Multiple myeloma is a blood cancer caused by the continuous over-proliferation of malignant plasma cells in the bone marrow. The cancer is characterized by osteolytic lesions, renal injury, and laboratory abnormalities such as anemia and hypercalcemia. Its nonspecific symptoms may be easily attributed to more common comorbidities or general aging, potentially resulting in diagnostic delay.1
Early myeloma diagnosis and prompt treatment can help patients avoid myeloma-related complications, preserve their quality of life, and extend survival.2,3 By ordering the right tests as soon as myeloma is suspected, physicians can reduce diagnostic delay and improve patient outcomes.1-4
When to suspect multiple myeloma
Some patient populations have an increased risk of developing multiple myeloma, including:
- Males5
- Patients aged 65 or older5
- Patients of Black/African American ancestry5
- Those with a personal history of monoclonal gammopathy of undetermined significance (MGUS)6
- Those with a family history of multiple myeloma or other lymphohematopoietic cancers7
- Patients with prior exposure to certain chemicals, such as Agent Orange8
Multiple myeloma symptoms can be nonspecific and different for each patient.
However, common signs and symptoms, without any other cause, that present prior to a multiple myeloma diagnosis include:1
- Persistent bone pain
- Pain in the back, hips, and/or skull
- Fatigue
- Persistent or frequent infections
- Bruising or bleeding
- Unexplained weight loss
- Neuropathy
- Elevated creatinine or renal insufficiency
- Hypercalcemia
- Anemia
- Lytic bone lesions, fractures, and osteoporosis
- Raynaud phenomenon
What tests to order: Guideline recommendations for the investigation of multiple myeloma
Numerous myeloma organizations—including the International Myeloma Working Group (IMWG) as well as groups from the United States, Canada, the United Kingdom, and Europe—have considerable overlap in bloodwork testing recommendations for initial multiple myeloma diagnostic tests.
Common serum tests recommended in guidelines for monoclonal protein (M protein) testing include:
- Serum protein electrophoresis (SPEP)
- Serum immunofixation electrophoresis (sIFE)
- Serum free light chain (sFLC) assay
- Serum quantitative immunoglobulins*
Organization-specific guidelines and recommendations
International Myeloma Working Group (IMWG)
The IMWG is a global collaborative of myeloma clinicians and researchers created to advance myeloma science and generate evidence-based consensus guidelines for practitioners around the world. Per IMWG criteria, the diagnostic workup of multiple myeloma should involve SPEP, serum and urine IFE, quantitative immunoglobulins*, sFLC, and serum light chain assay, as well as complete blood count and biochemistry tests.6 sFLC ratio and total level of involved free light chains are now included as a myeloma-defining event in the diagnostic criteria for myeloma.6 Many other professional groups also endorse IMWG guidance for myeloma testing and diagnosis, including:
- American Society of Clinical Oncology (ASCO)10
- Cancer Care Ontario (CCO)10
- Myeloma Canada Research Network Consensus Guideline Consortium (MCRN-CGC)11
College of American Pathologists (CAP)
CAP is the world’s largest board-certified pathologist member association. They recommend ordering sFLC and SPEP for initial detection of M protein in all patients with suspected monoclonal gammopathies, with follow-up sIFE and quantitative immunoglobulins* to confirm and type sFLC or SPEP abnormalities.12
European Myeloma Network (EMN)
These organizations collaborated to develop and review guidelines to assist European clinicians in diagnostic and treatment decisions. Their joint recommendations consider blood count and blood smear, biochemistry, SPEP, sIFE, sFLC, and serum immunoglobulin levels as obligatory tests for myeloma diagnosis.13
European Myeloma Network (EMN)
This international organization of clinicians aims to advance clinical research in myeloma and harmonize diagnostic and treatment practices across Europe. EMN recommends sIFE, urine and serum electrophoresis, and sFLC for investigation of a suspected plasma cell disorder.14 They also recommend complete blood counts, blood smears, and general biochemistry tests for myeloma diagnosis, as well as serum immunoglobulins for all patients with a gammopathy.14
National Comprehensive Cancer Network (NCCN)
An alliance of 33 U.S. cancer centers, NCCN develops clinical practice guidelines to guide quality improvement and enhanced cancer care and access. NCCN guideline Version 1.2025 recommends an initial diagnostic workup for potential myeloma or other plasma cell disorders that includes serum quantitative immunoglobulins*, SPEP, sIFE, urine protein electrophoresis, urine IFE, sFLC, complete blood count and differential with platelet count, blood smear, and general biochemistry tests, along with additional imaging, bone and blood tests.15
UK National Institute for Health and Care Excellence (UK NICE)
This organization develops guidance and standards to help UK practitioners provide standardized, evidence-based, and cost-effective care. UK NICE guidelines recommend SPEP and sFLC to confirm presence of M protein from suspected myeloma with follow-up sIFE to confirm M protein for abnormal results on SPEP or sFLC.16 They recommend against using SPEP, sIFE, sFLC, or urine protein electrophoresis in isolation to exclude a myeloma diagnosis.16
In addition to bloodwork and physical examination, diagnosis of myeloma requires bone imaging and/or bone marrow testing.1,6,13-16
For complete details on recommended tests and nuances regarding patient circumstances or diagnostic suspicions, as well as for recommendations regarding treatment and follow-up, please review the organizations’ full publications.
A common thread in the guidelines: sFLC for initial myeloma testing
All of the societies and guidelines listed above recommend sFLC testing upon initial suspicion of myeloma. Guidelines vary on which other tests are recommended for initial vs immediate follow-up testing based on results, but common co-recommended tests include SPEP, sIFE, serum immunoglobulins, complete blood count and smear, and general biochemistry tests. Bone marrow biopsy and various types of whole-body skeletal imaging are also uniformly recommended for their diagnostic and prognostic value for myeloma patients.
Be compliant with internationally accepted testing guidelines: order sFLC, SPEP, and sIFE as soon as you suspect multiple myeloma.6
*Where there is suspicion of or confirmation of an IgG, IgA or IgM paraprotein, guidelines indicate the use of SPE/UPE and/or sIFE/uIFE. Serum IgG, IgA or IgM concentrations can be useful to assess, after the monoclonal protein has been identified.
References
- Mikhael J et al. Multiple Myeloma for the Primary Care Provider: A Practical Review to Promote Earlier Diagnosis Among Diverse Populations. Am J Med 2023 Jan;136(1):33-41.
- Smith L et al. Diagnosing myeloma in general practice: how might earlier diagnosis be achieved? Br J Gen Pract 2022 Oct 30;72(723):462–3.
- Kariyawasan et al. Multiple myeloma: causes and consequences of delay in diagnosis. QJM 2007 Oct;100(10):635-40.
- Seesaghur A et al. Clinical features and diagnosis of multiple myeloma: a population-based cohort study in primary care. BMJ Open 2021;11:e052759.
- National Cancer Institute. Cancer Stat Facts: Myeloma. Surveillance, Epidemiology, and End Results Program. Accessed online 14 Nov 2024 at https://seer.cancer.gov/statfacts/html/mulmy.html.
- Rajkumar SV et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15(12):e538-e548.
- Schinasi LH et al. Multiple myeloma and family history of lymphohaematopoietic cancers: Results from the International Multiple Myeloma Consortium. Br J Haematol 2016; 175:87-101
- Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides Board on the Health of Select Populations; Institute of Medicine; National Academies of Sciences, Engineering, and Medicine. Veterans and Agent Orange: Update 2014. Washington (DC): National Academies Press (US); 2016 Mar 29.
- Shephard EA et al. Quantifying the risk of multiple myeloma from symptoms reported in primary care patients: a large case-control study using electronic records. Br J Gen Pract 2015 Feb;65(631):e106-13.
- Mikhael J, et al. Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline. J Clin Oncol 2019; 37:1228-1263
- Bergstrom DJ et al.; Myeloma Canada Research Network Consensus Guideline Consortium. Consensus Guidelines on the Diagnosis of Multiple Myeloma and Related Disorders: Recommendations of the Myeloma Canada Research Network Consensus Guideline Consortium. Clin Lymphoma Myeloma Leuk. 2020 Jul;20(7):e352-e367.
- Keren DF et al. Laboratory detection and initial diagnosis of monoclonal gammopathies: Guideline from the College of American Pathologists in collaboration with the American Association for Clinical Chemistry and the American Society for Clinical Pathology. Arch Pathol Lab Med. 2022; 146(5): 575–590.
- Dimopoulos et al. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals Onc. 2021;32:309-322
- Caers J et al. European Myeloma Network recommendations on tools for the diagnosis and monitoring of multiple myeloma: what to use and when. Haematologica. 2018;103(11):1772-1784
- NCCN Clinical Practice Guidelines in Oncology® for Multiple Myeloma V.1.2025. National Comprehensive Cancer Network. Accessed 20 March 2025 at https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf.
- NICE. Myeloma: Diagnosis and Management (NG35). National Institute for Health and Care Excellence. Updated October 2018. ISBN: 978-1-4731-1659-7. Accessed 20 March 2025 at https://www.nice.org.uk/guidance/ng35/resources/myeloma-diagnosis-and-management-pdf-1837394042821.
- Katzmann JA et al. Screening panels for detection of monoclonal gammopathies. Clin Chem. 2009 Aug;55(8):1517-22.
