Biomedical subjects
R Alexanian
Publications and source records attributed to R Alexanian.
2-Chlorodeoxyadenosine in the treatment of multiple myeloma.
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Primary dexamethasone treatment of multiple myeloma.
Intermittent courses of dexamethasone (DEX) were administered to 112 consecutive, previously untreated patients with multiple myeloma (MM). Using criteria based on a 75% or greater reduction of calculated tumor mass, the overall response rate was 43%. Among comparable patients, response rate were approximately 15% less than those observed previously with vincristine-doxorubicin by continuous infusion with intermittent DEX (VAD) and similar to those with melphalan-prednisone. The projected survival times with VAD or DEX were similar. Results indicated that DEX accounted for most of the plasma cell reduction achieved with VAD. Serious complications occurred in 27% of patients treated with VAD, but in only 4% of those who received DEX. In view of the similar outcome with fewer serious complications, DEX provided a simple, effective, and safe primary treatment for a large fraction of patients with MM. Patients who appear most likely to benefit include those with hypercalcemia or pancytopenia, or who require simultaneous radiotherapy for a pathologic fracture.
Irreversibility of drug resistance in VAD-refractory myeloma.
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Multiple myeloma: spinal MR imaging in patients with untreated newly diagnosed disease.
Spinal magnetic resonance (MR) imaging was performed in 29 patients with newly diagnosed, untreated multiple myeloma. Nineteen (66%) patients were asymptomatic. Sagittal pre- and postcontrast T1-weighted spin-echo images and gradient-recalled-echo images of the thoracic and lumbosacral spine were obtained. Marrow involvement was identified in 20 (69%) patients. There were three MR patterns: focal lesions in nine patients (31%), diffuse involvement in seven (24%), and an inhomogeneous pattern of tiny lesions on a background of normal marrow in four (14%). A statistically significant correlation between MR imaging patterns of marrow involvement and serum hemoglobin values (one-way, P = .0899; Kruskal-Wallis, P = .0620) and between MR imaging patterns and percentage of marrow plasmacytosis (Kruskal-Wallis, P = .0314) was noted, with patterns of diffuse and focal marrow involvement associated with more abnormal values. Spinal MR imaging in patients with early myeloma may reveal marrow involvement in both symptomatic and asymptomatic patients. Some correlation was found between MR imaging patterns and laboratory indexes of disease.
Curability of solitary bone plasmacytoma.
PURPOSE: The effects of involved-field radiotherapy were assessed in patients with a solitary plasmacytoma of bone (SBP). PATIENTS AND METHODS: Forty-five consecutive patients with an SBP received megavoltage irradiation of at least 3,000 cGy. The median age was 53 years, 67% of patients showed a myeloma protein, and uninvolved immunoglobulins (Igs) were preserved in 93% of patients. RESULTS: Permanent control of presenting disease was achieved in all but two patients, but 46% of patients developed multiple myeloma. When it occurred, progression of myeloma occurred within 3 years in two thirds of the patients, suggesting that the extent of disease was understaged at diagnosis. Myeloma protein disappeared in nine patients (30%) whose disease has not yet recurred. The median survival for all patients was 13 years and the myeloma-specific survival fraction at 10 years was 53%. CONCLUSION: In patients with an SBP, the disappearance of myeloma protein with involved-field radiotherapy predicted long-term disease-free survival and possible cure. Nonsecretory disease and persistent myeloma protein after treatment were adverse prognostic factors for which adjuvant therapy with interferon alfa should be considered.
Solitary plasmacytoma of bone and asymptomatic multiple myeloma.
There is a wide spectrum of disease among patients with plasma cell myeloma. A small fraction have a localized plasmacytoma of bone that requires specialized techniques for accurate staging, followed by local radiotherapy that may be curative in some patients. Other patients with multiple myeloma may be free of symptoms and the disease is recognized by chance laboratory studies. Some have a prolonged, stable course with little change in disease for many months or years and resemble patients with MGUS. These patients have low serum myeloma protein and are free of focal bone lesions even on MR imaging. Complications are more imminent among other patients with higher levels of myeloma protein and/or bone lesions, who usually require treatment within 2 years after diagnosis. Still other patients with more advanced generalized disease (intermediate tumor mass) or with a pathologic fracture that may be relieved with local radiotherapy usually require even earlier chemotherapy to prevent or treat complications.
Solid tumors in multiple myeloma.
The frequency of solid tumors was evaluated in 628 consecutive patients with multiple myeloma who had been treated with various melphalan-prednisone combinations. Among those patients who lived at least 2 months, the incidence and diversity of second tumors were similar to those in normal persons of the same age and duration at risk. The diagnosis was usually made within 2 years after the start of chemotherapy for the myeloma. Long-term melphalan therapy did not seem to contribute to the pathogenesis of second solid tumors in patients with multiple myeloma.
Unmaintained remissions in multiple myeloma.
Twenty-eight patients with multiple myeloma responding to prior melphalan-prednisone combinations, but without additional chemotherapy, were followed until relapse. Patients receiving no further treatment had a median survival time similar to that of those receiving indefinite courses of melphalan-prednisone or carmustine-prednisone. Prolonged periods of unmaintained remission occurred primarily in patients without extensive disease at the time of diagnosis or in whom the abnormal protein disappeared from the electrophoresis strip. The initial relapse after an unmaintained remission was controlled in 80% of patients with the resumption of melphalan-prednisone, but second remissions were usually less marked in degree and shorter in duration. Results supported the long-term evaluation without chemotherapy of selected patients with low numbers of plasma cells after treatment who were likely to experience long durations of disease stability and respond again to retreatment with melphalan-prednisone.
Tumor growth patterns in multiple myeloma.
Serial changes in tumor mass were evaluated in 61 patients with multiple myeloma who had received intermittent courses of melphalan-prednisone until death. The variations in the kinetics of tumor reduction and relapse could be explained by a mathematical model based on two cell populations, one sensitive to and one resistant to chemotherapy. For all responding patients, the median tumor halving-time was 1.3 months and the median doubling time was 2.9 months. The duration of a constant tumor mass during remission was brief in most patients. A larger fraction of resistant cells prior to therapy was associated with a slower tumor doubling-time during relapse. With a constant fractional reduction of sensitive cells and a tumor halving-time of one month or less, all cells sensitive to alkylating agents would be eliminated with 3 years of uninterrupted intermittent therapy.
Combination therapy for multiple myeloma.
The effect of six different chemotherapy regimens were evaluated in 462 previously untreated patients with multiple myeloma. In comparison with other treatments, drug combinations that included vincristine and were given at 3-week intervals were associated with higher response rates and longer survival times. No gain was noted from the use of Adriamycin or from combinations of alkylating agents unless vincristine was given and the treatment intervals were short. Seventy-one responding patients were allocated at random to maintenance treatment with intermittent courses of either azathioprine--prednisone or a combination of melphalan--cyclophosphamide--carmustine (BCNU)--prednisone. The survival time was not prolonged with either maintenance treatment in comparison with that for responding patients continued on other therapies or on no therapy in previous studies. Attempts to reduce tumor was maximally with a change in the therapeutic modality, such as with immunotherapy or radiotherapy, remain to be evaluated.
Clinical evaluation of Asaley.
Asaley is an L-leucine derivative of sarcolysin which is more active against some rodent tumors. Studies in the USSR demonstrated activity in patients with ovarian and breast carcinoma, Hodgkin's disease, and multiple myeloma. This study in 73 evaluable patients indicated that an appropriate oral dose for patients with adequate bone marrow is 800 mg/M2/day X 4 days at 5-6 week intervals. The most common toxicities were myelosuppression, nausea, and vomiting. Antitumor activity was observed in 2 of 24 evaluable patients with melanoma, and stabilization of previously progressive disease was observed in patients with adenocarcinoma of the colon, multiple myeloma, lymphoma, breast carcinoma, and thyroid carcinoma. Responses were minimal and of short duration but most of the patients had received extensive prior therapy.
Growth kinetics of plasma cell myeloma.
The plasma cell labeling index(ex) (LI) of 128 patients with multiple myeloma at various stages of disease was compared as a function of tumor mass load and length of treatment. No significant differences in LI were noted for patients with various degrees of tumor reduction. Patients observed during the first 3 months of treatment had significantly higher LI than did untreated patients and those studied after longer intervals. In vivo cell-cycle analysis of myeloma cells by the halving time of the grain-count method failed to establish the length of the cell cycle but defined the length of S+G2 phases as being longer than 60 hours. Similar studies conducted in vitro defined a shorter combined length of S+G2 phase. In 2 patients in whom continuous infusion with [3H] thymidine was performed, the generation time was established as 8 days. Both patients had similar initial LI (5.7 and 6.6) but different growth fractions (19 and 47%). The measured tumor mass doubling time was much longer than the calculated one, suggesting the presence of considerable intrinsic cell loss (83 and 47%). These observations were summarized by a hypothetical two-compartment model for the growth kinetics of multiple myeloma.
Acute leukemia in multiple myeloma.
Of 476 patients with multiple myeloma treated during a 9-year period, 11 developed acute myelogenous leukemia or sideroblastic anemia. In all, the myeloma was in remission from chemotherapy with melphalan-prednisone combinations that had been continued for a median duration of 3 years. The incidence of acute leukemia or sideroblastic anemia was about 100 times higher than found in normal individuals of the same age. In all patients studied, major cytogenetic abnormalities were present, with hypodiploidy and evidence of chromosomal damage being noted most frequently. The frequency and nature of the chromosome changes were attributed to effects resulting from the prolonged drug therapy. These findings supported the long-term follow-up of selected patients with myeloma without any chemotherapy when marked degrees of remission followed the initial treatment courses.
Blood volume in monoclonal gammopathy.
The plasma volume, red cell volume, or both were measured in 170 normal, anemic, or polycythemic subjects. For anemic subjects without a serum protein abnormality or splenomegaly, the relationship between hematocrit and red cell volume was linear and predictable. In patients with a serum monoclonal globulin on electrophoresis, the plasma voluem was significantly increased for the hematocrit in 30%, and the total blood volume was increased in 45%. The frequency of an elevated plasma volume was higher in patients with a markedly increased level of monoclonal protein. Reductions of abnormal proteins with chemotherapy were associated with declines in plasma volume. For a specific concentration, the serum viscosity was highest in patients with IgM proteins and lowest in patients with IgG globulins. Marked elevations in viscosity were noted only in sera with macroglobulinemia or with more than 5 g/dl of IgG or IgA globulins.
Erythrokinetics and androgens in bone marrow cancer.
Erythrokinetic studies were conducted in 60 patients with chronic anemia due to bone marrow involvement by cancer and other diseases. Fifty-seven percent had evidence of ineffective erythropoiesis contributing to the severity of their anemia. Enhanced bone marrow activity in the extremities was detected in 14% of patients. Maximal doses of several oral androgens were given to 31 patients for at least 3 months. Only 26% of the patients increased their red cell mass by at least 20%. All who benefitted had a minimum level of effective erythropoiesis and showed a decline in serum iron concentration at least 30 mug/100 ml after 1 month of treatment. Erythropoietin values were not helpful in identifying responding patients. These findings indicated the value of erythrokinetic studies in defining the bone marrow capacity of patients with cancer who are considered for androgen treatment trials.
Multiple myeloma in young persons.
Three young men were found to have multiple myeloma. Because their ages ranged from 17 to 22 years, the diagnosis was not considered initially, and then it was doubted until electrophoretic studies were completed. In none was the disease far advanced. These patients are the first well-documented group of young persons with multiple myeloma.
Prognostic factors in multiple myeloma.
The effect of certain disease parameters on remission and survial time was evaluated in 482 patients with multiple myeloma treated with intermittent courses of melphalan-prednisone combinations. Increasing degrees of anemia, hypercalcemia, azotemia, and high serum myeloma protein levels were associated with progressive lifespan shortening. The short survival of patients with anemia and hypercalcemia was associated with short remissions in responding patients with these abnormalities. The extent of tumor mass was defined from specific laboratory parameters reported by Durie to be associated with large numbers of plasma cells. More advanced stages of myeloma were associated with higher frequencies and degrees of normal immunoglobulin depression. The response rate was not affected by the tumor mass grade, but increasing tumor mass was associated with a shorter lifespan. Greater degrees of tumor reduction were associated with longer remission and survival times. Patients in whom a marked tumor reduction was rapid had shorter survival and remission times than patients who responded more slowly.