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Within a prospective protocol, the incidence and impact of achievement of molecular remission (mCR) and high-risk cytogenetics was investigated in 73 patients with multiple myeloma (MM) after autologous (auto)-allogeneic (allo) tandem stem cell transplantation (SCT). After induction chemotherapy, patients received melphalan 200 mg/m(2) before undergoing auto-SCT, followed 3 months later by melphalan 140 mg/m(2) and fludarabine 180 mg/m(2) before allo-SCT. Sixteen patients had high-risk cytogenetic features, defined by positive FISH for del(17p13) and/or t(4;14). Overall, 66% of the patients achieved CR or near-CR, and 41% achieved mCR, which was sustained negative (at least 4 consecutive samples negative) in 15 patients (21%), with no significant difference in incidence between the patients with high-risk cytogenetics and others (P = .70). After a median follow-up of 6 years, overall 5-year progression-free survival was 29%, with no significant difference between del 17p13/t(4;14)-harboring patients and others (24% versus 30%; P = .70). The 5-year progression-free survival differed substantially according to the achieved remission: 17% for partial remission, 41% for CR, 57% for mCR, and 85% for sustained mCR. These results suggest that auto-allo tandem SCT may overcome the negative prognostic effect of del(17p13) and/or t(4;14) and that achievement of molecular remission resulted in long-term freedom from disease., (Copyright © 2013. Published by Elsevier Inc.)

Relapse after dose-reduced allograft in advanced myeloma patients remains high. To reduce the risk of relapse, we investigated a myeloablative toxicity-reduced allograft (aSCT) consisting of i.v. BU and CY followed by lenalidomide maintenance therapy in 33 patients with multiple myeloma (MM) who relapsed following an autograft after a median of 12 months. The cumulative incidence of non-relapse mortality at 1 year was 6% (95% confidence interval (CI): 0-14). After a median interval of 168 days following aSCT, 24 patients started with a median dose of 5 mg (r, 5-15) lenalidomide without dexamethasone. During follow-up, 13 patients discontinued lenalidomide owing to progressive disease (n=6), GvHD (n=3), thrombocytopenia (n=2), or fatigue (n=2). Major toxicities of lenalidomide were GvHD II-III (28%), viral reactivation (16%), thrombocytopenia (III-IV°,16%), neutropenia (III/IV°, 8%), peripheral neuropathy (I/II°, 16%), or other infectious complication (8%). Cumulative incidence of relapse at 3 years was 42% (95% CI: 18-66). The 3-year estimated probability of PFS and OS was 52% (95% CI: 28-76) and 79% (95% CI: 63-95), respectively. Toxicity-reduced myeloablative allograft followed by lenalidomide maintenance is feasible and effective in relapsed patients with MM, but the induction of GvHD should be considered.

Infectious complications remain a major problem after allogeneic hematopoietic stem cell transplant (HSCT). Specifically Toxoplasma gondii infection is a life-threatening condition in immunocompromised patients. In order to highlight the difficulties in obtaining an early and definitive diagnosis, we report three cases of toxoplasmosis after HSCT for hematologic malignancies: two cases of T. gondii retinochoroiditis, and one case of encephalitis. All patients had unrelated donors and received antithymocyte globulin; none had received trimethoprim/sulfamethoxazole prophylaxis. Toxoplasmosis occurred early post-transplant and diagnosis was obtained by real-time PCR. In one case, the correct diagnosis could only be established by PCR analysis of a retinal biopsy specimen. Rapid diagnosis--by invasive approaches--and an immediate onset of antiparasite treatment are crucial to avoid disseminated and often lethal Toxoplasma infections in the post-transplant period. Post-transplant prevention strategies and treatment to control advanced infection in this setting are discussed.

Objective: To investigate post-transplant immunotherapy with escalating donor-lymphocyte infusions (DLI) and novel agents (thalidomide, bortezomib, and lenalidomide) to target complete remission (CR)., Materials and Methods: Thirty-two patients with multiple myeloma who achieved only partial remission after allogeneic stem cell transplantation were treated with DLI. If no CR was achieved, one of the novel agents was added to target CR., Results: CR defined either by European Group for Blood and Marrow Transplantation criteria, flow cytometry, or molecular methods as assessed by patient-specific immunoglobulin H-polymerase chain reaction or plasma cell chimerism polymerase chain reaction was accomplished in 59%, 63%, and 50% of patients, respectively. Achievement of CR resulted in improved 5-year progressive-free and overall survival, according to European Group for Blood and Marrow Transplantation criteria (53% vs 35%; p=0.03 and 90% vs 62%; p=0.06), flow cytometry (74% vs 15%; p=0.001 and 100% vs 52%; p=0.1), or molecular methods (84% vs 38%; p=0.001 and 100% vs 71%; p=0.03)., Conclusions: Our finding demonstrates the clinical relevance of posttransplantation therapies to upgrade remission, and of remission's depth for long-term survival in myeloma patients.

Background: Antithymocyte globulin or human Jurkat T-cell-line-derived antilymphocyte globulin is used in allogeneic stem cell transplantation to induce in vivo T-cell depletion to facilitate engraftment and lower graft-versus-host disease. In vitro studies suggest that antithymocyte globulin, besides causing T-cell depletion, has strong anti-myeloma activity., Design and Methods: We evaluated the anti-myeloma activity of antilymphocyte globulin in a melphalan/fludarabine-based reduced intensity conditioning regimen as well as the incidence of graft-versus-host disease in 138 multiple myeloma patients who underwent allogeneic stem cell transplantation with (n=79) or without (n=59) antilymphocyte globulin., Results: Leukocyte and platelet engraftment were faster in the group not receiving antilymphocyte globulin (13 vs. 16 days, p<0.001 and 11 vs. 19 days, p< 0.001, respectively). Inclusion of antithymocyte globulin led to a better day 100 overall response rate (93% vs. 78%, p=0.03) and complete response rate (59% vs. 39%, p=0.04), to a lower incidence of both acute grade III/IV graft-versus-host-disease (11% vs. 22%, p=0.10) and chronic graft-versus-host disease (23% vs. 65%, p<0.001) and to a trend to improved event-free survival at 3 years (39% vs. 27%, p=0.5). There was no difference in the estimated cumulative incidence of treatment-related mortality at 1 year between the groups receiving or not antilymphocyte globulin (25% vs. 26%). In a multivariate analysis treatment with antilymphocyte globulin was the only significant factor for achievement of a complete remission (RR:2.57, p=0.02)., Conclusions: Inclusion of antithymocyte globulin in allogeneic stem cell transplantation protocols for patients with multiple myeloma may increase remission rates and at the same time prevent graft-versus-host disease with no increase of relapses.

We analyzed the prognostic impact of the most frequent genetic abnormalities detected by fluorescence in situ hybridization in 101 patients with multiple myeloma, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after melphalan/fludarabine-based reduced conditioning. The incidences of abnormalities in the present analysis were as follows: del(13q14) (61%), t(11;14)(q13;q32) (14%), t(4;14)(p16.3;q32) (19%), MYC-gain gains (8q24) (21%), del(17p13) (16%) and t(14;16)(q32;q23) (5%). None of the patients had t(6;14)(p25;q32). The overall complete remission (CR) rate was 50% with no differences between the genetic abnormalities except for patients with del(17p13) who achieved less CR (7 vs 56%; P=0.001). Univariate analysis revealed a higher relapse rate in patients aged >50 years (P=0.002), patients with del(13q14) (P=0.006) and patients with del(17p13) (P=0.003). In multivariate analyses, only del(13q14) (HR: 2.34, P=0.03) and del(17p13) (HR: 2.24; P=0.04) significantly influenced the incidence of relapse, whereas for event-free survival, only age (HR 2.8; P=0.01) and del(17p13) (HR: 2.05; P=0.03) retained their negative prognostic value. These data show that del(17p13) is a negative prognostic factor for achieving CR as well as for event-free survival after HSCT. Translocation t(4;14) might be overcome by allogeneic HSCT, which will have implication for risk-adapted strategies.

Objective: We investigated the effect of at least two cycles of bortezomib (1.3 mg/m(2) intravenously, days 1, 4, 8, and 11) after dose-reduced allogeneic stem cell transplantation (SCT) on toxicity, CD3(+) cells, graft-versus-host disease (GvHD), and response in patients with multiple myeloma., Methods: Eighteen patients with multiple myeloma without progressive disease were included. The proteasome inhibitor was given at median of 8 months after allografting to enhance or maintain remission status., Results: Fourteen patients (78%) completed the proposed two cycles. Four patients had to discontinue therapy due to neurotoxicity (n = 3) or gastrointestinal toxicity (n = 1). Severe grade III/IV toxicity was seen for thrombocytopenia (50%), leukopenia (17%), or neuropathy (17%), which was more often seen in patients treated concomitantly with cyclosporine (p = 0.06). The median circulating CD3(+) cells decreased during treatment from 550 muL to 438 muL (p = 0.03), resulting in herpes zoster infection in three patients (17%). In three patients, a mild aggravation of existing acute or chronic GvHD of the skin, and in one patient de novo skin grade I acute GvHD was noted. In patients with measurable disease, complete remission, partial remission, and minor response was seen in 3 (30%), 5 (50%), and 2 (20%) patients, respective., Conclusion: Bortezomib after allogeneic SCT is effective but further studies are needed to balance the efficacy with potential hazards such as infectious complications, aggravation of GvHD, and neurotoxicity.

Objective: To investigate lineage-specific chimerism of plasma cells after allogeneic transplantation by real-time PCR based on bi-allelic sequence polymorphism or, in case of female-to-male transplantation, on the detection of the DFFRY gene and to determine its value to quantify minimal residual disease in myeloma patients., Methods: Forty-eight samples from bone marrow samples and peripheral blood from 34 nonmyeloma patients were analyzed at different times after transplantation. Sixty-two samples from 22 myeloma patients were analyzed at different times after allogeneic stem cell transplantation, and results were compared with immunofixation and, in some cases, with PCR data using patient-specific primers., Results: The median chimerism for T cells at day +100 was greater than 99.9% and remained stable on day +180 and 1 year after transplantation. In contrast, the median donor plasma cell chimerism at day +100 was 95.5%, at day +180 98.6%, at day +360 99.8%, and 2 or more years after transplantation greater than 99.9%. Sensitivity of real-time PCR using human short insertion/deletion polymorphisms (SIDP) was 10(-4) and in case of Y-PCR 10(-5). Sequential monitoring of donor plasma cell chimerism showed that increasing and stable chimerism were associated with ongoing remission in 15 out of 16 samples (93%), and decreases in chimerism predicted relapse in 5 out of 6 patients., Conclusion: We conclude that plasma cell chimerism after allogeneic stem cell transplantation is delayed in comparison to T-cell chimerism. Sequential quantitative measurement of plasma cells after allogeneic stem cell transplantation with highly sensitive real-time PCR allows monitoring of residual host-tumor cells in patients with multiple myeloma and allows guiding adoptive immunotherapy strategies to enhance remission status and to prevent clinical relapse.

We compared antithymocyte globulin (ATG) with alemtuzumab in 73 patients with multiple myeloma, who underwent reduced conditioning with melphalan/fludarabine, followed by allogeneic stem cell transplantation from human leucocyte antigen-matched or -mismatched unrelated donors. The ATG group had more prior high-dose chemotherapies (P < 0.001), while bone marrow was used more as the stem cell source in the alemtuzumab group (P < 0.001). Alemtuzumab resulted in faster engraftment of leucocytes (P = 0.03) and platelets (P = 0.02) and in a lower incidence of acute graft versus host disease (GvHD) grades II-IV (24% vs. 47%, P = 0.06). More cytomegalovirus (CMV) seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs. 47%, P = 0.001). The cumulative incidence of treatment-related mortality at 2 years was 26% [95% confidence interval (CI) = 12-37%] for ATG vs. 28% (95% CI = 15-55%) for alemtuzumab, P = 0.7. There was no significant difference in the estimated 2-year overall and progression-free survival between ATG and alemtuzumab: 54% (95% CI: 39-75%) vs. 45% (95% CI: 28-73%) and 30% (95% CI: 16-55%) vs. 36% (95% CI: 20-62%) respectively. In multivariate analysis, treatment with alemtuzumab had a higher risk for relapse (hazard ratio: 2.37; P = 0.05) while killer immunoglobulin-like receptor (KIR)-ligand mismatch was protective for relapse (P < 0.0001). We conclude that alemtuzumab produced less acute GvHD, but higher probability of relapse. The data implicated a major role of KIR-ligand mismatched transplantation in multiple myeloma.

To improve the antimyeloma effect of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation in multiple myeloma, we investigated in a phase 1/2 study the effect of low-dose thalidomide (100 mg) followed by DLI in 18 patients with progressive disease or residual disease and prior ineffective DLI after allografting. The overall response rate was 67%, including 22% complete remission. Major toxicity of thalidomide was weakness grade I/II (68%) and peripheral neuropathy grade I/II (28%). Only 2 patients experienced mild grade I acute graft versus host disease (aGvHD) of the skin, while no grades II to IV aGvHD was seen. De novo limited chronic GvHD (cGvHD) was seen in 2 patients (11%). The 2-year estimated overall and progression-free survival were 100% and 84%, respectively. Adoptive immunotherapy with low-dose thalidomide and DLI induces a strong antimyeloma effect with low incidence of graft versus host disease.

We evaluated prognostic factors of melphalan/fludarabine-based dose-reduced allografts in patients with multiple myeloma. From 1998 to 2002, 120 patients with multiple myeloma were treated with melphalan/fludarabine followed by allogeneic stem cell transplantation. The cumulative risk at 1 year for treatment-related mortality (TRM) was 18% (95% confidence interval [CI], 12%-28%). In a multivariate analysis, relapse after prior high-dose chemotherapy was the most significant risk factor for TRM (hazard ratio [HR], 2.80; 95% CI, 1.16-6.74; P =.02), relapse (HR, 4.14; 95% CI, 2.04-8.38; P <.001), event-free survival (HR, 3.11; 95% CI, 1.77-5.46; P <.001), and overall survival (HR, 2.69; 95% CI, 1.35-5.35; P =.005). In addition, relapse was also significantly diminished by chronic graft-versus-host disease (GVHD) in a time-dependent Cox model (HR, 0.37; 95% CI, 0.16-0.87; P =.02). At transplantation, 8% of the patients were in complete remission, whereas 27% had progressive disease. After allografting, 49% achieved complete remission, and 38% achieved partial remission. In a subgroup of patients with chemosensitivity at transplantation and no relapse after prior high-dose chemotherapy who underwent transplantation with peripheral blood stem cells (n = 46), the cumulative risk of TRM at 1 year was only 8% (95% CI, 1%-54%). The 2-year estimated event-free and overall survival was 60% (95% CI, 42%-78%) and 75% (95% CI, 59%-91%), respectively, for related donors (n = 34) and was 81% (95% CI, 59%-100%) and 92% (95% CI, 76%-100%), respectively, for unrelated donors (n = 12).

We investigated in a retrospective multicenter study the impact of chromosome arm 13q deletion (13q-) as detected by fluorescence in situ hybridization (FISH) on outcome after dose-reduced allografting in patients with multiple myeloma. In 68 of 140 patients, data on chromosome 13q status were available. Most patients included had advanced myeloma. At 2 years, patients with 13q deletion (n = 31) had a shorter event-free (18% vs 42%; P =.05) and overall survival (18% vs 67%; P =.03) than patients without 13q- (n = 37). Patients with 13q- experienced a higher relapse rate (77% vs 44%; P <.001) but a similar incidence of transplantation-related mortality at one year (24% vs 18%). In a multivariate analysis, 13q- remained a significant risk factor for a higher relapse rate (hazard ratio [HR], 3.28; 95% confidence interval [CI], 1.31-8.24; P =.01) and a shorter event-free survival (HR, 1.94; 95% CI, 1.03-3.67; P =.04). Concerning overall survival, 2 or more cycles of prior high-dose chemotherapy were associated with a significantly higher probability of death (HR, 2.48; 95% CI, 1.19-5.17; P =.02), while patients with deletion 13q had a nearly 2 times higher risk of death (HR, 1.94; 95% CI, 0.95-3.98; P =.07) after dose-reduced allogeneic stem cell transplantation.

We investigated toxicity and efficacy of in vivo T-cell depletion with anti-thymocyte globulin (ATG) as part of an intensified myeloablative conditioning regimen followed by allogeneic stem cell transplantation in patients with advanced multiple myeloma. The conditioning regimen consisted of modified total body irradiation, busulfan and cyclophosphamide (n=15) or in the case of prior dose-limiting radiotherapy of busulfan and cyclophosphamide (n=3). The median age was 44 years (range, 29-53) and the median time from diagnosis to transplant was 12 months (range, 6-144). Grade II-IV acute graft-versus-host disease (GvHD) occurred in six patients (35%). Severe grade III/IV GvHD developed in one patient (6%). Three patients died of therapy-related causes (17%). A complete remission (CR) with negative immunofixation after allogeneic transplantation was seen in eight of the evaluable patients (53%). After a median follow-up of 41 months (range, 8-84), the estimated overall survival at 6 years for all patients is 77% (CI 95%: 58-96%). The estimated progression-free survival at 6 years for all patients is 31% (CI 95%: 2-59%) and 46% (CI 95%: 9-83%) for patients with CR. In vivo T-cell depletion with ATG resulted in a low rate of severe GvHD with low treatment-related mortality, and a substantial number of long-term survivors.

We investigated the feasibility of unrelated stem cell transplantation in 21 patients with advanced stage II/III multiple myeloma after a reduced-intensity conditioning regimen consisting of fludarabine (150 mg/m(2)), melphalan (100-140 mg/m(2)), and antithymocyte globulin (ATG; 10 mg/kg on 3 days). The median patient age was 50 years (range, 32-61 years). All patients had received at least one prior autologous transplantation, in 9 cases as part of an autologous-allogeneic tandem protocol. No graft failure was observed. At day 40 complete donor chimerism was detected in all patients. Grade II to IV acute graft-versus-host disease (GVHD) was seen in 8 patients (38%), and severe grade III/IV GVHD was observed in 4 patients (19%). Six patients (37%) developed chronic GVHD, but only 2 patients (12%) experienced extensive chronic GVHD. The estimated probability of nonrelapse mortality at day 100 was 10% and at 1 year was 26%. After allografting, 40% of the patients achieved a complete remission, and 50% achieved a partial remission, resulting in an overall response rate of 90%. After a median follow-up of 13 months, the 2-year estimated overall and progression-free survival rates are 74% (95% CI, 54%-94%) and 53% (95% CI, 29%-87%), respectively. A shorter progression-free survival was seen in patients who already experienced relapse to prior autograft (26% versus 86%, P =.04). Dose-reduced conditioning with pretransplantation ATG followed by unrelated stem cell transplantation provides durable engraftment and donor chimerism, reduces substantially the risk of transplant-related organ toxicity, and induces high remission rates.

We evaluated toxicity, engraftment, chimerism, graft-versus-host disease (GVHD), and response to a dose-reduced allograft after cytoreductive autografting in 17 patients with advanced stage II/III multiple myeloma (MM). After autografting with melphalan (200 mg/m2) the patients received after a median interval of 119 days (range 60-210) a dose-reduced regimen consisting of fludarabine (180 mg/m2), melphalan (100 mg/m2), and antithymocyte globulin (3 x 10 mg/kg) followed by allografting from related (n = 7), mismatched related (n = 2), or unrelated (n = 8) donors to induce a graft-versus-myeloma effect. After dose-reduced allografting all patients became neutropenic (< 0.2 x 10(9)/L) for at least 8 days. All patients engrafted with a median time for leukocyte (> 1 x 10(9)/L) and platelet (> 20 x 10(9)/L) counts of 16 (range, 11-24) and 23 days (range, 12-43), respectively. Complete donor chimerism was detected after a median of 30 days (range, 19-38). Acute GVHD stage II occurred in 4 patients (25%) and grade III GVHD in 2 patients (13%). Chronic GVHD developed in 40% of the patients, but only 1 patient experienced extensive chronic GVHD requiring further immunosuppressive therapy. Two patients died of alveolar hemorrhage and pneumonia, resulting in a day 100 mortality rate of 11%. The rate of complete remission with negative immunofixation increased from 18% after autografting to 73% after allografting. After a median follow-up of 17 months after autologous and 13 months after allogeneic transplantation 13 patients are alive and 12 of them free of relapse or progression. The tandem auto-allotransplant protocol is highly active and provides rapid engraftment with complete donor chimerism and tolerable toxicity.

Two patients with persistent disease after allografting for multiple myeloma received donor T-cell lymphocyte infusion (DLI) (1.5 x 10(8) and 7 x 10(7)) to induce a graft-vs.-myeloma effect for further tumour regression after withdrawal of immunosuppression. The interval between stem cell transplantation and DLI was 8 and 14 months respectively. Both patients converted from partial to complete remission, lasting 12+ and 28+ months. Immunofixation became negative after 3 and 4 months. The main toxicity was grade II and III acute graft-vs.-host disease (GvHD) and limited or extensive chronic GvHD in each patient. We conclude that DLI induced further tumour reduction in patients with persistent disease after allografting for multiple myeloma.