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Understanding multiple myeloma for healthcare providers

  • Pathophysiology
  • Common symptoms
  • CRAB and SLiM criteria
  • Risk factors
  • Differential diagnosis
  • Importance of early detection

Introduction

What is multiple myeloma?

Multiple myeloma is a blood cancer caused by the clonal expansion of plasma cells in the bone marrow. It is the second-most common hematologic malignancy in the United States— and the most common among African Americans/Blacks1 —affecting more than 35,000 people per year.2 The cancer is characterized by bone lesions, renal injury, and laboratory abnormalities such as anemia and hypercalcemia. It can cause vague symptoms such as bone pain or fatigue that may overlap with comorbidities and more common age- or lifestyle-related diseases, resulting in diagnostic confusion or delay.1

 

While there is no cure for multiple myeloma, a variety of treatments exist, and many patients achieve years of progression-free survival.3 Survival has improved for patients with multiple myeloma over the past two decades, with more than 60% of patients now surviving 5 years or more after diagnosis.2

Standard laboratory testing can identify abnormalities indicative of multiple myeloma, meaning primary care providers (PCPs) may be the first healthcare providers to suspect the diagnosis. The majority of myeloma patients present to their PCP first for their symptoms, and visit their PCP three times on average before receiving a referral to hematology.1 Once patients present to their PCP, the mean time to get a diagnosis of myeloma is about 100 days.4

Early diagnosis and treatment can help patients avoid myeloma-related complications, preserve quality of life, and impact survival.5

Pathophysiology of multiple myeloma

In multiple myeloma, malignant plasma cells proliferate in the bone marrow. Over time, the clonal plasma cells destroy bone integrity, resulting in bone pain, osteolytic lesions, and fragility.6

Since plasma cells are responsible for producing antibodies, the clonal expansion of plasma cells seen in myeloma usually results in the excessive production of monoclonal proteins, called M proteins. These proteins, which can be in the form of free light chains and/or intact immunoglobulins (consisting of both heavy and light chains), are released into the blood.1

Although most patients with multiple myeloma have intact M protein in the blood, about 15-20% of patients only have free light chains, and <3% of patients secrete little or no monoclonal proteins at all.7 Tests that detect the presence of abnormal monoclonal protein, especially intact immunoglobulins (serum protein electrophoresis and immunofixation) and monoclonal excess of free light chains (serum free light chain assays), are therefore essential for myeloma diagnosis and together have diagnostic sensitivity of >99%.8

Precursors to multiple myeloma

Monoclonal gammopathy of undetermined significance (MGUS)

Multiple myeloma is preceded by a monoclonal gammopathy of undetermined significance (MGUS), a plasma cell disorder in which clonal plasma cells account for less than 10% of the bone marrow. In MGUS, there is no myeloma-related end-organ damage, but unfortunately most myeloma patients are not identified at this stage.9 MGUS prevalence in primarily White populations (aged 50+) is about 3.2%, but is estimated to be 2 to 3 times higher in Blacks/African Americans.10

About 1% of MGUS patients per year progress to multiple myeloma or another plasma cell or lymphoid disorder.11

Smoldering multiple myeloma (SMM)

As monoclonal plasma cells replicate, the condition may be classified as smoldering multiple myeloma, in which increased levels of M protein are detected in the blood, and 10%-60% of bone marrow is made up of clonal plasma cells, but no myeloma-related end-organ damage has occurred.9

About 51% of patients with smoldering myeloma progress to multiple myeloma within 5 years.12

Genetic and molecular mechanisms

The underlying cause of multiple myeloma is the topic of active study, but genetic causes of multiple myeloma have not been well established. However, being Black/African American or having a first-degree relative with the disease or other hematologic malignancy confers increased risk for diagnosis with myeloma, suggesting a genetic component.1,13 There are also high-risk cytogenetic features associated with progression to myeloma and more refractory disease.1

Common symptoms of multiple myeloma

Multiple myeloma symptoms can be nonspecific and vary from patient to patient. However, bone pain (often in the back) is one of the earliest symptoms of myeloma, with nearly half of patients (47.5%) reporting it to their care provider in the 2-year period leading up to diagnosis.14

Other common signs and symptoms of multiple myeloma include:1

  • Persistent pain in the lower back, hips and/or skull
  • Fatigue
  • Bruising or bleeding
  • Recurrent or lingering infections
  • Unintentional weight loss
  • Neuropathy
  • Elevated creatinine or renal insufficiency
  • Hypercalcemia
  • Lytic bone lesions, fractures, and osteoporosis
  • Raynaud phenomenon

Physicians should pursue further testing for myeloma when they suspect multiple myeloma based on laboratory abnormalities or other symptoms and be aware that having more than one symptom increases the likelihood of myeloma.15  

Understanding CRAB and SLiM in multiple myeloma

Key findings in physical examination and laboratory testing can suggest multiple myeloma.1  Common symptoms associated with myeloma, collectively known as the CRAB criteria, are considered in multiple myeloma diagnosis:1

C

HyperCalcemia

R

Renal insufficiency

A

Anemia

B

Bone lesions

The CRAB criteria have historically been used to identify myeloma, but they indicate advanced disease. To improve identification of patients at high risk of imminent end-organ damage, the SLiM criteria were adopted:9

S

Sixty percent or more clonal bone marrow plasma cells in a bone marrow biopsy

Li

Light chain ratio of involved-to-uninvolved light chains of at least 100 on serum free light chain (sFLC) testing, provided involved free light chains are at least 100 mg/L

M

MRI indicates at least one bone lesion

The diagnostic criteria for multiple myeloma requires a patient have at least 10% clonal bone marrow plasma cells or a biopsy-proven bony or extramedullary plasmacytoma and a myeloma defining event, defined as any single CRAB or SLiM criteria.9 However, laboratory testing can also identify patients with early-stage malignancy and precursors to myeloma; suspicion of and diagnostic testing for myeloma should not be reserved only for patients with evidence of advanced disease.14

Populations at risk for multiple myeloma

There are certain personal factors known to increase the risk of multiple myeloma:

  • Male sex2
  • Age of 65 or older2
  • Black/African American ancestry2
  • Personal history of MGUS9
  • Family history of multiple myeloma or another lymphohematopoietic cancer13
  • History of exposure to certain chemicals, such as Agent Orange16

Differential diagnosis

When evaluating patients for possible multiple myeloma, providers must consider other—often more common—diagnoses that could explain a patient’s symptoms. Multiple myeloma may be easily misdiagnosed, especially in patients with comorbidities that have overlapping signs and symptoms.1

Common conditions with overlapping symptoms include:1

  • Type 2 diabetes
  • Low back pain
  • Arthritis
  • Chronic kidney disease
  • Osteoporosis
Suspicion of multiple myeloma should prompt basic laboratory testing, including complete blood counts with differential and a serum biochemistry panel including electrolytes, creatinine, albumin, total protein and lactate dehydrogenase.1

Bone imaging and monoclonal protein tests such as serum protein electrophoresis (SPEP), immunofixation electrophoresis (IFE), serum free light chain (sFLC), and serum immunoglobulin (IgG, IgA, IgM) testing can also be ordered to aid in differential diagnosis.1,9,17,18

Results from these tests can help clinicians determine whether further work-up for multiple myeloma or another plasma cell disorder is merited, or whether another condition may explain the patient’s symptoms.1

Importance of early detection and diagnostics

Primary care providers play a key role in reducing diagnostic delay and identifying multiple myeloma at earlier stages in the disease course, which can improve disease-free survival, enhance treatment options, and help preserve quality of life.1,14,19 Patients who present with advanced disease or emergent complications such as spinal cord compression, severe infections, bone fractures, or renal failure have inferior outcomes.1

Prompt treatment is essential for improving outcomes in symptomatic myeloma. Patients with asymptomatic or premalignant diagnoses may require ongoing monitoring, and those with smoldering myeloma may be eligible for clinical trials.1

Prompt initiation of laboratory testing and proactive referral to hematology/oncology colleagues are important opportunities for PCPs to impact the diagnostic timeline and prognosis of their patients.1,17,19
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References
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  2. 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.
  3. Legarda MA et al. Recent advances in the treatment of patients with multiple myeloma. Cancers 2020 Nov 30;12(12):3576.
  4. Koshiaris C et al. Quantifying intervals to diagnosis in myeloma: a systematic review and meta-analysis. BMJ Open 2018 Jun 22;8(6):e019758.
  5. 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.
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  7. Kumar SK et al. Multiple myeloma. Nat Rev Dis Primers 2017; 3:17046. 
  8. Katzmann et al. Screening panels for detection of monoclonal gammopathies. Clin Chem. 2009 Aug;55(8):1517-22
  9. Rajkumar SV et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15(12):e538-e548.
  10. Wadhera RK & Rajkumar SV. Prevalence of monoclonal gammopathy of undetermined significance: a systematic review. Mayo Clin Proc 2010; 85:933-942.
  11. Kyle RA et al. Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance. N Engl J Med 2018 Jan 18;378(3):241-249.
  12. Kyle RA et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007 Jun 21;356(25):2582-90.
  13. 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
  14. Seesaghur A et al Clinical features and diagnosis of multiple myeloma: a population-based cohort study in primary care. BMJ Open 2021;11:e052759.
  15. 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.
  16. 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.
  17. 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; 2 Jan.
  18. Kumar SK et al. Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2023 Dec;21 12:1281-301.
  19. Kariyawasan et al. Multiple myeloma: causes and consequences of delay in diagnosis. QJM 2007 Oct;100(10):635-40.