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Treatment Modalities and Symptom Management
By Robert A. Kyle, MD, Mayo Clinic, Rochester, Minnesota
07.14.01

INTRODUCTION 

Multiple myeloma (MM) must be differentiated from monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and primary amyloidosis. Treatment is not recommended unless symptoms develop or abnormalities progress. If the patient is less than 70 years old, one should consider autologous peripheral stem cell transplant (SCT). Mortality is low, but this procedure is not curative, and most patients relapse. There is no convincing evidence that double or tandem autologous SCTs are superior to single SCTs. Mortality with allogeneic bone marrow transplantation (BMT) is high, so "mini-allogeneic" transplants are being developed. 

HIGHLIGHTS

Minimal criteria for the diagnosis of MM include bone marrow with more than 10% plasma cells or tissue biopsy specimen demonstrating monoclonal plasmacytosis and at least one of the following: monoclonal protein (M-protein) in the serum (usually >3 g/dL), M-protein in the urine, or lytic lesions. MGUS, SMM, and primary amyloidosis must be differentiated from MM. Patients with MGUS or SMM should be identified and not treated unless symptoms develop or laboratory abnormalities progress, because they may remain stable for many years. The size of the serum M-protein, amount of M-protein in the urine, and number of plasma cells in the bone marrow are helpful in differentiating between benign and malignant plasma cell proliferative disorders. The plasma cell labeling index (measurement of the synthesis of DNA by plasma cells) is useful. If this index increases, the patient has active MM or will soon have symptomatic disease. On the other hand, 40% of patients with MM have normal labeling indices. Increased numbers of circulating plasma cells of the same isotype are present in 80% of patients with active MM, but there are few or no circulating plasma cells in patients with MGUS or SMM. The patient must be followed with measurements of M-protein in the serum and urine and periodic evaluation of clinical and laboratory parameters.

Prognosis

Drs. Philip R. Greipp of the Mayo Clinic and Jesus San Miguel of the University of Salamanca in Spain reported on efforts to establish an international prognostic index for MM. They noted that the Durie-Salmon Staging System has been a standard for a quarter century, but it has many shortcomings. Newer prognostic factors are available, but there is no agreement on the best system. Prognostic factors were discussed at the International Myeloma Foundation retreat and at the American Society of Hematology Meeting in 2000. Criteria for treatment were developed, and Dr. Kyle presented the criteria at the International Prognostic Group Meeting in Banff.

Therapy

If the patient is less than 70 years old, the physician should seriously consider an autologous peripheral blood SCT. The stem cells must be collected before the patient is exposed to alkylating agents. The two major shortcomings of autologous SCT are that myeloma is not eradicated even with large doses of chemotherapy, total body irradiation (TBI), or both and that autologous peripheral stem cells are contaminated by myeloma cells or their precursors. The mortality rate with autologous SCT is only 1% to 2%. One can proceed with the transplant as soon as the patient has recovered from stem cell collection, or, following collection, one can treat the patient with alkylating agents and delay the transplant until progressive disease develops. Survival is the same with both approaches, but patients given early transplants are spared the inconvenience and cost of chemotherapy Currently autologous SCT is applicable for up to 50% of patients with MM.

In a prospective study comparing melphalan plus TBI with melphalan alone, the response rate, event-free survival (EFS), and overall survival (OS) were not different with the two regimens. The toxicity of melphalan 200 mg/m2 (MEL200) was significantly lower than that of melphalan plus TBI. In an effort to improve the preparative regimen, studies are being conducted with Holium-166-DOTMP or Samarium-153-EDTMP in conjunction with melphalan. Alfa2 interferon (a2-IFN) prolonged initial progression-free survival, but after longer follow-up there was no difference in survival. Idiotype-treated dendritic cells have been used to prolong the duration of response.

The selection of CD34 stem cells might be beneficial, because this results in a 2- to 3-log reduction in tumor cells. However, EFS and OS are not significantly different between patients with or without stem cell selection. At present, eradication of myeloma is the more important goal, but as preparative regimens improve, contamination of the reinfused cells will assume greater importance.

Dr. Mario Boccadoro and colleagues of the University of Torino reported the results of studies using intermediate doses of melphalan. They treated 71 MM patients with two or three courses of melphalan 100 mg/m2 (MEL100) followed by stem cell support. The median patient age was 64 years. The patients were matched on the basis of age and beta2-microglobulin (b2-MG) levels with patients treated with oral melphalan and prednisone (MP). Complete remission (CR) occurred in 47% of the MEL100 and 5% of the MP patients. Median EFS was 34 months in the MEL100 group and 17.7 months in the MP group (P <0.001). Median OS was 56+ months for MEL100 and 48 months for MP (P<0.01). In a multivariate analysis, superior EFS and OS were observed in patients presenting with low b2-MGlevels at diagnosis and in patients receiving MEL100. 

In a second analysis, Dr. Boccodoro compared the effect of MEL100 with that of standard MP in patients more than 65 years of age. Thirty-one patients aged 65 to 77 years (median 67) were treated with two or three courses of MEL100 and compared with a comparable group of 31 patients treated with MP. The patients were matched according to their stage at diagnosis and their serum b2-MGlevels. The EFS (P<0.005) and OS (P<0.01) were superior for the MEL100 patients to those for the patients receiving MP. Thus, MEL100 appeared to be superior to standard MP in both the general population and in patients more than 65 years of age.

The investigators next studied MEL100 versus MEL200. They compared 81 patients treated with MEL100 with 81 patients receiving MEL200 matched for b2-MG and stage. These patients were treated with single (n=45) or double (n=36) autologous transplantation. Treatment-related mortality was 4% with MEL100 and 7% with MEL200. The CR rate was 43% with MEL100 and 63% with MEL200. EFS was 30 months in the MEL100 group and 33 months in the MEL200 group. OS was 57 months for MEL100 and 53 months for MEL200. The investigators concluded that MEL100 was similar to MEL200 from the standpoint of CR, EFS, and OS despite a significant patient age difference (63 vs. 50 years) (P<0.0001Although the CR rate improved by 20% with MEL200, this was not enough to produce a significant outcome improvement. One should exercise caution when drawing conclusions from these nonrandomized trials. 

Dr. J. Anthony Child and colleagues of the Medical Research Council Trials in the United Kingdom reported their experience with standard ABCM chemotherapy versus intensive therapy with high-dose melphalan and stem cell support. Two hundred and three patients were randomized to ABCM (doxorubicin 30 mg/m2 IV and BCNU 30 mg/m2 IV, day 1; melphalan 6 mg/m2/day PO and cyclophosphamide 100mg/m2/day PO, days 22-25), with cycles repeated every 6 weeks until a plateau was achieved, and 204 were randomized to C-VAMP (doxorubicin 9 mg/m2/day and vincristine 0.4 mg/day as a mixed continuous infusion, days 1-4; methylprednisolone 1 g/m2 [max 1.5 g] IV or PO, days 1-5; cyclophosphamide 500 mg IV bolus, days 1, 8 and 15), with cycles repeated every 3 weeks to a maximum response. All C-VAMP patients except those showing disease progression went on to receive MEL200 with peripheral stem cell autograft. All patients in both regimens were offered maintenance therapy with a-IFN at 3 megaunits SC 3x/week escalating to 6 megaunits, if tolerated, until relapse. The majority of patients had bone pain (72%) and multiple lytic lesions (53%). The serum b2-MGvalue at presentation was 4.1 mg/L in patients in the standard arm and 4.2 mg/L in the intensive arm. Survival data will be forthcoming.

Double or tandem autologous SCT has been recommended, but in a randomized trial by the French Myeloma Group comparing single and double transplant, 2-year EFS and OS were not different. In a subsequent analysis, patients with double transplants at 5 years post-diagnosis had a survival rate of 85% compared with 70% for those with single transplants. 

Allogeneic BMT has the advantage that the graft contains no tumor cells and may produce a graft-vs-myeloma effect. However, only 5% to 10% of patients with MM are candidates for conventional allogeneic BMT from HLA-matched donors. The mortality rate is 20%-30%. In an effort to reduce mortality and increase the graft-vs-myeloma effect, investigators are using "mini-allogeneic" BMT with a nonmyeloablative regimen consisting of melphalan or fludarabine plus melphalan. The depletion of T cells may also decrease mortality. The use of donor peripheral blood mononuclear cells after allogeneic BMT often produces benefit. these efforts are both important avenues of investigation. 

Systemic chemotherapy is needed for patients older than 70 years who have symptomatic MM or younger persons for whom transplantation is not feasible. The most commonly used regimen is MP. The melphalan dosage must be altered so that there is some cytopenia 3 weeks after therapy is begun. MP produces an objective response in 50% to 60% of patients. Combinations of alkylating agents produce a better response rate but no significant difference in survival. Chemotherapy should be continued until the patient reaches a plateau state. Benefits of maintenance therapy with a2-IFN following conventional chemotherapy is controversial. In a large meta-analysis, there were modest response duration and survival benefits with a2-IFN in both induction and maintenance regimens.

Dr. Joan Bladé of the Hospital Clinic, Hematology in Barcelona pointed out that renal insufficiency is present at diagnosis in 20% of patients with MM, and one-third of them die within the first 2 months of therapy. Renal insufficiency is reversible in up to 50% of patients, particularly when its degree is moderate and it is related to precipitating factors such as hypercalcemia or dehydration. Factors associated with renal function recovery are serum creatinine level and amount of proteinuria as well as hypercalcemia. Patients who recover their renal function have a survival rate similar to that of patients with no renal failure at diagnosis. The response of renal failure to chemotherapy is approximately 40%. Response to therapy and severity of renal failure are factors significantly associated with survival. The treatment of choice for patients with creatinine >4.0 mg/dL with nonoliguric renal failure is VAD or dexamethasone along with early plasma exchange. However, plasma exchange is unlikely to be beneficial got patients with advanced myeloma cast formation and renal failure severe enough to necessitate dialysis. Long-term hemodialysis or peritoneal dialysis is worthwhile for patients with MM and end-stage renal failure. 

Almost all patients who respond to chemotherapy eventually relapse if they do not die of another disease. VAD has been the most effective regimen, but thalidomide produces an objective response in about one third of patients with refractory disease. The addition of dexamethasone to thalidomide may improve the response rate. Other new agents include the immunomodulatory drug CDC-501, an analogue of thalidomide. In addition, 2-methoxy estradiol, farnesyl transferase inhibitors, and the proteosome inhibitor PS-341 are all potential agents for therapy. The challenge is to develop new and better agents to prolong survival and ultimately cure MM.

Dr. Finn Wisløff of the Nordic Myeloma Study Group emphasized the importance of quality of life (QOL) for patients with MM. He reported on the experience of the Group‘s experience, which represents more than 100 hospitals in Denmark, Norway and Sweden. This comprises a population of approximately 15 million people. The group used the European Organization for Research and Treatment of Cancer questionnaire. It was completed prior to treatment and at intervals throughout the course of the disease by more than 80% of the patients. Quality of life was compared to reference data obtained from the Norwegian population adjusted for age and gender. They also obtained data on cost of therapy.

At diagnosis, myeloma patients have a substantial reduction in QOL. There is a large decrease in physical and role functioning and a moderate impairment of social and emotional function. Pain and fatigue are substantial problems. Patients who achieved objective response with MP experience substantial improvement in QOL. Those who had stabilization of their disease even without objective response also had improved QOL. The pain scores were substantially reduced and approached those of the reference population. The cost of MP was approximately $10,000. Dr. Wisløff concluded that oral treatment with MP prolongs survival by approximately 2 years, with good QOL. Consequently, it was considered cost-effective.

The addition of a-IFN to MP during induction and maintenance therapy produced a 5- to 6-month prolongation of the plateau state and a 3-month OS increase. Patients receiving a-IFN had a significant reduction in QOL during the first year of treatment. There was no improvement in QOL associated with the plateau phase. The cost was estimated at $110,000 per year, which was considered unacceptably high.

In a population-based study, the survival advantage of high-dose melphalan with autologous stem cell support was compared with that of conventional chemotherapy in newly diagnosed symptomatic myeloma patients less than 60 years of age. During the first 6 months, the patients in the high-dose group had significantly lower scores for QOL and for social functioning. At 12 and 24 months, QOL was similar in the high-dose and conventional chemotherapy groups, and at 36 months, there was a trend toward less fatigue and pain in the high-dose group. Thus, the 18 months of prolonged survival appeared to be associated with good QOL. The cost relative to conventional therapy with MP was estimated at $27,000, which was considered acceptable.


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