Document 99Q82Zm3ngYZnqX7jw5E1JEN5

Graft outcome Bone Marrow Transplantation (2001) 27, 10371043 2001 Nature Publishing Group All rights reserved 02683369/01 $15.00 www.nature.com/bmt Impact of complete remission with intensive therapy in patients with responsive multiple myeloma R Alexanian, D Weber, S Giralt, M Dimopoulos, K Delasalle, T Smith and R Champlin University of Texas MD Anderson Cancer Center, Houston, Texas, USA Summary: Clinical outcomes were assessed in 68 consecutive patients with multiple myeloma of high or intermediate tumor mass that had responded to VAD or dexamethasone-based therapy and were consolidated with early intensive therapy and autologous stem cell transplantation. Results were compared with those of 50 comparable patients who refused or were unable to receive intensive treatment for socioeconomic reasons. Following high-dose therapy, the rate of CR increased from 6 to 37%, with median survival prolonged by 10 months. Survival of 21 patients with disease converted from PR to CR (median 8.3 years) was significantly longer than that of similarly-treated patients who remained in PR (median 5.0 years). CR of myeloma represents the major surrogate marker of long survival and the primary goal of myeloablative treatment for patients in PR. Twelve of 18 patients with rapid reduction of myeloma protein (T. 0.5 months), and myeloma protein reduction to 1.0 g/dl after primary therapy achieved CR (67%), identifying pretransplant features favorable to intensive therapy. Among 35 patients with slower reduction or higher residual myeloma protein, CR occurred in eight patients (23%) (P 0.01), for whom other treatments should be considered. The kinetics of response to initial therapy should be considered in selecting patients more likely to achieve CR and consequent long survival after intensive treatment. Bone Marrow Transplantation (2001) 27, 10371043. Keywords: multiple myeloma; autologous cell transplantation; survival and remission times Numerous studies have assessed the role of myeloablative therapy supported by autologous stem cell transplantation for patients with multiple myeloma.18 Most reports have described a higher frequency of CR than that achieved with standard therapies, a potentially higher risk of morbidity or death among patients older than 65, and less benefit for patients in later phases of disease. One randomized com- Correspondence: Dr R Alexanian, Box 1, University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA Received 28 June 2000; accepted 1 February 2001 parison of standard vs intensive therapy in newly diagnosed patients confirmed a significantly higher frequency of PR, CR, and longer survival, for patients who received early myeloablative therapy.5 We and Blade et al observed similar survivals among patients transplanted during remission in a retrospective comparison with matched controls, while Fermand et al observed similar outcomes in a prospective study among patients aged 5565 assigned at random to intensive or standard treatments.3,9,10 Several analyses of prognostic factors have revealed significantly shorter survivals for patients with more advanced disease, high serum B2M or deletions of chromosome 13.5,11 Thus, there is concern whether myeloablative treatment is useful for all patients or whether meaningful benefit is limited to subgroups yet to be identified. We analyzed the outcomes of consecutive patients with disease of high or intermediate tumor mass that had responded to primary treatment, and who then received early intensive therapy with autologous stem cell transplantation. In comparison with a matched control group treated concurrently, results showed longer survivals for all patients, and significantly longer survivals and relapse-free survivals for the higher percentage of patients with disease converted to CR. These findings confirm and extend those reported by Attal et al5 and Lahuerta et al.12 In addition, rapid and marked reduction of myeloma with initial chemotherapy were associated with more frequent CR after intensive treatment, adding factors that reflect tumor sensitivity in selection of patients for consolidation treatment. Patients and methods Patients Between 1986 and 1999, 68 patients with advanced multiple myeloma in partial or complete response received intensive, myeloablative therapy supported by autologous marrow or blood stem cells within 1 year of primary therapy. Patient characteristics are summarized in Table 1. The median age of the transplanted group was 49 (range 32 60), all had good performance, and adequate cardiac, pulmonary and renal function. Only patients with high or intermediate tumor mass and serum myeloma protein were considered in order to focus on a uniform group of patients with advanced disease who received early consolidation Complete remission in multiple myeloma R Alexanian et al 1038 Table 1 Clinical features at diagnosis of patients who received inten- tumor mass required either Hb less than 8.5 g/dl or serum sive therapy during remission and of control patients calcium greater than 11.5 mg/dl; intermediate tumor mass No. patients Median age (range) Pretreatment features Tumor mass (%) High Intermediate Hgb 10.5 g/dl (%) Creatinine 2.0 mg/dl (%) Serum B2M (mg/l) (median and range) LDH 300 U/l (%) Median months to: Remission Ablative therapy Transplanted 68 49 (3260) 50 50 74 19 4.7 (2.014.8) 12 1.2 6.5 Control 50 53 (2560) 34 66 66 10 4.2 (1.914.4) 6 0.9 NA was defined by Hb between 8.5 and 10.5 g/dl or serum myeloma protein greater than 4.5 g/dl. Partial response was defined as 75% reduction of initial serum myeloma protein production, 95% reduction of Bence Jones protein, and reduction of marrow plasmacytosis to less than 5%; rapidity of response was assessed from the T. of IgG or IgA myeloma protein reduction;18 CR required disappearance of serum myeloma protein by immunofixation. All patients were maintained on IFN 1.53.0 MU s.c. 3 weekly from time of hematologic recovery. Relapse was defined by earliest of either recurrent serum myeloma protein that had disappeared, doubling of myeloma protein, new lytic bone lesions or marrow plasmacytosis 10%. Control patients NA = Not applicable. Fifty control patients were identified with the same clinical treatment; the data of five patients with prior disappearance of only Bence Jones protein were excluded. All received intensive therapy after at least two courses of vincristine doxorubucin by continuous infusion with pulse dexamethasone (VAD; 12 patients), pulse dexamethasone alone (30 patients), high-dose cyclophosphamideetoposide with dexamethasone (18 patients) or a combination of fractionated high-dose cyclophosphamide with VAD (eight patients).1315 Because disease features, response rate and survival were similar among large series of patients who received each of these treatments, all patients were analyzed together. features who were responsive to the same primary therapies and met the eligibility criteria for myeloablative therapy, but did not receive such treatment. Patients either refused intensive treatment or were denied coverage of the procedure by their insurance company. As in patients who received intensive therapy, control patients were 60 years old or less, had myeloma of high or intermediate tumor mass at diagnosis, presented with serum myeloma protein, received the same therapies during the same time period, were free of serious cardiac, pulmonary, or renal dysfunction, and would have received myeloablative treatment if possible. Major prognostic factors were similar for patients who received a transplant-supported program or were Treatment continued on standard treatment (Table 1). The median time between initial chemotherapy and intensive treatment was 6.5 months (range 212 months). Patients received one of two myeloablative regimens prior to autologous stem cell transplantation. Twenty-one patients received a combination of melphalan (140 mg/m2) and TBI (850 cGy) from 1987 to 1991;3 40 received a combination of thiotepa (750 mg/m2), busulfan (10 mg/kg) and cyclophosphamide (120 mg/kg) between 1991 and 1999;16 since 1994, cyclosporine was added to the latter program for seven patients in an attempt to exploit a possible graftversus-tumor effect.17 Within 48 h after completion of therapy, patients received either ABMT (1.0 104 granulocytemacrophage colony-forming units (CFU-GM)/kg) (19861991), or blood stem cells with 2 106 CD34+ mononuclear cells/kg (19921999). Because disease features and outcomes were similar for patients who received different intensive treatments or sources of stem cells, all patients were combined in the analysis of transplant-supported therapy.16 Specifically, there was no effect of source of stem cells and time of study on frequency of early death, frequency of CR or survival. Staging and response Prior to initial therapy, tumor mass was defined in each patient as high or intermediate by standard criteria. High Statistical analysis Chi-square tests were used to compare complete remission rates. The KaplanMeier method was used to calculate survival and progression-free survival times, and differences were compared by the log rank test. Survival was measured from initial therapy for all patients; progression-free survival was calculated from onset of partial response to first objective sign of relapse or death from unrelated disease. Results Complete remission CR had occurred with initial therapy in four responding patients who received later myeloablative treatment (6%) and in five control patients who received standard VAD or dexamethasone-based therapy (10%), similar to our previous experiences.13,14 After intensive treatment, CR was induced in 21 additional patients so that the total frequency of CR among transplanted patients of 37% was significantly higher than that of control patients (P 0.01). Conversion of PR to CR was recognized by a median 5.3 months after high-dose treatment (range, 112 months). Bone Marrow Transplantation Early death Treatment-related death occurred in five patients who received intensive treatment (7%), namely in two of 53 patients less than 55 years old (4%) and in three of 15 patients aged 5560 (20%) (P = 0.03). Causes of death were multiorgan failure (three patients), respiratory syncytial viral pneumonia (one patient) and failure of bone marrow engraftment (one patient). Transplant-related deaths occurred at a median 10 months after primary therapy (range 415 months) and 1.9 months after transplantation (range 1.13.1 months). No other factors were associated with early death, such as source of stem cells or pre-1990 vs later transplant. Survival and remission Deaths have occurred in 57% of all patients. The median survival was 10 months longer for transplanted patients in comparison with control patients (Figure 1, left panel) (P = 0.12). In order to focus on the role of intensive therapy in converting PR to CR, we excluded from subgroup analyses the four patients with CR prior to intensive therapy. Median survival of 21 patients with disease converted from PR to CR after intensive therapy (8.3 years) was more than 3 years longer than those of 43 patients who remained in PR (5.0 years), or of 45 patients with persistent PR after standard therapy (4.4 years) (P = 0.03) (Figure 1, right panel). Relapse-free survival was longer for patients converted to CR when relapse-free survival was defined by the earliest of either disease relapse or death from any cause. The median relapse-free survival of 21 patients with CR induced by ablative therapy was 4.1 years, approximately 2 years longer than the progression-free survival of 43 similar patients who remained in PR after intensive therapy (median 2.3 years), or of 45 patients with persistent PR Complete remission in multiple myeloma R Alexanian et al after standard therapy (median 2.1 years) (P = 0.26). CR has been sustained for more than 8 years in two patients who received intensive treatment and in two patients given standard therapy. Complete remission with standard therapy Survival and remission were assessed in 13 similar patients with CR only to standard therapy. These included the five control patients included here, as well as five patients age 60 treated earlier from 1975 to 1986 and three patients aged 6167 treated from 1987 to 1999, all with similar high or intermediate tumor mass and serum myeloma protein at diagnosis (both older age and treatments prior to 1986 have been associated with shorter survival than those observed with more recent treatments in younger patients9). Figure 2 shows similar survival and myelomaspecific survival for 13 patients in CR with standard therapy and 21 patients converted from PR to CR by intensive therapy; median relapse-free survival times were also similar at approximately 4 years when relapse was censored at death from causes other than myeloma. Prognostic factors Multiple factors were assessed in order to identify those that might be associated with conversion of PR to CR after intensive treatment. These included age, protein type, tumor mass, serum B2M, level of myeloma protein at diagnosis and prior to intensive treatment, prior speed of myeloma protein reduction and months to partial remission. The only suggestive factors are shown in Table 2 with combinations of features assessed in Figure 3. CR occurred in 12 of 18 patients with rapid reduction of serum myeloma protein to initial therapy (T . 0.5 months) and serum myeloma protein 1.0 g/dl prior to transplant, in eight of 20 patients 100 1039 Transplant (68) 50 Transplant CR (21) Percent living Transplant PR (43) Standard (50) Standard PR (45) 10 2 4 6 8 10 12 14 2 4 6 8 10 12 14 Years of treatment Figure 1 Left panel. Survival from primary treatment of 68 responding patients intensified during remission in comparison with 50 control patients continued on standard treatment. Right panel. Survival of 21 patients with disease converted from PR to CR, 43 patients with persistent PR despite intensive treatment, and 45 patients with disease in PR after standard therapy (P = 0.03). Bone Marrow Transplantation 1040 Complete remission in multiple myeloma R Alexanian et al Survival 100 Myeloma-specific survival Standard CR (13) Standard CR (13) Transplant CR (21) 50 Transplant CR (21) Percent living 30 2 4 6 8 10 12 2 4 6 8 10 12 Years of treatment Figure 2 Left panel. Survival from primary therapy of similar responding patients in complete remission who had received intensive or standard treatment. Right panel. Myeloma-specific survival of same patients with lifespan censored at death from unrelated disease. Table 2 Clinical features associated with complete remission after myeloablative therapy No. CR/Total (%) P Before primary treatment All patients LDH (U/L) (normal 225 U/l) 300 300 Missing data B2M (mg/l) 5.0 5.0 Missing data After primary treatment Myeloma protein halving (months) 0.5 0.5 Missing data Months to remission 1.0 1.0 Missing data Pretransplant myeloma protein (g/dl) 1.0 1.0 21/64 (33)a 15/34 (44) 0/5 (0) 6/25 (24) 14/30 (47) 6/24 (25) 1/10 (10) 0.06 0.10 17/28 (61) 3/25 (12) 1/11 (9) 13/26 (50) 8/36 (22) 0/2 16/31 (52) 5/33 (15) 0.01 0.02 0.01 aFour patients in complete remission prior to intensive therapy were excluded from this analysis. with either finding, and in none of 15 patients with neither feature (P 0.01). A similar relation was found when short time to PR (1.0 month) was substituted for rapid myeloma protein halving time. Discussion During the past 10 years, there have been many studies of myeloablative therapy supported by autologous stem cell transplantation for patients with multiple myeloma.18 Most centers have agreed on the potentially higher risk for older patients so that few patients older than 65 have received such treatment. Yet, a recent report has described similar outcomes among 49 selected patients older than 65 (representing 9% of treated patients) who received highdose melphalan alone supported by autologous stem cell transplantation, in comparison with 49 matched, younger patients.19 Patients treated later in their course, such as during resistant relapse or with more than 1 year of primary resistant disease, have also benefitted less than those treated earlier.3,11 One controlled study has described significantly longer progression-free survival and survival among patients randomized to myeloablative treatment in comparison with continued standard treatment,5 while a similar randomized study among patients aged 5565 found less difference.10 Two retrospective studies have described similar outcomes with intensive vs standard therapies for patients with responsive disease of comparable age and disease stage,3,9 while other retrospective comparisons showed longer survival for all transplanted patients vs matched controls.7,20 Because of the high morbidity, occasional mortality, expense and social dislocation associated with intensive treatment supported by autologous stem cell transplantation, we defined the efficacy of this procedure in a retrospective analysis of consecutive patients with advanced disease that had responded to VAD or similar programs with high-dose dexamethasone. Results were compared with those of control patients who were matched for major prognostic variables and qualified for transplantation in all respects but either refused or were denied treatment for Bone Marrow Transplantation Pretransplant serum peak (g/dl) Complete remission in multiple myeloma R Alexanian et al 1041 3 CR PR 2 1 0.5 1.0 Tumor halving (months) 24 Months to remission Figure 3 Left panel. Occurrence of CR or PR after intensive therapy in relation to pretransplant level of serum myeloma protein and rapidity of prior reduction. Right panel. Similar correlation of CR or PR with time to remission substituted for myeloma protein halving. socioeconomic reasons. Undetected selection factors may have excluded some patients from either group, perhaps biasing the outcomes, but such effects would have been small. Our patients were homogeneous in terms of their advanced disease at diagnosis, that was responsive to programs with repeated dexamethasone, consolidated with myeloablative treatment during the first year, and with outcomes compared with those of a matched control group. One shortcoming was the absence of consistent studies of special biologic features such as plasma cell labeling index or cytogenetics. Among patients with responsive disease, the overall frequency of CR (as defined by disappearance of serum myeloma protein by immunofixation) increased with intensive treatment from 6 to 37%. Similar high frequencies of CR have been described by others.2,48 Some of the slight differences in various studies could be due to the inclusion of patients with nonsecretory disease or only Bence Jones protein that had disappeared prior to treatment, where criteria for CR are less clear. The role of interferon in contributing to conversion of PR to CR after transplant was also uncertain, but probably had less impact on reduction of myeloma than the prior intensive therapy. Patients who developed CR after intensive therapy experienced longer survival and relapse-free survival than comparable patients with persistent PR. The median gains of approximately 3 years of survival and 2 years of relapsefree survival represent important indices of the potential magnitude of benefit to weigh against the medical risks, expense, and social adjustments. Since durations of disease stability and survival were similar for patients with disease in persistent PR after intensive or standard therapies, induction of CR represents the primary goal of consolidation treatment for patients in PR after initial therapy. These conclusions confirm those reached in larger series by Attal et al and Lahuerta et al, who have emphasized the importance of CR as a major factor for long survival. The similarly long survival of approximately 8 years for patients in CR after either standard or transplant-supported therapy indicated that achievement of CR as a surrogate marker of long survival was more important than the method used in reaching this goal. Not clear is whether patients already in CR with initial therapy gain further with intensification. While further studies are needed, the burden of proof appears to rest with those who favor intensive therapy for all patients in CR, especially older patients and others at high risk for serious complications. Treatment-related deaths were usually due to multiorgan failure and/or opportunistic infection attributed to the toxic effects of intense chemotherapy, especially in patients older than 55. Less intensive therapies, such as melphalan (200 mg/m2) given once or melphalan (140 mg/m2) given twice, have induced similar high frequencies of complete remission with less early mortality of 5%.2,7 In fact, a recent randomized comparison showed superior results with high dose melphalan alone (200 mg/m2) than with a lower dose of melphalan and total body irradiation.21 In addition, the substitution of blood stem cells for marrow as a source of transplanted cells has been associated with earlier and consistent engraftment.8,16 Thus, some of our treatmentrelated mortality should be avoided with less intensive therapy supported by autologous blood stem cells and should permit treatment of more older patients as proposed by the Arkansas group.19 The occurrence of CR after ablative therapy was more likely among patients with a high degree of myeloma sensitivity to initial therapy. Provided a VAD or dexamethasonebased primary therapy had been given, criteria were defined that were associated with a CR rate in the 67% range in comparison with a much lower frequency for other patients. Such kinetic considerations of primary tumor sensitivity should be considered with other factors, such as age, performance and major organ functions in balancing the overall benefit and risk of intensive treatment, especially for older patients. Our model should also permit more rapid assessment of innovative intensive treatments, by focusing on the frequency of CR for subgroups of patients with favorable or unfavorable kinetic features. The previously Bone Marrow Transplantation Complete remission in multiple myeloma R Alexanian et al 1042 observed relation between rapid disease response and early autologous transplantation over standard therapy for pre- relapse of myeloma has not been observed with recent VAD and high-dose dexamethasone regimens for reasons not clear. One factor may be the much more rapid onset of remission with repeated dexamethasone regimens in contrast to previous programs. Alternative strategies should be considered for responding patients with disease unlikely to meet the criteria for CR. These include experimental therapies that add 166holmium DOTMP (a bone-seeking radioisotope without viously untreated multiple myeloma. Blood 1997; 89: 789 793. 8 Fermand J-P, Chevret S, Ravaud P et al. High dose therapy and autologous blood stem cell transplantation in multiple myeloma. Blood 1998; 92: 31913196. 9 Blade J, San Miguel J, Fontanillas M et al. Survival of multiple myeloma patients who are potential candidates for early high-dose therapy intensification/autotransplantation who were conventionally treated. J Clin Oncol 1996; 14: 2167 2173. extramedullary toxicity) to established ablative therapies, or 10 Fermand J-P, Ravaud P, Katsahian S et al. High dose therapy that exploit a graft-versus-tumor effect with less intensive and autologous blood stem cell transplantation versus conven- treatment supported by HLA-matched allogeneic transplantation.22,23 Attempts to purge tumor cells by stem cell selection have not been useful presumably because of the large tumor burden that remains in most patients despite intensive treatment.24 Prolongation of remission by other techniques, such as with idiotypic or dendritic cell vaccination, or with thalidomide maintenance, are also worthy of study especially in attempts to convert PR to CR.25,26 For our patients whose disease relapsed on interferon, tional treatment in multiple myeloma. Blood 1999; 94: 396a (Abstr. 1754). 11 Tricot G, Barlogie B, Jagannath S et al. Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 and not with other karyotype abnormalities. Blood 1995; 86: 42504256. 12 Lahuerta J, Martinez-Lopez J, de la Serna J et al. Remission status defined by immunofixation vs electrophoresis after autologous transplantation has a major impact on the outcome of multiple myeloma patients. Br J Haematol 2000; 109: 438 several programs of therapy were given in sequential 446. phases, such as an alkylating agent-glucocorticoid combi- 13 Alexanian R, Barlogie B, Tucker S. VAD-based regimens as nation, a VAD-based regimen and in recent years a thalido- primary treatment for multiple myeloma. Am J Hematol 1990; midedexamethasone combination. Most patients achieved multiple remissions or prolonged stabilization of the myeloma. Such treatments were undoubtedly useful in prolonging lifespan for both transplanted and control patients after initial relapse. The systematic application of effective salvage therapies may well narrow current survival differences between transplanted and control patients. 33: 8689. 14 Alexanian R, Dimopoulos M, Delasalle K, Barlogie B. Pri- mary dexamethasone treatment of multiple myeloma. Blood 1992; 80: 887890. 15 Dimopoulos M, Weber D, Kantarjian H et al. HyperCVAD for VAD-resistant multiple myeloma. Am J Hematol 1996; 52: 7781. 16 Dimopoulos M, Alexanian R, Przepiorka D et al. A new pre- parative regimen for autologous marrow or blood stem cell transplantation in high-risk multiple myeloma. Blood 1993; Acknowledgements 82: 23242328. 17 Giralt S, Weber D, Colome M et al. Phase I trial of cyclospor- We thank Rose Guevara for the careful preparation of the manu- ine-induced graft-versus-host disease in patients with multiple script. This work was supported by the Lucille Murchison and myeloma undergoing high-dose chemotherapy with autolog- Kay Laro research funds. ous stem cell rescue. J Clin Oncol 1997; 15: 667673. 18 McLaughlin P, Alexanian R. Myeloma protein kinetics fol- lowing chemotherapy. Blood 1982; 60: 851855. References 19 Siegel D, Desikan K, Mehta J et al. Age is not a prognostic variable with autotransplants for multiple myeloma. Blood 1 Barlogie B, Alexanian R, Dicke K et al. High dose chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma. Blood 1987; 70: 868872. 2 Cunningham D, Pazares L, Gore M et al. High-dose melphalan and autologous bone marrow transplantation as consolidation in previously untreated multiple myeloma. J Clin Oncol 1994; 12: 759763. 3 Alexanian R, Dimopoulos M, Hester J et al. Early myeloablative therapy for multiple myeloma. Blood 1994; 84: 4278 4282. 4 Harousseau J, Attal M, Divine M et al. Autologous stem cell transplantation after first remission induction treatment in multiple myeloma. Blood 1995; 85: 30773085. 5 Attal M, Harousseau J, Stoppa J et al. Autologous bone mar- 1999; 93: 5154. 20 Lenhoff S, Hjorth M, Holmberg E et al. Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma. Blood 2000; 95: 711. 21 Harousseau J, Facon T, Moreau P et al. Comparison of highdose melphalan 140 mg/m2 plus total body irradiation and high-dose melphalan 200 mg/m2 as conditioning regimen for peripheral blood progenitor cell autotransplantation in patients with newly diagnosed multiple myeloma. Blood 1999; 94: 713a (Abstr. 3150). 22 Champlin R, Giralt S, Eary J et al. 166Holmium-DOTMP in combination with melphalan with or without total body irradiation as a preparative regimen for autologous stem cell row transplantation versus conventional chemotherapy in mul- transplant for patients with multiple myeloma. Blood 1999; tiple myeloma. New Engl J Med 1996; 335: 9197. 94: 709a (Abstr. 3133). 6 Bensinger W, Rowley S, Demirer T et al. High-dose therapy 23 Giralt S, Weber D, Aleman A et al. Non myeloablative con- followed by autologous hematopoietic stem-cell infusion for ditioning with fludarabine/melphalan for patients with mul- patients with multiple myeloma. J Clin Oncol 1996; 14: tiple myeloma. Blood 1999; 94: 347a (Abstr. 1549). 14471456. 24 Stewart A, Schiller G, Vescio R et al. CD34 selection does not 7 Barlogie B, Jagannath S, Vesole D et al. Superiority of tandem prolong disease free or overall survival in myeloma patients Bone Marrow Transplantation undergoing autologous stem cell transplant. Blood 1999; 94: 714a (Abstr. 3151). 25 Osterborg A, Yi Q, Henriksson L et al. Idiotype immunization combined with granulocytemacrophage colony-stimulating factor in myeloma patients induced type 1, major histocompat- Complete remission in multiple myeloma R Alexanian et al ibility complex-restricted, CD8- and CD4-specific T-cell responses. Blood 1998; 91: 24592464. 26 Singhal S, Mehta J, Desikan R et al. Antitumor activity of thalidomide in refractory multiple myeloma. New Engl J Med 1999; 341: 15651571. 1043 Bone Marrow Transplantation