Hospital Medicine

Multiple Myeloma

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Multiple Myeloma

I. What every physician needs to know.

Multiple myeloma is a hematologic malignancy characterized by clonal bone marrow plasma cells and monoclonal protein in the serum or urine. Symptomatic myeloma is associated with hypercalcemia, renal insufficiency, anemia, and bone disease manifested as bony pain (classically back pain) or atraumatic fractures. The symptoms and morbidity of multiple myeloma are directly related to clonal plasma cells and overabundance of monoclonal protein (M protein) causing organ and tissue dysfunction. Asymptomatic myeloma is known as "smoldering" myeloma. Virtually all cases of multiple myeloma are preceded by a phase known as MGUS (monoclonal gammopathy of unknown significance), although most of these are undiagnosed.

II. Diagnostic Confirmation: Are you sure your patient has Multiple Myeloma?

Multiple myeloma:

  • ≥10% clonal bone marrow plasma cells AND monoclonal protein in serum or urine (secretory myeloma)

OR

>30% monoclonal bone marrow plasma cells OR biopsy proven plasmacytoma (nonsecretory myeloma).

  • Symptomatic myeloma includes evidence of organ or tissue dysfunction.

  • Asymptomatic myeloma is known as smoldering myeloma.

  • A plasmacytoma is a malignant plasma cell tumor found in soft tissue or the bony skeleton.

A. History Part I: Pattern Recognition:

  • Bone pain, back pain, or pathologic fracture (80% at diagnosis).

  • Anemia (73% at diagnosis).

  • Renal insufficiency (20-40% at diagnosis).

  • Hypercalcemia (less common at diagnosis, more common in advanced myeloma).

  • Bacterial infections (incidence increases with active disease; especially susceptible to encapsulated bacteria).

B. History Part 2: Prevalence:

  • Multiple myeloma represents 1-2% of all malignancies.

  • Median age of diagnosis is 70.

  • African and Caribbean ethnic groups have an increased incidence.

  • Exposure to radiation, benzene, herbicides, and insecticides have been linked with a higher risk of developing multiple myeloma, though the data is not strong.

C. History Part 3: Competing diagnoses that can mimic Multiple Myeloma.

Asymptomatic (smoldering) myeloma: no evidence of tissue or organ damage, but with evidence of clonal plasma cells and monoclonal protein in serum or urine.

MGUS (monoclonal gammopathy of unknown significance): No evidence of tissue or organ damage; < 10% clonal bone marrow plasma cells.

Bone marrow biopsy, imaging, and serum/urine studies are necessary to distinguish these diagnostically from multiple myeloma.

D. Physical Examination Findings.

There is no diagnostic physical exam finding; some patients may have normal physical exams.

Consider looking for:

  • Conjunctival pallor indicating anemia.

  • Spinal tenderness to palpation.

  • Exam findings suggestive of infection (fever and other abnormal vital signs, pulmonary rales indicating pneumonia).

  • Exam findings suggestive of hypercalcemia (confusion, abdominal tenderness).

E. What diagnostic tests should be performed?

Bone marrow biopsy: Confirms diagnosis and establishes degree of bone marrow plasma cell involvement.

If needed, biopsy of mass (either palpable or found via imaging) to confirm/exclude plasmacytoma.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

To diagnose multiple myeloma, order the following tests:

  • Cell blood count (CBC) with differential: Usually reveals anemia; in advanced cases may also reveal thrombocytopenia and leukopenia/neutropenia.

  • Basic chemistry panel, including calcium, magnesium and phosphorus: May reveal renal insufficiency and/or hypercalcemia and hyperphosphatemia.

  • Liver function tests (LFTs): Needed as baseline for initiating treatment with chemotherapy.

  • Serum protein electrophoresis (SPEP) + urine protein electrophoresis (UPEP) and IFE (immunofixation electrophoresis): Reveals monoclonal protein (M-spike).

  • Quantitative Immunoglobulins (quantifies monoclonal protein).

  • Albumin: Indirect marker of severity of disease.

  • Lactate dehydrogenase (LDH): Marker of severity of disease.

  • Uric acid: Indicates degree of tumor lysis. If elevated, should be treated to prevent worsening renal dysfunction.

  • Beta-2 microglobulin: Marker of severity of disease.

  • When admitting patients with diagnosed multiple myeloma, order the same tests as above, with the exception of IFE.

  • SPEP, UPEP, Quantitative Immunoglobulins, albumin, LDH, uric acid, and beta-2 microglobulin allow for restaging of the multiple myeloma to determine how active the disease is.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

  • X-ray skeletal survey: Including skull, spine, chest, pelvis, humeri, femurs. For the purpose of identifying myeloma-related skeletal lesions (lytic lesions). It is important to not confuse this order with a Technetium-99m bone scan, which is less sensitive in detecting lytic lesions.

  • Magnetic resonance imaging (MRI) myeloma protocol: Including brain, cervical/thoracic/lumbar spine, and pelvis, for the purpose of identifying myeloma-related lesions. Gadolinium-free imaging should be used in patients with advanced renal disease (with a greater sensitivity compared to skeletal survey, but more resource-intensive; it is often used if the skeletal survey is negative but clinical suspicion remains or if there are neurologic deficits possibly due to spinal cord compression).

After diagnosis:

  • X-ray and MRI imaging studies are repeated at periodic intervals at the discretion of the treating hematologist.

  • Trauma, new bony pain, or change in bony pain warrants repeat imaging with X-rays.

  • Asymmetric or symmetric lower extremity swelling warrants venous duplex to rule out venous thrombosis.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Do not order computed tomography (CT) imaging with contrast. Even patients with normal creatinine are at high risk for developing myeloma-related renal insufficiency.

In the author's experience, and in contrast to the general medicine population, patients with multiple myeloma are at greater risk of being under-tested and under-treated. Given the complex nature of the disease and potentially life-threatening complications, have a low index of suspicion to look for common comorbidities (infection, hyperuricemia, hypercalcemia, bony fractures, venous thromboemboli).

III. Default Management.

Treatment of disease

The treatment of multiple myeloma should be managed by an experienced hematologist-oncologist, ideally specializing in multiple myeloma. A combination of steroids, chemotherapy, and agents such as thalidomide are often used, depending on disease stage, genetics, and age/comorbidities of patient. An autologous stem cell transplant is often recommended for patients.

Treatment of complications

Renal insufficiency:

  • Intravenous Fluids

  • Withdrawal and avoidance of any nephrotoxic medications

  • Rule out hyperuricemia, hypercalcemia, and hyperviscosity (by checking myeloma markers)

Hypercalcemia:

  • Intravenous fluids

  • IV bisphosphonate (such as pamidronate)

  • Consider steroids, calcitonin

Pathologic fractures:

  • Orthopedic surgery consult

  • Monthly bisphosphonate

Vertebral compression fractures:

  • Pain control

  • Assess need for spine stabilization depending on location and severity

  • Consider vertebroplasty

  • Monthly bisphosphonate

  • Physical therapy

Hyperuricemia:

  • Intravenous fluids

  • Rasburicase, 3 mg IVPB once

  • Renally-dosed allopurinol

Delirium:

  • Evaluate for infection, dehydration, renal insufficiency, hypercalcemia, and hyperviscosity

Symptomatic plasmacytoma:

  • Treatment of underlying disease (myeloma)

  • Consider localized radiation

  • Hyperviscosity Emergent/urgent plasmapheresis

Treatment of Complications of Myeloma Treatment:

Neutropenic fever:

  • “Pan”-culture (i.e., culture “all” or “every” site of potential infection, including blood, urine, sputum, etc.)

  • Broad-spectrum antibiotics such as cefepime or piperacillin-tazobactam +/- vancomycin

  • Growth factor such as granulocyte-colony stimulating factor (G-CSF)

  • Tailor treatment to culture results

Chemotherapy-induced nausea and vomiting:

  • Intravenous (IV) fluids

  • Scheduled IV antiemetics

Steroid-induced Hyperglycemia:

  • Emphasis on prandial insulin

A. Immediate management.

Immediate management of disease

The immediate management of multiple myeloma generally consists of managing complications.

For rapidly progressive myeloma or symptomatic myeloma (i.e., hyperviscosity):

  • High dose steroids (for example, 1 gram methylprednisolone IV piggy back [IVPB] daily for 3 days, in conjunction with consulting oncologist)

  • Emergent plasmapheresis for hyperviscosity

  • Blood transfusions for severe anemia or thrombocytopenia (typically hemoglobin <7 g/dL or platelet <10 k/µL)

Immediate management of complications of disease

Renal insufficiency:

  • Intravenous fluids

  • Withdrawal and avoidance of any nephrotoxic medications

  • Evaluate for hyperuricemia, hypercalcemia, and hyperviscosity

Hypercalcemia:

  • Intravenous fluids

  • IV Bisphosphonate (such as pamidronate)

Pathologic fractures:

  • Orthopedic surgery consult

Vertebral compression fractures:

  • Pain control

  • Assess need for spine stabilization depending on location and severity

Hyperuricemia:

  • Intravenous fluids

  • Rasburicase, 3 mg IVPB once

Delirium:

  • Evaluate for infection, dehydration, renal insufficiency, hypercalcemia, and hyperviscosity

Hyperviscosity:

  • Emergent plasmapheresis

B. Physical Examination Tips to Guide Management.

NA

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

  • CBC daily until values noted to be stable.

  • CBC with diff daily if neutropenia exists, until resolved and stable.

  • Basic metabolic panel (chemistry-7) daily until creatinine noted to be stable.

  • Calcium and ionized calcium daily if initially elevated, until resolved and stable.

  • Tumor lysis labs every 8-12 hours (calcium, phosphorus, potassium, and uric acid) if abnormal (elevated phos, K+, uric acid and low calcium), until resolved and stable.

  • Myeloma markers (serum free light chains, quantitative immunoglobulins, SPEP/UPEP, macroglobulin-beta 2, LDH) weekly while hospitalized or with active disease.

D. Long-term management.

  • Myeloma markers periodically.

  • Imaging periodically.

E. Common Pitfalls and Side-Effects of Management.

  • Not recognizing hyperuricemia.

  • Not recognizing Tumor Lysis Syndrome (although rare, this can result in significant morbidity)

  • Not recognizing Hyperviscocity Syndrome (may present as bleeding, particularly epistaxis, neurologic complaints [i.e., headache, blurred vision, tinnitus, delirium, stroke], respiratory compromise)

  • Not recognizing very early signs of infection (tachycardia, delirium).

  • Not protecting the kidneys.

  • Not recognizing progression of disease.

  • Not addressing end of life and goals of care in a timely manner.

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

Renal dosing of chemotherapy and medications such as allopurinol.

B. Liver Insufficiency.

Chemotherapy options may be limited.

C. Systolic and Diastolic Heart Failure.

Careful fluid management with hypercalcemia, hyperuricemia, dehydration, and infection.

D. Coronary Artery Disease or Peripheral Vascular Disease.

Judicious use of antiplatelet agents. Chemotherapy and advanced myeloma frequently cause thrombocytopenia.

Aspirin, Plavix, and other antiplatelet agents may need to be discontinued in anticipation of thrombocytopenia (depending on severity of cardiac disease) to prevent increased risk of bleeding.

Cardiology and oncology consults may be helpful, although no specific guidelines exist regarding this issue.

E. Diabetes or other Endocrine issues.

High dose steroids are frequently given to treat myeloma, either alone or in conjunction with chemotherapy. Steroid-induced hyperglycemia frequently ensues, and this is best treated with an emphasis on prandial insulin (even in insulin-naive patients). Steroid-induced hyperglycemia will usually resolve in 3-5 days following steroid cessation. In some cases, patients may need to be discharged with a short course of new insulin, additional insulin, or higher doses of oral diabetes medications.

F. Malignancy.

NA

G. Immunosuppression (HIV, chronic steroids, etc).

Patients with myeloma are immunosuppressed when their disease is active, either due to underlying disease (hypogammaglobulinemia), active treatment with steroids, or active chemotherapy.

Appropriate prophylactic medications are listed elsewhere.

Consider administering intravenous immunoglobulin (IVIG) to a patient with hypogammaglobulinemia and active infection.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

Caution with inhaled pentamidine for PJP prophylaxis.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

Thrombocytopenia is a frequent side effect of chemotherapy or advanced disease, increasing the risk of bleeding.

Venous thromboembolism (VTE, such as deep venous thrombosis or pulmonary embolism) treatment should consist of a LMWH in preference to oral warfarin, given the presence of malignancy.

If platelet counts fall below 50,000/microL, LMWH treatment should be stopped until platelet counts rebound above 50,000/microL. Alternatively, half treatment dose or prophylactic dose LMWH can be given at platelet counts between 30,000 and 50,000/microL. No pharmacologic anticoagulation should be given at platelet counts of <30,000/microL.

Pharmacologic VTE prophylaxis should be stopped at a platelet count of 50,000/microL or less.

K. Dementia or Psychiatric Illness/Treatment.

Degree of dementia and prognosis should be serious considerations in determining treatment options for myeloma.

Complications such as infection, hypercalcemia, and renal insufficiency are likely to cause delirium in a patient with underlying dementia.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

If fever > 100.4 degrees F, check blood cultures (including central line), UA, urine culture, and CXR. Have low threshold to start broad spectrum antibiotics.

Avoid all nephrotoxic medications, including ibuprofen.

B. Anticipated Length of Stay.

Variable, depending on reason for admission.

C. When is the Patient Ready for Discharge.

Depends on reason for admission.

Typically, complications (for example, hypercalcemia or acute renal insufficiency or infection) are stabilized or resolved.

D. Arranging for Clinic Follow-up.

A patient with multiple myeloma should follow up with a specialist in hematology-oncology, and ideally one specializing in the care of myeloma.

1. When should clinic follow up be arranged and with whom.

Hematology-oncology: within 1 week.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Myeloma markers.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

CBC, comprehensive metabolic panel, and myeloma markers if not conducted recently.

E. Placement Considerations.

Variable depending on each patient’s rehabilitation needs.

F. Prognosis and Patient Counseling.

Median survival for a patient with myeloma who has undergone stem cell transplant as part of treatment regimen is approximately 5 years. Myeloma is incurable, but treatable.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

NA

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

All patients should take acyclovir to prevent herpes simplex virus (HSV) and varicella zoster virus (VZV) reactivation.

If patients are discharged with steroids or have received high-dose steroids, consider Pneumocystis jiroveci (PJP) prophylaxis with sulfamethoxazole-trimethoprim, atovaquone, or pentamidine inhalation.

If patients are or are likely to develop neutropenia, consider antibiotic prophylaxis with a fluoroquinolone or penicillin-based antibiotic such as amoxicillin-clavulanate.

If patients are undergoing chemotherapy, consider oral candidiasis prevention with clotrimazole troches, nystatin swish and swallow, or oral fluconazole.

If patients are undergoing treatment with thalidomide, consider home deep venous thrombosis prophylaxis with aspirin if low-risk, or LMWH or warfarin if high-risk.

VII. What's the Evidence?

Palumbo, A, Anderson, K.. "Multiple myeloma". N Engl J Med. vol. 364. 2011. pp. 1046-1060.

Smith, D, Yong, K.. "Multiple myeloma". BMJ. vol. 346. 2013. pp. f3863.

Al-ani, F, Bermejo, JM, Mateos, MV, Louzada, M.. "Thromboprophylaxis in multiple myeloma patients treated with lenalidomide - A systematic review". Thromb Res.. vol. 141. 2016. pp. 84-90.

Carson, JL, Carless, PA, Hebert, PC.. "Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion". Cochrane Database Syst Rev.. vol. 4. 2012. pp. CD002042.

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