staging and monitoring response to treatment.
E. Myeloma-Defining Biomarkers
Aside from the classic CRAB features, the new IMWG diagnostic criteria include a series of myeloma-defining biomarkers for those who may not show overt end-organ damage yet. These biomarkers are crucial for an early time detection:
- Bone Marrow Plasma Cells ≥ 60%:
Increased bone marrow plasmacytosis to 60% or more is almost always consistent with multiple myeloma, even if the patient is asymptomatic.
- Involved/Uninvolved Serum Free Light Chain Ratio ≥ 100:
This criterion stems from the serum free light chain assay. A ratio of 100 or greater strongly suggests a clonal process and has, therefore, been added to the diagnostic criteria.
- More than one focal lesion on MRI:
More than one focal lesion of size at least 5 mm on MRI in a patient without the presence of CRAB features favors the diagnosis of multiple myeloma.
III. Integrative Diagnostic Considerations and Exam Preparation Tips
On coalescing the diagnostic picture for multiple myeloma, clinicians must integrate clinical findings with laboratory data. This interplay between evidence must be instilled within third-year medical students so that they appreciate how every piece of evidence contributes to the whole construct of diagnosis and management of the disease.
A. Diagnostic Integration
The modern-day diagnostic paradigm for multiple myeloma is a synergistic combination of clinical data, laboratory data, and imaging:
- A Definitive Diagnosis:
The combination of ≥10% clonal plasma cells in the bone marrow (or a biopsy-proven plasmacytoma) together with at least one myeloma-defining event (CRAB features or one of the specified biomarkers) is required for a definitive diagnosis. This dual approach ensures that patients who do not present with classic symptoms but have significant biological markers still receive a timely diagnosis.
- Minimal Residual Disease (MRD):
Including MRD data in the initial diagnostic criteria was not possible initially, but nowadays, it is much appreciated in evaluating the treatment response or prognosis. Flow cytometry or next-generation sequencing methods are used following treatment.
B. Key Points for Examination Recall
- Remember the CRAB Acronym:
The CRAB criteria (Hypercalcemia, Renal failure, Anemia, Bone lesions) designate clinical end-organ damage that ends up being associated with multiple myeloma and has always stood as a key part of diagnosis.
- Laboratory Diagnosis Tests:
Recall the key diagnostic tests of SPEP, SIFE, serum free light chain assay, and UPEP to detect the presence of monoclonal protein.
- Bone Marrow Evaluation:
Bone marrow biopsy measuring clonal plasma cells ≥10% must be considered along with clinical or biomarker evidence of disease activity to arrive at a diagnosis.
- Myeloma-Defining Biomarkers:
These are the biomarkers: in the bone marrow, plasma cells are equal to or more than 60%; the involved/uninvolved serum free light chain ratio has to be 100 or greater; and the presence of more than one focal lesion on MRI. These are to be considered for early diagnosis because these abnormalities can occur just as well without overt CRAB criteria.
- Role of Imaging:
Don’t let advanced imaging systems being treated with contempt. Be able to discuss the advantages and disadvantages of skeletal surveys, MRI, CT, and PET scanning methods in analyzing the ascertainment of disease burden.
C. Common Pitfalls and Differential Diagnosis
In examination settings, students might be presented with scenarios that mimic multiple myeloma. Any true multiple myeloma has to be differentiated from other conditions that can present with either monoclonal gammopathies or lytic bone lesions.
- Monoclonal Gammopathy of Undetermined Significance (MGUS):
This is a premalignant condition characterized by the presence of a monoclonal protein but without the end-organ damage of multiple myeloma. The deciding factors would be the percentage of plasma cells in the bone marrow (<10% plasma cells in MGUS) and absence of CRAB features.
- Smoldering Multiple Myeloma (SMM):
This represents the interim stage in which more monoclonal protein is produced and increased plasma cells (10-60%) are noted in the bone marrow-exceeding those of SMM-but there are yet no myeloma-defining events. Setting this distinction between SMM and active CRAB should be made to not overtreat the patient.
- Other Plasma Cell Dyscrasias:
Disorders such as Waldenström macroglobulinemia and light-chain amyloidosis could have similar presentations. Knowledge of the laboratory markers and clinical presentations that differentiate these from multiple myeloma is imperative.
D. Exam Preparation Strategies
In preparing for exams, it would be helpful to consider the strategies below, so you can internalize the diagnostic criteria of multiple myeloma:
- About Mnemonics:
Use CRAB as a cue for the mind. Moreover, create mnemonics for the myeloma-defining biomarkers. (For example, 60-100-MRI could remind you of 60 percent plasma cells, a 100 ratio in free light chains, and MRI-detected lesions.)
- V. Practicing Integrative Case Studies:
Clinicians must review examples of cases in which laboratory data are integrated with imaging and clinical symptoms. Formulation of a diagnostic plan from scratch based on patient scenarios definitely consolidates one’s comprehension.
- Review Algorithms and Flowcharts:
Many textbooks and review articles generate flowcharts on possible diagnostic steps for multiple myeloma. Visual representations of the diagnostic criteria into a logical sequence are often seen in exam questions.
- Know Exceptions and Updates:
One must maintain updates with new developments. Currently, with new biomarkers, the diagnostic criteria for multiple myeloma have undergone alterations. One must study the various changes and also learn the rationale behind them.
IV. Conclusion
The process of diagnosing multiple myeloma requires an overall view encompassing clinical presentation as well as laboratory findings. This outline went over the essential features to identify, chiefly the CRAB criteria, and then discussed laboratory tests used in confirming the diagnosis. Crucial laboratory investigations, among serum protein electrophoresis, immunofixation studies, and serum free light chain assay, confirm the presence of monoclonal proteins that identify the disease. Further, imaging reviews must be carried out alongside bone marrow biopsy to ascertain the full extent of myeloma involvement.
For the third-year medical student, mastering these diagnostic criteria is important not only for passing their examinations but also toward management and prognosis of multiple myeloma. Taking note of minute distinctions among these related plasma cell disorders, such as monoclonal gammopathy of undetermined significance and smoldering multiple myeloma, is fundamental. Thoroughly integrate clinical findings with laboratory findings for these disorders as you work through examination questions to achieve comprehensive diagnosis.
The continued review, practice with clinical cases, and a thorough understanding of CRAB features and newer myeloma-defining biomarkers will definitely boost your exam scores and will also produce excellent doctors someday. Keep up to date with the IMWG guidelines and incorporate this into your study plan so as to maximize your performance in the examinations.
In the end, remember that the diagnostic journey in myeloma is multifactorial, requiring a careful balancing of patient history, physical examination, and laboratory investigations. As the landscape evolves, the criteria will as well, but knowing these basics will be your foundation throughout your ever-so-long career.