Are the current criteria for response useful in the management of multiple myeloma?

One hundred seventy-three patients with multiple myeloma were treated from the time of diagnosis with standard oral melphalan and prednisone at 28-day intervals until they became refractory to treatment. Response to treatment was determined according to the Chronic Leukemia-Myeloma Task Force (TF) criteria, and independently according to the Southwest Oncology Group (SWOG) criteria. Survival by disease stage and response according to the two sets of criteria were analyzed for patients living longer than 3 months. The median survival of responding and nonresponding (TF criteria) stage II patients was 43.8 and 40.3 months, respectively (P = .29). By SWOG criteria, median survival for responding and nonresponding stage II patients was 48.3 and 39.0 months, respectively (P = .12). In stage III patients, median survival for responders and nonresponders (TF criteria) was 34.0 and 21.7 months, respectively (P = .01), compared with 35.5 and 24.4 months (P = .04) by SWOG criteria. These data would suggest that the TF criteria predicts a survival disadvantage only in very advanced myeloma and that applying the stricter limits for the definition of response of the SWOG does not further aid in selecting a subgroup of myeloma patients with poorer survival.

A randomized trial of melphalan and prednisone versus melphalan, prednisone, cyclophosphamide, MeCCNU, and vincristine in untreated multiple myeloma.

In a randomized study with 234 previously untreated patients with multiple myeloma, 129 were treated with melphalan (8 mg/m2 perorally for four days) and prednisone (40 mg/m2 perorally for seven days, both every four weeks) and 105 with melphalan and prednisone at the same doses plus cyclophosphamide (600 mg/m2 intravenously every four weeks), MeCCNU (100 mg/m2 PO every eight weeks), and vincristine (MPCCV, 0.6 mg/m2 IV every four weeks). A total of 49 (38%) of the 129 patients treated with melphalan and prednisone (MP) and 48 (46%) of the 105 patients treated with MPCCV showed good response (GR) (P not significant); the overall response rates were 58% and 70%, respectively. Thirty-seven percent of the MP group and 39% of the MPCCV group remain alive at 48 months from first treatment (P not significant). The estimated 48-month survival from first treatment, according to different prognostic factors at diagnosis, in both groups was as follows: stage 1,56%; stage II, 46%, and stage III, 23% (I and II v III P less than .001). Survival at 48 months according to response was GR, 68%; partial response (PR), 33%; and null, 16% (GR v null, P less than .0005; GR v PR, P less than .0005). Survival according to renal function was 43% for a creatinine level less than 2 mg/100 mL and 27% for a creatine level greater than or equal to 2 mg/100 mL (P less than .0005). No significant difference has been found between the two treatment schedules in terms of response rate and survival time, in any stage of disease.

Single, sequential, and multiple alkylating agent therapy for multiple myeloma: a CALGB Study.

Four intravenous (IV) alkylating agent regimens were tested in 615 previously untreated patients with multiple myeloma. Patients were randomized to receive melphalan, cyclophosphamide, and carmustine in combination (MCBP), sequentially (Seq-MCBP), or in combination with doxorubicin (MCBPA). The fourth group received IV melphalan (MP) as the only alkylating agent. All groups received a tapering dose of prednisone. Toxicity was similar for all regimens although the nadir of cytopenia was reached more quickly for the regime including melphalan only. Response as measured by reduction in myeloma protein or other parameters were similar for the four treatments. Survival was significantly poorer for the group receiving the alkylating agents in sequence. The survival of high tumor cell load patients who were azotemic was better in the groups treated with IV MP or with the combination of IV MCBP. In view of the simplicity and probable cost savings attached to single-agent treatment, a melphalan/prednisone regimen should be considered as initial therapy for all patients with myeloma.

Distal renal tubular acidosis in multiple myeloma.

A patient with early multiple myeloma was initially seen with a severe hyperchloremic metabolic acidosis with a normal anion gap and a urine pH of 6.3. The patient did not have glucosuria, aminoaciduria, of phosphaturia. A bicarbonate loading test showed that the fractional excretion of bicarbonate was less than 5% and confirmed the hypothesis that the patient had a distal renal tubular acidification defect. The pathophysiologic mechanism that caused this defect is unknown, but it is associated with the presence of a serum M component (IgG-lambda) and a urine M component (lambda light chains). Multiple myeloma should be considered in the differential diagnosis of conditions of patients who have a renal tubular acidification defect.

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.

Multiple myeloma with polyneuropathy and coagulopathy. A case report of the polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin change (POEMS) syndrome.

A patient with the syndrome of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) had multiple myeloma and IgA-kappa monoclonal gammopathy. To our knowledge, of over 50 cases in the literature, this is the only instance of kappa light chains noted in a patient with the complete syndrome. Sural nerve biopsy revealed increased immunofluorescence for IgA and kappa chains. Furthermore, this patient had a hemorrhagic diathesis characterized by a prolonged bleeding time and a prolonged thrombin time due to a qualitative platelet dysfunction and an apparent inhibition of fibrin monomer polymerization. In none of the other cases of POEMS syndrome was a coagulopathy reported. A short course of plasmapheresis improved the bleeding time but did not alter the polyneuropathy.

[Preparation and characterization of glycopeptides from human monoclonal immunoglobulin]. / Préparation et caractérisation des glycopeptides d'une immunoglobuline monoclonale humaine

The carbohydrate composition of an human IgM myeloma protein (IgM Du) has been determined. Seventeen homogeneous glycopeptides are described and exhibit a very large microheterogeneity. They appear as two different groups : the first one contains only mannose and N-acetyl glucosamine, while the other contains N-acetyl-glucosamine, mannose, galactose, fucose, and sialic acid in variable amounts. One glycopeptide termed IX1, which contains 6 mannose and 1 N-acetylglucosamine residues is located on the terminal portion of the Fc fragment and its aminoacid sequence has been determined : Tyr-Asx-Val-Ser.

Multiple myeloma in a patient with sickel cell anemia. Interacting effects on blood viscosity.

Described here is a case of multiple myeloma in a patient with sickle cell anemia. Viscometric studies were made by comparing the patient's whole blood, plasma and washed red blood cells with those of a normal control subject and a patient with sickle cell anemia. Results showed that the increased viscosity of the patient's whole blood as compared with that of the control patient with sickle cell anemia was mainly due to erythrocytic interaction with the circulating abnormal immunoglobulin. It is postulated that the increased frequency of vaso-occlusive crisis that occurred in our patient in the months before the diagnosis and treatment of multiple myeloma, was due to this cell-protein interaction with the resulting enhancement of whole blood viscosity and the sickling phenomena.

Massive polyclonal hyperimmunoglobulinemia E, eosinophilia and increased IgE-bearing lymphocytes.

A patient (E.M.) with marked eosinophilia and hyperimmunoglobulin E (IgE) has been followed for 4 years. Peripheral blood eosinophilia reached levels in excess of 18,000 cells/mm3 and serum IgE concentration increased to more than 210,000 units/ml (about 0.48 mg IgE/ml). The IgE has both lambda and kappa light chains and is therefore considered polyclonal. The patient has an increase in peripheral blood lymphocytes which stain for surface IgE. Transfer of the patient's plasma (plasmsEM) to a rhesus monkey did not induce peripheral boood eosinophilia. The half life of IgEEM in a rhesus monkey was 2.2 days, which is similar to the half life of myeloma IgE in human subjects. The condition was not associated with defined morbidity except for mild persistent pruritus. Various studies revealed no evidence for atopic parasitic, immune deficiency or neoplastic disease.

Kinetics of recombination of heavy and light chains of a human IgG1 myeloma protein.

The recombination of alkylated H and L chains of a human myeloma protein (Jo) was studied by means of circular dichroism (CD). Marked CD changes were observed at 295 and 235 nm when H and L chains recombined. The change in the CD maximum at 235 nm was followed with time after mixing preparations of H and L chains in the pH range between 4 and 6. The recombination reaction was slow and followed second order kinetics. The observed rate constants were markedly dependent on pH. The pH dependence of the rate constant was analyzed assuming that there are two forms of H chain which are in a pH-dependent equilibrium with each other.

Detection and identification of serum monoclonal immunoglobulin by immunoisoelectric focusing. Limits of sensitivity and use during relapse of multiple myeloma.

The limits of detection of four classes of monoclonal immunoglobulin and free light chain in serum by isoelectric focusing and immunoisoelectric focusing have been determined and the sensitivity of these techniques compared with that obtained using immunoelectrophoresis and zonal electrophoresis with immunofixation. Immunoisoelectric focusing was 10-40 times more sensitive than immunoelectrophoresis and could be used to detect concentrations of monoclonal immunoglobulin that were undetectable by zonal electrophoresis with immunofixation. The relevance of this work in monitoring multiple myeloma during treatment and relapse is discussed.

Screening for multiple myeloma using routine laboratory test results.

Characteristics of myeloma protein can be best detected through serum electrophoresis, and are also detected as abnormal results of flocculation tests or hyperglobulinemia by routine laboratory work. The authors identified 38 cases of multiple myeloma in 5 years, actively making use of the available informations in the laboratory. The number screened was 7 times as many as the incidence previously observed, and most of them were screened in subclinical conditions. A formula to discriminate multiple myeloma from other diseases was obtained referring to the thymol turbidity test (TTT) and zinc sulfate turbidity test (ZTT) results through analytical processing the data from the first examination of the 38 patients. The most efficient and practical screening method for multiple myeloma was then developed by combining the formula by which suspicious serum specimens in routine tests are screened, with electrophoresis which confirms the disease.

Artefactual decrease in total protein concentration in patients with monoclonal gammopathies: a method-dependent error.

We found total protein estimates in patients with monoclonal gammopathies to be erroneously low when using the Cobas-Bio centrifugal analyzer. This problem occurred only when a serum-water blank was used. This probably results from the precipitation of these proteins under conditions of low ionic strength resulting in high blank readings. The problem can be avoided if a serum-saline blank is used.

Staging of myeloma. A preliminary study of staging factors and treatment in different stages.

Attempts were made to find prognostic factors in myeloma. In 16 deceased patients, urinary light chains, skeletal lesions, and the quantity of the monoclonal protein fraction in the serum were correlated to prognosis, in contrast to the electrophoretic mobility of the monoclonal fraction, the hemoglobin, the serum creatinine value, the serum calcium, or the intestinal calcium absorption. Skeletal calcium uptake was only numerically higher in mild myeloma than in advanced myeloma. Since these findings partially agreed with the staging procedure previously proposed by Salmon, a modification of this procedure was used to stage 50 myeloma patients. Survival was statistically significantly shorter in stage III than in stage I. A differentiated treatement with melphalan-prednisone in stage I, cytoxan infusions in stage II, and vincristine-cytoxan-prednisone in stage III is proposed. A preliminary comparison of nine patients in stage II-III given intensive treatment with 23 given melphalan-prednisone suggests a numerically, but not as yet a statistically significant increase in survival in the intensively treated group, which seems to have an 80% 2-year survival.

Myeloma immunoglobulin interferes with serum thyroxine analysis by homogeneous enzyme immunoassay.

Myeloma immunoglobulin paraproteins interfere with a homogeneous enzyme immunoassay (EMIT) for serum thyroxine. The EMIT assay failed to detect any hormone in three hyperproteinemic sera from multiple myeloma patients, although thyroxine in these sera was accurately measured by our competitive protein-binding radio-assay on small, re-usable Sephadex columns. The interference was due to turbidity of the paraproteins in the EMIT reaction mixture, resulting in an increased absorbance and a marked underestimation of hormone concentration. Thyroxine was detected (82 to 107% recovery) by the EMIT assay in ethanol extracts of myeloma sera. With 82 other sera there was an excellent correlation (r = 0.985, slope = 0.912, Y intercept (EMIT) = 6.8) of the EMIT assay with our competitive radioassay. Thus, although the EMIT thyroxine assay possesses many desirable features and it is an attractive alternative method to competitive radioassays, its susceptibility to interferences by immunoglobulin paraproteins is a troublesome liability.

Serum beta 2-microglobulin in patients with monoclonal gammopathies.

Beta-2-microglobulin concentrations were determined in serum samples from 45 patients with benign and malignant monoclonal gammopathies. In the group of patients suffering from multiple myeloma or Waldenström macroglobulinemia the mean beta 2-microglobulin level was significantly higher than in the group with monoclonal gammopathy of undetermined significance. Values above 3 mg/L were highly indicative of a neoplastic process and were observed in all the Waldenström patients and in greater than 90% of myeloma patients. No significant correlation was noticed between beta 2-microglobulin and monoclonal protein levels in any of the groups examined.

Prevalence of M-proteins in serum of hospitalized patients. Physicians' response to finding M-proteins in serum protein electrophoresis.

M-proteins (tall, narrow spikes) are the major finding in serum protein electrophoresis (SPE), and their presence could signify lymphoproliferative diseases. The physicians' response to this finding in 73,630 patients in whom a SPE was performed as part of a routine screening at hospital admission was studied. Serum and urine immunoelectrophoresis (IEP) were requested on the report of SPE in all patients who showed M-proteins on SPE. In 59 percent of these patients, neither serum nor urine IEP were ordered, and it was assumed that the results of SPE were ignored by physicians. The frequency of M-proteins (1.1 percent) in the hospitalized patients was higher than that reported for normal individuals. It is suggested that SPE should not be performed as a screening test in hospitals.

Acute phase reactants and clinical stages in multiple myeloma.

Serum levels of seven specific proteins mostly acute phase reactants (APR) have been studied (transferrin, alpha 2-macroglobulin, alpha 1-antitrypsin, haptoglobin, C3, ceruloplasmin, orosomucoid) in 14 healthy subjects and in 55 patients with multiple myeloma. The alpha 2-macroglobulin and transferrin are significantly decreased in the myeloma group compared with healthy controls whereas the remaining proteins under study are elevated, significantly only orosomucoid and ceruloplasmin. The APR in the IgG3 myelomas seem to show differences from those of the IgG1 and IgG2 subclasses the levels of the negatively changed proteins being lower, whereas the positive APR higher in the IgG3 myeloma. In the IgA myeloma, however, decreased levels of haptoglobin and alpha 1-antitrypsin have been found in spite of being positive APR. Transferrin and haptoglobin serum level can be included as a new parameter in regression equations for calculation of IgA myeloma cell mass.

Prognostic factors in multiple myeloma treated with prednisolone and sequential melphalan and ifosfamide: MIP combination chemotherapy.

Response rates and survival times were studied in 47 patients who had multiple myeloma and who were being treated with Prednisolone and sequential Melphalan and Ifosfamide (MIP therapy). The clinical response was determined by objective parameters such as the reduction of M-protein level, tumor volume and healing of bone destruction. Twenty-eight of the patients (59.6%) responded to the MIP therapy. The 50% survival time as followed from the initiation of treatment to death was 19 months. Of the prognostic factors, the age (greater than or equal to 70 years), clinical stage III of Durie and Salmon, hypercalcemia, extensive bone lesions, and the patho-morphological type IV of Brücher were associated with a decreased life-span. Therefore, MIP therapy was more effective in poor risk (high tumor mass group) than in good risk (low or intermediate tumor mass group) patients, but the survival of patients on MIP therapy was shorter in the poor risk group than in the good risk one. In addition, the group which responded rapidly (i.e. within 2-5 weeks) had longer remission and longer survival than the group which improved slowly (i.e. after 6-16 weeks).

[Clinical effect of human lymphoblastoid interferon in patients with multiple myeloma].

Five patients with multiple myeloma were treated with human lymphoblastoid interferon (HLBI). HLBI, 3 X 10(6) IU/day, was administered daily for more than two weeks by intramuscular injection. Out of four evaluable patients, a minor response was obtained in 3 patients. In these responders, one patient developed pleural effusion due to the infiltration of myeloma cells during the administration of HLBI, and drug resistance was observed in another patient during the re-administration of HLBI. Therefore, out of six evaluable courses, a minor response was obtained in 3 courses of HLBI treatment. No severe side effects were observed. Thrombocytopenia, general malaise, liver dysfunction and anorexia were the main reasons for discontinuation of HLBI administration. On the basis of the preliminary study, it is concluded that HLBI is worth trying in the management of refractory multiple myeloma.