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Overview of
Multiple Myeloma

Diagnosis

Treatment

Supportive Care

Lifestyle Issues

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Overview of Multiple Myeloma

Multiple myeloma is a systemic malignancy of plasma cells that typically involves multiple sites within the bone marrow that secrete all or part of a monoclonal antibody.1 Abnormal accumulation of these monoclonal plasma cells in the bone marrow causes the primary characteristics of multiple myeloma2:

  1. Interference with primary bone marrow function leading to anemia and/or low white blood cell or platelet counts
  2. Bone destruction surrounding the bone marrow cavity
  3. Production of monoclonal proteins that are released into the blood and/or urine
  4. Reduced immune function indicated by decreased levels of normal immunoglobulins and increased susceptibility to infection

References:

  1. National Cancer Institute. Plasma cell neoplasms (including multiple myeloma) treatment (PDQ®). http://www.cancer.gov/cancertopics/pdq/treatment/myeloma/healthprofessional. Accessed August 14, 2014.
  2. Durie BGM. Concise review of the disease and treatment options: multiple myeloma cancer of the bone marrow. 2011/2012 ed. International Myeloma Foundation website. http://myeloma.org/pdfs/CR2011-Eng_b1.pdf. Accessed May 15, 2014.


Downloadable Tip Sheet: Multiple Myeloma Overview

Multiple Myeloma Overview Video

 

More than 90% of patients present with increased (≥10%) clonal bone marrow plasma cells and circulating monoclonal proteins in serum and/or urine as measured by immunofixation (or immunofixation plus serum free light chain assay). Other presenting characteristics include anemia; lytic bone lesions and pathologic fractures resulting in symptoms of bone pain; fatigue; weakness; renal insufficiency; hypercalcemia; weight loss; and paresthesias.1,2

References:

  1. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23(1):3-9.
  2. Nau KC, Lewis WD. Multiple myeloma: diagnosis and treatment. Am Fam Physician. 2008;78(7):853-859.

 

Downloadable Tip Sheet: CRAB Criteria

Multiple Myeloma Overview Video

CRAB Criteria Video

Myelosuppression Video

The most significant risk factor for multiple myeloma is age: 96% of cases are diagnosed in people older than 45 years, and more than 63% are diagnosed in people older than 65 years. Thus, it is thought that susceptibility to myeloma may increase with the aging process.1 The median patient age at diagnosis is 69 years.2 Men, and patients with African heritage, are at greater risk than women and whites.2 Other risk factors include exposure to radiation and environmental toxins, such as pesticides, herbicides, and petroleum products.1 Multiple myeloma may develop in individuals without these risk factors.1

References:

  1. Multiple Myeloma Research Foundation. Newly diagnosed patients: what is multiple myeloma? http://www.themmrf.org/living-with-multiple-myeloma/newly-diagnosed-patients/what-is-multiple-myeloma/. Accessed May 15, 2014.
  2. National Cancer Institute. SEER Cancer Statistics Review 1975-2011. http://seer.cancer.gov/csr/1975_2011/results_merged/sect_01_overview.pdf. Accessed May 15, 2014.

 

Multiple Myeloma Overview Video

Monoclonal gammopathy of undetermined significance (MGUS) is condition that may precede multiple myeloma.1 Patients with MGUS have monoclonal protein present without evidence of end organ damage (CRAB criteria [Calcium elevation, Renal dysfunction, Anemia, Bone disease]).2 The rate of progression from MGUS to multiple myeloma is 0.5% to 1% per year.2

Smoldering multiple myeloma (SMM) is the stage of the disease with no symptoms and no related organ or tissue impairment with one or more of the following criteria present2:

  • Higher level of serum monoclonal protein than MGUS (≥30 g/L)
  • Urinary monoclonal protein ≥500 mg per 24 hours
  • Bone marrow monoclonal plasma cells 10% to 60%

Patients with higher risk features in SMM have a 40% risk of progression to active myeloma.Transition from MGUS or SMM to multiple myeloma is characterized by increases in the number of multiple myeloma cells, angiogenesis, and osteolytic lesions.1

Active multiple myeloma is defined by the presence of clonal bone marrow cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma along with the presence of CRAB features or biomarkers of malignancy.2

In 2014, the International Myeloma Working Group made the following updates to the diagnostic criteria of multiple myeloma2:

  • Added biomarkers of malignancy to the disease definition in addition to the existing criteria of end organ damage (CRAB features)
  • Updated laboratory and radiographic results for the criteria of CRAB features
  • Revised histological and monoclonal protein requirements for diagnosis

A single pathological or molecular feature cannot be used to differentiate patients with SMM with only clonal premalignant plasma cells versus patients with clonal malignant cells.2 Inclusion of biomarkers in the updated disease definition accounts for those patients with SMM who are at high risk of developing CRAB features.2

NAME DEFINITION2,3
Non-IgM Monoclonal
Gammopathy of
Undetermined
Significance (MGUS)
  • Serum monoclonal protein present <30 g/L
  • Absence of end organ damage (CRAB features)
  • Clonal bone marrow plasma cells <10%
Smoldering Multiple Myeloma
(SMM)

Both criteria must be met:

  • Serum monoclonal protein ≥30 g/L or urinary
    monoclonal protein ≥500 mg per 24 hours and/or
    clonal bone marrow plasma cells 10%-60%
  • Absence of myeloma defining events (CRAB
    features) or amyloidosis
Multiple Myeloma
  • Clonal bone marrow cells ≥10% or biopsy-proven
    bony or extramedullary plasmacytoma and one or
    more of the following:
  • One or more CRAB features and/or indicators
    of organ damage* or
  • One or more biomarkers of malignancy:
    • Clonal bone marrow plasma cell percentage
      ≥60%
    • Involved:uninvolved serum free light chain ratio ≥100
    • >1 focal lesions on MRI studies
*Organ damage classified as “CRAB” or any other significant clinical problem linked to
myeloma progression such as recurrent infections or neuropathy unrelated to treatment
C – calcium elevation (>11 mg/dL)
R – renal dysfunction (creatinine >2 mg/dL or creatine clearance <40 mL/min)
A – anemia (hemoglobin <10 g/dL or >2 g/dL decrease from patient’s normal)
B – bone disease (lytic lesions shown on skeletal radiography, CT, or PET/CT)
One or more CRAB features or other significant problem required for diagnosis of
Multiple Myeloma
IgM, immunoglobulin; MRI, magnetic resonance imaging; CT, computed tomography;
PET, postiron emission tomography.

Reprinted from Durie BGM. Patient Handbook. 2015 ed. International Myeloma Foundation website:
http://myeloma.org/pdfs/PHB.pdf. Accessed October 1, 2015.
© International Myeloma Foundation (IMF), Patient Handbook 2015, www.myeloma.org, 800-452-CURE.

References:

  1. Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer. 2002;2(3):175-187.
  2. 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.
  3. Durie BGM. Patient handbook. 2015 ed. International Myeloma Foundation website. http://myeloma.org/pdfs/PHB.pdf. Accessed October 1, 2015.

 

Downloadable Tip Sheet: Multiple Myeloma Overview

Multiple Myeloma Overview Video

CRAB Criteria Video

Normal plasma cells produce immunoglobulins or antibodies which are made up of light chains and heavy chains.1 In myeloma, malignant plasma cells overproduce a specific antibody/immunoglobulin (monoclonal protein).1 Plasma cells tend to produce light chains in greater numbers than heavy chains, which results in free light chains (FLCs) circulating in the bloodstream.1 The quantity of FLC production is a marker of the activity of myeloma or the growth of plasma cells.1

Urine-based and plasma-based tests that detect and evaluate monoclonal protein levels, including the serum FLC assay, are part of a panel of tests recommended by the National Comprehensive Cancer Network (NCCN) guidelines for a patient’s initial diagnostic workup and for monitoring response to treatment.2 The use of serum FLC assays may reveal responses to treatment earlier than serum protein electrophoresis (SPEP); and because of its increased sensitivity compared with immunofixation electrophoresis, serum FLC may enable earlier detection of relapse.1

Recently, the US Food and Drug Administration cleared the HevyliteTM test as an in vitro test of heavy and light chains in serum3 that can be used for monitoring previously diagnosed patients with multiple myeloma.4

References:

  1. International Myeloma Foundation. Understanding serum free light chain assays. http://myeloma.org/pdfs/U-Freelite-Eng2011_g2web.pdf. Accessed May 28, 2014.
  2. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma. v2.2016. http://www.nccn.org. Accessed November 9, 2015.
  3. U.S. Food and Drug Administration. HevyliteTM test: 510(k) substantial equivalence determination decision summary. http://www.accessdata.fda.gov/cdrh_docs/reviews/K113823.pdf. Accessed July 7, 2014.
  4. Kraj M. Immunoglobulin heavy chain/light chain pairs (Hlc, Hevylite™) assays for diagnosing and monitoring monoclonal gammopathies. Adv Clin Exp Med. 2014;23(1):127-133.

Diagnosis

According to the National Comprehensive Cancer Network (NCCN) guidelines for multiple myeloma, the initial diagnostic workup includes a history and physical as well as a complete blood count with differential and platelet counts, blood urea nitrogen (BUN), serum creatinine, serum electrolytes, serum calcium, albumin, lactate dehydrogenase (LDH), and beta-2 microglobulin.1 Increases in BUN and creatinine signal renal impairment.1 LDH levels help assess tumor cell burden. Beta-2 microglobulin levels reflect tumor mass and burden.1

A myeloma panel includes protein electrophoresis (serum [SPEP] or urine [UPEP]), immunofixation electrophoresis (serum [SIFE] or urine [UIFE]), quantitative immunoglobulin levels, serum free light chain assay, and 24-hour urine for total protein.1 Once the myeloma or monoclonal protein assay is complete, it is important to continue using the same test to obtain accurate measures against the baseline.1 Serum immunofixation electrophoresis is roughly 10-fold more sensitive to monoclonal protein detection than serum protein electrophoresis.2

A skeletal survey is recommended by the NCCN guidelines for multiple myeloma as part of the initial diagnostic workup, and magnetic resonance imaging (MRI), computed tomography (CT) scan, and positron emission tomography (PET)/CT may be useful under some circumstances.1 In addition, the International Myeloma Foundation recommends MRIs and CT scans are used to assess bone when X-rays are negative and/or for more detailed imaging of particular areas.3 PET/CT combined scans provide a sensitive whole-body scanning technique.3 Unilateral bone marrow aspirate and biopsy, including bone marrow immunohistochemistry and/or bone marrow flow cytometry, cytogenetics, and fluorescence in situ hybridization (FISH) are also recommended.1

References:

  1. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma. v2.2016. http://www.nccn.org. Accessed November 9, 2015.
  2. Jenner E. Serum free light chains in clinical laboratory diagnostics. Clinica Chimica Acta. 2014;427:15-20.
  3. Durie BGM. Patient handbook. 2015 ed. International Myeloma Foundation website. http://myeloma.org/pdfs/PHB.pdf. Accessed October 1, 2015.

In 2015 the International Myeloma Working Group updated the staging system for multiple myeloma to include former International Staging System criteria. The staging system now includes chromosomal abnormalities as detected by interphase fluorescent in situ hybridization and serum lactate dehydrogenase.1

REVISED INTERNATIONAL STAGING SYSTEM1
R-ISS Stage Stage Criteria Criterion Definitions
l ISS stage l and Serum β2-microglobulin <3.5 mg/L, serum albumin ≥3.5 g/dL
Standard-risk CA by iFISH and No high-risk CA
Normal LDH Serum LDH
ll Not R-ISS stage l or lll
lll ISS stage lll and either Serum β2-microglobulin ≥5.5 mg/L
High-risk CA by iFISH or Presence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16)
High LDH Serum LDH >upper limit of normal
R-ISS, revised International Staging System; ISS, International Staging System; CA,
chromosomal abnormalities; iFISH, interphase fluorescent in-situ hybridization; LDH,
lactate dehydrogenase.
Adapted from Palumbo A et al. J. Clin Oncol. 2015;33(26):2863-2869.1

The Durie/Salmon PLUS staging system (2003) is also used in the classification of multiple myeloma (see table below for stage definitions).2

DURIE/SALMON PLUS STAGING SYSTEM (PLUS INCLUDES IMAGING)2
MGUS
  • Negative MRI and/or FDG PET
  • Low M-protein in serum and/or urine
  • Monoclonal bone marrow plasma cells <10%
  • Normal serum calcium, hemoglobin level, and serum creatinine
  • No bone lesions on full skeletal X-ray survey and/or other imaging
  • No clinical or laboratory features of amyloidosis or light-chain
    deposition disease
Stage lA
Smoldering
or lndolent
  • Single plasmacytoma and/or limited disease from imaging tests can be present
  • M-protein in serum and/or urine
  • Monoclonal plasma cells in bone marrow and/or tissue
  • Serum creatinine <2.0 mg/dL + no EMD
  • Not meeting criteria for MGUS, multiple myeloma, or solitary
    plasmacytoma of bone or soft tissue
Stage lB
Multiple
Myeloma
  • Mild diffuse disease
  • <5 focal lesions
  • Serum creatinine >2.0 mg/dL + EMD
  • ≥10% monoclonal plasma cells in bone marrow and/or plasmacytoma
  • M-protein in serum and/or urine
  • 1 or more CRAB criteria present
Stage ll A/B
  • Moderate diffuse disease
  • 5-20 focal lesions
  • Serum creatinine <2.0 mg/dL + no EMD
  • Serum creatinine >2.0 mg/dL + EMD
  • ≥10% monoclonal plasma cells in bone marrow and/or plasmacytoma
  • M-protein in serum and/or urine
  • 1 or more CRAB criteria present
Stage lll A/B
  • Severe diffuse disease
  • >20 focal lesions
  • Serum creatinine <2.0 mg/dL + no EMD
  • Serum creatinine >2.0 mg/dL + EMD
  • ≥10% monoclonal plasma cells in bone marrow and/or plasmacytoma
  • M-protein in serum and/or urine
  • 1 or more CRAB criteria present
MGUS, monoclonal gammopathy of undetermined significance; MRI, magnetic
resonance imaging; FDG PET, fluorodeoxyglucose positron emission tomography;
M-protein, monoclonal protein; EMD, extramedullary disease; CRAB, Calcium
elevation; Renal dysfunction; Anemia; Bone disease.

Durie BGM et al. Hematol J. 2003;4(6):379-398.2

References:

  1. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: a report from the International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863-2869.
  2. Durie BGM, Kyle RA, Belch A, et al; Scientific Advisors of the International Myeloma Foundation. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. Hematol J. 2003;4(6):379-398.

Multiple myeloma causes an imbalance resulting in increased osteoclast activation (bone damage) and inhibition of osteoblast formation (bone building).1 An estimated 90% of patients living with multiple myeloma will develop osteolytic bone lesions.2 Bone lesions can lead to fractures, pain, spinal cord compression, hypercalcemia, and renal dysfunction.2

References:

  1. Bladé J, Rosiñol L. Complications of multiple myeloma. Hematol Oncol Clin N Am. 2007;21(6):1231-1246.
  2. Bilotti E, Faiman BM, Richards TA, et al; International Myeloma Foundation Nurse Leadership Board. Survivorship care guidelines for patients living with multiple myeloma: consensus statements of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs. 2011;15(4 suppl):5-8.

 

Downloadable Tip Sheet: CRAB Criteria

CRAB Criteria Video

Renal insufficiency is associated with multiple myeloma.1 Elevated plasma cell excretion of monoclonal gammopathies causes renal failure by (1) light chain excretion; (2) immunoglobulin tissue deposition (eg, systemic amyloidosis); and (3) tubular dysfunction (Fanconi syndrome).1 Light chain tubular damage or “myeloma kidney” is the main cause of renal failure, and the presence of myeloma casts in the distal tubes and collecting ducts is the characteristic feature of myeloma kidney.1,2 Renal insufficiency is reversible in 20% to 60% of patients with appropriate multiple myeloma treatment.1 Predictive factors of recovery include serum creatinine <4 mg/dL, 24-hour urine protein excretion <1 g/24 h, and serum calcium ≥11.5 mg/dL.1,3

References:

  1. Bladé J, Rosiñol L. Complications of multiple myeloma. Hematol Oncol Clin N Am. 2007;21(6):1231-1246.
  2. Hill GS, Morel-Maroger L, Méry JP, Brouet JC, Mignon F. Renal lesions in multiple myeloma: their relationship to associated protein abnormalities. Am J Kidney Dis. 1983;2(4):423-438.
  3. Bladé J, Fernández-Llama P, Bosch F, et al. Renal failure in multiple myeloma. Arch Intern Med. 1998;158:1889-1893.

 

Downloadable Tip Sheet: CRAB Criteria

CRAB Criteria Video

Osteopenia describes reduced bone density that does not qualify as osteoporosis.1 Osteopenia can be detected by a bone density test.2 Osteolytic lesions are the result of increased bone resorption without increases in bone formation.2 Osteolytic lesions can be detected by a positron emission tomography/computed tomography (PET/CT) scan or skeletal survey.2

References:

  1. MedlinePlus. Osteopenia. U.S. National Library of Medicine website. http://vsearch.nlm.nih.gov/vivisimo/cgi-bin/query-meta?v%3Aproject=medlineplus&query=osteopenia&x=0&y=0. Accessed July 23, 2014.
  2. Miceli TS, Colson K, Faiman BM, Miller K, Tariman JD; International Myeloma Foundation Nurse Leadership Board. Maintaining bone health in patients with multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs. 2011;15(4 suppl):9-23.

Treatment Considerations/Response Criteria

Prior to beginning therapy, a patient diagnosed with multiple myeloma will be evaluated for stem cell transplant eligibility. This eligibility will determine initial treatment regimens. It is recommended that patients who are eligible for stem cell transplants should avoid alkylating agents (most notably melphalan) prior to the stem cell harvest. Refer to the National Comprehensive Cancer Network (NCCN) guidelines for preferred primary therapies for patients based on stem cell transplant eligibility.1

Reference:

  1. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma. v2.2016. http://www.nccn.org. Accessed November 9, 2015.

Although stem cell transplant is standard practice in the treatment of multiple myeloma, not all patients are eligible.1,2 Age, physical health, and performance status determine eligibility. Factors that may render a patient ineligible include age >77 years, direct bilirubin >2.0 mg/dL, serum creatinine >2.5 mg/dL unless the patient is on chronic stable dialysis, performance status of 3 or 4 on the Eastern Cooperative Oncology Group scale unless it is due to bone pain, or a New York Heart Association Functional Status Class III (cardiac disease causing marked limitations in physical activity) or Class IV (cardiac disease causing an inability to perform physical activity without discomfort).2,3 These criteria are considered guidelines, and patients and healthcare providers should work together to determine the optimal course of action.2

References:

  1. Rajkumar SV. Treatment of myeloma: cure vs control. Mayo Clin Proc. 2008;83(10):1142-1145.
  2. Rajkumar SV. Patient information: multiple myeloma treatment (beyond the basics). 2013. UpToDate, Inc. website. http://www.uptodate.com/contents/multiple-myeloma-treatment-beyond-the-basics. Accessed May 21, 2014.
  3. American Heart Association. Classes of heart failure. http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-Failure_UCM_306328_Article.jspp. Accessed June 17, 2014.

A widely used response criteria is the International Myeloma Working Group Uniform Response Criteria. Response categories require 2 consecutive assessments before new therapy is implemented. All categories of response require no known evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not required for fulfillment of the response criteria. Response categories include complete response, stringent complete response, immunophenotypic complete response, molecular complete response, very good partial response, partial response, minimal response for relapsed refractory myeloma only, stable disease, and progressive disease.1,2

RESPONSE CRITERIA2,a
CR—complete response Negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow; in patients for whom only measurable disease is by serum FLC level, normal FLC ratio of 0.26 to 1.65 in addition to CR criteria is requireda
sCR—stringent
complete response
  • CR as defined plus normal FLC ratio and absence of clonal plasma cells by immunohistochemistry or 2- to 4-color flow cytometrya
Immunophenotypic CR
  • sCR as defined plus absence of phenotypically aberrant plasma cells (clonal) in bone marrow with minimum of 1 million total bone marrow cells analyzed by multiparametric flow cytometry (with >4 colors)
Molecular CR
  • CR as defined plus negative allele-specific oligonucleotide polymerase chain reaction (sensitivity 10-5)
VGPR—very good
partial response
Serum and urine M-component detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-component plus urine M-component <100 mg/24 h; in patients for whom only measurable disease is by serum FLC level, >90% decrease in difference between involved and uninvolved FLC levels, in addition to VGPR criteria, is requireda
PR—partial response
  • ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg/24 h
  • If serum and urine M-protein are not measurable, ≥50%
    decrease in difference between involved and uninvolved
    FLC levels is required in place of M-protein criteria
  • If serum and urine M-protein and serum FLC are not measurable, ≥50% reduction in bone marrow plasma cells is required in place of M-protein, provided baseline percentage was ≥30%
  • In addition, if present at baseline, ≥50% reduction in size of soft tissue plasmacytomas is requireda,b
Minimal response for relapsed
refractory myeloma only
  • ≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein by 50% to 89%
  • In addition, if present at baseline, 25% to 49% reduction in size of soft tissue plasmacytomas is also required
  • No increase in size or number of lytic bone lesions (development of compression fracture does not exclude response)
PD—progressive diseasea Increase of 25% from lowest response value in any of the following:

  • Serum M component with absolute increase ≥0.5 g/dL; serum M component increases ≥1 g/dL are sufficient to define relapse if starting M component is ≥5 g/dL and/or;
  • Urine M component (absolute increase must be ≥200 mg/24 h) and/or;
  • Only in patients without measurable serum and urine M-protein levels: difference between involved and uninvolved FLC levels (absolute increase must be >10mg/dL);
  • Only in patients without measurable serum and urine M-protein levels and without measurable disease by FLC level, bone marrow plasma cell percentage (absolute percentage must be ≥10%)
  • Development of new or definite increase in size of existing bone lesions or soft tissue plasmacytomas
  • Development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder
SD—stable disease Not meeting criteria for CR, VGPR, PR or PDb
FLC, free light chain; M-protein, monoclonal protein.
aTwo consecutive assessments are needed.
bNo known evidence of progressive or new bone lesions if radiographic studies were performed.
For definitions of measurable disease, refer to Table 4 in Durie BGM et al. Leukemia.
2006;20:1467-1473.3

Reprinted with permission. © 2014 American Society of Clinical Oncology. All rights reserved. Palumbo A et al.
International Myeloma Working Group consensus statement for the management, treatment, and supportive
care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol.
2014;32(6):587-600.2

Clinicians may also look for minimal residual disease (MRD), a term used to describe disease detected only by laboratory techniques more sensitive than morphology (eg, flow cytometry or polymerase chain reaction).Presence or absence of MRD may provide prognostic value toward patient outcomes.5

IMWG UNIFORM RESPONSE CRITERIA: DISEASE PROGRESSION AND RELAPSE (2006)
RELAPSE SUBCATEGORY RELAPSE CRITERIA
Progressive diseasea

To be used for calculation
of time to progression and
progression-free survival
end points for all patients
including those in CR
(includes primary progressive disease and disease progression on or off therapy)
Progressive Disease: requires any one or more of the following:
Increase of ≥25% from baseline in

  • Serum M-component and/or (the absolute increase must be
    ≥0.5 g/dL)b
  • Urine M-component and/or (the absolute increase must be
    ≥200 mg/24 h)
  • Only in patients without measurable serum and urine
    M-protein levels: the difference between involved and
    uninvolved FLC levels. The absolute increase must be
    >10 mg/dL
  • Bone marrow plasma cell percentage: the absolute % must
    be ≥10%c
  • Definite development of new bone lesions or soft tissue
    plasmacytomas or definite increase in the size of existing
    bone lesions or soft tissue plasmacytomas
  • Development of hypercalcemia (corrected serum calcium
    >11.5 mg/dL or 2.65 mmol/L) that can be attributed solely to
    the plasma cell proliferative disorder
Clinical relapsea Clinical relapse requires one or more of:
Direct indicators of increasing disease and/or end organ
dysfunction (CRAB features).b It is not used in calculation of
time to progression or progression-free survival but is listed
here as something that can be reported optionally or for use
in clinical practice

  1. Development of new soft tissue plasmacytomas or bone
    lesions
  2. Definite increase in the size of existing plasmacytomas or
    bone lesions. A definite increase is defined as a 50% (and at
    least 1 cm) increase as measured serially by the sum of the
    products of the cross-diameters of the measurable lesion
  3. Hypercalcemia (>11.5 mg/dL) [2.65 mmol/L]
  4. Decrease in hemoglobin of ≥2 g/dL [1.25 mmol/L]
  5. Rise in serum creatinine by 2 mg/dL or more [177 μmol/L
    or more]
Relapse from CRa (to be used only if the end point studied is DFS)d Any one or more of the following:

  • Reappearance of serum or urine M-protein by immunofixation
    or electrophoresis
  • Development of ≥5% plasma cells in the bone marrowc
  • Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia)
CR, complete response; DFS, disease-free survival.aAll relapse categories require 2 consecutive assessments made at anytime before classification as
relapse or disease progression and/or the institution of any new therapy.
bFor progressive disease, serum M-component increases of ≥1 gm/dL are sufficient to define
relapse if starting M-component is ≥5 g/dL.
cRelapse from CR has the 5% cutoff versus 10% for other categories of relapse.
dFor purposes of calculating time to progression and progression-free survival, CR patients should also be evaluated using criteria listed above for progressive disease.

Reprinted by permission from Macmillan Publishers Ltd: Leukemia (Durie BGM, Harousseau J-L, Miguel JS, et al, on
behalf of the International Myeloma Working Group. International uniform response criteria for multiple myeloma.
Leukemia. 2006;20:1467-1473.3), © 2006.

References:

  1. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple
    Myeloma. v2.2016. http://www.nccn.org. Accessed November 9, 2015.
  2. Palumbo A, Rajkumar SV, San Miguel JF, et al. International Myeloma Working Group consensus statement for the
    management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell
    transplantation. J Clin Oncol. 2014; 32(6):587-600.
  3. Durie BGM, Harousseau J-L, Miguel JS, et al; International Myeloma Working Group. International uniform response criteria for
    multiple myeloma. Leukemia. 2006;20:1467-1473.
  4. Paietta E. Assessing minimal residual disease (MRD) in leukemia: a changing definition and concept? Bone Marrow Transplant.
    2002;29:459-465.
  5. Rawstron AC, Child JA, de Tute RM, et al. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the medical research council myeloma: impact on outcome in the medical research council myeloma IX study. J Clin Oncol. 2013:31(20):2540-2547.

The International Myeloma Foundation Nurse Leadership Board recommends that the prevention and prophylaxis of thrombotic events be based on institutional practices, drug therapies and combinations, and factors specific to individual patients (eg, concomitant illnesses, medical history, cost of therapy, insurance, patient abilities, adherence, allergies, and sensitivities).1

Pneumococcal and influenza vaccinations can be considered if appropriate (as per National Comprehensive Cancer Network [NCCN] guidelines).2 Pneumocystis carinii pneumonia, herpes, and antifungal prophylaxis is recommended if a high-dose dexamethasone regimen is used. Herpes zoster prophylaxis should be considered for individuals based on their therapeutic regimen.2

It is important to carefully evaluate individual patients and to read and understand prescribing information for all drugs before starting a treatment regimen.

References:

  1. Rome S, Doss D, Miller K, Westphal J; IMF Nurse Leadership Board. Thromboembolic events associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(3 suppl):21-27.
  2. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma. v2.2016. http://www.nccn.org. Accessed November 9, 2015.

Supportive Care

Multiple myeloma impacts many body systems. The CRAB features generally specify symptoms that lead to complications in multiple myeloma: Calcium elevation; Renal dysfunction; Anemia; Bone disease.1 The table below shows how each of these criteria can impact the patient. Other complications of multiple myeloma that impact the patient include organ dysfunction and abnormal immune function. These complications also translate into a variety of symptoms for the patient.1

EFFECTS OF INCREASED
MYELOMA CELLS
IN BONE MARROW
CRAB CRITERIA
CAUSE IMPACT ON
PATIENT
C – Increase in blood calcium Release in calcium from damaged bone
into bloodstream.
  • Mental confusion
  • Dehydration
  • Constipation
  • Fatigue
  • Weakness
  • Renal or kidney
    damage (R)
RRenal problems – kidney
damage
Abnormal monoclonal proteins
produced by the myeloma cells are
released into the bloodstream and can
pass into the urine and produce kidney
damage. High blood calcium, infections,
and other factors can also cause or
increase the severity of kidney damage.
  • Sluggish
    circulation
  • Fatigue
  • Mental confusion
A – Anemia Decrease in number and activity of red
blood cell-producing cells in the bone
marrow.
  • Fatigue
  • Weakness
BBone Damage

  • Thinning (osteoporosis) or
  • Areas of more severe damage (called lytic lesions), fracture, or collapse of a vertebra
The myeloma cells activate osteoclast
cells, which destroy bone, and block
osteoblast cells, which normally repair
damaged bone.
  • Bone pain
  • Bone swelling
  • Fracture or collapse of a bone
  • Nerve or spinal
    cord damage
Additional types of organ
dysfunction
Local or systemic effects of myeloma,
other than CRAB features.
  • Neuropathy
  • Recurrent infections
  • Bleeding problems
  • Other individual
    problems
Abnormal immune function The myeloma cells reduce the number
and activity of normal plasma cells
capable of producing antibodies
against infection.
  • Susceptibility to
    infection
  • Delayed recovery
    from infection

Adapted from Durie BGM. Patient Handbook. 2015 ed. International Myeloma Foundation website:
http://myeloma.org/pdfs/PHB.pdf. Accessed October 1, 2015.1
©International Myeloma Foundation (IMF), Patient Handbook 2015, www.myeloma.org. 800-452-CURE.

Reference:

  1. Durie BGM. Patient handbook. 2015 ed. International Myeloma Foundation website.
    http://myeloma.org/pdfs/PHB.pdf. Accessed October 1, 2015.

 

Downloadable Tip Sheet: CRAB Criteria

Downloadable Tip Sheet: Managing Myelosuppression in Patients Taking Multiple Myeloma Therapies

CRAB Criteria Video

Myelosuppression Video

Patients with multiple myeloma can develop hyperglycemia as a result of taking therapy regimens that include steroids.1 The International Myeloma Foundation Nurse Leadership Board recommends that serum glucose readings >200 mg/dL be monitored and possibly treated with oral antiglycemic agents. For glucose readings >300 mg/dL, insulin therapy may be indicated. Patients with hyperglycemia should be referred to a primary care provider or endocrinologist as needed.1

Reference:

  1. Faiman B, Bilotti E, Mangan PA, Rogers K; IMF Nurse Leadership Board. Steroid-associated side effects in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Onc Nurs. 2008;12(3 suppl):53-62.

Hypercalcemia, or too much calcium in the blood, results in tumor-induced bone resorption in patients with multiple myeloma.1,2 Hypercalcemia should be diagnosed based on the concentration of ionized calcium rather than serum calcium levels.2 In concentrations of 12 to 16 mg/dL, hypercalcemia can cause dry mouth, nausea, vomiting, anorexia, constipation, polydipsia (excessive thirst), polyuria (excessive urination), fatigue, depression, dehydration, confusion, and coma.2-4 Hypercalcemia can induce renal impairment as a result of interstitial nephritis.3 Hypercalcemia, defined as corrected serum calcium >11.5 mg/dL, is considered an oncologic emergency.5

References:

  1. MedlinePlus. Hypercalcemia. U.S. National Library of Medicine website. http://www.nlm.nih.gov/medlineplus/ency/article/000365.htm. Accessed July 23, 2014.
  2. Ludwig H, Zojer N. Supportive care in multiple myeloma. Best Pract Res Clin Haematol. 2007;20(4):817-835.
  3. Bladé J, Rosiñol L. Complications of multiple myeloma. Hematol Oncol Clin N Am. 2007;21(6):1231-1246.
  4. Abbott Point of Care. Ionized calcium/ICA. 2010. http://www.abbottpointofcare.com/. Accessed June 5, 2014.
  5. Miceli TS, Colson K, Faiman BM, Miller K, Tariman JD; International Myeloma Foundation Nurse Leadership Board. Maintaining bone health in patients with multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs. 2011;15(4 suppl):9-23.

 

Downloadable Tip Sheet: CRAB Criteria

The National Comprehensive Cancer Network (NCCN) guidelines recommend bisphosphonates as adjunctive therapy for all patients receiving primary myeloma therapy and for patients with smoldering or stage I disease in the context of a clinical trial.1 The American Society of Clinical Oncology (ASCO) recommends use of oral or intravenous bisphosphonates in patients with lytic disease apparent on plain radiographs or imaging studies and for patients with osteopenia based on normal plain radiograph or bone mineral density measurements.2,3 The International Myeloma Working Group (IMWG) concurs and adds magnetic resonance imaging (MRI), computed tomography (CT), and CT/positron emission tomography (PET) as other valid imaging methodologies to reveal myeloma-related bone disease.2,4

ASCO recommends that bisphosphonates be administered monthly for 2 years.2,3 Intravenous bisphosphonates are also recommended for patients with pain as a result of osteolytic disease and as adjunctive treatment for patients receiving radiation therapy, analgesics, or surgical intervention to stabilize fractures or impending fractures.3 IMWG suggests discontinuation after 1 year if complete response, very good partial response, and no active bone disease. Healthcare providers may continue at their own discretion if active bone disease is present.2,4

Patients taking bisphosphonates should be advised to have dental examinations and should avoid invasive dental procedures. Patients should also be informed of the importance of good dental hygiene and routine dental care.5

References:

  1. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma. v2.2016. http://www.nccn.org. Accessed November 9, 2015.
  2. Terpos E, Morgan G, Dimopoulos MA, et al. International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease. J Clin Oncol. 2013;31(18):2347-2357.
  3. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Onc. 2007;25:2464-2472.
  4. Durie BGM. Use of bisphosphonates in multiple myeloma: IMWG response to Mayo Clinic consensus statement. Mayo Clin Proc. 2007;82(4):516-522.
  5. Zometa [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014.

Bisphosphonates are recommended for patients with multiple myeloma with or without detectable osteolytic bone lesions who are receiving antimyeloma therapy and in patients with osteoporosis or osteopenia as a result of multiple myeloma.1 Bisphosphonates inhibit osteoclastic bone resorption in 4 ways: inhibiting osteoclastic recruitment and maturation, preventing the development of monocytes into osteoclasts, inducing osteoclastic cell death, and interrupting osteoclast attachment to bone.2 In addition to decreasing bone resorption, bisphosphonates promote an increase in calcium balance and mineral content within the bone.2

References:

  1. Terpos E, Morgan G, Dimopoulos MA, et al. International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease. J Clin Oncol. 2013;31(18):2347-2357.
  2. Terpos E, Rahemtulla A. Bisphosphonate treatment for multiple myeloma. Drugs of Today. 2004;40(1):29-40.

A complete skeletal survey is the standard method for visualizing bone changes in patients with multiple myeloma. However, it can only detect lytic disease when 30% or more of the trabecular bone has been destroyed.1 The National Comprehensive Cancer Network (NCCN) guidelines recommend a skeletal survey should be ordered at diagnosis and annually, or for symptoms, or as clinically indicated, in patients with active or smoldering multiple myeloma, or after response to primary therapy.1,2 Limitations of the skeletal survey have prompted use of computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT to supplement data from the skeletal survey.1,2

References:

  1. Miceli TS, Colson K, Faiman BM, Miller K, Tariman JD; International Myeloma Foundation Nurse Leadership Board. Maintaining bone health in patients with multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs. 2011;15(4 suppl):9-23.
  2. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma. v2.2016. http://www.nccn.org. Accessed November 9, 2015.

Bone densitometry is recommended by the National Comprehensive Cancer Network (NCCN) guidelines as potentially useful under some circumstances as part of the initial diagnostic workup.1,2 The International Myeloma Foundation Nurse Leadership Board recommends bone density tests if the patient shows risk factors for osteoporosis outside of new-onset pain or fracture.2

References:

  1. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma. v2.2016. http://www.nccn.org. Accessed November 9, 2015.
  2. Miceli TS, Colson K, Faiman BM, Miller K, Tariman JD; International Myeloma Foundation Nurse Leadership Board. Maintaining bone health in patients with multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs. 2011;15(4 suppl):9-23.

Lifestyle Issues

The frequency of follow-up visits to an oncologist or primary care provider after primary therapy will vary based on many patient- and disease-specific factors. The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, Multiple Myeloma offers guidance on follow-up visits for patients.1

Reference:

  1. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma. v2.2016. http://www.nccn.org. Accessed November 9, 2015.

As much as possible, patients should reduce or eliminate stress in any job, family, or social situations. They should avoid contact with school-age children, avoid crowds as much as possible, and wash hands frequently because their immune system is compromised.1 Alcohol consumption can exacerbate the side effects of multiple myeloma therapies, and alcohol misuse needs to be monitored. For patients who smoke, tobacco use should be curtailed because tobacco smoke increases the risk of pulmonary infections.2 Patients should check with their physicians to clarify the amount of physical activity that is feasible; but usually, some form of planned walking or swimming and/or flexibility or strengthening activity can be undertaken by patients.1

References:

  1. Durie BGM. Patient handbook. 2015 ed. International Myeloma Foundation website. http://myeloma.org/pdfs/PHB.pdf. Accessed October 1, 2015.
  2. Bilotti E, Gleason CL, McNeill A; International Myeloma Foundation Nurse Leadership Board. Routine health maintenance in patients living with multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs. 2011;15(4 suppl):25-40.

Screening and precautionary recommendations from the International Myeloma Foundation Nurse Leadership Board include the following1:

  • Routine screening for breast, cervical, prostate, colorectal, and skin cancers
  • Routine screening for opportunistic infections because multiple myeloma may increase the risk of infection
  • Multiple myeloma treatments may increase the risk of hypertension or hypotension, and blood pressure changes need to be monitored routinely. Steroid treatment may lead to hyperglycemia requiring therapeutic interventions
  • Patients receiving exogenous erythropoietin therapy need to be evaluated for the adequacy of their iron stores
  • Regular hearing and vision tests because multiple myeloma treatments may negatively impact both hearing and vision
  • Routine vaccinations, including the annual influenza vaccine, tetanus booster every 10 years, and pneumococcal vaccine every 5 years in patients aged ≥65. Varicella vaccine is contraindicated for patients with multiple myeloma who have a compromised immune system
  • Oral hygiene is important to mitigate the risk of osteonecrosis of the jaw, for which patients with multiple myeloma have an increased risk

Reference:

  1. Bilotti E, Gleason CL, McNeill A; International Myeloma Foundation Nurse Leadership Board. Routine health maintenance in patients living with multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs. 2011;15(4 suppl):25-40.

Spontaneous fractures, spinal cord compression, osteolytic lesions, recurrent infections, renal failure, anemia, mood disorders accompanied by reduced physical functioning, and side effects of different types of treatments negatively impact the well-being of patients with multiple myeloma.1 Other disease symptoms and treatment side effects that negatively impact patients include pain, fatigue, appetite loss, reduced physical functioning, increased risk for depression, emotional distress, and sexual dysfunction.2-4

References:

  1. Cömert M, Güne? AE, ?ahin F, Saydam G. Quality of life and supportive care in multiple myeloma. Turk J Hematol. 2013;30(3):234-246.
  2. Gulbrandsen N, Hjermstad MJ, Wisløff F; Nordic Myeloma Study Group. Interpretation of quality of life scores in multiple myeloma by comparison with a reference population and assessment of the clinical importance of score differences. Eur J Haematol. 2004;72(3):172-180.
  3. Richards TA, Bertolotti PA, Doss D, McCullagh EJ; International Myeloma Foundation Nurse Leadership Board. Sexual dysfunction in multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs. 2011;15(4 suppl):53-65.
  4. Sherman AC, Simonton S, Latif U, Spohn R, Tricot G. Psychosocial adjustment and quality of life among multiple myeloma patients undergoing evaluation for autologous stem cell transplantation. Bone Marrow Transplant. 2004;33(9):955-962.

 

Downloadable Tip Sheet: CRAB Criteria

CRAB Criteria Video

Myelosuppression Video

The following websites contain information that patients and caregivers may find useful.

This list of independent organizations is provided as an additional resource for obtaining information. Inclusion on this list does not indicate endorsement by Celgene Corporation of an organization or its communications.

The International Myeloma Foundation Nurse Leadership Board developed a set of recommendations for screening and disease prevention for this population. These recommendations include screening for malignancies, cardiovascular screening, routine hearing and vision tests, regular influenza vaccines, and frequent screening for cognitive or emotional decline.1

Reference:

  1. Bilotti E, Gleason CL, McNeill A; International Myeloma Foundation Nurse Leadership Board. Routine health maintenance in patients living with multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. Clin J Oncol Nurs. 2011;15(4 suppl):25-40.