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Multiple Myeloma

1. Diagnosis

Updated  22 Feb. 2012

Required tests:

  • Serum and urine protein studies as described in Append​ix II
    • serum protein electrophoresis (SPE)
    • serum protein immunofixation
    • quantitative immunoglobulins
    • serum free light chain levels (should be done if the SPEP does not demonstrate a monoclonal protein and suspicion for myeloma is high)
    • urine protein 24 hour quantitation and electrophoresis
  • Serum calcium, uric acid, creatinine
  • beta-2-microglobulin (required at diagnosis for staging only and should not be repeated as a marker of disease response)
  • CBC
  • Chest radiograph
  • Skeletal radiographic survey (skull, spine, humeri, pelvis, femora, ribs)
  • Urgent MRI or CT of the spine should be considered for patient with back pain and spinal cord compression is supected
  • Bone marrow aspiration and biopsy, with:
    • FISH probe for translocation t(4;14)
    • FISH probe for translocation t(14;16)
    • FISH probe for chromosome 17p deletion
  • Hepatitis Bsurface Ag, hepatitis Bcore Ab, hepatitis C Ab

Note: Bone scanning is seldom useful in myeloma. Intravenous radiographic contrast studies must be used with caution because they may cause renal injury.

The diagnostic criteria of myeloma have recently been modified by the International Myeloma Working Group (Anonymous B J Hematology 2003;121:749-757). All three of the following must be present:

  1. Monoclonal paraprotein
  2. Bone marrow plasmacytosis or biopsy proven plasmacy
  3. toma
  4. At least one end organ consequence not due to another detectable cause (note mnemonic CRAB)
    • HyperCalcemia
    • Renal failure
    • Anemia
    • Lytic Bone lesions

The following additional finding can be helpful supportive evidence for the diagnosis of myeloma if present: 

  • depression of the levels of the uninvolved immunoglobulins 
Remember that 2-5% of myeloma patients have no abnormal protein detectable in urine or serum, so-called non-secretory myeloma. Such cases should be accepted as myeloma only if criteria 2 and 3 above are present plus lytic bone lesions or two of the CRAB criteria. For such patients a serum free light chain level test should be requested as a significant number of these patients will have abnormal values.



2. Staging

BCCA uses both the traditional Durie and Salmon staging and the International Staging System (ISS) (Greipp, J Clin Oncol, 2005;23:3412). For ISS staging, the albumin can be obtained from the SPE.

Durie Salmon Staging

Stage   Findings
1Hgb > 100 g/L Calcium < 2.88 mmol/L Bones = no more than 1 lytic lesion
M-protein: IgG < 50 g/L IgA < 30 g/L
Total urinary light chain < 4 g/24 h
2Between 1 and 3
3Any one of these:
Hgb < 85 g/L Calcium > 2.88 mmol/L Bones = multiple lytic lesions

M-protein: IgG > 70 g/L IgA > 50 g/L

Total urinary light chain > 12 g/24 h
A = creatinine<180 mmol/
B = creatinine > 180 mmol/L

International Staging System

Stage  Findings
1 Serum beta-2microglobulin < 3.5 mg/L and serum albumin ≥ 35 g/L
2 Serum beta-2microglobulin < 3.5 mg/L and serum albumin < 35 g/L or
 Serum beta-2microglobulin 3.5 to < 5.5 mg/L
3 Serum beta-2microglobulin ≥ 5.5 mg/L​

3. Treatment of Myeloma

1. All patients should receive the immunizations recommended in Appendix III.

2. Standard chemotherapy 
Chemotherapy is the treatment of choice. Even though a cure is not possible, chemotherapy often offers satisfactory palliation. The standard treatment for younger fit patients (up to approximately 70 years of age) is high dose chemotherapy and autologous hematopoietic stem cell transplant. Patients who are candidates for high dose chemotherapy and stem cell transplantation (see section 3 below) should NOT be treated with melphalan prior to stem cell collection because this may make it impossible to gather adequate stem cells to support transplantation. Such patients should be discussed with a member of the Bone Marrow Transplant Team shortly after the diagnosis is made. For older or unfit patients who are not eligible for transplantation, melphalan based treatment such as melphalan prednisone and bortezomib (UMYMPBor) or melphalan, prednisone and thalidomide (UMYMPT) is used.


3. Hematopoietic stem cell transplantation

In co-operation with the Lymphoma Tumour Group, the Bone Marrow Transplantation Team offers treatment with high dose chemotherapy and hematopoietic stem cell transplantation to selected patients up to approximately 70 years of age. These patients will receive induction chemotherapy that includes dexamethasone and bortezomib (UMYBORPRE). It is recommended that cyclophosphamide also be added in combination to deepen the remission prior to transplant. Physicians with potentially eligible patients should initiate referral with a member of the Bone Marrow Transplant Team. Patients who are candidates for high dose chemotherapy and hematopoietic stem cell transplantation should NOT be treated with melphalan because this may make it impossible to gather adequate stem cells to support transplantation.

4. Bisphosphonates 

Third generation bisphosphonates are effective in preventing some of the skeletal destruction caused by myeloma (Berenson, NEJM, 1996;334:488). Intravenous pamidronate, 30 mg in 500 mL saline over 1 h, once every 4 to 6 weeks, should be given to all patients receiving chemotherapy for myeloma (MYPAM). In order minimize the risk of osteonecrosis or renal toxicity, the duration of pamidronate treatment should be kept to the time shown in the randomized trial to have been beneficial. For patients who undergo high dose chemotherapy and stem cell transplantation Pamidronate should be continued at approximately monthly intervals until assessment of response. Most patients reach a complete or very good partial response in which case Pamidronate should be stopped; otherwise, continued for 24 months then stop. For patients who do not undergo a stem cell transplant Pamidronate should be continued for 24 months then stopped. After the pamidronate is stopped, it should only be resumed, for another 24 month course if the myeloma again requires systemic treatment. Prior to the initiation of bisphosphonates, patients should have a proper dental examination and have acute dental problems addressed to avoid the risk of osteonecrosis of the jaw. All patients treated with bisphosphonates should be provided with guidelines for dental care.

5. Secondary chemotherapy 
Secondary treatments for recurrent myeloma include the following:

  • Lenalidomide and Dexamethasone (UMYLENDEX)
  • Bortezomib with Dexamethasone (UMYBORREL)
  • Thalidomide (MYTHALID) (currently drug funding is not available with the BCCA)

The choice of the timing and order of these drugs must be individualized. Active clinical research is being conducted for treatment of relapsed/refractory myeloma. Members of the Leukemia/BMT Program or BCCA staff should be contacted about the status of such investigations.

6. No initial therapy 
Rarely, multiple myeloma is asymptomatic and either progressing slowly or remaining static. Hence, therapy may be initially withheld in patients who fulfill all of the following criteria. Such patients do not need to be treated with bisphosphonates.

  • No symptoms
  • Satisfactory peripheral blood counts
  • No paraprotein in the urine
  • Normal serum calcium
  • Stable serum paraprotein level
  • No non-irradiated lytic bone lesions
  • No renal or neurological disease due to myeloma
  • No more than one lytic bone lesion

7. Radiation 
Local radiation should be considered for patients with any of the following:

  • A symptomatic lytic bone lesion or soft tissue plasmacytoma which is not responding to systemic treatment
  • Threatening or actual pathological fracture
  • Spinal cord compression (recall that spinal cord compression is an emergency; a radiation oncologist should be contacted immediately to discuss treatment plans)

8. Renal Impairment in Multiple Myeloma
Renal impairment occurs in up to 25% of patients upon presentation. Damage to the renal tubules is caused by free light chains. Other causes which contribute to renal impairment include dehydration, hypercalcemia, nephrotoxic drugs (such as NSAIDS) and infections. Patients presenting with renal failure have higher early death rate and worse overall prognosis. Renal impairment may be the initial manifestation of multiple myeloma for which reason, patients should be worked up for myeloma should they present with renal impairment. A renal biopsy should also be considered. Early diagnosis and treatment can influence the degree and the ability to reverse renal impairment and the ability to administer anti-myeloma medication.

Initial measures to control and reverse renal impairment include:

  • Vigorous rehydration
  • Discontinuation of nephrotoxic drugs
  • Treatment of precipitating factors (eg. Hypercalcemia, hyperuricemia and infections)

Once myeloma is suspected or diagnosed treatment should be initiated as soon as possible. The following are recommended:

  • Dexamethasone. Appropriate doses are 20-40mg po daily for 4 days. This can be started immediately.
  • Bortezomib: Dose adjusting is not necessary in renal impairment. Approval through the Compassionate Access Program (CAP) is required. For patients who will not be eligible for transplant due to age and fitness an application for bortezomib should be made through the UMYMPBOR protocol. For patients who may be eligible for transplant application for bortezomib should be made through the UMYBORPRE protocol.
  • Consultation with the nephrology service to guide renal management

4. Assessment of Treatment

Criteria of Adequate Response:

  • Reduction of serum paraprotein to less than 50% of the pretreatment level and urine paraprotein to less than 10% of pretreatment level is required to be considered a partial remission.
  • Improvement or stabilization of bone marrow function
  • Improvement or stabilization of kidney function
  • Normalization of serum calcium
  • No new osseous or extra-osseous lesions
  • Resolution of all symptoms

Criteria of Relapse or Progression:

  • Progressive rise in level of paraproteinemia and/or paraproteinuria by more than 25%
  • Development of hypercalcemia
  • Appearance of new osseous or extra-osseous lesions
  • Progressive bone marrow failure

Development of anemia, thrombocytopenia or neutropenia singly or in combination usually reflects one of two problems, drug toxicity or progressive disease. Concurrent assessment of bone marrow (aspiration + biopsy) and paraproteins (serum + urine) will usually resolve the question. If progressive disease, bone marrow examination shows heavy infiltration with abnormal plasma cells and rising paraprotein levels. If drug toxicity, bone marrow examination shows hypocellular marrow, usually with residual myeloma. Paraprotein levels are either falling or remaining stable. Pancytopenia developing unexpectedly in patients on long-term therapy with alkylating agents may be due to secondary leukemia or myelodysplasia.

The development of a falling paraprotein level and separate signs of progressive disease (such as new bone lesions) suggest that the myeloma is becoming non-secreting and the paraprotein may not be as useful to follow disease. For such patients, serum free light chain levels may be helpful to follow disease.​

5. Duration of Treatment

For non-transplant eligible patients, initial treatment may be stopped after attainment and maintenance of the deepest response for at least four months. Treatment should be changed to secondary regimens if progressive disease develops during primary treatment. If treatment has been stopped because of an adequate response it should be resumed on the first objective evidence of progressive disease.

6. Follow-up Evaluation

On treatment

TestsInterval
CBC with platelets
serum creatinine, calcium
Serum protein electrophoresis

1 month
Urine 24h protein3 months (if only means of detecting abnormal protein)

Skeletal surveyat least once yearly

Bone marrowonly as needed to assess marrow function


Off treatment

The same tests should be performed as when the patient is on treatment, but the interval can be up to 3 months between lab tests and yearly for the skeletal surveys.​

SOURCE: Multiple Myeloma ( )
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