treatment of multiple myeloma

Physicians must understand both the natural history of the disease and the limitations of current therapy in the treatment of multiple myeloma.
An important study by Dimopoulos and associates evaluated the risk of disease progression in asymptomatic subjects with multiple myeloma. This study evaluated 638 consecutive untreated subjects with myeloma. Of these subjects, 95 were asymptomatic and were not treated until their M protein value rose to greater than 5 g/dL. These subjects developed increased bone disease or symptoms of bone disease. The subjects in this group were designated as either low risk (ie, no bone disease, M protein level <3>3 g/dL or Bence Jones protein level >5 g/24 h). Intermediate-risk subjects did not have bone disease or an M protein level greater than 3 g/dL or a Bence Jones protein level of greater than 5 g/24 h. The patients were evaluated every 2 months.

The median time for disease progression was 10 months in the high-risk group, 25 months in the intermediate-risk group, and 61 months in the low-risk group. At the time of progression, subjects were treated with standard chemotherapy. The subjects' response rates did not significantly differ from those of unselected populations. The median survival time from the institution of chemotherapy did not differ among the groups. To summarize, asymptomatic subjects did not benefit from early treatment, and delayed treatment did not affect the efficacy of the treatment (ie, survival).

Patients for whom therapy is indicated typically receive chemotherapy. Physicians treat many patients with high-dose therapy and peripheral blood or bone marrow stem cell transplantation. A randomized prospective study shows that this approach results in higher response rates and better disease-free survival rates.

Adjunctive therapy for myeloma includes radiation therapy to target areas of pain, impending pathologic fracture, or existing pathologic fracture. Bisphosphonate therapy serves as prophylaxis (ie, primary, secondary) against skeletal events (eg, hypercalcemia, spinal cord compression, pathologic fracture, need for surgery, need for radiation). Erythropoietin may ameliorate anemia resulting from either myeloma alone or from chemotherapy and has been shown to improve quality of life.

Patients with spinal cord compression due to multiple myeloma should begin corticosteroid therapy immediately to reduce swelling. Urgent arrangements must be made for radiation therapy in order to reverse or maintain neurologic function. Although surgical decompression is sometimes appropriate, posterior laminectomy in this population has been reported to have a mortality rate of 6-10% and to not be superior to radiation. This surgical approach is probably best reserved for patients in whom radiation fails. Newer surgical interventions, such as kyphoplasty, in which cement is injected into compressed vertebrae, have been shown to improve function with few complications, although the studies reported have been small.
Patients presenting with acute renal failure may benefit from plasmapheresis. Hydration (to maintain a urine output of >3 L/d), management of hypercalcemia, and avoidance of nephrotoxins (eg, intravenous contrast media, antibiotics) are also key factors.

Transplantation
Using the patient's own (ie, autologous) bone marrow or peripheral blood stem cells facilitates more intense antimyeloma therapy. Physicians can use otherwise lethal doses of total body irradiation and chemotherapy and then "rescue" patients by infusing patients' own stem cells. This sequence of myeloablative therapy, followed by the reinfusion of stem cells, is termed an autologous stem cell transplantation. This sequence of therapy allows physicians to use melphalan at an approximately 10-20 times higher dose than is used in standard therapy. In autologous transplantation, the reinfused stem cells or bone marrow act as a support to the patient but do not offer additional anticancer effects.
Tandem autologous transplants have been proposed as a way of overcoming the incomplete response to a single transplant. A recently reported 2 arm trial of single versus tandem transplants revealed no difference in overall survival at 54 months (Moreau, 2005).
In highly selected patients with multiple myeloma, physicians may use allogeneic (ie, from someone else) transplantation. In this approach, physicians administer myeloablative therapy and infuse stem cells (ie, peripheral blood or bone marrow) obtained from a donor, preferably an HLA-identical sibling. The advantage of this approach is that the patient is not at risk of being reinfused with myeloma cells. Also, the donor's immune system may fight the recipient's cancer (ie, graft vs myeloma effect). Unfortunately, the donor's immune system also may attack the recipient's body (ie, graft vs host effect).

Two randomized prospective studies compared standard chemotherapy with high-dose autologous transplantation. In the first study of 200 subjects, researchers observed better response rates (ie, 81% for the transplantation group vs 57% for the conventionally treated group) and better 5-year event-free survival rates (ie, 28% vs 10%). The second study also showed a significant improvement in event-free survival rates and superior quality of life for subjects treated with the high-dose approach.

Physicians treat myeloma with allogeneic transplantation less often than autologous transplantation for several reasons.

First, the risks of complications and death from allogeneic transplantation increase with age, and most patients with myeloma are older than the ideal age for allogeneic transplantation.
Second, the transplantation-related mortality rate is quite high in patients with myeloma who undergo allogeneic transplantation. The death rate within 100 days of transplantation ranges from 10-56% in different series.
Third, although some survivors experience long-term disease-free results after allogeneic transplantation, a retrospective case-matched analysis of allogeneic versus autologous transplantation showed a median survival of 34 months for the autologous transplantation group and 18 months for the allogeneic group.
The exception to this rule is the rare patient with a twin donor. In a limited study of 25 transplantations involving twins, outcomes with syngeneic transplantations were superior, with reduced transplantation-related mortality.

The development of a nonmyeloablative preparative regimen for myeloma allogeneic transplantation is changing the equation. A recently republished report of 52 high-risk patients who underwent nonmyeloablative transplants described a 17% mortality rate. Progression-free survival at 18 months was roughly 30% (Gerull, 2005).

Radiation
Myeloma is extremely sensitive to radiation.
Physicians use radiation to treat symptomatic lesions and to stabilize bones at risk for fracture.
Physicians also use radiation to treat spinal cord compression.
Some researchers tried low-dose, double-hemibody irradiation as systemic therapy but did not observe dramatic success.

Surgical Care:
Surgical therapy for myeloma is limited to adjunctive therapy.

Consultations:
Patients often benefit from the expertise of an orthopedic surgeon versed in oncologic management because prophylactic fixation of impending pathologic fractures is occasionally warranted.

Diet: Patients with myeloma who are receiving bisphosphonate therapy should include adequate calcium in their diet.
Activity:
Encourage patients with myeloma to be physically active, as appropriate to their individual bone status. Physical activity may help