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The Leukemia/Bone Marrow Transplant Program of BC

Healthcare Professionals
Cancer Management Guidelines

Multiple Myeloma

Updated: May 2016

Diagnosis

Required Tests

  • Serum and urine protein studies
    • Serum protein electrophoresis
    • Serum protein immunofixation and quantitative immunoglobulin
    • Urine protein 24 hour quantitation and electrophoresis
    • Serum free light chain levels: should be considered particularly where there is a high suspicion of myeloma but the serum protein electrophoresis is negative.
  • Serum calcium, uric acid, creatinine, albumin, LDH
  • Beta-2-microglobulin for staging at diagnosis only (not used for monitoring)
  • CBC
  • Skeletal radiographic survey (skull, spine, humeri, pelvis, femora, ribs)
  • MRI should be considered for patients with high clinical suspicion for cord compression or to exclude soft tissue lesions in a painful area.  CT may be considered but intravenous contrast studies are relatively contra-indicated because they may cause renal injury.
  • PET scan for patients with a solitary plasmacytoma.
  • Bone marrow aspiration and biopsy, with:
    • FISH probe translocation t(4;14)
    • FISH probe for Del(17p)
    • FISH probe for translocation t(14;16)
  • Hepatitis Bsurface Ag, hepatitis Bcore Ab, hepatitis C Ab

Note: Bone scanning is seldom useful in myeloma.

The diagnostic criteria of myeloma have recently been modified (Lancet Oncol 2014 Nov;15(12):e538-548). To be diagnosed with myeloma, there must be clonal bone marrow plasma cells =10% or biopsy proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events:

  • Myelomadefining events:
    • Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
      • Hypercalcemia: serum calcium >0.25mmol/L higher than the upper limit of normal or >2.75mmol/L
      • Renal insufficiency: creatinine clearance <40ml/min or serum creatinine >177µmol/L.
      • Anemia: Hemoglobin value of >20g/L below the lower limit of normal, or a hemoglobin value <100g/L.
      • Bone Lesions: one or more osteolytic lesions on skeletal radiography, CT or PET-CT.
    • Any one or more of the following biomarkers of malignancy:
      • Clonal bone marrow plasma cell percentage ≥60%
      • Involved:uninvolved serum free light chain ratio ≥100 minimum involved FLC level of at least 100mg/L required)
      • >1 focal lesion on MRI studies

A diagnosis of smouldering myeloma is made when both of the below critera are met:

  • Serum monoclonal protein (IgG or IgA) ≥30g/L or unrinary monoclonal protein ≥500mg per 24h and/or clonal bone marrow plasma cells 10-60%.
  • Absence of myeloma defining events or amyloidosis

Staging

Durie and Salmon Staging System

 Stage

Findings 

1

Hgb > 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

2

Between 1 and 3

3

 Any 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/L

B = creatinine > 180 mmol/L

(Durie, Cancer, 1975;36:842-54)

International Staging System (ISS)

The International Staging System (ISS) for myeloma is currently the more widely used. It depends only on the serum albumin and beta-2-microglobulin (B2M) and is actually more of a prognostic score than a staging system.

 Stage

Findings 

 I

Serum B2M < 3.5 mg/L and serum albumin ≥ 35 g/L 

 II

Neither stage I or III

 III

Serum B2M ≥ 5.5 mg/L 

(Greipp, J Clin Oncol, 2005;23:3412)

Revised International Staging System (ISS)

Recently, the International Myeloma Working Group have incorporated cytogenetic abnormalities and the LDH as a part of the staging system. 

Stage

Findings

I

ISS stage I and standard-risk CA by FISH and normal LDH

II

Neither R-ISS stage I or III

III

ISS stage III and either high-risk CA by FISH or high LDH

(Palumbo, J Clin Oncol, 2015;33:2863)

  • Del(17p), translocation t(4;14), translocation t(14;16) detected by FISH are considered high-risk CA
  • LDH is classified as normal or high according to local laboratory definition of normal range. High is a value greater than normal.

Treatment

Treatment Options

1. Immunizations

All patients should receive the immunizations recommended in the BCCA guidelines. (see BCCA website)

2. Standard chemotherapy

Chemotherapy is the treatment of choice. Even though a cure is not possible, chemotherapy often offers satisfactory palliation. The standard regimen for younger patients (approximately below 65 to 70 years of age) is high dose chemotherapy and autologous hematopoietic stem cell transplant. For older patients combination therapy with melphalan, prednisone and bortezomib  is considered standard therapy (see BCCA website). Patients who are candidates for high dose chemotherapy and stem cell transplantation (see section 3 below) should NOT be treated with melphalan because this may make it impossible to gather adequate stem cells to support transplantation. Such patients should be discussed with a member of the Leukemia/BMT group before treatment is initiated.

3. Hematopoietic stem cell transplantation

Selected patients younger than approximately 65-70 years of age are considered eligible for high-dose chemotherapy followed by hematopoietic stem cell transplantation. These patients should receive induction chemotherapy which is not toxic to the stem cells. Currently such patients will receive induction chemotherapy that includes dexamethasone and bortezomib. It is recommended that cyclophosphamide also be added in combination to deepen the remission prior to transplant. Physicians with potentially eligible patients should discuss referral with a member of the Leukemia/BMT group. Patients who are candidates for high dose chemotherapy and hematopoietic stem cell transplantation should NOT be treated with melphalan or other alkylating agents 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 and improve survival (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. Prior to initiation of pamidronate the patients should be seen by the dentist to address their dental health and have necessary invasive dental procedure done to reduce the risk of osteonecrosis of the jaw. 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 after 12 doses; otherwise, continued for 24 months then stopped. 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. All patients treated with bisphosphonates should be provided with guidelines for dental care (see BCCA website)

5. Secondary chemotherapy

Secondary treatments for recurrent myeloma include the following:

The choice of the timing and order of these drugs must be individualized. Active research is being conducted into alternative salvage treatments. The Leukemia/BMT group should be contacted about the status of such investigations.

6. No initial therapy

Rarely, multiple myeloma is an indolent disease either progressing slowly or remaining static (Smouldering multiple myeloma; please see diagnosis section). 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
  • Normal serum calcium
  • Stable paraprotein in the serum or urine
  • 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

Assessment of Response

The response criteria have been evolving based upon the availability of newer more sensitive testing and more effective treatments.  The most commonly used criteria are:

  • The EBMT/IBMTR criteria (BJH, 1998;102, 1115-1123)
  • IMWG critieria (Durie, Leukemia, 2006;20;1467-1473)

Simplified criteria that can be used for clinical management is the following:

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
  • 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 paraprotenuria 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 typically shows heavy infiltration with abnormal plasma cells and rising paraprotein levels. If drug toxicity, bone marrow examination shows hypocellular marrow, usually with residual myeloma and the 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 or stable paraprotein level and separate signs of progressive disease (such as new bone lesions) suggest that the myeloma is becoming non-secreting or light chain escape is occurring and the intact paraprotein may not be as useful to follow disease.  Consider testing serum free light chain levels if light chain escape is suspected.

Follow-up Evaluation

On Treatment

Tests

Interval

CBC with platelets, serum creatinine, calcium Serum protein electrophoresis

1 month

Serum free light chain levels

At least every 3 months or as needed

Urine 24h protein

3 months or as needed

Skeletal survey

at least once yearly

Bone marrow

only 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 3 months between lab tests and yearly for the skeletal surveys.

Algorithms

Click image to enlarge.

Multiple Myeloma Treatment Algorithm

Protocols

BCCA Chemotherapy Protocols and PPOs

Publications

  1. Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF. International Myeloma Working Group updated criteria for the diagnosis of myeloma. Lancet Oncol. 2014 Nov; 15(12):e538-48.  
  2. Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV; International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006 Sep;20(9):1467-73.
  3. Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and the MM010 phase III trials of lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov 23(11);2147-52.  
  4. Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Miguel JS, Bladé J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A, Esseltine DL, Schenkein D, Anderson KC. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 2007; Nov 15; 110(10): 3557-60.
  5.  San Miguel JS, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1055-66.

The information contained in these guidelines is a statement of consensus of Leukemia/BMT Program of BC professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patientís care or treatment. Use of these guidelines and documents is at your own risk and is subject to the Leukemia/BMT Program of BCís terms of use available at Terms of Use.

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