Optimizing peripheral blood progenitor cell autologous transplantation in multiple myeloma.

As in other malignancies, peripheral blood progenitor cells (PBPC) have almost completely replaced bone marrow as the source of stem cells for autologous transplantation in multiple myeloma. PBPC collection could be optimized either by reducing contamination by the malignant clone or by increasing hematopoietic quality of the graft. Currently, the most promising technique for purifying the harvest is CD34 cell selection. Several pilot studies have shown the feasibility of this method in MM. However controlled studies are necessary to assess the clinical impact of CD34+ cell selection. In the IFM 94 study, CD34+ selection was optional. There was no significant difference between 50 patients receiving a CD34+ selected graft and 133 patients receiving non-selected PBPC, as regards duration of neutropenia, duration of thrombocytopenia, response rate, EFS or survival. Hematopoietic recovery after transplantation is related to the number of CD34+ cells infused. The optimal regimen for mobilizing the requested CD34+ yield is not yet known. We have completed a randomized study comparing the combination of SCF plus G-CSF and G-CSF alone after priming with cyclophosphamide 4 g/m2. The median number of leukaphereses to reach the target yield of 5x10(6) CD34+ cells/kg was 1 in the SCF group (N=55) versus 2 in the G-CSF group (N=47) (p=0.008). The median number of CD34+ cells collected in the first leukapheresis was 11. 6x10(6) in the SCF group versus 4x10(6) in the G-CSF group (p=0.003). These results are in line with those observed in other trials testing the combination of SCF and G-CSF to improve PBPC collection.     

Allogeneic hematopoietic cell transplantation for multiple myeloma

Some patients with multiple myeloma (MM) who have undergone allogeneic hematopoietic stem cell transplants remain free of disease 5 to 13 years later-a major accomplishment for a malignancy that had been resistant to all investigational therapies. Although it will require longer follow-up to determine how many are truly cured, results for patients with MM transplanted from identical twins suggest that long-term progression-free survival is possible. While 3- to 5-year survival is similar after allogeneic or autologous stem cell transplant for MM, only allograft recipients appear to enjoy long-term disease-free survival, most likely due to an allogeneic graft-versus-myeloma (GVM) effect. The very high transplant-related mortality associated with standard allogeneic stem cell transplantation is currently the major limitation to wider use of this potentially curative treatment. The challenge for clinical investigators will be to reduce the incidence of posttransplant complications. Strategies include the use of nonablative conditioning for allografts, the administration of peripheral blood stem cells (PBSC) rather than bone marrow, and the application of more focused, targeted conditioning therapies such as bone-seeking radioisotopes.     

Secondary MGUS after autologous hematopoietic progenitor cell transplantation in plasma cell myeloma: a matter of undetermined significance

Plasma cell myeloma, characterized by clonally aberrant plasma cells that produce abnormal monoclonal Igs, is the most common indication for autologous hematopoietic progenitor cell transplantation (AHPCT) in North America. We observed appearance of new monoclonal gammopathies different from the original protein in the post-AHPCT setting and termed this condition 'secondary MGUS' (monoclonal gammopathy of undetermined significance). Hence, we performed a retrospective, single institution review of serum protein electrophoresis/immunofixation electrophoresis data in 92 AHPCT recipients from the period 2000-2009. In all, 22 of 92 patients (24%) undergoing AHPCT met criteria for secondary MGUS. Contrary to previous studies, often referred to as 'abnormal protein banding,' we did not observe this condition as a favorable prognostic indicator in affected patients when compared with the control group (P=0.686). However, we did note that a subgroup of the study cohort who developed secondary MGUS after a prolonged latency (>10 months) had an improved median OS compared with the remainder of the study cohort (75 months vs 41 months, P=0.005). As there have been significant advancements in understanding the pathobiology and clinical significance of MGUS, we believe that secondary MGUS merits dedication of resources for investigation to determine its true clinical relevance, prognostic value and pathophysiology.     

Donor cell leukemia developing after hematopoietic stem cell transplantation for multiple myeloma

The development of secondary leukemia in donor cells after allogeneic stem cell transplantation is a rare event. We describe the occurrence of acute myeloid leukemia in donor cells 4 years after a stem cell transplantation for multiple myeloma. The multiple myeloma was relapsing at the time of the onset of acute myeloid leukemia. Secondary leukemia in donor cells after transplantation for multiple myeloma has not yet been reported.     

Cytomegalovirus colitis after autologous transplantation for multiple myeloma

Bone marrow or stem cell transplantation is an established therapy for haematological malignancies. We report a cytomegalovirus (CMV) IgG +ve 56-year-old patient who underwent autologous rescue with CD34(+) selected peripheral blood stem cells as part of consolidation therapy for multiple myeloma and subsequently developed CMV colitis. In contrast to infection secondary to human immunodeficiency virus (HIV), CMV colitis has not previously been described in this context. We discuss this case and issues arising from it related to the use of CD34+ selected stem cells for transplantation.     

多发性骨髓瘤的自体造血干细胞移植治疗

多发性骨髓瘤(multiple myeloma,MM)是一种好发于中老年人的血液系统恶性疾病,由骨髓中的浆细胞单克隆性增生引起。典型临床表现为骨骼系统破坏,如病理性骨折、本-周蛋白尿、贫血以及慢性肾功能不全,并伴随高钙血症、血沉增快及免疫球蛋白电泳出现单克隆免疫球蛋白峰等。MM常规化学治疗(化疗)反应率低,其中位生存期多为2～3年。临床研究证明经自体造血干细胞移植(AHSCT)治疗可     

Long-term follow-up of multiple myeloma after autologous hematopoietic stem cell transplantation:a single center results

正Objective To evaluate the efficacy and long-term outcome of a combined protocol for multiple myeloma(MM),including induction therapy,autologous hematopoietic stem cell transplantation(ASCT)and consolidation and maintenance therapy.Methods Clinical records of 144 patients with MM from January 1,2005 to February 1,2016 were retrospectively analyzed.Results The overall response rate(ORR)after ASCT was 100.0%,     

Myelodysplastic syndrome after autologous peripheral blood stem cell transplantation for multiple myeloma

Long-term survivors after autologous peripheral blood stem cell transplantation (APBSCT) for lymphoma or Hodgkin's disease are known to have a high risk of developing myelodysplastic syndrome (MDS), but the risk of MDS is not clear for patients transplanted for myeloma. We reviewed the outcomes for 82 myeloma patients who underwent APBSCT at our center. The group included 47 men and 35 women of median age 56 years (range: 37-74 years). Median time from diagnosis to APBSCT was 8.2 months (range: 2.6-86.1 months). Before coming to transplantation, 28% had received oral melphalan (MEL), 98% received other chemotherapy and 34% received radiation. A single APBSCT was provided for 68, and 32% underwent APBSCT more than once. High-dose MEL alone was used as the preparative regimen for 83%, and the remainder received at least one APBSCT with a more intensive preparative regimen. Ten patients (12%) developed MDS. The 5-year cumulative incidence is 18% (95% confidence interval, 9-30%). There were no demographic factors associated with an increased risk of developing MDS. Median survival after the diagnosis of MDS was 18 months. There is a relatively high risk of MDS after APBSCT for myeloma, and optimal therapy has not been established for these patients.     

Trajectories of quality of life recovery and symptom burden after autologous hematopoietic cell transplantation in multiple myeloma

Early autologous hematopoietic cell transplantation (AHCT) with post-transplant maintenance therapy is standard of care in multiple myeloma (MM). While short-term quality of life (QOL) deterioration after AHCT is known, the long-term trajectories and symptom burden after transplantation are largely unknown. Toward this goal, a secondary analysis of QOL data of the BMT CTN 0702, a randomized controlled trial comparing outcomes of three treatment interventions after a single AHCT (N = 758), was conducted. FACT-BMT scores up to 4 years post-AHCT were analyzed. Symptom burden was studied using responses to 17 individual symptoms dichotomized as ‘none/mild’ for scores 0–2 and ‘moderate/severe’ for scores of 3 or 4. Patients with no moderate/severe symptom ratings were considered to have low symptom burden at 1-year. Mean age at enrollment was 55.5 years with 17% African Americans. Median follow-up was 6 years (range, 0.4–8.5 years). FACT-BMT scores improved between enrollment and 1-year and remained stable thereafter. Low symptom burden was reported by 27% of patients at baseline, 38% at 1-year, and 32% at 4 years post-AHCT. Predictors of low symptom burden at 1-year included low symptom burden at baseline: OR 2.7 (1.8–4.1), p < 0.0001; older age: OR 2.1 (1.3–3.2), p = 0.0007; and was related to being employed: OR 2.1 (1.4–3.2), p = 0.0004). We conclude that MM survivors who achieve disease control after AHCT have excellent recovery of FACT-BMT and subscale scores to population norms by 1-year post-transplant, though many patients continue to report moderate to severe severity in some symptoms at 1-year and beyond.     

多发性骨髓瘤患者自体造血干细胞移植后感染的临床特征

目的 了解多发性骨髓瘤(MM)自体造血干细胞移植(ASCT)后感染的临床特点.方法 回顾性分析在中山大学附属第一医院住院诊治并接受ASCT治疗的37例MM患者,记录移植后6个月内的感染类型、时间、病原体以及疗效和转归.结果 在ASCT后6个月内有33例(89.2%)患者在观察期间出现59例次感染,其中30例患者在观察期间出现34例次(57.6%)细菌感染,12例患者在观察期间出现15例次(25.4%)真菌感染.既往曾合并真菌感染患者在移植后发生真菌感染比例高于没有合并真菌感染的患者(P=0.040).观察期间分别出现4例(6.8%)巨细胞病毒(CMV)、3例(5.1%)带状疱疹病毒感染及3例(5.1%)HBV再激活.移植后早期感染中细菌感染占62.8%,真菌感染28.6%,病毒感染8.6%,其中病毒感染均为CMV感染,移植后早期未见水痘带状疱疹病毒和HBV感染.移植后中期感染中细菌感染占50.0%、真菌感染20.8%、病毒感染29.3%,移植后早期与中期感染比例差异无统计学意义(P=0.106).38例次(64.4%)感染在应用首选抗感染治疗即得到控制.3例(8.1%)由于感染相关死亡.结论 MM患者ASCT后感染发生率高,各种病原体均易感,需要尽早合理抗感染治疗,降低感染相关病死率.

Abstract：

Objective To explore the clinical features of infection in multiple myeloma (MM)undergoing autologous hematopoietic stem cell transplantation (ASCT). Methods Thirty-seven patients with MM undergoing ASCT were retrospectively analyzed for type and time of infection, pathogen, and outcome. Results Fifty-nine cases of infectious complications occurred in 33 patients (89. 2% ) after ASCT, with 34 cases (57.6%) of bacterial infections in 30 patients, 15 cases (25.4%) of fungal infections in 12 patients, 4 cases (6. 8% ) of cytomegalovirus (CMV) infection, 3 cases (5. 1% ) of herpes zoster virus infection and 3 cases (5. 1% ) of HBV reactivation. The proportion of bacterial infection, fungal infection and virus infection were 62. 8%, 28.6% and 8. 6% respectively in the early stage after ASCT, and 50. 0%, 20. 8% and 29. 3% respectively in the median stage. Response to first-line antibiotic therapy was seen in 38 cases (64. 4% ). Infection-related mortality was 8. 1% (3 cases). Conclusions The incidence of infection in MM patients undergoing ASCT is high and they are susceptible to all pathogens. It is important to choose the right antifungal agents as quickly as possible to reduce infection-related mortality.     

Predictors of prolonged survival after allogeneic hematopoietic stem cell transplantation for multiple myeloma

A total of 149 patients with multiple myeloma (MM) who received allogeneic hematopoietic stem cell transplantation (allo-HCT) with myeloablative (MAC; n = 38) or reduced-intensity conditioning (RIC; n = 110) regimens at MD Anderson Cancer Center were evaluated. Of the total, 120 (81%) patients had relapsed or had refractory disease. Median age of MM patients was 50 (28-70) years with a followup time of 28.5 (3-164) months. The 100-day and 5-year treatment related mortality (TRM) rates were 17% and 47%, respectively. TRM was significantly lower with RIC regimens (13%) vs. 29% for MAC at 100 days (P = 0.012). The cumulative incidence of Grade II-IV acute graft-versus-host disease (GVHD) was 35% and chronic GVHD was 46%. PFS and OS at 5 years were 15% and 21%, respectively. In multivariate analysis, allo-HCT for primary remission consolidation was associated with longer PFS (HR 0.35; 95% CI, 0.18-0.67) and OS (HR 0.29; 95% CI 0.15-0.55), while absence of high-risk cytogenetics was associated with longer PFS only (HR 0.59; 95% CI 0.37-0.95). We observe that TRM has decreased with the use of RIC regimens, and long-term disease control can be expected in a subset of MM patients undergoing allo-HCT. Further studies should be conducted in carefully designed clinical trials in this patient population.     

Early lymphocyte recovery predicts superior survival after autologous hematopoietic stem cell transplantation in multiple myeloma or non-Hodgkin lymphoma

Autologous stem cell transplantation (ASCT) improves survival in patients with previously untreated multiple myeloma (MM) and relapsed, chemotherapy-sensitive, aggressive non-Hodgkin lymphoma (NHL). Lower relapse rates seen in allogeneic stem cell transplantation have been related to early absolute lymphocyte count (ALC) recovery as a manifestation of early graft-verus-tumor effect. In ASCT, the relation between ALC recovery and clinical outcomes in MM and NHL was not previously described. This is a retrospective study of patients with MM and NHL who underwent ASCT at the Mayo Clinic between 1987 and 1999. The ALC threshold was determined at 500 cells/microL on day 15 after ASCT. The study identified 126 patients with MM and 104 patients with NHL. The median overall survival (OS) and progression-free survival (PFS) times for patients with MM were significantly longer in patients with an ALC of 500 cells/microL or more than patients with an ALC of fewer than 500 cells/microL (33 vs 12 months, P <.0001; 16 vs 8 months, P <.0003, respectively). For patients with NHL, the median OS and PFS times were significantly longer in patients with an ALC of 500 cells/microL or more versus those with fewer than 500 cells/microL (not reached vs 6 months, P <.0001; not reached vs 4 months, P <.0001, respectively). Multivariate analysis demonstrated day 15 ALC to be an independent prognostic indicator for OS and PFS rates for both groups of patients. In conclusion, ALC is correlated with clinical outcome and requires further study. (Blood. 2001;98:579-585)     

Unrelated stem cell transplantation after reduced intensity conditioning for patients with multiple myeloma relapsing after autologous transplantation

From 2002 to 2007, 49 myeloma patients who relapsed following autologous SCT were included in a prospective multicenter trial to determine the efficacy of a reduced melphalan/fludarabine regimen followed by allogeneic SCT from unrelated donors. All patients showed leucocyte and platelet engraftment after a median of 15 and 19 d, respectively. Grade II–IV acute graft- versus -host disease (GvHD) occurred in 25% of patients and 35% had chronic GvHD. Overall response rate at day 100 was 95% including 46% complete remission (CR). Cumulative incidence of non-relapse mortality at 1 year was 25% [95% confidence interval (CI): 13–37%] and was significantly lower for human leucocyte antigen (HLA)-matched compared to -mismatched SCT (10% vs. 53%, P  = 0·001). The cumulative incidence of relapse at 3 years was 55% (95% CI: 40–70%). After a median follow up of 43 months, the estimated 5-year progression-free and overall survival rates were 20% and 26% respectively and were significantly better for matched in CR at day 100 (41% vs. 7%, P  = 0·04 and 56% vs. 16%, P  = 0·02). We conclude that optimal donor selection is mandatory for a low non-relapse mortality and high relapse incidence, which remains a major concern, should be improved by including post-transplant strategies to upgrade remission status.     

Autologous peripheral blood progenitor cell transplantation for multiple myeloma.

Autologous stem cell transplantation (ASCT) is increasingly used in the treatment of cases of multiple myeloma (MM) where there has been no significant improvement in the patient's condition following conventional chemotherapy. Peripheral blood progenitor cells (PBPC) have replaced bone marrow as a source of stem cells and offer easier accessibility and availability, faster haematopoietic recovery and possibly lower tumour contamination. The IFM 90 randomized trial has shown that autologous bone marrow transplantation significantly improves response rate, event-free survival (EFS) and overall survival (OS) in younger patients with MM. For MM, this review discusses the role of ASCT, the use of PBPC for autologous transplantation, and current developments of ASCT.     

Long-term outcomes of innovator versus generic melphalan formulation in autologous hematopoietic cell transplantation for multiple myeloma

BackgroundMost data on autologous hematopoietic cell transplantation (auto-HCT) in myeloma are based on the use of innovator formulation of melphalan. Comparative bioequivalence and efficacy studies of generic melphalan are lacking.MethodsIn this retrospective study, we report long-term outcomes of auto-HCT in myeloma using innovator (Alkeran, Aspen Pharma; n = 41) and generic melphalan (Alkacel, Celon Labs, India; n = 55) formulations. All consecutive patients at a single center from the period 2011–2018 were included.ResultsThe median follow-up in the innovator and generic groups was 61.7 and 32.5 months, respectively. Both groups were matched for age, sex, stage, and myeloma response. There were significantly more patients in the innovator melphalan group who were administered melphalan at a reduced dose at physician discretion (26.8% vs. 3.6%, p = .001). There were significantly more patients with grade 3 or higher mucositis (68.3% vs. 38.1%, p < .0001) and grade 3 or higher diarrhea (85.4% vs. 50.1%, p < .0001) in the innovator group. The median duration of hospital stay was significantly longer in the innovator group (19 days vs. 15.5 days, p < .0001). There were significantly more patients in the generic group who received standard maintenance (94.5% vs. 34.1%, p < .0001). Despite the differences in the melphalan dose and post-transplant strategies, the 4-year progression-free survival and overall survival were not significantly different in the two groups (58% vs. 63%, p = .7, 71% vs. 72%, p = .4, respectively).ConclusionLong-term efficacy comparison is helpful in the absence of postmarketing bioequivalence studies of generic melphalan.     

Risk factors for acute GVHD and survival after hematopoietic cell transplantation

Risk factors for acute GVHD (AGVHD), overall survival, and transplant-related mortality were evaluated in adults receiving allogeneic hematopoietic cell transplants (1999-2005) from HLA-identical sibling donors (SDs; n = 3191) or unrelated donors (URDs; n = 2370) and reported to the Center for International Blood and Marrow Transplant Research, Minneapolis, MN. To understand the impact of transplant regimen on AGVHD risk, 6 treatment categories were evaluated: (1) myeloablative conditioning (MA) with total body irradiation (TBI) + PBSCs, (2) MA + TBI + BM, (3) MA + nonTBI + PBSCs, (4) MA + nonTBI + BM, (5) reduced intensity conditioning (RIC) + PBSCs, and (6) RIC + BM. The cumulative incidences of grades B-D AGVHD were 39% (95% confidence interval [CI], 37%-41%) in the SD cohort and 59% (95% CI, 57%-61%) in the URD cohort. Patients receiving SD transplants with MA + nonTBI + BM and RIC + PBSCs had significantly lower risks of grades B-D AGVHD than patients in other treatment categories. Those receiving URD transplants with MA + TBI + BM, MA + nonTBI + BM, RIC + BM, or RIC + PBSCs had lower risks of grades B-D AGVHD than those in other treatment categories. The 5-year probabilities of survival were 46% (95% CI, 44%-49%) with SD transplants and 33% (95% CI, 31%-35%) with URD transplants. Conditioning intensity, TBI and graft source have a combined effect on risk of AGVHD that must be considered in deciding on a treatment strategy for individual patients.