The outcome of unrelated donor stem cell transplantation for patients with multiple myeloma

We performed a retrospective analysis of outcome in 45 patients with multiple myeloma receiving unrelated donor stem cell transplants (UD-SCT) in the UK between 1993 and 2002; 17 received myeloablative conditioning regimens and 28 received reduced intensity conditioning (RIC) protocols. Forty patients received pretransplant CAMPATH serotherapy. Forty-two of 45 patients had detectable disease at transplant, but 33 of 45 were chemoresponsive. Sixty per cent of patients had received a previous autograft. Myeloid engraftment was seen in 95% of recipients and was significantly faster in recipients receiving peripheral blood stem cells (P = 0.07) and RIC (P = 0.001). The incidence of severe (grade 3/4) acute graft versus host disease (aGvHD) was 5% (2/40). The 100-d non-relapse mortality was 18% (5/38) following RIC and 53% (9/17) following myeloablative regimens. Twenty-nine per cent of patients achieved a complete remission, 61% a partial remission, giving a 90% overall response rate. At median follow-up (513 d), overall survival was 40%: 54% in the RIC group (median follow-up: 489 d) and 18% in the myeloablative group (median follow-up: 560 d). In recipients of UD-SCT, RIC protocols that incorporated CAMPATH were associated with faster myeloid engraftment, less severe aGvHD and lower 100-d non-relapse mortality than myeloablative regimens, without a corresponding rise in relapse rate during the period of observation.     

Unrelated donor haematopoietic cell transplantation after non-myeloablative conditioning for patients with high-risk multiple myeloma

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.     

Consequences of ABO incompatibility in multiple myeloma patients undergoing peripheral blood stem cell transplantation after reduced intensity conditioning

Background

Although the ABO blood group is one of two major antigen systems of relevance for transplantation in humans, there are still conflicting data concerning the influence of ABO-incompatibility on transplant outcome. This study investigated the effect of ABO incompatibility in recipients of haematopoietic progenitor cell transplants from related donors after reduced intensity conditioning (RIC) regimens.

Materials and Methods

We retrospectively analysed data from 19 multiple myeloma patients included in a prospective RIC allogeneic haematopoietic progenitor cell transplantation protocol, focusing on engraftment, transfusion requirement, Graft-versus-Host Disease, transplant-related mortality and survival.

Results

Five out of the 19 patients (26%) received an ABO-incompatible transplant, with minor ABO-mismatch in two patients (10%), major ABO-mismatch in one case (5%), and bidirectional incompatibility in two cases. Neutrophil recovery was not significantly different between the ABO-compatible and ABO-incompatible groups (p=0.85). At 30 days after transplantation, 12 of 19 patients tested (63%) had engraftment with all cells of donor origin (100% chimeric), and continued to be fully chimeric on day 100+ evaluations. Patients with major/bidirectional ABO incompatibility required more red blood cell and platelet units after transplantation and were transfused for longer periods of time, as compared with patients with minor or no ABO incompatibility. Transient, mild haemolysis was noted in one patient between days 10 and 30. Graft-versus-Host Disease, disease progression and transplant-related mortality were not affected by ABO matching.

Discussion

Although delayed red blood cell engraftment and increased transfusion requirements were documented, in this study ABO incompatibility after the RIC protocol used did not impair the clinical outcome.     

Progress in allogeneic transplantation for multiple myeloma

Allogeneic hematopoietic stem cell transplantation to treat multiple myeloma has been attempted since the early 1980s. The original conditioning regimen including high‐dose total body irradiation (TBI) plus cyclophosphamide was myeloablative and associated with a relatively low relapse/progression rate, but high transplant‐related mortality and no obvious improvement in progression‐free survival or overall survival. Some risk groups may benefit from this transplant modality and occasional patients may be cured, but due to the high‐transplant‐related mortality it is mainly abandoned. Reduced intensity conditioning (RIC), non‐myeloablative allogeneic transplantation reduces transplant‐related mortality significantly when compared with myeloablative conditioning, but the relapse/progression rate is somewhat higher. However although the treatment‐related mortality is higher than after autologous transplantation, the progression‐free and overall survival was better or tended to be better in three of five prospective trials comparing tandem autologous/RIC allogeneic transplantation to single or tandem autotransplantation due to lower relapse/progression rate. Adding donor lymphocyte infusions post‐transplant, new drugs like bortezomib, thalidomide, lenalidomide or pomalidomide pre‐ and/or post‐transplant, and more specific antimyeloma cell therapy like NK cells post‐transplant, may in future studies prove to improve results.     

Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning

Allogeneic stem cell transplantation (allo-SCT) after reduced-intensity conditioning was evaluated in 22 patients (median age 53, range 36-66 years) with multiple myeloma with progression after an autologous SCT. Seven patients received a transplant from a human leucocyte antigen (HLA)-identical sibling and 15 patients (68%) from an unrelated donor [including 3/22 (14%) from a HLA-mismatched unrelated donor]. Graft-versus-host disease (GVHD) prophylaxis consisted of serotherapy with antithymocyte globulin (ATG) and cyclosporine (CSA) (n = 12) or CSA plus mycophenolate mofetil (n = 10). Despite of heavy pretreatment, the transplant-related mortality (TRM) for all grafted patients was acceptable at 5/22 patients (23%). Seven of 21 patients (33%) that were evaluated developed grade II GVHD and one (5%) patient developed grade III/IV acute GVHD. Seven patients developed chronic GVHD (cGVHD), but only one was extensive. Eleven patients died of progressive disease within a median of 7 months (2-19 months) post transplant. Thirteen of all 22 patients (59%) achieved a partial or complete remission with six of these 13 patients (46%) remaining event free at a median of 24 months (range 8-36 months) post allografting. Estimated 2 year overall and event-free survival was, respectively, 25.5% and 22.0% for the whole patient group, and 62.5% and 57.1% for patients with chemosensitive disease. Chemorefractory disease prior to allogeneic stem cell transplantation (P = 0.0182) and absence of cGVHD (P = 0.069) were associated with shorter event-free survival. Thus long-term disease control can be achieved, but is restricted to patients responding to prior salvage chemotherapy.     

Busulfan,cyclophosphamide, and etoposide as conditioning for autologous stem cell transplantation in multiple myeloma

Autologous stem cell transplantation (ASCT) has enabled the use of high-dose alkylating agents either as a single agent or in combination with other cytotoxic agents and/or total body irradiation (TBI) for the treatment of multiple myeloma. Despite improved complete remission rates, relapse and regimen-related toxicities remain challenging. In an effort to increase event-free survival and decrease the high incidence of regimen-related toxicity, we have studied the use of etoposide in combination with reduced-dose busulfan and cyclophosphamide as a conditioning regimen for ASCT in a group of 26 patients with advanced multiple myeloma. Median follow-up for the group was 30 months. There was no early treatment-related mortality. The main toxicity was mucositis. Otherwise, there was 1 case of reversible, clinically diagnosed hepatic veno-occlusive disease. Post-engraftment, 10 patients (38%) achieved CR, 15 (58%) patients achieved PR or SD, and 1 patient developed progressive disease (4%). Five patients in PR and 1 with progressive disease before transplant attained a CR post-transplant. The median times for event-free survival and overall survival after transplantation were 24 and 43 months, respectively. In conclusion, conditioning with busulfan, cyclophosphamide, and etoposide followed by ASCT is a safe regimen with comparable effectiveness to other previously used preparative regimens, thus providing another approach of non-TBI containing high-dose chemotherapy for patients with multiple myeloma.     

Progress in haematopoietic stem cell transplantation for multiple myeloma

High-dose myeloablative treatment followed by autologous haematopoietic stem cell transplantation has significantly improved survival of patients younger than 65 years of age with multiple myeloma as compared with conventional chemotherapy. However, all patients seem to relapse and molecular remissions are rare. Results of allogeneic transplantation, still hampered by high transplant-related mortality, have improved dramatically over the last 5-6 years and this is an option for patients younger than 50-55 years old. The relapse rate is lower than with autologous transplantation and molecular remissions are frequent. Some patients are still in complete haematological remission more the 10 years following transplantation. Autologous transplantation followed by nonmyeloablative allogeneic transplantation is on trial and may be a way to eventually cure a fraction of younger patients with multiple myeloma.     

Outcome after autologous stem cell transplantation for multiple myeloma in patients with preceding plasma cell disorders

A third of patients with multiple myeloma (MM) have a preceding diagnosis of plasma cell proliferative disorder (PCPD), mostly monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM) or plasmacytoma. While autologous stem cell transplantation (SCT) improves survival in MM, it is not clear if patients with preceding PCPD have a different outcome. We identified 151 patients with preceding PCPD from among 804 patients undergoing SCT, and their outcomes were compared. The response rates, including complete responses, were similar between the groups. Patients with a preceding diagnosis of MGUS had longer time to progression (TTP; 27·5 months vs. 17·2 months, P  = 0·01), and longer overall survival (OS) from transplant (80·2 months vs. 48·3 months, P  = 0·03) compared to those with de novo myeloma. However no differences were seen among those with a preceding diagnosis of SMM or plasmacytoma in terms of TTP or OS from transplant when compared to those with de novo myeloma. Multivariate analysis indicated that the presence of MGUS prior to myeloma was prognostic for post-transplant relapse independent of other known risk factors. Patients with pre-existing MGUS prior to myeloma diagnosis have a better outcome following HDT, reflecting more indolent disease and a favourable biology than those presenting with de novo myeloma.     

Successful reduced intensity allogeneic stem cell transplantation for systemic AL amyloidosis

No established treatments for systemic AL amyloidosis have been determined, and only four reports have described allogeneic stem cell transplantation for this disease. We report the case of a patient with orthostatic hypotension, diarrhea, nephrotic syndrome, and cardiac amyloidosis due to systemic AL amyloidosis. Reduced intensity allogeneic stem cell transplantation (RIST) was performed using a conditioning regimen comprising fludarabine 125 mg/m2 and melphalan 90 mg/m2. Hematologically complete remission and symptomatic improvement were obtained without severe transplantation-related complications. RIST may thus offer a useful treatment strategy for systemic AL amyloidosis complicated by cardiac amyloidosis.     

Outcomes of alemtuzumab-based reduced intensity conditioning stem cell transplantation using unrelated donors for myelodysplastic syndromes

This prospective study evaluated the outcomes of 75 successive patients receiving a FBC (fludarabine, busulphan, alemtuzumab) reduced-intensity conditioning (RIC) regimen for myelodysplastic syndromes (MDS) using volunteer unrelated donors(VUD). The prognostic significance of a variety of clinical variables including the recently described haematopoietic cell transplantation co-morbidity index (HCT-CI) was assessed. The median age of the cohort was 52.0 years (range: 19-68 years) with a median follow-up of 1038.5 d. Forty-nine patients (65%) had an International Prognostic Scoring System stage of > or = Intermediate-2, 35 (46%) had intermediate or poor risk cytogenetics, and 23 patients(31%) were human leucocyte antigen-mismatched. The actuarial 3-year overall survival (OS) and disease-free survival (DFS) was 43% [95% confidence interval (CI): 37-49] and 41% (95%CI: 35-47) respectively, and the cumulative incidence of extensive chronic graft-versus-host disease was 22%. On multivariate analysis, presence of either one class II mismatch or a two-antigen mismatch adversely influenced transplant-related mortality, DFS and OS. In addition, disease status at transplantation and the haematopoietic cell transplantation-specific comorbidity index were independent variables for overall survival. In contrast, both advanced age and pre-transplant cytogenetic status did not significantly affect overall outcomes. RIC regimens using VUD was associated with durable long-term survival even in older patients with MDS, and the use of a pre-transplant comorbidity index may help to improve patient selection for transplantation.     

Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning regimen in children: a single-center experience

This single-center retrospective study reported the outcome of 19 children treated with a reduced-intensity conditioning (RIC) regimen prior to allogeneic stem cell transplantation (allo-SCT), for hematologic malignancies (n = 17), bone marrow failure (n = 1), and neuroblastoma (n = 1). Children were ineligible for standard myeloablative conditioning because of severe comorbidities (n = 9), a previous auto or allo-SCT (n = 7) or a prior history of extensive chemotherapy (n = 3). All patients underwent a fludarabine-based RIC regimen, and received grafts from matched-related donors (n = 5), match-unrelated donors (n = 6), or unrelated cord blood (UCB, n = 8). In this series, two patients treated with UCB failed to engraft and 63% achieved full donor chimerism at day 100 after allo-SCT. With a median follow-up of 537 d (range, 115-4136), treatment-related mortality was 16% and overall survival was 47%. The principal cause of death was disease relapse (n = 7). Acute graft versus host disease (GVHD) occurred in 53% of patients, while only 10% developed extensive chronic GVHD. Overall, results from this series suggest that RIC allo-SCT can be a valid alternative treatment option in unfit children with malignant hematological diseases. Prospective studies are needed to enlarge pediatric experience in this domain and better identify those children more suitable for a RIC allo-SCT approach.     

Allogeneic stem cell transplantation for patients with refractory anaemia with matched related and unrelated donors: delay of the transplant is associated with inferior survival

Allogeneic stem cell transplantation (alloSCT) for patients with refractory anaemia may result in a 50% event-free survival, but the high non-relapse mortality (NRM) precludes a general application of this therapeutic modality. This study evaluated the impact of various pre-transplant variables, including disease duration, intensity of the conditioning regimen, type of donor and year of transplantation on outcome. The study population consisted of 374 patients; 244 were transplanted from human leucocyte antigen (HLA)-identical siblings and 130 patients from matched unrelated donors. The median age was 39 years. One hundred and two patients were transplanted after reduced intensity conditioning (RIC). The overall 4-year survival was 52%. The 4-year survival of patients transplanted with HLA-identical sibling donors and matched unrelated donors was 52% and 50%, respectively. Multivariate analysis showed an improved survival ( P  = 0·05) and a lower NRM ( P  = 0·02) when the transplantation was performed in recent years. Increasing age, and disease duration of >12 months were associated with inferior survival. RIC resulted in a similar survival despite an increased relapse risk ( P  = 0·02). This improved outcome permits alloSCT in patients older than 50 years of age, even with the use of matched unrelated donors. AlloSCT should be preferentially performed early after diagnosis after careful analysis of prognostic variables.     

Continuous complete clinical and molecular remission in two patients with refractory lymphoid malignancies after autografting followed by allogeneic stem cell transplantation with reduced intensity conditioning

We present a 60-year-old patient with primary refractory non-Hodgkin's lymphoma and a 58-year-old patient with multiple myeloma with relapse after first autologous stem cell transplantation (ASCT), who underwent ASCT followed by allogeneic stem cell transplantation (alloSCT) with reduced intensity conditioning consisting of fludarabine and a single dose of total body irradiation. For graft-versus-host disease prophylaxis cyclosporine and mycophenolate mofetyl were given. Complete donor chimaerism was observed on d 28 after SCT. Both patients achieved sustained complete haematological and molecular remission of the immunoglobulin kappa light chain (Igkappa) rearrangement and are alive and well 17 and 16 months after SCT respectively.     

Long-term follow up of patients with multiple myeloma after high-dose chemotherapy and allogeneic stem cell transplantation

OBJECTIVES: Allogeneic transplantation may offer a curative approach to multiple myeloma (MM). We retrospectively analyzed the outcome of patients with multiple myeloma undergoing allogeneic stem cell transplantation in the context of beta(2) microglobulin and chromosome 13q. METHODS: All 13 patients with MM, who were referred to our center for allogeneic stem cell transplantation, were evaluated. Median age of patients was 38 yr, eight patients had chemo-sensitive disease, and median time between diagnosis of MM and transplantation was 15 months. Engraftment, acute and chronic graft vs. host disease, response to treatment, disease-free survival, and overall survival were evaluated according to standard criteria. RESULTS: There was one transplant-related death. Among 12 evaluable patients, seven patients (58%) achieved a complete remission (CR), and four patients (33%) achieved a partial remission. Acute graft vs. host disease occurred in 46% of patients, and chronic graft vs. host disease in 42% of available patients. After a median follow-up of 69.5 months (range, 5-128) nine patients (70%) are still alive, and six of them have remained progression free. Among five patients with low beta(2) microglobulin and normal chromosome 13q, four patients achieved a CR, with CR duration >5 yr in three of them. Among seven patients with elevated ss(2) microglobulin and/or deletion of chromosome 13q, only three CR were observed, with two patients still in CR on days +920 and +161, respectively. CONCLUSIONS: Allogeneic stem cell transplantation in patients with MM results in promising rates of CR, but durable remissions are predominantly seen in patients with favorable prognostic parameters.     

Late relapses following reduced intensity allogeneic transplantation in patients with multiple myeloma: a long‐term follow‐up study

We analysed the long‐term outcomes of 60 multiple myeloma patients who underwent reduced intensity allogeneic stem cell transplantation between August 2000 and March 2008. Regimens included fludarabine and melphalan conditioning (flu‐mel regimen) for allogeneic haematopoietic cell transplant (HCT) or a planned tandem regimen consisting of high‐dose melphalan conditioning for autograft followed by low‐dose total body irradiation conditioning for allogeneic HCT (auto‐allo regimen). Donors included human‐leucocyte‐antigen‐matched siblings (n = 55) or matched unrelated donors (n = 5). With a median follow‐up of 9·8 years, 7‐year overall survival (OS) and progression‐free survival (PFS) were 60% and 31%, respectively. By multivariate Cox regression analysis, disease status of complete response (CR) or partial response (PR) at transplant and the presence of chronic graft‐versus‐host disease were significantly associated with improved OS. Only disease status was significantly associated with improved PFS. We noted a surprising number of very late relapses, with six patients (10%) relapsing between 6 and 12 years post‐transplant. Among the six late relapse patients, all were transplanted within 14 months of diagnosis, five had normal karyotypes, and five were in CR/PR. Our data provide additional evidence that, while survival may be extended by reduced intensity allogeneic transplant, ultimately, it may not offer a cure.     

Stem cell transplantation after reduced‐intensity conditioning for sickle cell disease

Sickle cell disease (SCD) is still associated with substantial morbidity and reduced life expectancy. Disease‐related mortality rises to 14% in adolescents and young adults. Overall and disease‐free survival following haematopoietic stem cell transplantation (HSCT) is 90% and 95%, respectively. To reduce transplant‐associated late effects, the feasibility of a highly immunosuppressive reduced‐intensity conditioning (RIC) regimen was explored in children with SCD and a matched sibling donor. Eight patients (median age, 9 yr) and symptomatic SCD were included. The conditioning regimen consisted of fludarabine, melphalan and either thiotepa or total lymphoid irradiation plus antithymocyte globuline or alemtuzumab. The graft was bone marrow in seven and cord blood in one case. The conditioning regimen was well tolerated and no severe infectious complications occurred. All patients displayed mixed chimaerism on day +28. After a median follow‐up of 4 yr, 3/8 patients have mixed leucocyte chimaerism and 8/8 patients have 100% donor erythropoiesis. HSCT from matched sibling donors following a RIC regimen was well tolerated and resulted in cure in all patients studied. If confirmed in larger patient cohorts, these observations will have important implications for the indications of HSCT in children with SCD.     

Granular lymphocyte proliferative disorder after autologous peripheral blood stem cell transplantation for multiple myeloma

A 57-yr-old woman with multiple myeloma underwent tandem autologous peripheral blood stem cell transplantation (APBSCT). Fever, anemia, and thrombocytopenia, followed by the proliferation of granular lymphocytes in the peripheral blood occurred, after a second APBSCT. Clonal rearrangement of the T-cell receptor was detected using Southern blot analysis of peripheral blood samples. Granular lymphocyte proliferative disorders (GLPD) were diagnosed. After steroid therapy, the symptoms resolved. Lymphocytosis did not recur after the discontinuation of steroids. There have been a few reports of GLPD after solid organ and allogeneic hematopoietic stem cell transplantations. We report a first case of GLPD after APBSCT.