Multiple Myeloma: Laboratory Support of Diagnosis and Management

Multiple myeloma is a serious plasma cell malignancy with a relatively low 5-year survival rate (55%).^1-3 Disease manifestations include anemia, bone loss, neurological problems, and organ damage.^1,2 Almost all cases of multiple myeloma are preceded by a premalignant stage called monoclonal gammopathy of undetermined significance (MGUS). However, relatively few patients with MGUS progress to multiple myeloma.^4,5 Because multiple myeloma is usually not diagnosed until end-organ damage has developed, early detection is key for providing treatment and more favorable outcomes.³

This article reviews the epidemiology, pathophysiology, and presentation of multiple myeloma and its premalignant stages. It also discusses the important role the laboratory plays in the diagnosis and management of multiple myeloma.

Epidemiology

Multiple myeloma accounts for about 10% of hematological malignancies^6,7 and about 1.8% of new cancer cases in the United States.⁶ The median age at diagnosis of multiple myeloma is about 70 years; it is more common in males than females (male:female ratio 3:2); and it is twice as common among Black Americans than White Americans.⁸ In the United States, the lifetime risk of getting multiple myeloma is about 1 in 132 (0.76%).³ The American Cancer Society estimates that in 2021 there will be about 35,000 new cases of multiple myeloma, and 12,500 people will die from the disease.³ Notably, the number of cases diagnosed annually is expected almost to double in 20 years.³

The causes of multiple myeloma are unknown. Postulated factors include radiation exposure, industrial or agricultural toxins, viruses, and obesity.⁹ Chromosomal abnormalities⁹ and oncogenes, such as CMYC, NRAS, and KRAS¹⁰, may be involved in plasma cell proliferation.

Early Pre-Malignant Stages

MGUS, an early premalignant stage of multiple myeloma, occurs in almost all persons who develop multiple myeloma. The risk of progression from MGUS to multiple myeloma is about 1% per year.¹¹ MGUS is detectable in around 3% of persons above age 50.¹¹ MGUS is defined by a serum non-IgM-type monoclonal protein of <3 g/dL (other types of monoclonal protein can be present), <10% clonal bone marrow plasma cells, and the absence of end-organ damage.¹¹

There is no treatment for MGUS, but close monitoring and follow-up have been shown to improve outcomes in patients who progress to a more advanced premalignant stage, smoldering multiple myeloma (SMM), and eventually multiple myeloma.¹¹ The progression risk of SMM to multiple myeloma is about 10% per year.¹¹

Features of MGUS and SMM can identify patients who may benefit from early intervention (see Sidebar).¹¹ Guidelines recommend annual testing of monoclonal protein and serum free light chain (sFLC) ratio for patients with MGUS who are at low risk of progression.¹² However, a recent study suggests more frequent monitoring may be appropriate. In some patients relatively rapid changes in serum markers (eg, monoclonal protein spike of ≥15 g/L, sFLC ratio <0.1 or >10) change the risk of progression from low to high.¹³

Pathophysiology

In multiple myeloma the proliferation of malignant plasma cells in bone marrow displaces normal bone marrow cells, resulting in essentially non-functional bone marrow.^6,14 The abundance of malignant plasma cells and absence of normal bone marrow leads to anemia, thrombocytopenia, leukopenia, and bone loss.^6,14 The malignant plasma cells also secrete excessive monoclonal immunoglobulin, which can result in hyperviscosity, renal tubular damage, platelet dysfunction, and neurological damage.^6,14

Presentation: Signs and Symptoms

The presentation of multiple myeloma can vary greatly depending on the disease stage and patient age and overall health. Common symptoms include¹⁴

• Bone pain, often in the back or ribs
• Fractures
• Weakness or fatigue
• Weight loss
• Frequent infections and fevers
• Feeling very thirsty
• Frequent urination

Patients may be asymptomatic; an abnormality such as anemia on routine examination of an older person should raise the suspicion of multiple myeloma. On the other hand, a patient may present as seriously ill. Worsening symptoms may include heart failure or angina, renal failure, and an altered mental status as a result of electrolyte abnormalities, dehydration, and acidosis due to renal failure.¹⁴ Symptoms of hyperviscosity include paresthesia, headache, dyspnea, nasal bleeding, and blurry vision.¹⁴

Features observed on physical examination vary with the extent of disease, but will typically include pallor, tachycardia, tachypnea, petechiae or ecchymoses, bone tenderness, edema or signs of dehydration, and central or peripheral neurologic signs.¹⁴

Diagnosis

Diagnosis of multiple myeloma is based on the presence of serum monoclonal protein, Bence Jones protein, and clonal bone marrow plasma cells identified on bone marrow biopsy.^6,12 Both the National Comprehensive Cancer Network^® (NCCN^®) and the International Myeloma Working Group (IMWG) classify multiple myeloma as asymptomatic (SMM) or active (symptomatic).^6,15

NCCN and IMWG have 2 criteria (both criteria must be met) for diagnosis of SMM:

• Serum monoclonal IgG or IgA ≥3 g/dL or Bence Jones protein ≥500 mg per 24 hours and/or clonal bone marrow plasma cells of 10% to 59%
• The absence of myeloma-defining events or amyloidosis

NCCN and IMWG have 2 criteria (both criteria must be met) for diagnosis of active multiple myeloma:

• Bone marrow clonal plasma cells ≥10% or bony or extramedullary plasmacytoma (confirmed by biopsy)
• One or more myeloma-defining events:
  • Serum calcium level >1 mg/dL higher than the upper limit of normal or >11 mg/dL
  • Renal insufficiency: creatinine >2 mg/dL or creatinine clearance <40 mL per minute
  • Anemia: hemoglobin <10 g/dL or hemoglobin >2 g/dL below the lower limit of normal
  • One or more osteolytic bone lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT

IMWG criteria also include any one of the following biomarkers of malignancy¹⁵:

• Clonal bone marrow plasma cells ≥60%
• sFLC ratio ≥100
• >1 focal lesions (≥5 mm)

IMWG criteria use CRAB features (hypercalcemia, renal failure, anemia, lytic bone lesions) for identification of end-organ damage and diagnosis of multiple myeloma.¹⁵ NCCN guidelines no longer use this terminology.⁶

In addition to routine laboratory testing such as complete blood count (CBC), erythrocyte sedimentation rate (ESR), and tests of liver and kidney function, studies for patients with or suspected multiple myeloma include¹¹

• Serum levels of creatinine, calcium, beta-2-microglobulin, lactate dehydrogenase (LDH), and albumin
• Total serum protein and serum electrophoresis (identification of monoclonal immunoglobulin)
• 24-hour urine for protein electrophoresis (urine monoclonal immunoglobulin)
• Measurement of sFLC ratio
• Bone marrow aspirate/biopsy for histopathological examination and cytogenetic studies

Serum electrophoresis may show monoclonal IgG or IgA, but any class of immunoglobulin may be identified.¹⁶ Reduced levels of normal immunoglobulins are consistent with a diagnosis of multiple myeloma.¹⁶ Excess serum free light chains, either kappa or lambda, may be present as in some cases the plasma cell clone only makes light chains.¹⁶

Staging

The Revised International Staging System (R-ISS) is commonly used to stage multiple myeloma and provides prognostic information:^15,17

• Stage 1: Serum-beta-2 microglobulin <3.5 mg/L, albumin ≥3.5 g/dL, normal LDH, and standard-risk cytogenetics
• Stage 2: Neither stage 1 nor stage 3
• Stage 3: Serum beta-2 microglobulin >5.5 mg/L and high-risk cytogenetics, ie, del(17p), and/or t(4;14), and/or t(14,16), or elevated LDH

A multicenter study reported that, of approximately 4,500 patients with newly diagnosed multiple myeloma, 36% were R-ISS stage 1, 37% were R-ISS stage 2, and 22% were R-ISS stage 3.¹⁷ The 5-year overall survival (OS) for patients was 82% (stage 1), 62% (stage 2), and 40% (stage 3).¹⁷

Treatment

Specific treatment for a person with multiple myeloma depends on the person’s general health status, the presence of comorbidities, and prognostic factors (eg, R-ISS stage).⁶

There is no cure for multiple myeloma, but some patients can achieve a stable remission, lasting for many years, with a combination of chemotherapy and autologous stem-cell transplantation.⁶ Patients who are not candidates for standard treatment can participate in clinical trials investigating new treatments. In addition, study of the molecular characteristics of multiple myeloma is leading to the development of new treatments such as immunotherapies with monoclonal antibodies that hold great promise for improving survival.¹⁸

Premalignant Features Indicating High Risk of Progression to Multiple Myeloma

Any one of these risk factors increases risk of progression to multiple myeloma from MGUS¹¹

• Monoclonal protein concentration of 2.5 g/dL: 49% risk of progression at 20 years
• Monoclonal IgM or IgA: higher risk of progression than monoclonal IgG
• Plasma cell bone marrow infiltration >5%
• Abnormal serum FLC ratio: increased risk of progression regardless of type and concentration of monoclonal protein

SMM (50% chance of progression at 2 years)¹¹

• Clonal plasma cell bone marrow infiltration ≥10%, serum monoclonal protein ≥3 g/dL, and sFLC ratio between 0.125 and 8
• Bence Jones proteinuria (positive 24-hour urine collection)
• Peripheral plasma cells >5×10⁶/L
• Cytogenetic findings: presence of t(4;14) or del17p, 1q24 gain, hyperdiploidy, gene expression profiling risk score > -0.26
• Imaging studies positive for new focal lesions, increase in size of existing focal lesion, new or progressive diffuse infiltration

Importance of Early Diagnosis and Prevention

Because initial symptoms of multiple myeloma can be nonspecific, diagnosis is frequently delayed and only made when a serious medical event occurs (eg, a pathological fracture).⁹ Unfortunately, around 60% of multiple myeloma cases are diagnosed at a late stage (R-ISS stage 2 or 3).¹⁷

The PROMISE Study is a multicenter study for persons who are at increased risk of developing multiple myeloma. This includes individuals self-identifying as being of black or African decent and those who have a precursor condition, or a close family member with a precursor condition such as lymphoma, leukemia, or Waldenström macroglobulinemia. The goal of the study is to learn how to prevent persons at increased risk from developing multiple myeloma.

How the Laboratory Can Help

Quest Diagnostics offers a comprehensive test menu for screening, diagnosis, and management of multiple myeloma, as well as the premalignant conditions MGUS and SMM.

The Myeloma Detection Panel, Basic (test code 38479) includes

• Protein Electrophoresis, Serum (test code 747)
• Immunofixation, Serum (test code 549)
• Kappa/Lambda Light Chains, Free, Serum (test code 11234); aka, sFLCs

The Myeloma Detection Panel, Comprehensive (test code 38480) also includes the basic panel components as well as

• Protein Electrophoresis, 24-Hour Urine (test code 750)
• Immunofixation, Urine (test code 213)

Panel components may be ordered separately.

Quest also offers testing for chromosomal anomalies associated with multiple myeloma, including

• FISH, Multiple Myeloma, 1q21(test code 91388)
• FISH, Multiple Myeloma, IGH/FGFR3, t(4;14) (test code 16872)
• FISH, Multiple Myeloma, IGH/MAFB, t(14;20) (test code 91387)
• FISH, Myeloma, Chromosomes CEP 9, 11, 15 (test code 92495)
• FISH, Myeloma, 17p-, rea 14q32 with Reflexes (test code 92497)

These tests were developed and their analytical performance characteristics have been determined by Quest Diagnostics. They have not been cleared or approved by FDA. The assays have been validated pursuant to the CLIA regulations and are used for clinical purposes.

Reflex testing will be performed at an additional charge with additional CPT code(s).

Quest also offers Multiple Myeloma, Daratumumab-Specific, Immunofixation (test code 94514) as an aid in selecting patients with multiple myeloma who are eligible for Darzalex^® (daratumumab) therapy.

The analytical performance characteristics of this assay have been determined by Quest Diagnostics. The modifications have not been cleared or approved by the FDA. This assay has been validated pursuant to the CLIA regulations and is used for clinical purposes.

More details can be found at

• QuestDiagnostics.com/Home/Physicians/Testing-Services/by-Test-Name/Companion-Diagnostics/Multiple-Myeloma-Daratumumab-Specific-Immunofixation-Offering/

And in the Test Directory

• TestDirectory.QuestDiagnostics.com

References

1. Dhodapkar MV. MGUS to myeloma: a mysterious gammopathy of underexplored significance. Blood. 2016;128(23):2599-2606. doi:10.1182/blood-2016-09-692954

2. van Nieuwenhuijzen N, Spaan I, Raymakers R, et al. From MGUS to multiple myeloma, a paradigm for clonal evolution of premalignant cells. Cancer Res. 2018;78(10):2449-2456. doi:10.1158/0008-5472.CAN-17-3115

3. Survival rate by stage for multiple myeloma. American Cancer Society. Reviewed January 21, 2021. Accessed June 25, 2021. https://www.cancer.org/cancer/multiple-myeloma/detection-diagnosis-staging/survival-rates.html

4. Ho M, Patel A, Goh CY, et al. Changing paradigms in diagnosis and treatment of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Leukemia. 2020;34(12):3111-3125. doi:10.1038/s41375-020-01051-x

5. Atkin C, Richter A, Sapey E. What is the significance of monoclonal gammopathy of undetermined significance? Clin Med (Lond). 2018;18(5):391-396. doi:10.7861/clinmedicine.18-5-391

6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®). Multiple Myeloma. Version 7.2021. April 26, 2021. https://www.nccn.org

7. Key statistics about multiple myeloma. American Cancer Society. Revised January 12, 2021. Accessed June 25, 2021. https://www.cancer.org/cancer/multiple-myeloma/about/key-statistics.html

8. Risk factors for multiple myeloma. American Cancer Society. Revised February 28, 2018. Accessed July 14, 2021. https://www.cancer.org/cancer/multiple-myeloma/causes-risks-prevention/risk-factors.html

9. Medical Masterclass contributors, Firth J. Haematology: multiple myeloma. Clin Med (Lond). 2019;19(1):58-60. doi:10.7861/clinmedicine.19-1-58

10. Walker BA, Mavrommatis K, Wardell CP, et al. Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma. Blood. 2018;132(6):587-597. doi:10.1182/blood-2018-03-840132

11. Mateos MV, Landgren O. MGUS and smoldering multiple myeloma: diagnosis and epidemiology. Cancer Treat Res. 2016;169:3-12. doi:10.1007/978-3-319-40320-5_1

12. 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;24(6):1121-1127. doi:10.1038/leu.2010.60

13. Landgren O, Hofmann JN, McShane CM, et al. Association of immune marker changes with progression of monoclonal gammopathy of undetermined significance to multiple myeloma. JAMA Oncol. 2019;5(9):1293-1301. doi:10.1001/jamaoncol.2019.1568

14. Rajkumar SV, Kumar S. Multiple myeloma current treatment algorithms. Blood Cancer J. 2020;10(9):94. doi:10.1038/s41408-020-00359-2

15. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-e548. doi:10.1016/S1470-2045(14)70442-5

16. Morrison T, Booth RA, Hauff K, et al. Laboratory assessment of multiple myeloma. Adv Clin Chem. 2019;89:1-58. doi:10.1016/bs.acc.2018.12.001

17. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863-2869. doi:10.1200/JCO.2015.61.2267

18. Pawlyn C, Davies FE. Toward personalized treatment in multiple myeloma based on molecular characteristics. Blood. 2019;133(7):660-675. doi:10.1182/blood-2018-09-825331

Models used for illustrative purposes only.

Published date: Aug 2021