Search

Before the introduction of new drugs, we designed a trial where treatment of newly diagnosed myeloma patients was based on the presence or absence of HLA-identical siblings. First-line treatments included a cytoreductive autograft followed by a nonmyeloablative allograft or a second melphalan-based autograft. Here, we report long-term clinical outcomes and discuss them in the light of the recent remarkable advancements in the treatment of myeloma. After a median follow-up of 7 years, median overall survival (OS) was not reached (P = .001) and event-free survival (EFS) was 2.8 years (P = .005) for 80 patients with HLA-identical siblings and 4.25 and 2.4 years for 82 without, respectively. Median OS was not reached (P = .02) and EFS was 39 months (P = .02) in the 58 patients who received a nonmyeloablative allograft whereas OS was 5.3 years and EFS 33 months in the 46 who received 2 high-dose melphalan autografts. Among patients who reached complete remission in these 2 cohorts, 53% and 19% are in continuous complete remission. Among relapsed patients rescued with "new drugs," median OS from the start of salvage therapy was not reached and was 1.7 (P = .01) years, respectively. Allografting conferred a long-term survival and disease-free advantage over standard autografting in this comparative study.

Background: The prognostic value of changes in paraprotein markers after stem cell transplantation is unknown. We evaluated disease response using serum immunofixation (s-IFIX), total kappa and lambda ratio (KLR), and free light chain (FLC) ratio in myeloma patients who underwent autologous or autologous plus allogeneic stem cell transplantation., Methods: We studied s-IFIX, KLR, and FLC ratio in sera from 203 patients, 3 months after transplantation. We evaluated overall and event-free survival (OS and EFS, interval between date of study enrollment and date of death from any cause or date of progression, relapse, or death from any cause, respectively) by the Kaplan-Meier method., Results: Of the 203 patients, 51 were negative by s-IFIX, 99 reached a normal KLR, and 92 had a normal FLC ratio. Of the 51 patients with negative s-IFIX, 40 (78%) also had a normal FLC ratio. The median duration of OS was 54.3 months, and the median EFS was 19.5 months. None of the measured paraprotein parameters showed an association with OS. Only a normal KLR was associated with prolonged EFS (P = 0.016). Even a negative s-IFIX associated with a normal FLC ratio did not show a significant difference in terms of EFS and OS., Conclusions: Our analysis with a small cohort of patients did not show a significant impact of achieving complete response (CR) or stringent CR on patient survival.

The hematopoietic cell transplantation specific comorbidity index (HCT-CI) has been developed to identify patients at high risk of mortality after an allograft. Reduced-intensity/non-myeloablative regimens have decreased the non-relapse mortality (NRM) in elderly and/or heavily pretreated patients. We performed a retrospective study to assess whether HCT-CI may predict clinical outcomes in a cohort of 203 patients with non-Hodgkin's (NHL; n=108), Hodgkin's lymphomas (HL; n=26), and multiple myeloma (MM; n=69), who were transplanted from a human leucocyte antigen (HLA)-matched sibling (n=121) or an unrelated donor (n=82) after a reduced-intensity regimen (n=154) or a low-dose total body irradiation-based non-myeloblative regimen (n=49). Cumulative incidence of NRM was 5, 16 and 20% at 1 year and 6, 24 and 27% at 2 years, for patients with an HCT-CI of 0, 1-2 and > or =3, respectively. By multivariate analysis, HCT-CI significantly predicted NRM (hazard ratio (HR)=1.6, P=0.03), overall survival (OS; HR=1.62, P<0.001) and progression-free survival (PFS; HR=1.43, P=0.002). Moreover, the Karnofsky performance status was also significantly associated with OS and NRM (HR=1.62, P<0.001 and HR=2.12, P=0.04, respectively). Conditioning type did not affect outcome after stratifying patients by HCT-CI. In the light of our study, all future prospective trials of the Gruppo Italiano Trapianti di Midollo (GITMO) will include the HCT-CI to stratify patients.

Despite recent advances, allografting remains the only potential cure for myeloma. From July 1999 to June 2005, 100 newly diagnosed patients younger than 65 years were enrolled in a prospective multicenter study. First-line treatment included vincristin, adriamycin, and dexamethasone (VAD)-based induction chemotherapy, a cytoreductive autograft (melphalan 200 mg/m(2)) followed by a single dose of nonmyeloablative total body irradiation and allografting from an human leukocyte antigen (HLA)-identical sibling. Primary end points were the overall survival (OS) and event-free survival (EFS) from diagnosis. After a median follow-up of 5 years, OS was not reached, and EFS was 37 months. Incidences of acute and chronic graft-versus-host disease (GVHD) were 38% and 50%, respectively. Complete remission (CR) was achieved in 53% of patients. Profound cytoreduction (CR or very good partial remission) before allografting was associated with achievement of posttransplantation CR (hazard ratio [HR] 2.20, P = .03) and longer EFS (HR 0.33, P < .01). Conversely, development of chronic GVHD was not correlated with CR or response duration. This tandem transplantation approach allows prolonged survival and long-term disease control in patients with reduced tumor burden at the time of allografting. We are currently investigating the role of "new drugs" in intensifying pretransplantation cytoreduction and posttransplantation graft-versus-myeloma effects to further improve clinical outcomes. (http://ClinicalTrials.gov; NCT-00702247.).

High-dose chemotherapy with autologous stem cell rescue has been regarded as the standard of care for young newly diagnosed myeloma patients. Moreover, the development of new agents with potent anti-tumor activity has further improved survival. However, relapse is a continuous risk primarily due to the inability of current therapies to eradicate all myeloma cells. Allografting is the only potentially curative treatment at least for a subset of multiple myeloma patients due to its well documented graft-versus-myeloma effects. Given the high transplant mortality of the high-dose myeloablative conditionings used until recently, allografting has for a long time been limited to younger relapsed/refractory patients. These limitations have been reduced significantly by the use of reduced-intensity conditionings. Although results of recent trials are encouraging, the subset of patients who may benefit most from an allograft remains to be determined. An overview of the clinical outcomes obtained with allografting and possible future developments are reported.

Background: Allografting induces long-term molecular remissions and possibly cure in myeloma patients. The development of non-myeloablative conditionings has reduced the transplant-related mortality (TRM) associated with myeloablation and extended the eligible age for transplantation. Moreover, high response rates are reported especially when allografting is preceded by cytoreductive high-dose chemotherapy. We investigated the feasibility of unrelated donor non-myeloablative transplantation as either part of the initial treatment plan or as salvage treatment in heavily pretreated patients., Methods: Twenty-two patients underwent non-myeloablative allografting, 10 as part of their initial treatment and 12 at relapse. Donors were matched for HLA-A, B, C, DRB1 and DQB1 by high-resolution typing. Only one single class I allele disparity was allowed. Conditioning consisted of fludarabine 90 mg/m(2) and 2 Gy total body irradiation. Graft-vs.-host disease (GVHD) prophylaxis included cyclosporin and mycophenolate mofetil., Results: All patients except two (91%) readily engrafted. After a median follow-up of 20 (10-30) months, incidences of grade II-IV acute and extensive chronic GVHD were 50% and 61%. Overall response (OR) was 55%, with four (20%) complete and seven (35%) partial remissions. However, in patients allografted up-front OR was 89% whereas in the heavily pretreated group OR was 27% (P = 0.01). Two-year overall and event-free survivals were both 79% in the group transplanted up-front and 27% and 25% among relapsed patients (P = 0.025 and P = 0.006, respectively). Overall, six patients died of TRM and three of disease progression., Conclusions: Unrelated donor non-myeloablative allografting is feasible in myeloma. Disease control appears more pronounced when patients are treated soon after diagnosis.

Background: In this trial of the treatment of newly diagnosed multiple myeloma, we compared a protocol that entailed a hematopoietic stem-cell autograft followed by an allograft from an HLA-identical sibling with a protocol of tandem autografts., Methods: We enrolled 162 consecutive patients with newly diagnosed myeloma who were 65 years of age or younger and who had at least one sibling. All patients were initially treated with vincristine, doxorubicin, and dexamethasone, followed by melphalan and autologous stem-cell rescue. Patients with an HLA-identical sibling then received nonmyeloablative total-body irradiation and stem cells from the sibling. Patients without an HLA-identical sibling received two consecutive myeloablative doses of melphalan, each of which was followed by autologous stem-cell rescue. The primary end points were overall survival and event-free survival., Results: After a median follow-up of 45 months (range, 21 to 90), the median overall survival and event-free survival were longer in the 80 patients with HLA-identical siblings than in the 82 patients without HLA-identical siblings (80 months vs. 54 months, P=0.01; and 35 months vs. 29 months, P=0.02, respectively). Among patients who completed their assigned treatment protocols, treatment-related mortality did not differ significantly between the double-autologous-transplant group (46 patients) and the autograft-allograft group (58 patients, P=0.09), but disease-related mortality was significantly higher in the double-autologous-transplant group (43% vs. 7%, P<0.001). The cumulative incidence rates of grades II, III, and IV graft-versus-host disease (GVHD) combined and of grade IV GVHD in the autograft-allograft group were 43% and 4%, respectively. Overall, 21 of 58 patients (36%) were in complete remission after a median follow-up of 38 months (range, 10 to 72) after allografting. Of the 46 patients who received two autografts, 25 (54%) died., Conclusions: Among patients with newly diagnosed myeloma, survival in recipients of a hematopoietic stem-cell autograft followed by a stem-cell allograft from an HLA-identical sibling is superior to that in recipients of tandem stem-cell autografts. (ClinicalTrials.gov number, NCT00415987 [ClinicalTrials.gov].)., (Copyright 2007 Massachusetts Medical Society.)

We retrospectively evaluated the efficacy of bortezomib in 23 patients with multiple myeloma who had relapsed after allografting. Bortezomib was given as single agent to 9 patients (39%) and in combination with steroids in the other 14 (61%). Major toxicities were thrombocytopenia (10/23, 43%) and peripheral neuropathy (12/23, 52%). The overall response rate was 61% (14/23), including 22% (5/23) immunofixation-negative complete remissions. No significant differences in toxicity and response rates were seen between patients treated with bortezomib plus steroids and bortezomib alone. After a median follow-up of 6 months, progression free survival was 6 months. Twenty-one patients are alive, two and five in continuous very good partial and complete remissions, respectively.

Human herpesvirus 8 (HHV-8) is causally associated with Kaposi's sarcoma (KS). KS is most frequently observed in HIV patients and in solid organ transplant recipients. The role of HHV-8 in allogeneic haematopoietic cell transplantation (HCT) remains to be determined. Here we describe a case in which KS concomitantly occurred with CMV reactivation after a non-myeloablative allogeneic HCT and presented with skin lesions, but not visceral involvement. Skin biopsy confirmed the diagnosis and ruled out graft versus host disease or disease recurrence. Molecular findings indicated viral reactivation of the recipient's primary infection. Tumour lesions completely receded when immunosuppression was tapered. Prevalence studies in donors and recipients are needed to determine the clinical impact of HHV-8 in HCT.