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Multiple Myeloma

Severe pain is a common and continuous problem with multiple myeloma; pathologic fractures may occur; bacterial infections recur with distressing frequency; and anemia, renal disease, and other manifestations may be multiple myeloma. In addition, the disease is almost invariably fatal. To ease the patient's lot, it is important to call attention to the improving prognosis with therapy, and it is necessary to alleviate exaggerated fears of pathologic fractures and to stress the dangers of immobilization with the consequent further skeletal demineralization with hypercalcemia. Above all, the physician must show a sincere and continuing interest in the patients and their inevitably recurring complaints,

Mobilization is of prime importance, but it often is made difficult by pain, fractures, and fear. The milder forms of pain frequently respond to salicylates or NSAIDs, but sometimes more potent analgesics such as codeine, morphine or hydromorphone.

Corticosteroids are often helpful in the treatment of pain caused by lytic lesions, soft tissue infiltration, and acute nerve or spinal cord compression; dexamethasone in doses of 4 to 20 mg daily or equivalent doses of other steroids may be used. Neuropathic pain often responds to tricyclic antidepressants such as amitriptyline.

When pain originates from a readily identifiable bone lesion, local radiotherapy usually is effective (see below). Orthopedic supports for the spine, the rib cage, or the extremities often are helpful.

Anemia is a common complication of MM and causes disabling symptoms, often requiring blood transfusions. Recombinant human erythropoietin has been shown to correct the anemia in most patients.

Irradiation Therapy

Radiotherapy is the treatment of choice for individual painful bone lesions that do not respond to chemotherapy, for pathologic fractures, and for lesions that impair the function of vital structures. Relief of pain is prompt, pathologic fractures may heal, and impending compression of the spinal cord is prevented. Unfortunately, patients frequently return in a short time with trouble in another area and, although radiation may be given again, its use is ultimately limited by the development of bone marrow suppression, which also interferes with effective chemotherapy. Thus, it is important to restrict the field of therapy and the total administered dose, especially when the aim is relief of pain, rather than the treatment or prevention of a pathologic fracture. For the management of pain, single fractions are preferred increasingly to fractionated treatment. There was no difference in rapidity of onset or duration of pain relief between a single fraction of 8 Gy and a fractionated 2-week course of 30 Gy in a randomized study of 288 patients who had widespread bony metastases, including 23 patients with myeloma. In myeloma, tumor doses of 5 Gy frequently are effective and seldom is it necessary to exceed 15 Gy. Tumor doses in excess of 30 Gy given over a period of 3 weeks may be necessary to treat paraspinal lesions or large lytic lesions.

Solitary Plasmacytomas

Solitary plasmacytomas of bone of extra-medullary sites should receive potentially curative local radiotherapy, using wider fields in doses of 35 to 50 Gy over 5 to 6 weeks. Unfortunately, despite adequate curative surgery and radiotherapy, up to 12% of solitary plasmacytomas will relapse locally within 10 years and 15% of patients.

Before initiating local radiotherapy for a presumed solitary plasmacytoma, the diagnostic criteria for this rare plasma cell neoplasm must be satisfied: Bone marrow aspirated at a distance must be free of monoclonal plasma.

Chemotherapy

General Considerations

Because MM is a generalized disease, systemic chemotherapy is the treatment of choice. However, treatment is not indicated for asymptomatic patients (usually stage I) until previously stable disease has entered the progressive phase as indicated by clinical and laboratory changes. Ominous clinical signs of disease progression include the appearance of lytic bone lesions; most patients develop symptoms or disease progression within a year.

Primary Chemotherapy, Conventional Dose

Intermittent courses of melphalan and prednisone represent standard chemotherapy for newly diagnosed, symptomatic myeloma. Melphalan is administered at a dose of 9 mg/m2 daily by mouth for 4 consecutive days, together with prednisone 60 mg/m2 /day or 100 mg by mouth for four days. Because the absorption of melphalan is decreased by as much as 40% with food intake, the drug should be taken on an empty stomach.

TABLE 99-9 -- Dosage Schedules
1.Melphalan and prednisone (MP)
  M--9 mg/m2 per day for 4 days (or 0.25 mg/kg dayŚ4) orally, on an empty stomach, e.g., 1 hour before breakfast
   P--100 mg/day with breakfast for 4 days
2.Cyclophosphamide and prednisone
  (A)High-dose cyclophosphamide and prednisone (HiD CP)
    C--1.0 g/m2 IV on one day only, or 0.25 g/m2 orally in the morning for 4 days, every 3 weeks
    P--100 mg/day with breakfast for 4 days, orally, every 3 weeks
  (B)Low-dose, weekly cyclophosphamide and prednisone (LoD CP)
    C--300 mg/m2 IV, or orally, once a week
    P--100 mg orally, with breakfast, every other day
  (C)Low-dose, daily cyclophosphamide
    C--60 to 150 mg/m2 /day
 

(16 mg/m2 every 2 weeks for four treatments, then reducing the frequency of therapy to once every 4 weeks), but the response to therapy and survival are no better than with conventional oral therapy.

The renal clearance of melphalan has been thought to play an important role in limiting hematologic toxicity. The incidence of severe leukopenia following intravenous melphalan has been shown to be much greater in myeloma patients with renal insufficiency than in those with normal renal function, but a similar relationship.

Cyclophosphamide, another alkylating agent, is as effective as melphalan in the therapy of myeloma. Unlike other alkylating agents, which are equally toxic for resting and proliferating cells, cyclophosphamide is more toxic for rapidly proliferating than for resting populations. In addition, cyclophosphamide is schedule dependent, producing more effective tumor cell kill and yielding a better therapeutic ratio when given in large doses intermittently.

Although both melphalan and cyclophosphamide are alkylating agents, their respective mechanisms of action probably differ to some degree--patients resistant to one may still respond to the other. Prolonged remissions have been obtained with the second agent after the patient developed resistance to the first.

A simple treatment method, consisting of cyclophosphamide given weekly at a dose of 200 to 300 mg/m2.

Ifosfamide, another alkylating agent, has produced good responses as a single agent in two patients with plasma cell leukemia, including one complete remission, and deserves further study.

Carmustine (BCNU), like melphalan, is not schedule-dependent, but the intermittent administration of this agent permits the patient to be followed at less frequent intervals. The most common dosage is 150 mg/m2 intravenously.

Many other drug combinations have been studied, including regimens using multiple alkylating agents, vincristine, nitrosurea and anthracyclines. Most have failed to show significantly better response rates or median survivals.

VAD

The VAD regimen combines vincristine 0.4 mg/day and doxorubicin 9 mg/m2 /day administered by continuous infusion for 4 days with oral dexamethasone, 20 mg/m2 /day for days 1-4, 9-12, and 17-20. In newly diagnosed patients, the response rate is in excess of 50%, with a median survival comparable to that of standard regimens. A similar combination using methyl-prednisone (VAMP) is equally effective, but neither has prolonged survival.