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Detecting multiple myeloma for healthcare providers

  • Importance of early diagnosis
  • When to suspect multiple myeloma
  • What tests to order
  • Interpreting lab tests

Introduction

Multiple myeloma detection and monoclonal protein test interpretation

Although nearly 30% of patients may present in urgent care or emergency settings, the majority of patients first present to their primary care provider (PCP) with symptoms of multiple myeloma, visiting their PCP an average of 3 times for their symptoms prior to referral to hematology.1

 

Early suspicion of possible multiple myeloma patients in the primary care setting can help enable earlier diagnosis and treatment.2 Early diagnosis can also improve clinical outcomes; patients presenting with advanced disease—often with organ damage or other complications—tend to have worse outcomes.3,4

Routine laboratory tests and simple blood tests for monoclonal proteins can be helpful in identifying potential multiple myeloma or identifying an alternative explanation for symptoms.2

The importance of early diagnosis

Early symptoms of multiple myeloma can be attributed to comorbidities or common alternative diagnoses, such as diabetes, low back pain, or arthritis.2 Basic laboratory abnormalities may also offer insight as to whether an underlying cause other than diagnosed comorbidities may be producing the symptoms.2


Proactive testing may also help identify cases of premalignant disease, such as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma.2 Patients who are diagnosed with precursors to multiple myeloma have improved survival after progression to myeloma compared to those identified after the start of malignant disease.5

Challenges in early diagnosis
Genetic and Molecular Mechanisms

Detecting multiple myeloma

Suspicion of multiple myeloma may begin with the report of common symptoms, but the nonspecific nature of fatigue and back pain may mean that basic laboratory tests become the first indicator of possible myeloma or another disorder.6 Therefore, even a slight suspicion of multiple myeloma should result in appropriate investigations.

When to suspect multiple myeloma

The following signs and symptoms of unknown cause, are suggestive of multiple myeloma and may merit testing for a monoclonal gammopathy:2

  • Bone pain
  • Fatigue
  • Neuropathy
  • Bruising/bleeding
  • Recurrent infections
  • Raynaud phenomenon
  • Hyperviscosity
  • Pathologic fractures
  • Hypercalcemia
  • Renal insufficiency
  • Anemia
  • Elevated erythrocyte sedimentation rate (ESR)
  • Elevated total protein
  • Low anion gap
  • Low albumin
  • Unexplained proteinuria
  • Hypo- or hyper-gammaglobulinemia

Other abnormalities or isolated signs and symptoms may merit further evaluation for alternative conditions.2

Common Symptoms of Multiple Myeloma

What tests to order for suspected multiple myeloma

Multiple professional groups, including the International Myeloma Working Group (IMWG) and the National Comprehensive Cancer Network, recommend the following work-up for suspected multiple myeloma:6,7,9,14

Together, the combination of SPEP and sFLC and sIFE tests identify >99% of patients with multiple myeloma.8 Relying on SPEP alone may miss 1 in 8 patients with myeloma.8

In addition, a full health history and physical exam can inform decisions about add-on testing, such as a frailty assessment, bone scans, serum viscosity tests, infectious disease screening, or echocardiogram.7 In cases where AL amyloidosis is suspected, 24-hour urine studies may be useful; however, sFLC plus SPEP and sIFE together have high sensitivity for myeloma, negating the need for urine for myeloma detection alone.9

To quantify monoclonal proteins (M-protein) in the blood, especially intact immunoglobulin M-proteins.

To identify the type of monoclonal protein (for example, IgG, IgA, or IgM) present in the blood.

To detect kappa and lambda free light chains in the blood and their relative quantity; results are presented both as individual kappa and lambda FLC measurements as well as a kappa-to-lambda FLC ratio.

To measure the amount of immunoglobulin (Ig) present in the blood.

Interpreting monoclonal protein lab tests

Not all abnormal results on SPEP/IFE and sFLC indicate multiple myeloma. M protein and/or abnormal free light chain ratios may also be present in cases of premalignant plasma cell disorders such as MGUS, immune suppression or autoimmunity, renal impairment, infection, and other plasma cell disorders.6,9 Test results must be interpreted in context with the patient’s signs and symptoms.

Referrals to hematology/oncology should be informed by the patient's current medical conditions, along with concerning findings from their laboratory tests, suggestive of the possibility of multiple myeloma.

Urgent referrals are appropriate for patients with an identified IgD or IgE paraprotein, as well as for patients with significantly abnormal M protein concentrations or sFLC ratios.14

Any detection of M protein or free light chain ratio imbalance merits consultation with a hematology/oncology specialist.2 Patients with slight abnormalities or borderline results may require follow-up testing or ongoing monitoring; discussion with a specialist can inform the best course of action.14

The decision to act upon SPEP, IFE, or sFLC is case dependent. Lab results should always be evaluated in the context of clinical symptoms of an individual patient. The considerations above are not a substitute for hematologist consultation.

The following test interpretation information may offer insights and appropriate next steps. For more details regarding the considerations provided below, please refer to the cited references.

Myeloma is rare in patients with normal laboratory results; any monoclonal gammopathy is unlikely.2 Consider alternative diagnoses.

  • If kappa and lambda free light chains are both high, but no monoclonal protein is detected, consider possible infection, autoimmunity, or renal impairment.9
  • If kappa and lambda are both low, but no monoclonal protein is detected, consider general immune suppression.9
  • If the kappa-lambda ratio is borderline abnormal, but no monoclonal protein is detected, consider renal impairment and renal function testing.10
  • If no monoclonal protein is detected but either kappa or lambda is elevated by sFLC testing, consider the following:
    • Many labs and professional practice guidelines provide cut-offs for sFLC ratios to assist with identifying cases warranting immediate referral.10-12
    • Not all abnormal sFLC results indicate multiple myeloma; they may instead indicate a precursor condition. The probability of malignant disease increases with the ratio of involved-to-uninvolved free light chains.11-13
    • An elevated sFLC ratio in combination with hypercalcemia, renal insufficiency, anemia or lytic bone lesions (CRAB criteria) merits immediate referral to hematology.6 Up to 1 in 8 patients with multiple myeloma will not have abnormal SPEP results.8
  • If one free light chain type is elevated and the other is low, immune suppression of the uninvolved free light chain is possible.9
  • Supportive tests, such as whole-body, low-dose CT scans, may inform next steps.2
  • An abnormal SPEP/IFE result in combination with CRAB criteria merits immediate referral to hematology.6
  • Not all abnormal SPEP/IFE results indicate multiple myeloma; they may instead indicate a precursor condition. The probability of malignant disease increases with the concentration of M-protein in the blood.6
  • Supportive tests, such as whole-body, low-dose CT scans, may inform next steps.2
  • Abnormal SPEP/IFE and sFLC results in combination with CRAB criteria merit immediate referral to hematology.6
  • Not all abnormal SPEP/IFE and sFLC results indicate multiple myeloma; they may instead indicate a precursor condition. The probability of malignant disease increases with the ratio of involved-to-uninvolved free light chains and the serum concentration of M-protein.6,11-13
  • Many labs and professional practice guidelines provide cut-offs for free light chain ratios to assist with identifying cases warranting immediate referral.10-12
  • Supportive tests, such as whole-body, low-dose CT scans, may inform next steps.2
Imaging and Bone Marrow

Imaging and bone marrow evaluation

Depending on patient symptoms, skeletal imaging may be appropriate prior to referral to a hematology/oncology specialist.2 Fluorodeoxyglucose whole-body positron emission tomography/computed tomography (FDG-PET/CT) is the preferred option for suspected myeloma, and whole-body low-dose CT is also acceptable.7 In cases where these tests do not detect bone lesions, whole-body MRI without contrast may help identify smoldering myeloma.7

Identification of lesions on skeletal imaging merits referral to a specialist.2

Bone marrow biopsy is typically conducted by a specialist to quantify plasma cell percentage, which informs myeloma staging or alternative diagnoses.2

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References
  1. Hossain MI, Hampson P, Nowell C, et al. An in-depth analysis of factors contributing to diagnostic delay in myeloma: a retrospective UK study of patients journey from primary care to specialist secondary care. Blood. 2021;138(Supplement 1):3007.
  2. Mikhael J, Bhutani M, Cole CE. Multiple Myeloma for the Primary Care Provider: A Practical Review to Promote Earlier Diagnosis Among Diverse Populations. Am J Med. 2023;136(1):33-41.
  3. Kariyawasan CC, Hughes DA, Jayatillake MM, Mehta AB. Multiple myeloma: causes and consequences of delay in diagnosis. QJM. 2007;100(10):635-640.
  4. Seesaghur A, et al. Clinical features and diagnosis of multiple myeloma: a population-based cohort study in primary care. BMJ Open 2021; 11:e052759.
  5. Goyal G, Rajkumar SV, Lacy MQ, Gertz MA, Buadi FK, Dispenzieri A, Hwa YL, Fonder AL, Hobbs MA, Hayman SR, Zeldenrust SR, Lust JA, Russell SJ, Leung N, Kapoor P, Go RS, Gonsalves WI, Kourelis TV, Warsame R, Kyle RA, Kumar SK. Impact of prior diagnosis of monoclonal gammopathy on outcomes in newly diagnosed multiple myeloma. Leukemia. 2019 May;33(5):1273-1277.
  6. Rajkumar SV, Kumar S, Lonial S, Mateos MV. Smoldering multiple myeloma current treatment algorithms. Blood Cancer J. 2022 Sep 5;12(9):129.
  7. Kumar SK, Callander NS, Adekola K, et al. Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2023 Dec;21(12):1281-1301.
  8. Katzmann JA, et al. Screening panels for detection of monoclonal gammopathies. Clin Chem. 2009 Aug;55(8):1517-22.
  9. Dispenzieri A, Kyle R, Merlini G, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009;23(2):215-224.
  10. Long TE, et al. Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: Results of the iStopMM study. Blood Cancer J 2022; 12:133.
  11. Vermeersch P, et al. Use of interval-specific likelihood ratios improves clinical interpretation of serum FLC results for the diagnosis of malignant plasma cell disorders. Clin Chim Acta 2009; 410:54-58.
  12. Heaney JLJ, et al. Excluding myeloma diagnosis using revised thresholds for serum free light chain ratiosand M-protein levels. Haematologica 2019; 105:e169-e171.
  13. Keren DF, et al. Laboratory Detection and Initial Diagnosis of Monoclonal Gammopathies. Arch Pathol Lab Med 2022; 146:575-590.
  14. Drayson M, et al. For Myeloma UK working group for laboratory best practice. Laboratory practice is central to earlier myeloma diagnosis: Utilizing a primary care diagnostic tool and laboratory guidelines integrated into haematology services. Br J Haematol. 2024; 2Jan.