The goals of treatment include:

• Controlling disease activity to prevent organ damage
• Extending disease-free survival (the length of time a patient has no evidence of disease) and length of life
• Providing lasting relief from pain and other disease symptoms
• Preserving normal performance and quality of life for as long as possible

Patients may be classified into one of three myeloma categories to help to determine treatment options. These categories are:

• Monoclonal gammopathy of undetermined significance (MGUS)
• Asymptomatic multiple myeloma
• Symptomatic multiple myeloma

Some of these patients may not need to receive immediate treatment for the myeloma, but they may receive bisphosphonates if osteoporosis is present or other supportive care for symptoms and complications. Postponing therapy, if appropriate, may help avoid or delay side effects and the risk of complications associated with chemotherapy; it also may delay development of resistance to chemotherapy.¹

With MGUS, a monoclonal protein (M protein) is present, but there are no symptoms, no other criteria for a myeloma diagnosis, and no apparent cause for the increased protein. This condition occurs in about 1% of the general population and in about 3% of normal individuals over the age of 70. While MGUS itself is harmless, approximately 16% of individuals with MGUS will progress to a malignant plasma cell disorder.

Characteristics of MGUS include:

• Serum M protein <3 g/dL
• Bone marrow plasma cells <10%
• Absence of anemia, renal failure, hypercalcemia, and lytic bone lesions

Disease management is limited to observation.¹

Patients with asymptomatic multiple myeloma have M protein and slightly increased numbers of plasma cells in the bone marrow. They may have mild anemia and/or a few bone lesions, but they do not exhibit the renal failure and frequent infections that characterize active multiple myeloma. In these patients, the myeloma is static and may not progress for months or even years. Asymptomatic multiple myeloma includes both smoldering multiple myeloma and indolent multiple myeloma.¹

• Smoldering multiple myeloma
  – Characteristics
     - Serum M protein >3 g/dL and/or bone marrow plasma cells ≥10%
      - Absence of anemia, renal failure, hypercalcemia, and lytic bone lesions
  – Disease management
     - Observation, with treatment beginning at disease progression
     - Bisphosphonates
     - Supportive care
     - Participation in a clinical trial
• Indolent multiple myeloma
  – Characteristics
      - Stable serum/urine M protein
      - Bone marrow plasmacytosis
      - Mild anemia or a few small lytic bone lesions
      - Absence of symptoms
  – Disease management
      - Monitoring every 3 months, with treatment beginning at disease progression
     - Bisphosphonates
     - Supportive care
     - Participation in a clinical trial

Patients who present with symptoms typically have M protein and increased numbers of plasma cells in the bone marrow. They also have anemia, kidney failure, hypercalcemia, or bone lesions. Patients with symptomatic myeloma require immediate treatment.¹

As with all cancers, treatment for multiple myeloma depends on many factors, including the stage and symptoms of the disease, as well as the patient's age and overall health. Treatment options for myeloma are summarized in Table 1.² The chemotherapeutic drugs that are used for this condition include the alkylating agents, melphalan and cyclophosphamide.

Source: Durie BGM. International Myeloma Foundation. Concise Review of the Disease and Treatment Options: Multiple Myeloma. 2003 ed. North Hollywood, Calif: International Myeloma Foundation; 2003. Adapted with permission.

There are options for treating the complications observed in patients with multiple myeloma. These options are outlined in Table 2.³

Source: Kyle RA, Rajumar SV. NEJM. 2004;351:1860-1873. Reprinted with permission.

Bisphosphonates provide a meaningful supportive benefit to multiple myeloma patients with lytic bone disease. Available data show superior performance of bisphosphonates versus placebo in reducing skeletal complications. In addition, a consistent reduction in vertebral fractures has been seen with these agents.

Bisphosphonate therapy can be used for the following disease characterizations:

• Osteolytic bone destruction⁴
  – Osteolytic activity is increased by the release of osteoclast-stimulating factors by myeloma, and stromal cells in marrow, and bone destruction is prevalent.
  – Abnormalities (lytic lesions, osteoporosis, or fractures) are present in 79% of patients at diagnosis.
• Presenting symptoms related to bone destruction that require prompt treatment (within 24 hours of diagnosis).⁵
  – Hypercalcemia
  – Spinal cord compression
  – Pathologic fracture
  – Vertebral body collapse

Table 3 summarizes the available bisphosphonates, their approval status, and their relative potencies.⁴ Only pamidronate and zoledronic acid are currently approved by the US Food and Drug Administration for use in multiple myeloma.

Abbreviations: FDA, Food and Drug and Administration-approved for: O, postmenopausal osteoporosis; PO, orally; IV, intravenous; HC, hypercalcemia; B&MM, breast cancer and multiple myeloma patients with lytic bone disease.
*Relative to etidronate.

Source: Berenson JR, Hillner BE, Kyle RA, et al. American Society of Clinical Oncology Clinical Practice Guidelines: The role of bisphosphonates in multiple myeloma. J Clin Oncol. 2002;20:3719-3736.

Clinical trial information and updates on current trials of drugs used for skeletal wellness will be available in the Clinical Trials section of this website.

Randomized clinical trials that evaluated bisphosphonates for the treatment of myeloma are shown in Table 4.

1.	Multiple Myeloma Research Foundation. About Myeloma. Available at http://www.multiplemyeloma.org/about_myeloma/2. Accessed December 2004.
2.	Durie BGM. International Myeloma Foundation. Concise Review of the Disease and Treatment Options: Multiple Myeloma. 2003 ed. North Hollywood, Calif: International Myeloma Foundation; 2003.
3.	Kyle RA, Rajkumar SV. Drug therapy: multiple myeloma. NEJM. 2004;351:1860-1873.
4.	1. Berenson JR, Hillner BE, Kyle RA, et al. American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2002;20:3719-3736.
5.	Sirohi B, Powles R. Multiple myeloma. Lancet. 2004;363:875-887.
6.	Belch AR, Bergsagel DE, Wilson K, et al. Effect of daily etidronate on the osteolysis of multiple myeloma. J Clin Oncol. 1991;9:1397-1402.
7.	Lahtinen R, Laasko M, Palva I, et al. Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Finnish Leukaemia Group. Lancet. 1992;340:1049-1052.
8.	McCloskey EV, MacLennan IC, Drayson MT, et al. A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma. MRC Working Party on Leukaemia in Adults. Br J Haematol. 1998;100:317-325.
9.	Brincker H, Westin J, Abildgaard N, et al. Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: a double-blind placebo-controlled trial. Danish-Swedish co-operative study group. Br J Haematol. 1998;101:280-286.
10.	Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of pamidtonate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. NEJM. 1996;334:529-530.
11.	Menssen HD, Sakalova A, Fontana A, et al. Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. J Clin Oncol. 2002;20:2353-2359.
12.	Berenson JR, Vescio R, Henick K, et al. A phase I, open label, dose ranging trial of intravenous bolus zoledronic acid, a novel bisphosphonate, in cancer patients with metastatic bone disease. Cancer. 2001;91:144-154.
13.	Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J. 2001;7:377-387.