Multiple Myeloma – TREATMENT

Posted by Alex

About 10 percent of patients with myeloma will have an indolent course demonstrating only very slow progression of disease over many years. Such patients only require antitumor therapy when the serum myeloma protein level rises above 50 g/L (5 g/dL) or progressive bone lesions develop. Patients with solitary bone plasmacytomas and extramedullary plasmacytomas may be expected to enjoy prolonged disease-free survival after local radiation therapy to a dose of around 40 Gy. There is a low incidence of occult marrow involvement in patients with solitary bone plasmacytoma. Such patients are usually detected because their serum M component falls slowly or disappears initially only to return after a few months. These patients respond well to systemic chemotherapy.

The vast majority of patients with myeloma require therapeutic intervention. In general, such therapy is of two sorts: systemic chemotherapy to control the progression of myeloma, and symptomatic supportive care to prevent serious morbidity from the complications of the disease. All patients with stage II or III disease and stage I patients exhibiting Bence Jones proteinuria, progressive lytic bone lesions, vertebral compression fractures, recurrent infections, or rising serum M component should be treated with systemic combination chemotherapy. Therapy can prolong and improve the quality of life for myeloma patients.

The standard treatment has consisted of intermittent pulses of an alkylating agent [L-phenylalanine mustard (L-PAM, melphalan), cyclophosphamide, or chlorambucil] and prednisone administered for 4 to 7 days every 4 to 6 weeks. The alkylating agents appear to be roughly equally active, but resistance to one agent is often accompanied by resistance to the others. The usual doses are as follows: melphalan, 8 mg/m2 of body surface area per day; cyclophosphamide, 200 mg/m2 per day; chlorambucil, 8 mg/m2 per day; prednisone, 25 to 60 mg/m2 per day. Melphalan is used most commonly, but because of their near equivalence in antitumor efficacy, we favor cyclophosphamide as the alkylating agent because it is less toxic to the marrow stem cell compartment and results in a lower incidence of acute myelodysplastic syndromes than do the other alkylating agents. Doses may need adjustment based on marrow tolerance. However, there are few constraints on the dose of the steroid pulse, and it appears that more is better. Patients responding to therapy generally have a prompt and gratifying reduction in bone pain, hypercalcemia, and anemia and often have fewer infections. The serum M component lags substantially behind the symptomatic improvement, often taking 4 to 6 weeks to fall. This fall depends on the rate of tumor kill and the fractional catabolic rate of immunoglobulin, which in turn depends on the serum concentration (for IgG). Light chain excretion, with a functional half-life of approximately 6 h, may fall within the first week of treatment. However, since urine light chain levels may relate to renal tubular function, they are not a reliable measure of tumor cell kill. Calculations of tumor cell kill are made by extrapolation of the serum M component level and rely heavily on the assumption that every tumor cell produces immunoglobulin at a constant rate. About 60 percent of patients will achieve at least a 75 percent reduction in serum M component level and tumor cell mass in response to an alkylating agent and prednisone. Although this is a tumor reduction of less than one log, clinical responses may last many months. The important feature of the level of the M protein is not how far or how fast it falls, but the rate of its increase after therapy. Efforts to improve the fraction of patients responding and the degree of response have involved adding other active chemotherapeutic agents to the treatment program. Patients with more advanced disease may benefit most from such an approach. High-dose therapy with hematopoietic support is also being tested in younger patients. Sequential treatment with combination chemotherapy regimens followed by two successive high-dose melphalan treatments, each supported with peripheral blood stem cell transplants, have achieved complete responses in 50 percent of patients treated within a year of diagnosis. Complete responses are rare (<10 percent) with standard therapy. Long-term follow-up is not yet available. Allogeneic transplants may also produce high response rates, but treatment-related mortality may be as high as 40 percent.

The ideal duration of therapy has not been determined. Most physicians treat every 4 to 6 weeks for 1 or 2 years. Cessation of therapy is followed by relapse, usually within a year. Retreatment may be associated with a second response in up to 80 percent of patients. Maintenance therapy (e.g., with IFNa) may prolong the duration of response, but this therapy is toxic and has generally not prolonged survival. The regrowth rate of the tumor during relapse accelerates with each relapse. This observation suggests that kinetic resistance to therapy (i.e., increase in cycling cells) is perhaps more important than drug resistance controlled by mdr-1 expression. Patients often respond to treatment, but the length of the response progressively shortens. Patients primarily resistant to initial therapy have a median survival of less than a year. High-dose pulsed steroids used alone (200 mg prednisone every other day or 1 g/m2 per day methylprednisolone for 5 days) or VAD combination chemotherapy (vincristine, 0.4 mg/d in a 4-day continuous infusion; doxorubicin, 9 mg/m2 per day in a 4-day continuous infusion; dexamethasone, 40 mg/d for 4 days per week for 3 weeks) may offer useful palliation in patients resistant to primary therapy.

About 15 percent of patients die within the first 3 months after diagnosis, and subsequently, the death rate is about 15 percent per year. The disease usually follows a chronic course for 2 to 5 years before developing an acute terminal phase, usually marked by the development of pancytopenia with a cellular marrow that is refractory to treatment. Widespread organ infiltration by myeloma cells occurs, and survival is less than 6 months. About 46 percent of patients die in the chronic phase of disease from progressive myeloma (16 percent) and renal failure (10 percent), sepsis (14 percent), or both (6 percent). Death in the acute terminal phase (26 percent) is chiefly from progressive myeloma (13 percent) and sepsis (9 percent). Five percent of patients die of acute leukemia, myeloblastic or monocytic, and although it has been debated that this is related to the primary disease, it appears more likely to be the result of chronic therapy with alkylating agents. Nearly 23 percent of patients die of myocardial infarction, chronic lung disease, diabetes, or stroke, all intercurrent illnesses related more to the age of the patient group than to the tumor.

Supportive care directed at the anticipated complications of the disease may be as important as primary antitumor therapy. The hypercalcemia generally responds well to glucocorticoid therapy, hydration, and natriuresis. Calcitonin may add to the inhibitory effects of steroids on bone resorption. Bisphosphonates (e.g., pamidronate 90 mg once a month) reduce osteoclastic bone resorption and preserve performance status and quality of life. Treatments aimed at strengthening the skeleton, such as fluorides, calcium, and vitamin D, with or without androgens, have been suggested but are not of proven efficacy. Iatrogenic worsening of renal function may be prevented by the use of allopurinol during chemotherapy to avoid urate nephropathy and by maintaining a high fluid intake to prevent dehydration and to help excrete light chains and calcium. In the event of acute renal failure, plasmapheresis is approximately 10 times more effective at clearing light chains than peritoneal dialysis, and acutely reducing the protein load may result in functional improvement. Urinary tract infections should be watched for and treated early. Chronic dialysis probably should not be initiated in patients who have failed to respond to antitumor therapy. Plasmapheresis may be the treatment of choice for hyperviscosity syndromes. Although the pneumococcus is a dreaded pathogen in myeloma patients, pneumococcal polysaccharide vaccines may not elicit an antibody response. The advent of intravenous gamma globulin preparations raises some hope that prophylactic administration may prevent some serious infections, but this has not been tested. Chronic oral antibiotic prophylaxis is probably not warranted. Patients developing neurologic symptoms in the lower extremities, severe localized back pain, or problems with bowel and bladder control may need emergency myelography and radiation therapy for palliation. Most bone lesions respond to analgesics and chemotherapy, but certain painful lesions may respond most promptly to localized radiation. The chronic anemia may respond to hematinics (iron, folate, cobalamin), and some have responded to androgens. The pathogenesis of the anemia should be established and specific therapy instituted, where possible.