Nurse Bea is reviewing the laboratory results of a client diagnosed with multiple myeloma

Find answers to some of the most commonly asked questions about multiple myeloma from nurses and patients.

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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 and secretes all or part of a monoclonal antibody.1 The malignant plasma cells, or myeloma cells, accumulate in the bone marrow.2 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

The Revised International Myeloma Working Group [IMWG] defines myeloma as: clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytomaa and any 1 or more of the following myeloma-defining events [also known as CRAB features]3:

• Hypercalcemia: serum calcium >0.25 mmol/L [>1 mg/dL] higher than the upper limit of normal or >2.75 mmol/L [>11 mg/dL]
• Renal insufficiency: creatinine clearance 177 μmol/L [>2 mg/dL]
• Anemia: hemoglobin value of >2 g/dL below the lower limit of normal or a hemoglobin value 100 involved and uninvolved serum FLC [not urine FLC] ratio ≥100 [with involved FLC >10 mg/dL]
• MRI ≥1 focal lesion 5 mm.

Anemia is the most common hematologic complication present in patients with MM. Approximately 35% of patients have a hemoglobin 1 mg/dL] higher than the upper limit of normal or >2.75 mmol/L [>11 mg/dL]
R – Renal insufficiency [creatinine >2 mg/dL] [>177 μmol/L] or creatinine clearance 1 focal lesion on MRI studies ≥5 mm1

Concise review of the disease and treatment options: multiple myeloma cancer of the bone marrow. 2018 ed.
International Myeloma Foundation. Accessed May 29, 2019.2
Rajkumar SV, et al. Lancet Oncol. 2014;15[12]:e538-e548.

Normal plasma cells produce immunoglobulins or antibodies which are made up of light chains and heavy chains.11 In myeloma, malignant plasma cells overproduce a specific antibody/immunoglobulin [monoclonal protein also known as M-protein].11 Plasma cells tend to produce light chains in greater numbers than heavy chains, which results in free light chains [FLCs] circulating in the bloodstream.11 The quantity of FLC production is a marker of the activity of myeloma or the growth of plasma cells.11

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 NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines®] for a patient’s initial diagnostic workup and for monitoring response to treatment.12 Monitoring the individual’s FLC levels and the kappa/lambda ratio during treatment is useful to see if treatment is working.11 Monitoring FLC can be beneficial. During a relapse, small amounts of myeloma cells produce measurable amounts of light chains, in most cases. These light chains may increase before the heavy chains and intact immunoglobulins can be detected by SPEP or immunofixation tests.11

Diagnosis

According to the NCCN Guidelines® for Multiple Myeloma, the initial diagnostic workup includes a history and physical exam, complete blood count with differential and platelet counts, a peripheral blood smear, serum blood urea nitrogen [BUN]/creatinine, electrolytes, albumin, liver function tests, calcium, serum uric acid, serum lactate dehydrogenase [LDH], and beta-2 microglobulin, among other tests.12 Increases in BUN and creatinine signal renal impairment.12 LDH and beta-2 microglobulin levels help indicate tumor cell characteristics.12

A myeloma panel includes protein electrophoresis [serum [SPEP]], immunofixation electrophoresis [serum [SIFE]], quantitative immunoglobulin levels, serum free light chain assay, and 24-hour urine for total protein, as well as the other tests mentioned previously.12 Serum immunofixation electrophoresis is roughly 10-fold more sensitive to monoclonal protein detection than serum protein electrophoresis.13

A whole-body low-dose computed tomography [CT] scan or a whole-body fluorodeoxyglucose [FDG] positron emission tomography [PET]/CT scan is recommended by NCCN Guidelines for Multiple Myeloma as part of the initial diagnostic workup.12 A whole-body magnetic resonance imaging [MRI] may be useful to distinguish active from smoldering multiple myeloma if the whole-body low-dose CT is negative.12 If FDG PET/CT has been performed on the patient, there is no need for a skeletal survey.12 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.12

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.14

REVISED INTERNATIONAL STAGING SYSTEM1

R-ISS Stage	Stage Criteria	Criterion Definitions
	ISS stage I and Standard-risk CA by iFISH and	Serum β2-microglobulin 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 Development of new soft tissue plasmacytomas or bone lesions 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 Hypercalcemia [>11.5 mg/dL] [2.65 mmol/L] Decrease in hemoglobin of ≥2 g/dL [1.25 mmol/L] 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.

• All relapse categories require 2 consecutive assessments made at any time before classification as relapse or disease progression and/or the institution of any new therapy.
• For progressive disease, serum M-component increases of ≥1 g/dL are sufficient to define relapse if starting M-component is ≥5 g/dL.
• Relapse from CR has the 5% cutoff versus 10% for other categories of relapse.
• For purposes of calculating time to progression and progression-free survival, CR patients should also be evaluated using criteria listed above for progressive disease.

Reproduced 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;20:1467-1473.29], © 2006.

Supportive Care

The International Myeloma Foundation Nurse Leadership Board recognizes that prevention of venous thromboembolism [VTE] is essential for patients with multiple myeloma who are at risk for thrombosis.30

A heightened awareness of VTE prevention has occurred and many standards of care for VTE prevention have been implemented.30 In patients at risk, suggestions include anti-coagulation therapy.30

Pneumococcal vaccinations should be considered if appropriate [as per NCCN Guidelines].12 Pneumocystis jiroveci pneumonia [PJP], herpes zoster, and antifungal prophylaxis is recommended if a high-dose dexamethasone regimen is used. Herpes zoster prophylaxis is recommended in all patients treated with proteasome inhibitors, daratumumab, isatuximab-irfc, or elotuzumab.12

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

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.31 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.31

EFFECTS OF INCREASED MYELOMA CELLS IN BONE MARROW CRAB CRITERIA31CAUSEIMPACT ON PATIENT

C – Increase in blood calcium

Release in calcium from damaged bone into bloodstream.

Dehydration Constipation Fatigue Weakness Renal or kidney damage

EFFECTS OF INCREASED MYELOMA CELLS IN BONE MARROW CRAB CRITERIA29CAUSEIMPACT ON PATIENT

R – Renal 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

EFFECTS OF INCREASED MYELOMA CELLS IN BONE MARROW CRAB CRITERIA29CAUSEIMPACT ON PATIENT

A – Anemia

Decrease in number and activity of red blood cell-producing cells in the bone marrow.

Fatigue Weakness

EFFECTS OF INCREASED MYELOMA CELLS IN BONE MARROW CRAB CRITERIA29CAUSEIMPACT ON PATIENT

B – Bone 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

EFFECTS OF INCREASED MYELOMA CELLS IN BONE MARROW CRAB CRITERIA29CAUSEIMPACT ON PATIENT

Additional types of organ dysfunction

Local or systemic effects of myeloma, other than CRAB features.

Neuropathy Recurrent infections Bleeding problems Other individual problems

EFFECTS OF INCREASED MYELOMA CELLS IN BONE MARROW CRAB CRITERIA29CAUSEIMPACT ON PATIENT

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. 2018 ed. International Myeloma Foundation website: //www.myeloma.org/sites/default/files/resource/patient-handbook.pdf. Accessed June 5, 2019. © International Myeloma Foundation [IMF], Patient Handbook 2018, www.myeloma.org. 800-452-CURE.31

Patients with multiple myeloma can develop hyperglycemia as a result of taking therapy regimens that include steroids.32 Patients should be monitored for signs of raised glucose levels.32 Patients and caregivers should be educated on the signs and symptoms of hypo- and hyperglycemia.32 For those at risk for diabetes, increased surveillance is recommended.32

Hypercalcemia, or too much calcium in the blood, often results in tumor-induced bone resorption in patients with multiple myeloma.33,34 Hypercalcemia should be diagnosed based on the concentration of ionized calcium rather than serum calcium levels.34 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.4,34 Hypercalcemia can induce renal impairment as a result of interstitial nephritis.4 Hypercalcemia, defined as corrected serum calcium >11.5 mg/dL, is considered an oncologic emergency.19

The NCCN Guidelines for Multiple Myeloma recommend bisphosphonates or denosumab for all patients receiving myeloma therapy for symptomatic disease regardless of documented bone disease.12 In patients with renal disease, National Comprehensive Cancer Network® [NCCN®] Multiple Myeloma Panel members prefer denosumab.12 A baseline dental exam and monitoring for osteonecrosis of the jaw is also recommended by NCCN Guidelines for all patients receiving a bone-modifying agent.12 The Guidelines also recommend monitoring for renal dysfunction with use of bisphosphonate therapy.12

The American Society of Clinical Oncology [ASCO] recommends that bisphosphonates be administered monthly for up to 2 years.35 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.35 IMWG also concurs for a duration of 2 years. However, IMWG suggests discontinuation after 1 year if complete response, very good partial response, and no active bone disease.36

Patients taking bisphosphonates should be advised to have dental examinations and should avoid invasive dental procedures.35 Patients should also be informed of the importance of good dental hygiene and routine dental care.35 Osteonecrosis of jaw is an uncommon, but potentially serious, side effect.

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.35 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.37 In addition to decreasing bone resorption, bisphosphonates promote an increase in calcium balance and mineral content within the bone.37

As part of the initial diagnostic work up, NCCN recommends whole-body low-dose CT or FDG PET/CT for patients suspected to have multiple myeloma or solitary plasmacytoma. A skeletal survey is acceptable in some circumstances, but has been shown to be less sensitive than whole-body low-dose CT or FDG PET/CT in detecting osteolytic lesions. If a negative result is obtained for the whole-body low-dose CT or FDG PET/CT, whole-body MRI without contrast may be considered to discern smoldering myeloma from multiple myeloma.12

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.19

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 NCCN Guidelines for Multiple Myeloma offer guidance on follow-up visits for patients.12

Patients may consider the following suggestions: 1] reduce stress from jobs, family, or social situations31; 2] limit contacts with school-aged children, crowds, and consider increasing hand washing; 3] reduce alcohol consumption, as it may exacerbate side effects of multiple myeloma therapies; 4] reduce tobacco use because tobacco smoke increases risk of pulmonary infections38; 5] consult with their physicians about the level of physical activity in which they can engage — typically, some form of planned walking, swimming, and/or flexibility or strengthening activity can be undertaken by patients.31

Screening and precautionary recommendations from the International Myeloma Foundation Nurse Leadership Board include the following38:

• 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

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.39 Other disease symptoms and treatment side effects that negatively impact patients include pain, neuropathy, fatigue, gastrointestinal symptoms, reduced physical functioning, increased risk for depression, emotional distress, and sexual dysfunction.40

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.38

References:

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12. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines®] for Multiple Myeloma V.3.2021. © National Comprehesive Cancer Network, Inc. 2021. All rights reserved. Accessed October 27, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
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32. King T, Faiman B. Steroid-associated side effects: a symptom management update on multiple myeloma treatment. Clin J Nurs Oncol. 2017;21[12]:240-249.
33. MedlinePlus. Hypercalcemia. U.S. National Library of Medicine website. //medlineplus.gov/ency/article/000365.htm. Accessed October 27, 2020.
34. Ludwig H, Zojer N. Supportive care in multiple myeloma. Best Pract Res Clin Haematol. 2007;20[4]:817-835.
35. Anderson K, Ismaila, N, and Kyle RA. Role of bone-modifying agents in multiple myeloma: American Society of Clinical Oncology clinical practice guideline update summary. J Clin Pract. 2018;14[4]:266-269.
36. 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.
37. Terpos E, Rahemtulla A. Bisphosphonate treatment for multiple myeloma. Drugs of Today. 2004;40[1]:29-40.
38. 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.
39. Cömert M, Güneş AE, Şahin F, Saydam G. Quality of life and supportive care in multiple myeloma. Turk J Hematol. 2013;30[3]:234-246.
40. Catamero D, Noonan K, Richards T, et al. Distress, fatigue, and sexuality: understanding and treating concerns and symptoms in patients with multiple myeloma. Clin J Oncol Nurs. 2017;21[5 suppl]:7-18.