Multiple Myeloma (MM)
Treatment Options & Assessment of Response

Updated: February 2012

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 4 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 ttransplant. 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, 90 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; 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 and 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:

• Dexamethasone-based protocol (see BCCA website)

• Bortezomib-based protocol (see BCCA website)

• Lenalidomide-based protocol (see BCCA website)

• Thalidomide-based protocol (see BCCA website)

The choice of the timing and order of these drugs must be individualized; however, ordinarily Health Canada will not authorize release of thalidomide until the other approaches have failed. 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 (Assymptomatic myeloma). 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

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 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.  

Follow-up Evaluation

On Treatment

Tests	Interval
CBC with platelets,  serum creatinine, calcium  Serum protein electrophoresis	1 month
Urine 24h protein	3 months (if only means of detecting abnormal protein)
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.