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Multiple Myeloma for the Primary Care Provider: A Practical Review to Promote Earlier Diagnosis Among Diverse Populations

  • Joseph Mikhael
    Correspondence
    Corresponding author: Prof Joseph Mikhael, Translational Genomics Research Institute (TGen), 445 N. Fifth Street, Phoenix, AZ 85004, Phone: 602-343-8445
    Affiliations
    Applied Cancer Research and Drug Discovery Division at the Translational Genomics Research Institute (TGen), City of Hope Cancer Center, Phoenix, AZ, USA; International Myeloma Foundation, Studio City, CA, USA
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  • Manisha Bhutani
    Affiliations
    Department of Hematologic Oncology and Blood Disorders, Division of Plasma Cell Disorders, Atrium Health / Wake Forest Baptist, Levine Cancer Institute, Charlotte, NC, USA
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  • Craig E. Cole
    Affiliations
    Department of Medicine, Michigan State University-Karmanos Cancer Institute at McLaren Greater Lansing, Lansing, MI, USA
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Open AccessPublished:September 20, 2022DOI:https://doi.org/10.1016/j.amjmed.2022.08.030

      ABSTRACT

      Multiple myeloma is the second most common hematologic malignancy in the United States and the most common hematologic malignancy among Blacks/African Americans. Delay in diagnosis is common and has been associated with inferior disease-free survival and increased rates of myeloma-related complications. Despite a roughly two-times higher risk of multiple myeloma, diagnostic delay appears more common and improvements in 5-year survival rates have been slower among Blacks/African Americans than their White counterparts. When patient symptoms and basic laboratory findings are suggestive of multiple myeloma, the primary care provider should initiate extended laboratory work-up that includes serum protein electrophoresis, serum immunoglobulin free light chain assay, and serum immunofixation. Heightened awareness within high-risk populations such as Blacks/African Americans may help to eliminate racial disparities in the diagnosis and treatment of multiple myeloma.

      Keywords

      INTRODUCTION

      Multiple myeloma is a hematologic malignancy of terminally differentiated plasma cells in the bone marrow that can lead to destructive bone lesions, renal injury, and laboratory abnormalities such as anemia and hypercalcemia. Representing the second most common hematologic malignancy (behind Non-Hodgkin lymphoma),

      2022 estimates. American Cancer Society Cancer Statistics Center. Accessed April 3, 2022. https://cancerstatisticscenter.cancer.org/#!/

      multiple myeloma comprises 1.8% of all new cancer cases and 18% of all hematologic malignancies in the United States.

      Cancer stat facts: myeloma. National Institutes of Health Surveillance, Epidemiology, and End Results Program. Accessed May 24, 2022. https://seer.cancer.gov/statfacts/html/mulmy.html

      ,
      Multiple myeloma, version 5.2022.
      In 2022, an estimated 34 470 cases will be diagnosed and the malignancy will result in 12 640 deaths.
      Multiple myeloma is slightly more common in men than in women and is most frequently diagnosed among people aged 65-74 years.

      Cancer stat facts: myeloma. National Institutes of Health Surveillance, Epidemiology, and End Results Program. Accessed May 24, 2022. https://seer.cancer.gov/statfacts/html/mulmy.html

      The rate of new cases is over 2 times higher among Blacks/African Americans than Whites,

      Cancer stat facts: myeloma. National Institutes of Health Surveillance, Epidemiology, and End Results Program. Accessed May 24, 2022. https://seer.cancer.gov/statfacts/html/mulmy.html

      and Black/African American patients are younger, on average, at diagnosis than their White and Asian counterparts.
      • Ailawadhi S
      • Aldoss IT
      • Yang D
      • et al.
      Outcome disparities in multiple myeloma: a SEER-based comparative analysis of ethnic subgroups.
      ,
      • Waxman AJ
      • Mink PJ
      • Devesa SS
      • et al.
      Racial disparities in incidence and outcome in multiple myeloma: a population-based study.
      In fact, multiple myeloma is the most common hematologic cancer among Blacks/African Americans.

      Cancer stat facts: myeloma. National Institutes of Health Surveillance, Epidemiology, and End Results Program. Accessed May 24, 2022. https://seer.cancer.gov/statfacts/html/mulmy.html

      ,
      • Waxman AJ
      • Mink PJ
      • Devesa SS
      • et al.
      Racial disparities in incidence and outcome in multiple myeloma: a population-based study.
      In 2019, nearly 33 000 Blacks/African Americans were alive with the malignancy, with an incidence rate of 16.1 per 100 000 people.

      Cancer stat facts: myeloma. National Institutes of Health Surveillance, Epidemiology, and End Results Program. Accessed May 24, 2022. https://seer.cancer.gov/statfacts/html/mulmy.html

      An estimated 7810 new cases are expected to be diagnosed within the Black/African American population in 2022. Though Blacks /African Americans currently comprise only 14.2% of the total US population, it is estimated that they will comprise roughly 24% of the newly diagnosed multiple myeloma population by 2034.
      • Rosenberg PS
      • Barker KA
      • Anderson WF.
      Future distribution of multiple myeloma in the United States by sex, age, and race/ethnicity.
      The majority of patients diagnosed with multiple myeloma initially present to their primary care provider (PCP).
      • 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.
      ,
      • Kariyawasan CC
      • Hughes DA
      • Jayatillake MM
      • Mehta AB.
      Multiple myeloma: causes and consequences of delay in diagnosis.
      Unfortunately, the highly variable presentation of multiple myeloma often echoes signs and symptoms of conditions more commonly encountered by the generalist, such as diabetes, arthritis, and chronic renal insufficiency. This nonspecific presentation contributes to delays in both diagnosis and time to treatment. Early referral to hematology has the potential to improve survival and quality of life, underscoring the need for PCPs to be adept at recognizing typical signs and symptoms of multiple myeloma so that an appropriate diagnostic algorithm can be initiated. This review will summarize the pathophysiology, prognosis, and clinical presentation of the disease, while focusing on key diagnostic considerations for the general practitioner. Disparities between Black/African American and White patients in both disease characteristics and access to appropriate care will be discussed throughout.

      PATHOPHYSIOLOGY

      Abnormal, clonal myeloma cells primarily reside in the bone marrow and can invade adjacent bone, causing bone pain and fractures from associated skeletal destruction.
      • Kumar SK
      • Rajkumar V
      • Kyle RA
      • et al.
      Multiple myeloma.
      ,
      • Kyle RA
      • Gertz MA
      • Witzig TE
      • et al.
      Review of 1027 patients with newly diagnosed multiple myeloma.
      These cells typically secrete an intact, abnormal monoclonal immunoglobulin (M protein), which can lead to both hyperviscosity of the blood and renal failure.
      • Kyle RA
      • Gertz MA
      • Witzig TE
      • et al.
      Review of 1027 patients with newly diagnosed multiple myeloma.
      The complete M protein is not found in all cases of multiple myeloma, as myeloma cells secrete only monoclonal free light chains in up to 20% of patients (Figure 1).
      • Kumar SK
      • Rajkumar V
      • Kyle RA
      • et al.
      Multiple myeloma.
      Figure 1
      Figure 1Intact M protein and free light chain (FLC) structure. In MM, malignant plasma cells in the bone marrow secrete an abnormal immunoglobulin called M protein. Intact M protein is composed of 2 heavy chains and 2 light chains. In up to 20% of patients, only free light chains (FLCs) are present; these FLCs feature exposed epitopes that are targets of the serum FLC assay. Overproduced free light chains are of either the kappa or lambda type. Hence, monoclonality is suggested by an abnormal kappa:lambda ratio (<0.26 or >1.65).
      Multiple myeloma belongs to a class of disorders known as plasma cell dyscrasias, which include an often-progressive spectrum of conditions ranging from asymptomatic and premalignant states (monoclonal gammopathy of undetermined significance and smoldering multiple myeloma) to active, clinical disease. Monoclonal gammopathy of undetermined significance progresses to multiple myeloma or another lymphoproliferative disorder at a rate of roughly 1% per year,
      • Kyle RA
      • Larson DR
      • Therneau TM
      • et al.
      Long-term follow-up of monoclonal gammopathy of undetermined significance.
      whereas smoldering multiple myeloma progresses at a faster pace and in over 70% of patients at 15 years.
      • Kyle RA
      • Remstein ED
      • Therneau TM
      • et al.
      Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma.
      The presence of certain high-risk cytogenetic features, such as deletion of 17p [del(17p)] and translocation t(4;14), influence the likelihood of progression to multiple myeloma and are associated with more refractory disease.
      • Rajkumar SV
      • Gupta V
      • Fonseca R
      • et al.
      Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma.
      ,
      • Palumbo A
      • Avet-Loiseau H
      • Oliva S
      • et al.
      Revised International Staging System for multiple myeloma: a report from International Myeloma Working Group.
      As a key precursor to multiple myeloma, monoclonal gammopathy of undetermined significance presents at an earlier age and is up to 4 times more common among Blacks/African Americans, in whom the prevalence may be as high as 17%.
      • El-Khoury H
      • Lee DJ
      • Alberge JB
      • et al.
      Prevalence of monoclonal gammopathies and clinical outcomes in a high-risk US population screened by mass spectrometry: a multicentre cohort study.
      • Landgren O
      • Graubard BI
      • Kumar S
      • et al.
      Prevalence of myeloma precursor state monoclonal gammopathy of undetermined significance in 12372 individuals 10-49 years old: a population-based study from the National Health and Nutrition Examination Survey.
      • Landgren O
      • Weiss BM.
      Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis.
      The higher risk of both conditions among Blacks/African Americans with affected family members suggests that genetic predisposition may play a role in this population.
      • Landgren O
      • Weiss BM.
      Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis.
      • Brown LM
      • Linet MS
      • Greenberg RS
      • et al.
      Multiple myeloma and family history of cancer among blacks and whites in the U.S.
      • VanValkenburg ME
      • Pruitt GI
      • Brill IK
      • et al.
      Family history of hematologic malignancies and risk of multiple myeloma: differences by race and clinical features.

      PROGNOSIS

      The 5-year relative survival rate among all patients with multiple myeloma is 55.6%.

      Cancer stat facts: myeloma. National Institutes of Health Surveillance, Epidemiology, and End Results Program. Accessed May 24, 2022. https://seer.cancer.gov/statfacts/html/mulmy.html

      Survival has improved for patients over the last several decades with the advent of novel therapies including autologous stem cell transplant, immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies. However, improvement in survival rates was generally slower among Blacks/African Americans than Whites through 2012.
      • Waxman AJ
      • Mink PJ
      • Devesa SS
      • et al.
      Racial disparities in incidence and outcome in multiple myeloma: a population-based study.
      ,
      • Costa LJ
      • Brill IK
      • Omel J
      • Godby K
      • Kumar SK
      • Brown EE.
      Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States.
      Black race has been associated with underuse of transplant and novel medications such as the PI bortezomib.
      • Waxman AJ
      • Mink PJ
      • Devesa SS
      • et al.
      Racial disparities in incidence and outcome in multiple myeloma: a population-based study.
      ,
      • Fiala MA
      • Wildes TM.
      Racial disparities in treatment use for multiple myeloma.
      Underuse of these treatments significantly increases the hazard ratio for death among this population of patients.
      • Fiala MA
      • Wildes TM.
      Racial disparities in treatment use for multiple myeloma.
      Blacks are also less likely to receive other novel therapies, including the IMiDs lenalidomide and pomalidomide, as well as the PI carfilzomib.
      • Ailawadhi S
      • Parikh K
      • Abouzaid S
      • et al.
      Racial disparities in treatment patterns and outcomes among patients with multiple myeloma: a SEER-Medicare analysis.
      Triplet induction therapies, which may contain a PI, IMiD, or monoclonal antibody as well as dexamethasone, are preferred regimens for newly diagnosed patients,
      Multiple myeloma, version 5.2022.
      as they are more likely than doublet therapies to induce a response, slow disease progression, and extend survival.
      • Durie BGM
      • Hoering A
      • Abidi MH
      • et al.
      Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial.
      ,
      • Facon T
      • Kumar S
      • Plesner T
      • et al.
      Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma.
      Importantly, the use of frontline triplet induction therapy containing a PI and IMiD is less common in Blacks than Whites.
      • Derman BA
      • Jasielec J
      • Langerman SS
      • Zhang W
      • Jakubowiak AJ
      • Chiu BC.
      Racial differences in treatment and outcomes in multiple myeloma: a multiple myeloma research foundation analysis.
      Access barriers such as lower socioeconomic status, inadequate health insurance, and geographical location do not fully explain treatment disparities between Blacks/African Americans and Whites.
      • Fiala MA
      • Wildes TM.
      Racial disparities in treatment use for multiple myeloma.
      Additional contributors likely include structural barriers within the healthcare system (eg, bias among physicians, cultural barriers, a lack of coordination of care) as well as differences in individual decision-making that may be influenced by personal preferences or a general mistrust of the medical system.
      • Fiala MA
      • Wildes TM.
      Racial disparities in treatment use for multiple myeloma.
      When Blacks/African Americans receive equal access to care, their survival outcomes are equal and, in patients less than 65 years old, often better than their White counterparts.
      • Fillmore NR
      • Yellapragada SV
      • Ifeorah C
      • et al.
      With equal access, African American patients have superior survival compared to white patients with multiple myeloma: a VA study.
      This survival benefit has been partially attributed to more favorable cytogenetics, as African ancestry has been associated with a higher prevalence of low-risk cytogenetic features such as t(11;14) and a numerically lower prevalence of high-risk features such as del(17p).
      • Kazandjian D
      • Hill E
      • Hultcrantz M
      • et al.
      Molecular underpinnings of clinical disparity patterns in African American vs. Caucasian American multiple myeloma patients.
      ,
      • Baughn LB
      • Pearce K
      • Larson D
      • et al.
      Differences in genomic abnormalities among African individuals with monoclonal gammopathies using calculated ancestry.
      Contributions from other differences in disease biology are also suspected.
      • Fillmore NR
      • Cirstea D
      • Munjuluri A
      • et al.
      Lack of differential impact of del17p on survival in African Americans compared with White patients with multiple myeloma: a VA study.

      CLINICAL PRESENTATION

      Patients with multiple myeloma present with variable and oftentimes nonspecific symptoms (Figure 2). A study of 1027 patients found that bone pain and fatigue were present in 58% and 32% of patients, respectively, at diagnosis. Additional findings included anemia in 73% of patients, elevated creatinine in 48%, hypercalcemia in 13%, and bone abnormalities (primarily lytic lesions followed by fractures and osteoporosis) in 79%.
      • Kyle RA
      • Gertz MA
      • Witzig TE
      • et al.
      Review of 1027 patients with newly diagnosed multiple myeloma.
      These latter findings reflect the most typical “CRAB” (hypercalcemia, renal impairment, anemia, or lytic bone lesions) manifestations of multiple myeloma.
      • Rajkumar SV.
      Multiple myeloma: 2020 update on diagnosis, risk-stratification and management.
      Other common symptoms include neuropathy, repeated infections, unintentional weight loss, and bruising/bleeding.

      Signs and symptoms of multiple myeloma. American Cancer Society. Accessed March 13, 2022. https://www.cancer.org/cancer/multiple-myeloma/detection-diagnosis-staging/signs-symptoms.html

      Notably, Blacks/African Americans are more likely to present with certain markers of aggressive disease, including anemia and elevated lactate dehydrogenase.
      • Ailawadhi S
      • Jacobus S
      • Sexton R
      • et al.
      Disease and outcome disparities in multiple myeloma: exploring the role of race/ethnicity in the Cooperative Group clinical trials.
      • Schoen MW
      • Carson KR
      • Luo S
      • Sanfilippo KM.
      Outcomes in mutliple myeloma based on comorbidities and race.
      • Ailawadhi S
      • Frank RD
      • Sharma M
      • et al.
      Trends in multiple myeloma presentation, management, cost of care, and outcomes in the Medicare population: a comprehensive look at racial disparities.
      • Bhatnagar V
      • Wu Y
      • Goloubeva OG
      • et al.
      Disparities in black and white patients with multiple myeloma referred for autologous hematopoietic transplantation: a single center study.
      Figure 2
      Figure 2Key points to help the primary care provider recognize and test for multiple myeloma.
      • Kyle RA
      • Gertz MA
      • Witzig TE
      • et al.
      Review of 1027 patients with newly diagnosed multiple myeloma.
      ,

      Signs and symptoms of multiple myeloma. American Cancer Society. Accessed March 13, 2022. https://www.cancer.org/cancer/multiple-myeloma/detection-diagnosis-staging/signs-symptoms.html

      , Abbreviations: Ca, calcium; CBC, complete blood count; Hgb, hemoglobin; LDH, lactate dehydrogenase; MM, multiple myeloma; sFLC, serum free light chain assay; sIFE, serum immunofixation electrophoresis; SPEP, serum protein electrophoresis. aDefined as serum calcium ≥11 mg/dL. Corrected calcium can be calculated using the following equation: corrected calcium = serum calcium + 0.8 (4 - serum albumin). bDefined as serum creatinine ≥1.3 mg/dL. If a serum creatinine of ≥2 mg/dL is used as the cutoff for renal insufficiency, the incidence changes to 19%. cDefined as Hgb concentration ≤12 g/dL. SI conversion factors: To convert serum calcium to mmol/L, multiply values by 0.25; to convert serum creatinine to μmol/L, multiply values by 88.4; to convert Hgb to g/L, multiply values by 10.
      Many symptoms of multiple myeloma overlap with other conditions, including low back pain, diabetes, chronic kidney disease, and arthritis. Diabetes and multiple myeloma have multiple symptoms in common, including excessive thirst and urination, fatigue, frequent infections, and neuropathy. Similarly, without targeted testing, renal insufficiency caused by multiple myeloma can be difficult to distinguish from that caused by diabetes or chronic kidney disease. Bone pain or low back pain are often attributed to arthritis or osteoporosis and not taken seriously.
      Attributing symptoms of multiple myeloma to comorbidities has been associated with prolonging the diagnostic process.
      • Friese CR
      • Abel GA
      • Magazu LS
      • Neville BA
      • Richardson LC
      • Earle CC.
      Diagnostic delay and complications for older adults with multiple myeloma.
      ,
      • Koshiaris C
      • Oke J
      • Abel L
      • Nicholson BD
      • Ramasamy K
      Van den Bruel A. Quantifying intervals to diagnosis in myeloma: a systematic review and meta-analysis.
      This may be particularly problematic among Black/African American patients who, despite a younger mean age at diagnosis, present with a greater number of pre-existing comorbidities, including renal disease, diabetes, and mild liver disease.
      • Schoen MW
      • Carson KR
      • Luo S
      • Sanfilippo KM.
      Outcomes in mutliple myeloma based on comorbidities and race.
      ,
      • Blue BJ
      • Luo S
      • Sanfilippo KM
      • et al.
      Race-based differences in routine cytogenetic profiles of patients with multiple myeloma.
      Notably, the US Centers for Disease Control and Prevention estimates the crude prevalence of diabetes (diagnosed and undiagnosed) as higher among patients identified as Black, non-Hispanic than as White, non-Hispanic (17.4% vs 13.6%, respectively),

      Prevalence of both diagnosed and undiagnosed diabetes. United States Centers for Disease Control and Prevention. Updated December 29, 2021. Accessed April 26, 2022. https://www.cdc.gov/diabetes/data/statistics-report/diagnosed-undiagnosed-diabetes.html

      underscoring the heightened need for PCPs to be able to distinguish multiple myeloma symptoms from those caused by diabetes in this population.

      DIAGNOSIS

      Time to diagnosis and implications of delayed diagnosis

      The time between first symptom of multiple myeloma and actual diagnosis is often substantial, with a mean diagnostic interval (time from first presentation to diagnosis) of roughly 100 days.
      • Friese CR
      • Abel GA
      • Magazu LS
      • Neville BA
      • Richardson LC
      • Earle CC.
      Diagnostic delay and complications for older adults with multiple myeloma.
      ,
      • Koshiaris C
      • Oke J
      • Abel L
      • Nicholson BD
      • Ramasamy K
      Van den Bruel A. Quantifying intervals to diagnosis in myeloma: a systematic review and meta-analysis.
      A recent real-world analysis of 104 patients with newly diagnosed multiple myeloma found that 62% of patients experiencing diagnostic delay were African American.
      • Ghalehsari N
      • Kancharla P
      • Nimkar NS
      • et al.
      Are we asleep at the wheel in diagnosing of myeloma.
      Black patients have also been shown to be less likely than White patients to undergo a complete initial diagnostic evaluation, including Revised/International Staging System testing and proper imaging.
      • Notardonato LD
      • Langerman SS
      • Zhou J
      • Calip GS
      • Chiu BCH
      • Derman BA.
      Racial disparities in the diagnostic evaluation of multiple myeloma.
      Initial presentation for multiple myeloma is most commonly via primary care, and patients, on average, visit their PCP 3 times prior to hematology referral.
      • 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.
      The diagnostic interval is twice as long (6 vs 3 months) in patients presenting to their PCP vs a hematologist.
      • Kariyawasan CC
      • Hughes DA
      • Jayatillake MM
      • Mehta AB.
      Multiple myeloma: causes and consequences of delay in diagnosis.
      Delay in diagnosis has been associated with a higher incidence of myeloma-related complications and a significant decrease in disease-free survival, but not overall survival.
      • Kariyawasan CC
      • Hughes DA
      • Jayatillake MM
      • Mehta AB.
      Multiple myeloma: causes and consequences of delay in diagnosis.
      ,
      • Friese CR
      • Abel GA
      • Magazu LS
      • Neville BA
      • Richardson LC
      • Earle CC.
      Diagnostic delay and complications for older adults with multiple myeloma.
      ,
      • Goldschmidt N
      • Zamir L
      • Poperno A
      • Kahan NR
      • Paltiel O.
      Presenting signs of multiple myeloma and the effect of diagnostic delay on the prognosis.
      ,
      • Graziani G
      • Herget GW
      • Ihorst G
      • et al.
      Time from first symptom onset to the final diagnosis of multiple myeloma (MM) - possible risks and future solutions: retrospective and prospective 'Deutsche Studiengruppe MM' (DSMM) and 'European Myeloma Network' (EMN) analysis( ).
      Presenting with late-stage complications (eg, severe infection, spinal cord compression, fractures, renal failure) has been associated with inferior outcomes.
      • Elliss-Brookes L
      • McPhail S
      • Ives A
      • et al.
      Routes to diagnosis for cancer - determining the patient journey using multiple routine data sets.
      ,
      • Howell D
      • Smith A
      • Appleton S
      • et al.
      Multiple myeloma: routes to diagnosis, clinical characteristics and survival - findings from a UK population-based study.

      Testing and differential diagnosis

      In addition to findings of anemia, hypercalcemia, and elevated creatinine, routine laboratory testing may reveal other abnormalities including an elevated total protein level, low anion gap, low albumin, elevated lactate dehydrogenase, and elevated erythrocyte sedimentation rate. Key takeaways for the PCP are presented in Figure 2; expanded signs and symptoms of multiple myeloma as well as a full primary-care–appropriate diagnostic algorithm are provided in Figure 3.
      Figure 3
      Figure 3Inclusion of multiple myeloma in the differential diagnosis and primary care-appropriate diagnostic work-up. Abbreviations: CT, computed tomography; ESR, erythrocyte sedimentation rate; MM, multiple myeloma; MRI, magnetic resonance imaging; PET-CT, positron emission tomography-computed tomography. aWhere available and financially feasible, whole-body, low-dose CT is preferable to a basic skeletal survey due to improved sensitivity for detecting lytic lesions. When CT is not possible, a basic skeletal survey can be considered. When bony pain exists but CT does not detect lytic lesions, advanced imaging with PET-CT or MRI can be considered, though ordering of such imaging is generally reserved for hematology.
      When multiple myeloma is suspected based on clinical presentation and routine blood testing, serum protein electrophoresis and serum free light chain assays should be ordered to detect M protein and/or monoclonal excess of free light chains. Serum protein electrophoresis will separate serum proteins based on size and charge and provides a quantitative and relatively inexpensive, though somewhat insensitive, measure of serum M protein.
      • Leung N.
      Clinical tests for monoclonal proteins. Onco-Nephrology Curriculum.
      ,
      • Katzmann JA
      • Kyle RA
      • Benson J
      • et al.
      Screening panels for detection of monoclonal gammopathies.
      By targeting the hidden epitopes normally found at the interface of the heavy and light chains of an intact M protein (Figure 1), the serum free light chain assay detects both kappa and lambda free light chains. Though not specific for monoclonal light chains, monoclonality is inferred when an abnormal kappa:lambda ratio is found, with a ratio of <0.26 indicating a lambda clone and a ratio of >1.65 suggesting a kappa clone.
      • Leung N.
      Clinical tests for monoclonal proteins. Onco-Nephrology Curriculum.
      As 20% of patients with multiple myeloma will have light chains only,
      • Kumar SK
      • Rajkumar V
      • Kyle RA
      • et al.
      Multiple myeloma.
      adding serum free light chain testing to serum protein electrophoresis is critical and improves detection rates (Table 1) to the extent where reliance on burdensome 24-hour urine testing for detection of Bence Jones protein is eliminated.
      • Katzmann JA
      • Kyle RA
      • Benson J
      • et al.
      Screening panels for detection of monoclonal gammopathies.
      Additional testing should include serum immunofixation electrophoresis, a qualitative assay that detects the type of abnormal monoclonal protein (eg, IgA, IgM, IgG) and light chain type (kappa or lambda) present in the serum.
      • Leung N.
      Clinical tests for monoclonal proteins. Onco-Nephrology Curriculum.
      Though combining all 3 assays does not improve the diagnostic sensitivity for multiple myeloma (Table 1), it does increase the diagnostic sensitivity for monoclonal gammopathy of undetermined significance by 8% and smoldering multiple myeloma by 0.5%.
      • Katzmann JA
      • Kyle RA
      • Benson J
      • et al.
      Screening panels for detection of monoclonal gammopathies.
      Table 1Diagnostic sensitivity of various screening algorithms among 467 patients with multiple myeloma.
      • Katzmann JA
      • Kyle RA
      • Benson J
      • et al.
      Screening panels for detection of monoclonal gammopathies.
      Screening AlgorithmDiagnostic Sensitivity for Multiple Myeloma, No. (%)
      SPEP alone409 (87.6)
      sIFE alone441 (94.4)
      sFLC alone452 (96.8)
      SPEP + sIFE + uIFE461 (98.7)
      SPEP + sIFE + sFLC467 (100)
      SPEP + sFLC467 (100)
      Abbreviations: sFLC, serum free light chain; sIFE, serum immunofixation electrophoresis; SPEP, serum protein electrophoresis; uIFE, urine immunofixation electrophoresis.
      Where available and financially feasible, low-dose whole-body computed tomography (CT) should be considered, as it offers better sensitivity than a basic skeletal survey for the detection of osteolytic lesions, particularly within the spine and pelvis.
      • Hillengass J
      • Usmani S
      • Rajkumar SV
      • et al.
      International Myeloma Working Group consensus recommendations on imaging in monoclonal plasma cell disorders.
      Because lytic lesions only become visible on plain radiographs once 30% of the trabecular bone substance is lost,
      • Collins CD.
      Multiple myeloma.
      a skeletal survey should be reserved for instances where whole-body CT is not possible. In cases where bony pain is present but lytic lesions are absent on CT, advanced imaging with positron emission tomography CT (PET-CT) or magnetic resonance imaging (MRI) can be considered,
      • Rajkumar SV.
      Multiple myeloma: 2020 update on diagnosis, risk-stratification and management.
      though is typically reserved for ordering by the hematologist/oncologist.

      Referral of appropriate patients to hematology/oncology

      Detection of serum monoclonal protein, an abnormal free light chain ratio, and/or an elevated involved free light chain level may be suggestive of multiple myeloma or another plasma cell disorder. In the absence of overt signs and symptoms of multiple myeloma, these abnormalities may indicate the pre-malignant stages of either monoclonal gammopathy of undetermined significance or smoldering multiple myeloma. To establish a definitive diagnosis of a plasma cell disorder and determine the type of disorder (Table 2),
      • Rajkumar SV.
      Multiple myeloma: 2020 update on diagnosis, risk-stratification and management.
      ,
      • Rajkumar SV
      • Dimopoulos MA
      • Palumbo A
      • et al.
      International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.
      patients with abnormal serum protein electrophoresis and/or serum free light chain results should be referred to hematology/oncology, as should patients whose test results lead to diagnostic uncertainty. Presence of other signs or symptoms indicative of multiple myeloma (eg, bone pain, fatigue, or CRAB features) can be used to inform the urgency of the referral.
      Table 2International Myeloma Working Group diagnostic criteria for multiple myeloma and certain related plasma cell disorders.
      • Rajkumar SV.
      Multiple myeloma: 2020 update on diagnosis, risk-stratification and management.
      ,
      • Rajkumar SV
      • Dimopoulos MA
      • Palumbo A
      • et al.
      International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.
      DisorderDisorder Definition
      MGUS (non-IgM
      For diagnostic criteria associated with other types of MGUS (ie, IgM MGUS and light-chain MGUS), see Rajkumar et al 2014.52
      )
      All 3 criteria must be met:
      • Serum monoclonal protein (non-IgM type) <3 g/dL
      • Clonal bone marrow plasma cells <10%
        Bone marrow biopsy can be deferred in patients with low-risk MGUS (IgG-type, M protein <15 g/L, normal FLC ratio) who lack clinical features concerning for MM.
      • Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder
      SMMBoth criteria must be met:
      • Serum monoclonal protein (IgG or IgA) of ≥3 g/dL, or urinary monoclonal protein ≥500 mg/24 h, and/or clonal bone marrow plasma cells 10-60%
      • Absence of MDEs or amyloidosis
      MMBoth criteria must be met:
      • Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma
      • ≥1 of the following MDEs:
        • Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
          • Hypercalcemia: serum calcium >1 mg/dL higher than the ULN or >11 mg/dL
          • Renal insufficiency: CrCl <40 mL/min or serum creatinine >2 mg/dL
          • Anemia: Hgb of >2 g/dL below the LLN or <10 g/dL
          • Bone lesions: ≥1 osteolytic lesion(s) on skeletal radiography, CT, or PET-CT
        • Clonal bone marrow plasma cell percentage ≥60%
        • Involved:uninvolved sFLC ratio ≥100 (involved FLC level must be ≥100 mg/L)
        • >1 focal lesions on MRI (at least 5 mm in size)
      Solitary plasmacytomaAll 4 criteria must be met:
      • Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
      • Normal bone marrow with no evidence of clonal plasma cells
      • Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
      • Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) that can be attributed to a lympho-plasma cell proliferative disorder
      Abbreviations: CrCl, creatinine clearance; CT, computed tomography; FLC, free light chain; Hgb, hemoglobin; Ig, immunoglobulin; LLN, lower limit of normal; MDE, myeloma-defining events; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; MRI, magnetic resonance imaging; PET-CT, positron emission tomography-computed tomography; sFLC, serum free light chain; SMM, smoldering multiple myeloma; ULN, upper limit of normal. SI conversion factors: To convert serum calcium to mmol/L, multiply values by 0.25; to convert serum creatinine to μmol/L, multiply values by 88.4; to convert Hgb to g/L, multiply values by 10.
      a For diagnostic criteria associated with other types of MGUS (ie, IgM MGUS and light-chain MGUS), see Rajkumar et al 2014.52
      b Bone marrow biopsy can be deferred in patients with low-risk MGUS (IgG-type, M protein <15 g/L, normal FLC ratio) who lack clinical features concerning for MM.
      Prompt treatment is clearly indicated for multiple myeloma, and asymptomatic patients with intermediate or high-risk smoldering multiple myeloma may be eligible for treatment or clinical trials rather than monitoring.
      Multiple myeloma, version 5.2022.
      Similarly, monoclonal gammopathy of undetermined significance may indicate the presence of another plasma cell-related disorder (eg, immunoglobulin light-chain amyloidosis, light chain deposition disease, POEMS syndrome, monoclonal gammopathy of renal significance, or lymphoma) that can be appropriately diagnosed and managed by hematology/oncology. Notably, patients with low-risk monoclonal gammopathy of undetermined significance (eg, those with small M protein spikes <1.5 g/dL, IgG-type, and normal free light chain ratio) may be considered for follow up within primary care, as they do not routinely require bone marrow examination or extensive imaging.
      • 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.
      Such patients should be followed with serum protein electrophoresis at 6 months and, if stable, every 2 to 3 years unless symptoms suggestive of a plasma cell malignancy arise.
      • 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.
      Upon hematology/oncology referral, a bone marrow biopsy will likely be used to determine clonal bone marrow plasma cell percentage.
      • Rajkumar SV
      • Dimopoulos MA
      • Palumbo A
      • et al.
      International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.
      Urine evaluation (via a 24-hour urine sample and urine protein electrophoresis) may be used to monitor disease and detect albuminuria, while advanced imaging can help judge the extent of skeletal involvement.
      • Rajkumar SV.
      Multiple myeloma: 2020 update on diagnosis, risk-stratification and management.
      Together with serum free light chain results, bone marrow biopsy and MRI results can be used to diagnose multiple myeloma in patients who lack traditional CRAB features. These additional “SLiM” criteria (greater than or equal to Sixty percent clonal plasma cells in the bone marrow; involved:uninvolved free light chain ratio of ≥100 with the involved free light chain being ≥100 mg/L; MRI with more than one focal marrow lesion) were added to the diagnostic criteria in 2014 (Table 2); each of these criteria is associated with an approximately 80% risk of progression to symptomatic end-organ damage.
      • Rajkumar SV.
      Multiple myeloma: 2020 update on diagnosis, risk-stratification and management.
      ,
      • Rajkumar SV
      • Dimopoulos MA
      • Palumbo A
      • et al.
      International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.
      The diagnosis of multiple myeloma requires evidence of either 10% or more clonal plasma cells in the bone marrow or a biopsy-proven plasmacytoma. In addition, 1 or more myeloma-defining events (any of the traditional CRAB criteria or any of the SLiM criteria added in 2014) must be present (Table 2).
      • Rajkumar SV.
      Multiple myeloma: 2020 update on diagnosis, risk-stratification and management.
      ,
      • Rajkumar SV
      • Dimopoulos MA
      • Palumbo A
      • et al.
      International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.
      If the diagnosis of multiple myeloma is made, additional work-up used to determine prognosis and stage of disease will include fluorescent in situ hybridization to detect high-risk cytogenetic abnormalities [eg, t(4;14), t(14;16) or del(17p)], serum β2 microglobulin, and lactate dehydrogenase.
      • Palumbo A
      • Avet-Loiseau H
      • Oliva S
      • et al.
      Revised International Staging System for multiple myeloma: a report from International Myeloma Working Group.

      FUTURE DIRECTIONS FOR CARE

      To avoid unnecessary anxiety for patients and financial toxicity to both patients and the health care system, heightened awareness of multiple myeloma must be accompanied by the appropriate level of discretion for testing. Routine screening is not currently recommended, as it can lead to overtesting and overdiagnosis of monoclonal gammopathy of undetermined significance, which requires costly annual monitoring and can negatively impact quality of life.
      • Go RS
      • Swanson KM
      • Sangaralingham LR
      • Habermann EB
      • Shah ND.
      Clinical prevalence (diagnosed cases) of monoclonal gammopathy of undetermined significance in the US: estimating the burden on health care.
      • Hildebrandt MAT
      • Callender RA
      • Belachew AA
      • et al.
      Quality of life and cancer worry in a follow-up cohort of patients with asymptomatic monoclonal gammopathies.
      • Koshiaris C.
      Methods for reducing delays in the diagnosis of multiple myeloma.
      Interestingly, recent research suggested that screening for monoclonal gammopathy of undetermined significance among patients at high risk for progression to multiple myeloma (eg, Black/African Americans or first-degree relatives of patients with hematologic malignancies) may be appropriate, and that such screening may not increase cancer-related worry or compromise quality of life.
      • El-Khoury H
      • Alberge J-B
      • Barr H
      • et al.
      High prevalence of monoclonal gammopathy in a population at risk: the first results of the Promise study.
      A recent study found that investigations to evaluate all CRAB criteria for multiple myeloma were underused in the primary care setting.
      • Seesaghur A
      • Petruski-Ivleva N
      • Banks VL
      • et al.
      Clinical features and diagnosis of multiple myeloma: a population-based cohort study in primary care.
      Diagnostic pathways aided by electronic medical record (EMR) functionality and/or artificial intelligence may assist PCPs in evaluating appropriate patients for possible multiple myeloma. Clinical prediction rules that estimate a patient's risk of disease and trigger interventions can be built into EMR systems. These have been shown to reduce time to diagnosis in colorectal and prostate malignancies,
      • Murphy DR
      • Wu L
      • Thomas EJ
      • Forjuoh SN
      • Meyer AN
      • Singh H.
      Electronic trigger-based intervention to reduce delays in diagnostic evaluation for cancer: a cluster randomized controlled trial.
      and recently developed prediction rules for multiple myeloma show promise but must be validated.
      • Koshiaris C
      • Van den Bruel A
      • Nicholson BD
      • Lay-Flurrie S
      • Hobbs FR
      • Oke JL.
      Clinical prediction tools to identify patients at highest risk of myeloma in primary care: a retrospective open cohort study.
      EMRs that facilitate consultation with a hematologist/oncologist may expedite diagnosis of multiple myeloma; such “E-consults” to hematology have been shown to aid in the evaluation of monoclonal gammopathy of undetermined significance.
      • Burwick N
      • Stein J
      • Garcia DA
      • Broudy VC
      • Richard RE.
      Monoclonal gammopathies: electronic subspecialty consultation.
      Various artificial intelligence techniques are being investigated for their ability to integrate routine laboratory results into screening models to expedite diagnosis.
      • Yan W
      • Shi H
      • He T
      • et al.
      Employment of artificial intelligence based on routine laboratory results for the early diagnosis of multiple myeloma.
      In addition to utilizing appropriate and validated advances in technology, the ability of PCPs to improve multiple myeloma diagnostic speed and accuracy is likely to be informed by future research and influenced by heightened educational efforts. Most publications detailing time to diagnosis, impacts of diagnostic delay on outcomes, and disparities in access to novel and improved therapies (particularly within the Black/African American population) arise from data collected over a decade ago. Recent research presented at conferences
      • 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.
      ,
      • Notardonato LD
      • Langerman SS
      • Zhou J
      • Calip GS
      • Chiu BCH
      • Derman BA.
      Racial disparities in the diagnostic evaluation of multiple myeloma.
      have presented emerging data on these topics and their associated publications are eagerly awaited.

      CONCLUSION

      As the majority of patients diagnosed with multiple myeloma initially present to their PCP, generalists must be adept at recognizing typical signs and symptoms of the disease, with a heightened awareness among particularly high-risk groups such as Blacks/African Americans. When multiple myeloma is included in the differential diagnosis, a basic initial testing strategy that includes a complete blood count, basic chemistry, serum protein electrophoresis, serum free light chain assay, and serum immunofixation electrophoresis can expedite early referral to a hematologist/oncologist and prevent delays in both accurate diagnosis and treatment.

      CLINICAL SIGNIFICANCE

      • Most patients diagnosed with multiple myeloma see their primary care provider several times prior to hematology referral.
      • A series of protein assays can dramatically increase the diagnostic sensitivity for multiple myeloma and may prevent delays in treatment.
      • Blacks/African Americans are less likely than Whites to receive a full diagnostic workup for multiple myeloma.
      • When access to healthcare is equal, Blacks/African Americans have equivalent, if not better, myeloma outcomes than Whites.

      AUTHORSHIP

      All authors participated in the preparation of this manuscript.

      Funding

      Medical writing support was funded by Sanofi.

      CONFLICT OF INTEREST

      JM: Consulting or Advisory role – Amgen, BMS, GSK, Janssen, Karyopharm, Sanofi, and Takeda. MB: None. CEC: Honoraria – AstraZeneca, PRIME Education, Sanofi, and Oncopeptides; research funding – GSK.

      ACKNOWLEDGMENTS

      Medical writing support was provided by Lindsay Gasch, PharmD, and Camile Semighini Grubor, PhD, of Elevate Scientific Solutions, contracted by Sanofi for publication support services.

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