Gösta Gahrton

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.

CRITERIA FOR EVALUATING DISEASE RESPONSE AND PROGRESSION IN PATIENTS WITH MULTIPLE MYELOMA TREATED BY HIGH‐DOSE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION

Multiple myeloma (MM) is a malignant plasma cell disorder accounting for about 10% of haematological malignancies. The disease is characterized by the clonal proliferation of plasma cells which produce a monoclonal immunoglobulin heavy and/or light chain (paraprotein, M-protein or Mcomponent). This patient-specific paraprotein is present in the serum and/or urine of all patients except in the 1–2% of patients with non-secretory myeloma. Typical clinical and laboratory features in patients with MM include bone pain (due to lytic lesions or osteoporosis), anaemia, renal insufficiency, hypercalcaemia, increased susceptibility to infection and constitutional symptoms resulting in poor performance status. Less common complications include cord compression due to extramedullary plasmacytomas or vertebral collapse, peripheral neuropathy, amyloidosis and hyperviscosity syndrome (Malpas, 1998). Prior to the introduction of alkylating agents, the median survival of patients with MM was less than a year (Korst et al, 1964; Holland et al, 1966). Approximately 60% of patients respond to initial treatment with conventional chemotherapy, but although survival is prolonged by treatment the median survival remains approximately 3 years (Bergsagel, 1998). Complete remissions are rare and all patients ultimately relapse, resulting in c 25% survival at 5 years and <10% survival at 10 years. Criteria by which different treatment regimens can be evaluated include the proportion of patients achieving an objective response, the duration of response, and survival. Over the past 10–15 years high-dose therapy followed by haemopoietic stem-cell rescue, either allogeneic or autologous, has been increasingly employed in the treatment of multiple myeloma. For a number of reasons the existing criteria for the assessment of disease response have not proved entirely satisfactory for the analysis of disease outcome after high-dose therapy. In particular, there has been no generally agreed definition of complete response. Agreed definitions of response and progression are essential to ensure consistency of reporting within the transplant registries and to enable comparison of results from different studies and/or different treatment centres. New criteria for response and progression have therefore been developed as a result of discussions between representatives of the Myeloma Subcommittee of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) and representatives of the Myeloma Working Committee of the Autologous Blood and Marrow Transplant Registry (ABMTR) and the International Bone Marrow Transplant Registry (IBMTR). These criteria will now form the working definitions of response and progression for the purposes of data collection and registry-based studies. Currently none of the registries include specific diagnostic criteria, although all record the relevant investigations performed at diagnosis. However, we wish to emphasize that all patients undergoing high-dose therapy should have proven myeloma which requires treatment. At present highdose therapy is not recommended for patients with equivocal myeloma or those with stage I disease. We have not at this stage reviewed the criteria for the diagnosis of myeloma, but there may be a requirement for this in the future. For example, because of the increasing use of high-dose therapy for the treatment of primary amyloidosis, it will be important to establish clear guidelines for the differential diagnosis between this condition and multiple myeloma with amyloid.

Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group

Summary. The monoclonal gammopathies are a group of disorders associated with monoclonal proliferation of plasma cells. The characterization of specific entities is an area of difficulty in clinical practice. The International Myeloma Working Group has reviewed the criteria for diagnosis and classification with the aim of producing simple, easily used definitions based on routinely available investigations. In monoclonal gammopathy of undetermined significance (MGUS) or monoclonal gammopathy, unattributed/unassociated (MG[u]), the monoclonal protein is < 30 g/l and the bone marrow clonal cells < 10% with no evidence of multiple myeloma, other B‐cell proliferative disorders or amyloidosis. In asymptomatic (smouldering) myeloma the M‐protein is ≥ 30 g/l and/or bone marrow clonal cells ≥ 10% but no related organ or tissue impairment (ROTI)(end‐organ damage), which is typically manifested by increased calcium, renal insufficiency, anaemia, or bone lesions (CRAB) attributed to the plasma cell proliferative process. Symptomatic myeloma requires evidence of ROTI. Non‐secretory myeloma is characterized by the absence of an M‐protein in the serum and urine, bone marrow plasmacytosis and ROTI. Solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas (± recurrent) are also defined as distinct entities. The use of these criteria will facilitate comparison of therapeutic trial data. Evaluation of currently available prognostic factors may allow better definition of prognosis in multiple myeloma.

Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation

Summary Background Transplantation of blood or bone-marrow stem cells is the treatment of choice for selected patients with chronic myeloid leukaemia (CML). Transplantation is used with increasing frequency and success, but remains associated with substantial risks of morbidity and mortality. Other treatments with satisfactory short-term outcome are available. For appropriate counselling of patients, a rapid and simple way to assess risk is needed. Methods Data from 3142 patients (1873 [60%] male, 1269 [40%] female; mean age 34 years, range Findings At the time of analysis, 1922 (61%) of the 3142 patients were alive—1567 (65%) of those with HLA-identical sibling donors and 417 (57%) of those with unrelated donors. 1682 (54%) were alive without relapse. 1220 (39%) patients had died, 1013 (83%) of transplant-related causes, 207 (17%) of relapse. 447 (14%) patients had relapsed. The final scoring system was highly predictive for leukaemia-free survival, survival and transplant-related mortality. Survival at 5 years was 72%, 70%, 62%, 48%, 40%, 18%, and 22% for patients with scores 0, 1, 2, 3, 4, 5, and 6, respectively. Risk of transplant-related mortality was 20%, 23%, 31%, 46%, 51%, 71%, and 73%. Data showed the same trends for HLA—identical sibling transplants and unrelated transplants for transplants done in 1989–93 and 1994–96. Interpretation Pretransplant risk factors are cumulative for individual patients with CML having blood or marrow transplantation. A simple system based on five main factors gives adequate risk assessment for counselling of patients and taking decisions.

Prognostic Subgroups in B-Cell Chronic Lymphocytic Leukemia Defined by Specific Chromosomal Abnormalities

BACKGROUND AND METHODS Specific chromosomal abnormalities have been shown to affect the overall survival of patients with acute leukemia, but the possibility that specific chromosomal defects may influence the course of B-cell chronic lymphocytic leukemia (CLL) is controversial. We assessed this possibility as follows: blood mononuclear cells from 433 patients with B-cell CLL in five European centers were cultured with B-cell mitogens, and banded metaphases were studied. RESULTS Three hundred ninety-one patients could be evaluated cytogenetically, and 218 had clonal chromosomal changes. The most common abnormalities were trisomy 12 (n = 67) and structural abnormalities of chromosome 13 (n = 51; most involving the site of the retinoblastoma gene) and of chromosome 14 (n = 41). Patients with a normal karyotype had a median overall survival of more than 15 years, in contrast to 7.7 years for patients with clonal changes. Patients with single abnormalities (n = 113) did better than those with complex karyotypes (P less than 0.001). Patients with abnormalities involving chromosome 14q had poorer survival than those with aberrations of chromosome 13q (P less than 0.05). Among patients with single abnormalities, those with trisomy 12 alone had poorer survival than patients with single aberrations of chromosome 13q (P = 0.01); the latter had the same survival as those with a normal karyotype. A high percentage of cells in metaphase with chromosomal abnormalities, indicating highly proliferative leukemic cells, was associated with poor survival (P less than 0.001). Cox proportional-hazards analysis identified age, sex, the percentage of cells in metaphase with chromosomal abnormalities, and the clinical stage of the disease (Binet classification system) as independent prognostic variables. CONCLUSIONS Chromosomal analysis provides prognostic information about overall survival in addition to that supplied by clinical data in patients with B-cell CLL.

Allogeneic bone marrow transplantation in multiple myeloma

Abstract Background and Methods. In contrast to autologous bone marrow transplants for hematologic cancers, allogeneic transplants contain no tumor cells that might cause a relapse. We report the results of such allogeneic bone marrow transplantation using HLA-compatible sibling donors in 90 patients with multiple myeloma performed in 26 European centers between 1983 and 1989. Results. At the time of the most recent follow-up, 79 months after the start of the study, 47 patients were alive and 43 were dead. The rate of complete remission after bone marrow transplantation was 43 percent for all patients and 58 percent for the patients who had engraftment. The actuarial survival at 76 months was 40 percent. The median duration of relapse-free survival among patients who were in complete remission after bone marrow transplantation was 48 months. The stage of the disease at diagnosis and the number of treatment regimens tried before bone marrow transplantation were predictive of the likelihood of complete remi...

Progress in allogeneic bone marrow and peripheral blood stem cell transplantation for multiple myeloma : a comparison between transplants performed 1983-93 and 1994-98 at European Group for Blood and Marrow Transplantation centres

Out of 690 allogeneic matched sibling donor transplants for multiple myeloma reported to the European Group for Blood and Marrow Transplantation (EBMT) registry, 334 were performed during the period 1983–93 (all with bone marrow) and 356 during 1994–98 [223 with bone marrow and 133 with peripheral blood stem cells (PBSCs)]. The median overall survival was 10 months for patients transplanted during the earlier time period and 50 months for patients transplanted with bone marrow during the later period. The use of PBSCs was associated with earlier engraftment but no significant survival benefit compared to bone marrow transplants during the same time period. The improvement in survival since 1994 was the result of a significant reduction in transplant‐related mortality, which was 38%, 21% and 25% at 6 months and 46%, 30% and 37% at 2 years during the earlier period, and the later period with bone marrow and PBSCs respectively. Reasons for the reduced transplant‐related mortality appeared to be fewer deaths owing to bacterial and fungal infections and interstitial pneumonitis, in turn a result of earlier transplantation and less prior chemotherapy. Better supportive treatment and more frequent use of cytokines may also play a role. The improvement in survival was not directly related to the increased use of PBSCs.

Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma.

PURPOSE To analyze prognostic factors for allogeneic bone marrow transplantation (BMT) in multiple myeloma. PATIENTS AND METHODS One hundred sixty-two reports of allogeneic matched sibling-donor transplants in multiple myeloma received by the European Group for Blood and Marrow Transplantation (EBMT) registry between 1983 and early 1993 were analyzed for prognostic factors. End points were complete remission, survival, and duration of complete remission. RESULTS Following BMT, 44% of all patients and 60% of assessable patients entered complete remission. The overall actuarial survival rate was 32% at 4 years and 28% at 7 years. The overall relapse-free survival rate of 72 patients who were in complete remission after BMT was 34% at 6 years. Favorable pretransplant prognostic factors for survival were female sex (41% at 4 years), stage I disease at diagnosis (52% at 4 years), one line of previous treatment (42% at 4 years), and being in complete remission before conditioning (64% at 3 years). The subtype immunoglobulin A (IgA) myeloma and a low beta 2-microglobulin level (< 4 g/L) also tended to have a favorable prognostic impact. The most important post-transplant prognostic factor was to enter a complete remission. Grade III to IV graft-versus-host disease (GVHD) was associated with poor survival. CONCLUSION Patients with a low tumor burden who respond to treatment before BMT and are transplanted after first-line therapy have the best prognosis following BMT.

HLA-Identical Sibling Bone Marrow Transplantation in Younger Patients with Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is considered a disease of the elderly, but it is being increasingly diagnosed in younger people. About 40% of patients with CLL are less than 60 years old [1]. The median survival is about 3 years for patients with Rai stage 3 or 4 disease [1]. Prognostic variables associated with reduced survival include high blood lymphocyte levels, short lymphocyte doubling time, chromosome abnormalities, and a diffuse pattern of bone marrow infiltration with leukemia cells [1-7]. The short median survival of patients with Rai stage 3 or 4 CLL and of those with additional adverse prognostic features has led to studies of intensive treatments [8-10]. Bone marrow transplants from HLA-identical siblings reportedly result in long-term survival in some patients [11]. We analyzed results of HLA-identical sibling bone marrow transplantation for CLL in 54 patients who were younger than 60 years old; these transplantations were done between 1984 and 1992 and reported to either the European Group for Blood and Marrow Transplantation or the International Bone Marrow Transplant Registry. We estimate that this analysis includes more than half of all HLA-identical sibling donor transplants for CLL done before 1993 [12]. Methods Patients Data on 54 patients receiving HLA-identical sibling bone marrow transplants for CLL were reported to the European Group for Blood and Marrow Transplantation or the International Bone Marrow Transplant Registry or both between 1984 and 1992. Patient and disease characteristics are described in Table 1. The median age of the 54 patients was 41 years (range, 21 to 58 years). The median interval from diagnosis to transplantation was 37 months (range, 5 to 130 months). Seventeen patients have been previously described [11]. Six transplantations were done in the first year after diagnosis; 17 were done 1 to 3 years after diagnosis; 19 were done 3 to 5 years after diagnosis; and 12 were done more than 5 years after diagnosis. Forty-seven patients had B-cell CLL, and the immunotype was unknown in 7 patients. Table 1. Characteristics and Transplant Outcomes for 54 Patients Receiving HLA-Identical Sibling Transplants for Chronic Lymphocytic Leukemia* The therapy administered before transplantation varied. Four patients received no treatment; 19 received chlorambucil alone or with prednisone; 5 received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); and 21 received cyclophosphamide, vincristine, doxorubicin, bleomycin, and interferon, alone or in combination. No data on previous treatment were available in 5 patients. Two patients received local irradiation and 3 received total lymphoid irradiation and chemotherapy. Ten patients had a splenectomy. Of 47 evaluable patients, 7 were considered to have disease responsive to chemotherapy at the time of transplantation, 19 had stable disease, and 21 had progressive disease according to previously published criteria [13]. Patients were selected for transplantation according to criteria set at each transplantation center. Most received transplants for advanced (Rai stage 3 or 4) or longstanding disease. In patients with Rai stage 0 to 2 CLL whose disease had been diagnosed less than 3 years previously, indications varied from consolidation of a good response to chemotherapy, poor response to conventional-dose therapy, or young age. Donors Donors were HLA-identical siblings; 39 were men and 15 were women. The median age was 41 years (range, 21 to 55 years). Pretransplant Conditioning All patients received cyclophosphamide (median dose, 120 mg/kg body weight; range, 90 to 150 mg/kg). Fifty-one also received total body irradiation (median dose, 12 Gy [range, 8 to 14 Gy]; median fractions, 5 [range, 1 to 9 fractions]). Three patients received cyclophosphamide and busulfan (16 mg/kg) without irradiation. Nineteen patients received one or more additional drugs including etoposide (n = 13), cytarabine (n = 5), chlorambucil (n = 1), melphalan (n = 1), and daunorubicin (n = 1). Prophylaxis for Graft-versus-Host Disease All patients received prophylactic therapy for graft-versus-host disease. Two received methotrexate, 8 received cyclosporine, and 35 received both methotrexate and cyclosporine. Eight patients received a T-cell-depleted graft; 7 of these patients also received cyclosporine. One patient received a monoclonal anti-interleukin-2 receptor antibody and cyclosporine. Four patients had prednisone added to these regimens. Outcome Measures Patients were considered evaluable for engraftment if they survived more than 30 days after transplantation. Those with engraftment who survived more than 21 days were considered at risk for acute graft-versus-host disease, and those with engraftment who survived more than 100 days were considered at risk for chronic graft-versus-host disease. Hematologic remission was defined as normalization of leukocyte counts, hemoglobin level, and platelet counts and absence of lymphadenopathy and hepatosplenomegaly. There was no requirement for bone marrow normalization. The focus of the study was hematologic remission and survival; we did not study leukemia-free survival because bone marrow examinations were not routinely done after transplantation and because leukemia-free survival is poorly defined in CLL. Data from immunologic and molecular tests were not used to define remission; tests for assessing clonality, such as immunoglobulin gene rearrangement and dual antibody-labeling flow cytometry, are not commonly done and are of unproven clinical significance. However, these data are reported when available. Kaplan-Meier survival estimates and CIs were calculated using BMDP software (BMDP Statistical Software, Los Angeles, California). Results Patient outcomes are shown in Table 1. Forty-five of 49 evaluable patients (92%) had stable engraftment, and 4 (8%) had graft failure. Acute (grade II-IV) graft-versus-host disease developed in 17 of 46 patients at risk (37%); 9 of these patients (53%) died. Chronic graft-versus-host disease developed in 17 of 35 patients at risk (49%) and was extensive in 6. Thirty-eight patients (70%) achieved hematologic remission. Twenty-four were alive at a median of 27 months (range, 5 to 80 months) after transplantation. Three-year survival probability was 46% (95% CI, 32% to 60%) (Figure 1). The 3 patients receiving transplants at Rai stage 0 were alive 21, 32, and 45 months after transplantation. Three-year survival probabilities were 68% (CI, 38% to 98%) in the 10 patients receiving transplants at Rai stage 1, 30% (CI, 2% to 58%) in the 10 patients receiving transplants at Rai stage 2, 57% (CI, 21% to 93%) in the 7 patients receiving transplants at Rai stage 3, and 34% (CI, 12% to 56%) in the 22 patients receiving transplants at Rai stage 4. Three-year survival probability was 86% (CI, 62% to 100%) in patients with disease responsive to pretransplant chemotherapy; 61% (CI, 38% to 84%) in those with stable disease; and 23% (CI, 2% to 44%) in those with progressive disease. Figure 1. Probability of survival among 54 patients after HLA-identical sibling bone marrow transplantation for chronic lymphocytic leukemia. Of the 24 transplant recipients who are alive, 23 (96%) are in hematologic remission. Ten of these 23 patients had immune phenotyping of the peripheral blood: Seven had a normal profile (patients 7, 10, 12, 21, 23, 27, and 42), whereas 3 (patients 3, 24, and 30) had an excess of cluster differentiation antigen 5 (CD5) expression, which is known to be associated with CLL. Four patients had molecular studies after transplantation; these studies did not show gene rearrangement that would suggest persistent leukemia (patients 12, 21, 27, and 49). Of the 30 patients who died, 5 died of disease and 25 died of treatment-related causes. Ten treatment-related deaths were from acute or chronic graft-versus-host disease; 4 from hepatic veno-occlusive disease; 2 each from graft failure, adult respiratory distress syndrome, interstitial pneumonitis, and bacterial infection; and 1 each from hemorrhage, fungal infection, and viral infection. Discussion The 54 patients we evaluated all had CLL, were less than 60 years of age, and received HLA-identical sibling transplants. About half of this patient group achieved hematologic remission. Although we studied data from more than half the transplant recipients for CLL worldwide, the small number of patients precluded adjustment for potential prognostic variables like interval from diagnosis to transplantation and response to conventional chemotherapy. Treatment-related mortality in this study was highnearly 50%a figure similar to that observed after allografts for adults with acute lymphoblastic leukemia in first remission, acute myelogenous leukemia in second remission, and Hodgkin disease [14-16]. It may result, in part, from effects of extensive previous treatment. The focus of this study was on hematologic remission and survival after transplantation. We did not consider leukemia-free survival, because this is poorly defined in CLL. We also did not use data from immunologic or molecular tests because these are not uniformly performed and are of unproven clinical import. Our study was not designed to evaluate the role of HLA-identical sibling bone marrow transplantation in the treatment of CLL. However, we believe that the results in 54 patients treated at different centers suggest that allogeneic transplantation is feasible in patients less than 60 years of age. These results must be compared with those for other therapies, such as traditional chemotherapy, fludarabine, 2-chlorodeoxyadenosine, and autotransplantation [17-20]. Appendix Other contributors to this manuscript were Mary M. Horowitz, MD, MS, John P. Klein, PhD, and Mortimer M. Bortin, MD (deceased), of the International Bone Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, Wisconsin; Kerry Atkinson, MD, of the Depar

Allogeneic Bone Marrow Transplantation in Multiple Myeloma

Abstract Background and Methods. In contrast to autologous bone marrow transplants for hematologic cancers, allogeneic transplants contain no tumor cells that might cause a relapse. We report the results of such allogeneic bone marrow transplantation using HLA-compatible sibling donors in 90 patients with multiple myeloma performed in 26 European centers between 1983 and 1989. Results. At the time of the most recent follow-up, 79 months after the start of the study, 47 patients were alive and 43 were dead. The rate of complete remission after bone marrow transplantation was 43 percent for all patients and 58 percent for the patients who had engraftment. The actuarial survival at 76 months was 40 percent. The median duration of relapse-free survival among patients who were in complete remission after bone marrow transplantation was 48 months. The stage of the disease at diagnosis and the number of treatment regimens tried before bone marrow transplantation were predictive of the likelihood of complete remi...