Allogeneic hematopoietic stem cell transplantation for advanced mycosis fungoides and Sézary syndrome. An updated experience of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option in advanced-stage mycosis fungoides (MF) and Sézary syndrome (SS). This study presents an updated analysis of the initial experience of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT) describing the outcomes after allo-HSCT for MF and SS, with special emphasis on the impact of the use of unrelated donors (URD). METHODS AND PATIENTS: Eligible for this study were patients with advanced-stage MF or SS who underwent a first allo-HSCT from matched HLA-identical related or URD between January/1997 and December/2011. Sixty patients have been previously reported. RESULTS: 113 patients were included [77 MF (68%)]; 61 (54%) were in complete or partial remission, 86 (76%) received reduced-intensity protocols and 44 (39%) an URD allo-HSCT. With a median follow up for surviving patients of 73 months, allo-HSCT resulted in an estimated overall survival (OS) of 38% at 5 years, and a progression-free survival (PFS) of 26% at 5 years. Multivariate analysis demonstrated that advanced-phase disease (complete remission/partial remission >3, primary refractory or relapse/progression in patients that had received 3 or more lines of systemic treatment prior to transplant or the number of treatment lines was not known), a short interval between diagnosis and transplant (<18 months) were independent adverse prognostic factors for PFS; advanced-phase disease and the use of URDs were independent adverse prognostic factors for OS. CONCLUSIONS: This extended series supports that allo-HSCT is able to effectively rescue over one third of the population of patients with advanced-stage MF/SS. High relapse rate is still the major cause of failure and needs to be improved with better strategies before and after transplant. The negative impact of URD is a matter of concern and needs to be further elucidated in future studies.

Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation in Sweden, long-term results from all patients treated in 1994-2009.

High-dose melphalan and autologous stem cell transplantation (HDM/ASCT) is widely used in immunoglobulin light chain (AL) amyloidosis, but the benefit is debated mainly because of the high treatment-related mortality (24% in a randomised study comparing HDM/ASCT with oral melphalan/dexamethasone). We report here on the long-term outcome of all patients treated with HDM/ASCT for AL amyloidosis in Sweden between 1994 and 2009. Seventy-two patients were treated at eight Swedish centres. Median follow-up was 67.5 months. At least partial response (organ or haematological) was seen in 64% of the patients. Median overall survival was 98 months or 8.2 years, with 5-year survival 63.9% and 10-year survival 43.4%. In patients with cardiac involvement or multiple organ involvement, survival was significantly shorter, median overall survival 49 and 56 months, respectively. All mortality within 100 days from ASCT was 12.5% for all patients and 17.2% in the patients with cardiac involvement. For patients treated in the earlier time period (1994-2001), 100-day mortality was 23.8% compared with 7.8% in the later period (2002-2009). In conclusion, long survival times can be achieved in patients with AL amyloidosis treated with HDM/ASCT, also in smaller centres. Early mortality is high, but with a decreasing trend over time.

Salvage bortezomib-dexamethasone and high-dose melphalan (HDM) and autologous stem cell support (ASCT) in myeloma patients at first relapse after HDM with ASCT. A phase-2 trial.

Until recently, only retrospective studies had been published on salvage high-dose melphalan (HDM) with autologous stem cell 'transplantation' (ASCT). In a prospective, nonrandomized phase-2 study, we treated 53 bortezomib-naïve patients with bortezomib-dexamethasone as induction and bortezomib included in the conditioning regimen along with the HDM. Median progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS) after start of reinduction therapy were 21.6, 22.8 and 46.6 months, respectively. For 49 patients who completed salvage bortezomib-HDM(II) with ASCT, there was no significant difference of PFS and TNT after HDM (II) compared with after the initial HDM(I), and thus patients were their own controls (PFS (I: 20.1 vs II: 19.3 months (P=0.8)) or TNT (I: 24.4 vs II: 20.7 months (P=0.8)). No significant differences in the response rates after salvage ASCT compared with the initial ASCT. Bortezomib-HDM conditioning combo was feasible, and toxicity was as expected for patients treated with bortezomib and ASCT. In conclusion, in bortezomib-naïve patients treated at first relapse with salvage ASCT including bortezomib, PSF and TNT did not differ significantly from initial ASCT and median OS was almost 5.5 years with acceptable toxicity. A recent prospective randomized study confirms salvage ASCT to be an effective treatment.

Potential adult sibling stem cell donors' perceptions and opinions regarding an information and care model.

The first international recommendations and guidelines for the care of sibling stem cell donors were established in 2010, and have not yet been evaluated. However, a model for information and care of adult potential sibling stem cell donors (the IC model) developed and introduced at the Skåne University Hospital, Lund, Sweden, in 2005 conforms closely to them. The IC model aims to protect the privacy of potential donors, support and respect their free choice, and identify quickly those unwilling or unable to donate and thus minimize delay in seeking alternative donors. To evaluate the IC model a questionnaire survey in 2010 gathered the perceptions and views on information provision; influences over decision making; and care provision under the IC model of 148 adult siblings informed about SCT donation, and asked to undergo HLA-typing since September 2005 at the hospital. The results suggest the IC model works well but highlights areas for improvement, such as in delivery of HLA typing results to non-matched siblings, and a need to further prevent complicating influence from health professionals and relatives on the decision to undergo HLA typing. Thus improved, the IC model could provide the groundwork for other SCT units seeking to implement the recommendations and guidelines.

Factors associated with changes in quality of life in patients undergoing allogeneic haematopoietic stem cell transplantation.

It is well known that patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) experience changes in quality of life. We investigated factors associated with quality of life changes in adult HSCT patients. The Functional Assessment of Cancer Therapy - Bone Marrow Transplantation (FACT-BMT) scale, supplemented with the Functional Assessment of Chronic Illness Therapy - Spiritual Well-being (FACIT-Sp) subscale, was administered on three occasions, immediately before transplantation, 100 days and 12 months after transplantation. Analyses of nine selected factors were made where changes in quality of life were found. Seventy-five patients were included and 40 of these completed the study. Emotional well-being was found to improve between the baseline and 100 days, while all other dimensions deteriorated, including overall quality of life. Physical and social/family well-being deteriorated between the baseline and the 12-month follow-up, while emotional well-being improved. The main factors associated with deteriorating quality of life over time were found to be significant infections, female gender and transplantation with stem cells from a sibling donor. In our further studies we aim to focus on the relationships between patients and sibling donors in order to improve the care. Careful attention must be paid to continuous adequate information during the transplantation procedure.

Outcomes and prognostic factors of adults with acute lymphoblastic leukemia who relapse after allogeneic hematopoietic cell transplantation. An analysis on behalf of the Acute Leukemia Working Party of EBMT.

To describe outcomes, treatment and prognostic factors that influence survival of adult patients with acute lymphoblastic leukemia (ALL), who relapsed after allogeneic hematopoietic cell transplantation (HCT), we retrospectively analyzed 465 ALL adult patients from European Group for Blood and Marrow Transplantation (EBMT) centers who relapsed after a first HCT performed in complete remission (CR1 65%, CR2/3 35%). Salvage treatments were: supportive care (13%), cytoreductive therapy (43%), donor lymphocyte infusion without or with prior chemotherapy (23%) and second HCT (20%). Median time from HCT to relapse was 6.9 months, median follow-up was 46 months and median survival after relapse was 5.5 months. Estimated 1-, 2- and 5-year post-relapse survival was 30 ± 2%, 16 ± 2% and 8 ± 1%, respectively. In a multivariate analysis, adverse factors for survival were: late CR (CR2/3) at transplant (P<0.012), early relapse after transplant (<6.9 months, P <0.0001) and peripheral blast percent at relapse (P <0.0001). On the basis of multivariate model for survival, three groups of patients were identified with estimated 2 year survival of 6 ± 2, 17 ± 3 and 30 ± 7%. Outcome of ALL patients relapsing after HCT is dismal and there is a need for new therapies. Our study provides the standard expectations in ALL relapse and may help in the decision of post-relapse therapy.

The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries.

Between 1982 and 2009 a total of 92 patients with myelofibrosis (MF) in chronic phase underwent allo-SCT in nine Nordic transplant centers. Myeloablative conditioning (MAC) was given to 40 patients, and reduced intensity conditioning (RIC) was used in 52 patients. The mean age in the two groups at transplantation was 46±12 and 55±8 years, respectively (P<0.001). When adjustment for age differences was made, the survival of the patients treated with RIC was significantly better (P=0.003). Among the RIC patients, the survival was significantly (P=0.003) better for the patients with age <60 years (a 10-year survival close to 80%) than for the older patients. The type of stem cell donor did not significantly affect the survival. No significant difference was found in TRM at 100 days between the MAC- and the RIC-treated patients. The probability of survival at 5 years was 49% for the MAC-treated patients and 59% in the RIC group (P=0.125). Patients treated with RIC experienced significantly less aGVHD compared with patients treated with MAC (P<0.001). The OS at 5 years was 70, 59 and 41% for patients with Lille score 0, 1 and 2, respectively (P=0.038, when age adjustment was made). Twenty-one percent of the patients in the RIC group were given donor lymphocyte infusion because of incomplete donor chimerism, compared with none of the MAC-treated patients (P<0.002). Nine percent of the patients needed a second transplant because of graft failure, progressive disease or transformation to AML, with no significant difference between the groups. Our conclusions are (1) allo-SCT performed with RIC gives a better survival compared with MAC. (2) age over 60 years is strongly related to a worse outcome and (3) patients with higher Lille score had a shorter survival.

Outcome of patients developing GVHD after DLI given to treat CML relapse: a study by the Chronic Leukemia Working Party of the EBMT.

We studied GVHD after donor lymphocyte infusion (DLI) in 328 patients with relapsed CML between 1991 and 2004 . A total of 122 patients (38%) developed some form of GVHD. We analyzed GVHD by clinical presentation (acute or chronic GVHD) and onset time after the first DLI (early (< or =45 days) or late (>45 days)). There was a significant overlap between onset time and clinical presentation. Some form of GVHD occurred at a median of 104 days, acute GVHD at 45 days and chronic GVHD at 181 days after DLI. The clinical presentation was acute GVHD in 71 patients, of whom 31 subsequently developed chronic GVHD subsequently. De novo chronic GVHD was seen in 51 patients. OS for all patients was 69% (95% confidence interval (CI) 63-75) at 5 years, DLI-related mortality was 11% (95% CI 8-15) and disease-related mortality was 20% (95% CI 16-25). Risk factors for developing GVHD after DLI were T-cell dose at first DLI, the time interval from transplant to DLI and donor type. In time-dependent multivariate analysis, GVHD after DLI was associated with a risk of death of 2.3-fold compared with patients without GVHD. Clinical presentation as acute GVHD and early onset GVHD were associated with increased mortality.

Cytogenetic evolution patterns in CML post-SCT.

The cytogenetic evolution patterns in chronic myeloid leukemia (CML) after allogeneic (allo) stem cell transplantation (SCT) are different from the ones observed in non-transplanted patients, a phenomenon suggested to be caused by the conditioning regime. We reviewed 131 CMLs displaying karyotypic evolution after SCT (122 allo, nine autologous (auto)), treated at Lund University Hospital or reported in the literature. Major route abnormalities (i.e., +8, +Ph, i(17q), +19, +21, +17 and -7) were seen in 14%, balanced aberrations in 61%, hyperdiploidy in 19%, pseudodiploidy in 79%, divergent clones in 14%, and Ph-negative clones in 21%. The breakpoints involved in secondary structural rearrangements clustered at 1q21, 1q32, 7q22, 9q34, 11q13, 11q23, 12q24, 13q14, 17q10 and 22q11. Cytogenetic abnormalities common in AML after genotoxic exposure, that is, der(1;7)(q10;p10), del(3p), -5, del(5q), -7, -17, der(17p), -18, and -21, were only rarely seen post-SCT. Comparing the cytogenetic features in relation to type of SCT revealed that balanced aberrations were significantly more common after allo than after auto SCT (64 and 22%, respectively, P=0.03). In addition, there was a trend as regards hyperdiploidy being more common after auto (P=0.07) and pseudodiploidy being more frequent after allo SCT (P=0.09). Possible reasons for these differences are discussed.

Allogeneic haematopoietic stem cell transplantation for metastatic renal carcinoma in Europe.

BACKGROUND: An allogeneic antitumour effect has been reported for various cancers. We evaluated the experience of allogeneic haematopoietic stem cell transplantation (HSCT) for renal cell carcinoma (RCC) in 124 patients from 21 European centres. PATIENTS AND METHODS: Reduced intensity conditioning and peripheral blood stem cells from an HLA-identical sibling (n = 106), a mismatched related (n = 5), or an unrelated (n = 13) donor were used. Immunosuppression was cyclosporine alone, or combined with methotrexate or mycophenolate mofetil. Donor lymphocyte infusions (DLI) were given to 42 patients. The median follow-up was 15 (range 3-41) months. RESULTS: All but three patients engrafted. The cumulative incidence of moderate to severe, grades II-IV acute GVHD was 40% and for chronic GVHD it was 33%. Transplant-related mortality was 16% at one year. Complete (n = 4) or partial (n = 24) responses, median 150 (range 42-600) days post-transplant, were associated with time from diagnosis to HSCT, mismatched donor and acute GVHD II-IV. Factors associated with survival included chronic GVHD (hazards ratio, HR 4.12, P < 0.001), DLI (HR 3.39, P < 0.001), <3 metastatic sites (HR 2.61, P = 0.002) and a Karnofsky score >70 (HR 2.33, P = 0.03). Patients (n = 17) with chronic GVHD and given DLI had a 2-year survival of 70%. CONCLUSION: Patients with metastatic RCC, less than three metastatic locations and a Karnofsky score >70% can be considered for HSCT. Posttransplant DLI and limited chronic GVHD improved the patient survival.

Quality assessment of autografting by probability evaluation: model estimation by clinical end-points in newly diagnosed multiple myeloma patients.

BACKGROUND: Pre-transplant clinical evaluation of autografting is an important step in predicting post-transplant support, complications and safety. Today, unfavorable outcomes such as early death or graft failure are rare, making them unsuitable for quality assessment of supportive autografting. However, end-points constructed from frequently occurring clinical events may estimate clinically relevant prognostic models. METHODS: The present retrospective analysis was based on two consecutive clinical trials in the Nordic area including up to 640 newly diagnosed multiple myeloma patients. RESULTS: In the model, the efficacy (time on antibiotics and use of transfusions) was influenced by pre-transplant variables, including sex, nationality, serum creatinine, hemoglobin, disease stage at diagnosis, response following induction therapy, length of priming and average graft CD34+ cell number per day of harvest. The toxicity end-point (time to blood cell recovery) was influenced by nationality, marrow plasma cell percentage, serum creatinine, M-component isotype, response to induction therapy, length of priming and graft CD34+ cell number. The safety (early disease recurrence or death) was influenced by serum creatinine, hemoglobin, treatment response and CD34+ cell number. DISCUSSION: In conclusion, the model illustrates that intervention strategies in quality assessment of autografting may benefit from probability estimates of graded clinical end-points.

Haematopoetic stem cell transplantation for refractory autoimmune cytopenia.

This study describes the outcome of patients receiving haematopoietic stem cell transplantation (HSCT) to treat severe refractory autoimmune cytopenia. The registry of the European Group of Blood and Marrow Transplantation holds data on 36 patients receiving 38 transplants, the first transplant was autologous for 27 and allogeneic for nine patients. Patients had autoimmune haemolytic anaemia (autologous: 5; allogeneic: 2), Evans's syndrome (autologous: 2; allogeneic: 5); immune thrombocytopenia (autologous: 12), pure red cell aplasia (autologous: 4; allogeneic: 1), pure white cell aplasia (autologous: 1; allogeneic 1), or thrombotic thrombocytopenic purpura (autologous: 3). Patients had longstanding disease having failed multiple prior treatments. Among 26 evaluable patients mobilized for autologous HSCT, three died of treatment-related causes, one died of disease progression, seven were non-responders, six patients had transient responses and nine had continuous partial or complete remission. Of the seven evaluable patients receiving allogeneic HSCT, one died of treatment-related complications, one with transient response died of progressive disease and five had a continuous response. Autologous and allogeneic HSCT may induce a response in a subset of patients with autoimmune cytopenia of long duration albeit at the price of considerable toxicity.

Autologous del(20q)-positive erythroid progenitor cells, re-emerging after DLI treatment of an MDS patient relapsing after allo-SCT, can provide a normal peripheral red blood cell count.

A 54-year-old RhD-negative male with del(20q)-positive myelodysplastic syndrome was transplanted with bone marrow from an HLA-identical RhD-positive sibling donor. Cytogenetic relapse was detected 21 months after stem cell transplantation (SCT), with reappearance of the original del(20q)-positive clone and reversion to recipient RhD-negative blood group. The patient received sequential donor lymphocyte infusions (DLIs), resulting in mild graft-versus-host disease and pure red cell aplasia. At 2 years post DLI, the patient remains in a stable condition, despite a dominance of recipient-derived erythro- and granulopoiesis originating in del(20q)-carrying progenitor cells. We conclude that reappearance of autologous erythropoiesis, upon relapse after allogeneic SCT, may be predictive of erythropenia after DLI and that re-emerging autologous del(20q)-positive erythropoiesis post DLI can provide a normal peripheral red blood cell count. Furthermore, in patients relapsing after blood-group-mismatched transplantation, a possible reversion to recipient blood group should be considered prior to blood transfusion or DLI.

Cytogenetic features of multiple myeloma: impact of gender, age, disease phase, culture time, and cytokine stimulation.

Relatively little is known about the cytogenetic features of multiple myeloma (MM) when compared to other hematologic malignancies. The reasons for this are most likely manifold, and include a low mitotic index of the malignant cells and the presence of cytogenetically cryptic abnormalities as well as of complex karyotypes with poor chromosome morphology. In the present study, we have investigated whether various culture conditions may influence the yield of abnormal metaphases in MM and, in the related plasma cell dyscrasias, monoclonal gammopathy of undetermined significance (MGUS) and plasmacytomas (PC). In addition, the possible impact of age, gender, and disease phase on the cytogenetic features has been analyzed. A total of 95 samples from 74 cases (68 MM, three PC, and three MGUS patients) were obtained for cytogenetic analysis. The samples were cultured either in conventional medium or in medium containing IL-6 and GM-CSF, and the culture times varied from 24 to 120 h. In total, 186 cultures were analyzed. Metaphase fluorescence in situ hybridization analysis using probes specific for 14q32, i.e. IGH rearrangements, could be performed in 57 of the 74 cases, and revealed 14q32 aberrations in 10 cases not seen by conventional G-banding. Abnormal karyotypes were detected in 77 (41%) of the 186 cultures, 46 (48%) of the 95 samples, and in 41 (55%) of the 74 patients, revealing a total of 20 chromosomal aberrations previously not reported in plasma cell dyscrasias. We found no evidence that gender, age, disease phase, culture time, or cytokine stimulation significantly influences the karyotypic features of MM.

Cost-utility analysis of high-dose melphalan with autologous blood stem cell support vs. melphalan plus prednisone in patients younger than 60 years with multiple myeloma.

We evaluated the costs and the cost utility of high-dose melphalan and autologous stem cell support followed by interferon maintenance relative to conventional treatment with melphalan and prednisone, in patients less than 60 yr of age with multiple myeloma. From March 1994 to July 1997, 274 patients with newly diagnosed, symptomatic multiple myeloma were enrolled in a prospective, non-randomized, population-based, multicenter study to evaluate the treatment with high-dose melphalan and autologous blood stem cell support. Health-related quality-of-life was measured prior to treatment and during follow-up, using the EORTC QLQ-C30 questionnaire. Resource consumption was also recorded prospectively. The intensive treatment yielded a significant increase in median survival time from 44 to 62 months compared to conventionally treated patients. The corresponding gain in quality-adjusted life years (QALY) was found to be 1.2. Cost per QALY gained by the treatment with high-dose melphalan and autologous blood stem cell support was estimated at NOK 249,000 (USD 27,000).

Alpha-interferon maintenance treatment is associated with improved survival after high-dose treatment and autologous stem cell transplantation in patients with multiple myeloma: a retrospective registry study from the European Group for Blood and Marrow Transplantation (EBMT).

The purpose of this study was to evaluate the effect of alpha-IFN maintenance treatment after autologous stem cell transplantation (ASCT) for multiple myeloma in a retrospective registry analysis. 473 patients with multiple myeloma who received IFN maintenance treatment ASCT were compared with 419 patients who did not receive IFN-treatment. Patients who were evaluable for response and in complete or partial remission at 6 months after ASCT were eligible, after excluding patients with graft failure. Cox proportional hazards assumptions were checked and handled by stratification. The prognostic variables unevenly distributed between the two groups were statistically corrected for in the Cox analysis. 391 patients reached complete remission (CR) after ASCT (203 in the IFN group and 188 in the no-IFN group) and 501 were in partial remission (PR, IFN 270, no-IFN 231). Overall survival (OS) and progression-free survival (PFS) were significantly better in the IFN-group (OS, 78 vs 47 months, P = 0.007, and PFS, 29 vs 20 months, P = 0.006, respectively). The difference in OS and PFS was most strongly pronounced in the PR patients. 209 patients have died (IFN, 84; no-IFN, 125). Progressive myeloma was the cause of death in 94% of the IFN-treated patients and in 83% of the no-IFN group (P = NS). Thus, IFN maintenance treatment after ASCT was associated with better OS and PFS. Treatment seemed to be most beneficial in patients who did not achieve CR. The difference in median survival was as long as 2.5 years, and although part of this difference is attributable to differences in other prognostic factors, it might justify possible differences in quality-of-life due to adverse effects of interferon treatment.

Health-related quality of life in multiple myeloma patients receiving high-dose chemotherapy with autologous blood stem-cell support.

In a population-based study, the Nordic Myeloma Study Group found a survival advantage for high-dose melphalan with autologous blood stem-cell support compared to conventional chemotherapy in myeloma patients under 60 yr of age (risk ratio: 1.62; confidence interval [CI] 1.22-2.15; p = 0.001). A study of health-related quality of life (HRQoL) was integrated in the trial, using the EORTC QLQ-C30 questionnaire. Of the 274 patients receiving intensive therapy 221 (81%) were compared to 113 (94%) of 120 patients receiving conventional melphalan-prednisone treatment. Prior to treatment, there were no statistically significant differences in any HRQoL score between the two groups. One month after the start of induction chemotherapy, the patients on intensive treatment had more sleep disturbance than the control patients. At 6 mo, corresponding to a mean of 52 d after high-dose melphalan, the patients on intensive treatment had moderately lower scores for global QoL and role and social functioning and there was also a significantly higher score for appetite loss. At 12 and 24 mo, the HRQoL was similar to that of the control patients. At 36 mo, there was a trend toward less fatigue, pain, nausea, and appetite loss in the intensive-treatment group. Thus, the 18 mo of prolonged survival seem to be associated with a good health-related quality of life. Despite the moderate HRQoL reduction associated with the early intensive chemotherapy phase, this treatment modality must be regarded as an important step forward in the care of multiple myeloma.

[High-dose melphalan with stem cell support is now an established myeloma therapy. Treatment of myeloma from a 30-year perspective]. / Högdos melfalan med stamcellsstöd nu etablerad terapi vid myelom. Myelombehandling i ett 30-årsperspektiv.

Melphalan and prednisone have been the backbone in myeloma therapy for more than 40 years. New developments in chemotherapy and supportive therapy, achieved during the two decades which preceded the use of high-dose chemotherapy with stem cell rescue, have not changed the overall prognosis. A study of high-dose melphalan with autologous stem cell support on 274 patients < 60 years, performed by the Nordic Myeloma Study Group, has shown a prolongation of the median survival by 1.5 years. The results confirm that this therapy is a major step forward in myeloma therapy. Cost-utility and quality-of-life studies show that high-dose therapy has acceptable costs and leads to a favorable long-term quality-of-life.

Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma.

Twenty-three patients with advanced and heavily pretreated myeloma were treated with thalidomide. Starting dose was 200 mg/d, and 20 patients had dose escalations up to 400 (n = 5), 600 (n = 12) or 800 mg/d (n = 3), usually in divided doses. Nineteen patients were refractory to recent chemotherapy, and four had untreated relapse after prior intensive therapy. Ten out of 23 patients (43%) achieved partial response (PR; nine with refractory and one with relapsed disease), six patients had minor response or stabilization of the disease and four had disease progression. Another three patients died early from advanced myeloma at less than 3 weeks of thalidomide therapy. Of the 10 patients with PR, seven had a better response than after any prior therapy, despite vincristine-doxorubicin-dexamethasone (VAD)-based treatment in all but one and high-dose melphalan with autologous stem cell support in four. Time to achieve PR was rapid in patients receiving thalidomide in divided doses (median 31 d). Responses also included reduced bone marrow plasma cell infiltration and improved general status. Normalized polyclonal gammaglobulin levels were seen in four cases. Six out of 10 patients with PR remained in remission with a median time on treatment of 23 weeks (range 15-50 weeks). Sedation was common but usually tolerable, and some patients continued full- or part-time work. Four patients had skin problems, three patients had pneumonia, one hypothyrosis, one sinus bradycardia and one minor sensory neuropathy. Thalidomide may induce good partial remissions in advanced refractory myeloma with tolerable toxicity, and should be evaluated in other settings for myeloma patients. Divided thalidomide doses seem to reduce time to achieve remission and may improve response rate.