Erythropoiesis in the anemia of bone marrow failure.

The quantitative relationship between red cell volume, erythropoietin level, and erythropoiesis was evaluated in 43 human beings. Results in normal man were compared with studies in patients with anemia from bone marrow failure and with polycythemia vera. The maximum erythropoietin excretion after bleeding normal men was similar to the basal levels found in patients with chronic anemia of similar magnitude. Although erythropoietin values were low in patients with polycythemia vera, bleeding evoked a normal response. In patients anemic from bone marrow failure, basal levels were elevated, and phlebotomy resulted in an increase consistent with the new level of anemia. These observations indicate that erythropoietin level is affected primarily by the degree of anemia and is not influenced by the duration of anemia. In normal subjects, a fivefold increase in urinary erythropoietin was associated with a doubling of erythropoiesis. Despite similar degrees of erythropoietin production, anemic patients with evidence of bone marrow in the lower extremities had greater red cell production. In patients with polycythemia vera, red cell production was inappropriately elevated with regard to the urinary erythropoietin excretion. Bone marrow maturation time was not shortened in patients anemic from bone marrow failure to the same degree as in bled, normal volunteers. In addition to an adequate level of erythropoietin production, normal bone marrow function is necessary for maximal shortening of maturation time.

Cytoplasmic immunoglobulin content in multiple myeloma.

Bone marrow cells of 82 patients with multiple myeloma were subjected to flow cytometric analysis of DNA and cytoplasmic immunoglobulin (CIg) content using propidium iodide and direct immunofluorescence assays. Except for two patients with nonsecretory myeloma, there was conformity in the immunoglobulin type derived from immunoelectrophoresis and plasma cell CIg staining. One patient with nonsecretory myeloma exhibited monotypic CIg staining, while the second showed no reaction. In eight patients with IgG lambda myeloma, the same tumor cells contained both lambda and kappa light chains, suggesting the productive rearrangement of both light chain genes. 14 patients with previously unrecognized plasma cells of low RNA content, all of whom were resistant to chemotherapy, were identified by CIg staining. By revealing previously unrecognized plasma cells with low RNA content, CIg analysis identified more patients with treatment-refractory myeloma.

Marrow cytometry and prognosis in myeloma.

We have previously shown that flow cytometric analysis of acridine orange-stained bone marrow cells is useful for the objective enumeration and characterization of plasma cells from patients with myeloma, frequently exhibiting an abnormal DNA and an elevated RNA content. In this report on 77 previously untreated patients, we have investigated the biologic and prognostic implications of these quantitative tumor cell parameters. The degree of marrow involvement by tumor, both by microscopic and cytometric analysis, correlated with the clinically derived tumor mass stage. Examination of the product of relative tumor cell RNA content and marrow tumor infiltrate (as a measure of metabolic capacity for immunoglobulin production) in relationship to the myeloma protein concentration in the serum revealed differences in the efficiency of immunoglobulin production and/or catabolism. There was an inverse relationship between the degree of marrow tumor involvement and RNA index, suggesting a more aggressive behavior of myeloma in patients with a low tumor cell RNA content. Prognostically, high tumor cell RNA content identified patients with a high likelihood of response to both initial treatment (32 patients, P = 0.004) and salvage therapy (29 patients, P = 0.01). Favorable factors for survival were low clinical tumor mass stage (P = 0.07) and low marrow tumor infiltrate as determined morphologically (P = 0.04) and cytometrically (P = 0.004). Thus, the direct examination of marrow cellular DNA and RNA content permitted assessment of tumor burden and was useful in the prediction of response and survival.

International uniform response criteria for multiple myeloma.

New uniform response criteria are required to adequately assess clinical outcomes in myeloma. The European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry criteria have been expanded, clarified and updated to provide a new comprehensive evaluation system. Categories for stringent complete response and very good partial response are added. The serum free light-chain assay is included to allow evaluation of patients with oligo-secretory disease. Inconsistencies in prior criteria are clarified making confirmation of response and disease progression easier to perform. Emphasis is placed upon time to event and duration of response as critical end points. The requirements necessary to use overall survival duration as the ultimate end point are discussed. It is anticipated that the International Response Criteria for multiple myeloma will be widely used in future clinical trials of myeloma.

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.

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.

Etoposide, dexamethasone, cytarabine, and cisplatin in vincristine, doxorubicin, and dexamethasone-refractory myeloma.

Based on remarkable activity in refractory lymphomas, a combination of etoposide, cisplatin (both administered by 4-day continuous infusions), cytarabine (Ara-C), and dexamethasone (EDAP) was evaluated in 20 patients with advanced myeloma refractory to standard melphalan and prednisone (MP) and/or vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and dexamethasone (VAD) and even to high doses of melphalan (HDM) (seven patients). Forty percent of patients responded regardless of previously recognized risk factors (eg, duration of drug resistance, tumor mass, and serum lactic dehydrogenase [LDH] level). While the median survival was only 4.5 months, patients with good performance (Zubrod less than 2) and low or intermediate tumor stage survived more than 14 months compared with only 2 months for the remaining group. EDAP could be readily administered in the outpatient clinic, but neutropenic fever prompted hospital admission in 80% of patients, half of whom developed penumonia and sepsis, a fatal outcome in four patients. Severe myelosuppression was of short duration, so that subsequent cycles could be administered every 3 to 4 weeks. No serious extramedullary toxicity, including renal toxicity, was encountered. Marrow toxicity and hence infectious complications may be reduced by elimination of Ara-C without compromising treatment efficacy. We conclude that the lack of cross-resistance with VAD and even HDM makes EDAP or a similar combination an attractive regiment to be formally explored in an alternating sequence with VAD in high-risk myeloma.

Magnetic resonance imaging in the staging of solitary plasmacytoma of bone.

PURPOSE: To assess prospectively the role of magnetic resonance (MR) imaging in the staging of patients with a solitary bone plasmacytoma (SBP). PATIENTS AND METHODS: Twelve consecutive patients with an apparent SBP underwent MR imaging of both the primary tumor and the thoracic and lumbosacral spine to seek additional foci of marrow involvement that might have been undetected by standard skeletal survey. All patients received megavoltage irradiation (total dose, 40 Gy) to the primary lesion. RESULTS: MR imaging of the thoracic and lumbosacral spine showed additional foci of marrow replacement in four of 12 patients, with signal characteristics identical to those of the primary tumor. In all four patients, the abnormal protein persisted at greater than 50% of the pretreatment value following radiation treatment. In contrast, the myeloma protein disappeared or was reduced by greater than 50% in five of the six patients with secretory disease and without additional marrow abnormalities. One of four patients progressed to multiple myeloma 10 months after diagnosis with new lesions on conventional radiographs in the same areas as detected previously by MR imaging. CONCLUSION: Four of 12 patients considered to have a SBP by standard criteria may have been understaged, because MR imaging showed additional marrow abnormalities consistent with myeloma. MR imaging of the spine may contribute to the initial staging of SBP, especially since some patients may be cured with radiotherapy.

Primary therapy of Waldenström's macroglobulinemia with 2-chlorodeoxyadenosine.

PURPOSE: To assess the activity of 2-chlorodeoxyadenosine (2CdA) as primary therapy for patients with Waldenström's macroglobulinemia. PATIENTS AND METHODS: 2CdA was given to 26 consecutive, previously untreated and symptomatic patients with Waldenström's macroglobulinemia. Two courses were administered to outpatients at a dose of 0.1 mg/kg body weight per day for a 7-day continuous infusion using a portable pump through a central venous catheter. Responding patients were followed up without further therapy and were scheduled to receive two additional treatments with 2CdA on disease relapse. RESULTS: Twenty-two of 26 patients responded to the 2CdA therapy (85%; 95% confidence interval [CI], 65% to 96%), including three patients who achieved a complete response and 19 patients who had a partial response. Treatment was well tolerated, with no acute hematologic toxicity. A marked and sustained reduction of CD4+ lymphocytes occurred in all patients and may have contributed to a fatal infection with disseminated herpes simplex in one patient. With a median follow-up of 13 months, five patients have relapsed and all re-treated patients have responded again to 2CdA. CONCLUSION: 2CdA is highly active in previously untreated patients with Waldenström's macroglobulinemia. A limited program of treatment induced responses of good quality and long duration in more than 80% of patients.

Prognostic significance of magnetic resonance imaging in patients with asymptomatic multiple myeloma.

PURPOSE: To assess the prognostic significance of magnetic resonance (MR) imaging in patients with newly diagnosed asymptomatic multiple myeloma. PATIENTS AND METHODS: Thirty-eight consecutive patients with asymptomatic myeloma of low tumor mass and negative skeletal surveys underwent MR imaging of the thoracic and lumbosacral spine. The presence and patterns of marrow involvement were correlated with standard laboratory parameters and time to disease progression. RESULTS: Nineteen patients (50%) had evidence of marrow involvement at spinal MR imaging. MR patterns of marrow involvement were classified as diffuse (five patients), variegated (nine), and focal (five). Patients with abnormal MR imaging studies required therapy after a median of 16 months, versus 43 months for those with normal MR studies (P < .01). CONCLUSION: Abnormal marrow patterns were present in half of patients with asymptomatic myeloma. An abnormal MR study of the spine identified asymptomatic patients who were likely to require treatment earlier than those with a normal MR study. A normal MR pattern provided additional justification to defer institution of chemotherapy. However, MR imaging remains an investigational tool to stage patients with multiple myeloma until more data are accumulated.

Phase I trial of cyclosporine-induced autologous graft-versus-host disease in patients with multiple myeloma undergoing high-dose chemotherapy with autologous stem-cell rescue.

PURPOSE: To determine the feasibility and toxicity of inducing autologous graft-versus-host disease (GVHD) with cyclosporine in patients with multiple myeloma undergoing autologous stem-cell transplantation. PATIENTS AND METHODS: Fourteen multiple myeloma patients with a median age of 50 years (range, 41 to 63) were enrolled. The median time from diagnosis to transplant was 651 days (range, 229 to 3,353). Ten patients had primary refractory disease, two were in first remission, and two were responsive to salvage therapy. The preparative regimen consisted of thiotepa, busulfan, and cyclophosphamide. Cyclosporine was administered daily for 28 days after the stem-cell infusion, and the dose was adjusted to maintain whole-blood cyclosporine levels between 50 and 150 ng/dL in the first seven patients (low-level group) and between 150 and 300 ng/dL in the other seven patients (high-level group). RESULTS: All patients achieved neutrophil engraftment a median of 11 days after transplant. Four patients developed > or = grade 2 hepatic toxicity, six developed > or = grade 2 nephrotoxicity, and four developed reversible cardiac toxicity. Only one treatment-related death occurred. Cyclosporine was withheld in seven patients for a median of 6 days because of renal and/or liver dysfunction. One patient developed clinical skin GVHD, which responded to corticosteroid therapy. Six patients developed histologic evidence of GVHD without clinical signs of GVHD (subclinical GVHD). The incidence of clinical and subclinical GVHD was similar in both cyclosporine groups. Three of 11 patients assessable for response achieved remissions. Three patients experienced disease progression 80, 160, and 354 days after transplant. Ten patients are alive without progression between 56 and 444 days after transplant. CONCLUSION: Induction of autologous GVHD by posttransplant cyclosporine is feasible and well tolerated in patients with multiple myeloma.

Ten-year survival in multiple myeloma.

Of 305 consecutive patients with symptomatic multiple myeloma treated between 1965 and 1974, a total of 4% survived ten years. Virtually all were less than 65 years old, presented with low or intermediate stage disease, and responded well to chemotherapy. Prolonged unmaintained remissions, slow tumor growth, and recontrol of relapsing disease were common. Acute leukemia caused the death of two of six long-term survivors. Patients treated since 1974 lived longer than those seen previously, a finding attributed to better control of complications and more effective combination chemotherapy.

Monoclonal gammopathy in lymphoma.

Serum protein electrophoresis was performed in 68% of 1,682 consecutive patients with lymphoma. Of 400 patients with chronic lymphocytic leukemia and lymphocytic lymphoma, 2.3% had an IgG peak, a frequency significantly higher than that found in normal individuals of comparable age. IgM peaks occurred in 4.5% of patients with lymphomas characterized by diffuse histologic infiltration of lymph nodes. This frequency was about 100 times greater than predicted and indicated that most IgM peaks detected by electrophoresis are produced by lymphomas. Clinical responses to therapy were associated with reductions of tumor mass usually ranging from 10% to 50% of the pretreatment level. A much greater magnitude of tumor reduction is needed to improve remission duration for patients with chronic lymphocytic leukemia and lymphocytic lymphoma.

Clinical classification of plasma cell myeloma.

Clinical and electrophoretic data were evaluated in 334 consecutive patients with myeloma or monoclonal peaks on serum or urine electrophoresis. Of the 242 patients with myeloma, 7% had localized plasmacytomas with absent or low level monoclonal peaks on electrophoresis and received only radiotherapy to focal disease areas. Chemotherapy was also withheld from eight other patients in an indolent clinical phase of multiple myeloma. Disease progression was apparent in about one third of the patients with localized and indolent myeloma within 12 months. Forty-three patients had idiopathic peaks on serum electrophoresis; more than 90% were of the IgG type with levels less than 3.0 gm/100 ml. Serial elecrtophoreses, immunoglobulin quantitations, and skeletal radiographs are recommended for the evaluation of patients with idiopathic peaks, the classification of early phases of myeloma, and the confirmation of tumor mass change.

Renal failure in multiple myeloma. Pathogenesis and prognostic implications.

The pathogenesis, prognosis, and reversibility of renal failure were assessed in 494 consecutive, previously untreated patients with multiple myeloma. For patients with a similar extent of disease, the presence or degree of azotemia did not adversely affect prognosis. Hypercalcemia and/or Bence Jones proteinuria explained the renal failure in 97% of patients. After treatment with a combination of hydration and chemotherapy, normal renal function was achieved in 51% of patients, reversibility usually being rapid and occurring more often in those with slight elevation of serum creatinine. Myeloma control was much more important for survival prolongation than reversal of renal failure, supporting the prompt institution of effective therapy for the underlying malignancy.

Prognosis of asymptomatic multiple myeloma.

Prognostic factors were assessed in 35 consecutive, asymptomatic patients with multiple myeloma. The presence of any lytic bone lesion or a serum myeloma protein concentration of at least 3.0 g/dL was followed by early disease progression and the need for chemotherapy within two years. Such patients require frequent monitoring of electrophoretic data. In patients without these features, the myeloma did not progress for a median of three years and the subsequent median survival time was seven years, identifying those likely to live for ten years after diagnosis. Because the treatment of myeloma remains palliative, chemotherapy should be withheld until symptoms develop or complications are imminent.

Amyloidosis in multiple myeloma or without apparent cause.

Thirty-two patients with primary amyloidosis (AL) either due to multiple myeloma or without apparent cause were studied. The most common manifestations were carpal tunnel syndrome and nephrosis. Rectal biopsy specimens showed amyloid infiltrates in 65% (15 of 23) of the patients studied, but virtually all biopsies of normal skin were negative. lambda Light chains were present in 75% (21 of 28) of patients with a monoclonal gammopathy. The median survival time was 14 months after histologic diagnosis, following a median delay of seven months from the recognition of disease by a physician. An earlier diagnosis would have been possible in most of the patients if the initial findings of amyloidosis had been recognized and evaluated definitively. The prognosis remains poor, because effective therapy is not available.

Standard-dose therapy for multiple myeloma: The Southwest Oncology Group experience.

We summarize the Southwest Oncology Group (SWOG) experience with standard therapy for multiple myeloma by reviewing and updating data from seven consecutive SWOG trials. Some modest progress has been made since the introduction of melphalan and prednisone (MP) for induction therapy, using regimens that involve vincristine and doxorubicin, and which save alkylating agents for possible later high-dose therapy. For maintenance, it appears that prednisone plays a useful role. We demonstrate the use of the data collected in these trials with a proposed new staging system.

Asymptomatic Waldenstrom's macroglobulinemia.

A study was undertaken to evaluate the frequency and natural history of disease in patients with asymptomatic Waldenstrom's macroglobulinemia (WM). Among 132 consecutive, newly diagnosed patients with monoclonal IgM, 82 (27%) had symptomatic WM indicated by anemia, lymphadenopathy, or splenomegaly. Thirty-one patients had similar clinical features but were asymptomatic and followed without therapy until disease progression. There were 19 patients with monoclonal gammopathy of undetermined significance of IgM type (MGUS). In comparison to overt WM, patients with asymptomatic WM had significantly higher hemoglobin (Hgb) level (median, 12.1 v 9.7 g/dL), lower serum beta(2)-microglobulin (B(2)M) level (median, 2.4 v 3.4 mg/L), and similar IgM peaks (median, 2.2 and 1.8 g/dL). The IgM component was 3.6 g/dL or less in all patients with asymptomatic disease. For asymptomatic WM, median time to disease progression was 6.9 years with rare morbidity. Prognostic factors for early progression were Hgb <11.5 g/dL, B(2)M >or= 3.0 mg/L, and IgM peak >3.0 g/dL. Combinations of these variables defined three risk groups for progression with markedly different median times to progression of >5 years, 2 years, and 0.5 year, respectively. Response rate and survival after institution of treatment were similar to those of patients treated promptly for overt disease. We conclude that, among patients with WM, 27% were asymptomatic with slow disease progression before the need for chemotherapy. Since disease outcomes after treatment were similar to those of patients treated at diagnosis, patients with asymptomatic disease should be identified and followed without treatment for as long as risks of complications remain low.

Biclonal and hypodiploid multiple myeloma.

Plasma cell DNA and RNA content was measured by flow cytometry of acridine orange-stained bone marrow cells from 72 untreated patients with multiple myeloma. Biclonal or hypodiploid DNA stemlines were identified in 10 patients, nine of whom had a low RNA content and did not have response to chemotherapy. Biclonal tumors often showed atypical myeloma protein changes with chemotherapy, suggesting that one clone was reduced whereas the other remained unchanged. These findings suggest a genetic basis for the resistance of low RNA tumors to chemotherapy.