Bone marrow transplantation in multiple myeloma

Experience from around the world now suggests that high response rates can be achieved in patients with multiple myeloma treated with high-dose therapy followed by hematopoietic stem cell transplantation. However, patients are destined to relapse and few, if any, are cured. Major obstacles to cure are the excessive toxicity noted after allografting in multiple myeloma, contaminating tumor cells in multiple myeloma autografts, and most importantly, the persistence of minimal residual disease after high-dose therapy and either allogeneic or autologous stem cell transplantation. In this context, strategies are being developed to decrease the toxicity of allografting and to enhance allogeneic anti-multiple myeloma immunity after transplantation to improve outcome. To improve autografting, better ablative regimens, more efficacious purging of tumor cells from autografts, and enhancement of autologous anti-multiple myeloma immunity post-transplantation are modalities being tested to enhance overall and event-free survival.     

Graft-vs.-lymphoma effect in various histologies of non-Hodgkin's lymphoma

Generally, there is a significantly lower risk of lymphoma relapse following allogeneic than after autologous stem cell transplant. Factors contributing to this lower risk of relapse include an absence of the use of ablative conditioning, with a tumor-free graft, and the generation of a graft-vs.-tumor (GVT) immune response. Allogeneic transplantation, however, has the possibility of graft-vs.-host disease (GVHD). The use of autologous and conventional allogeneic hematopoietic stem cell transplantation (HSCT) in follicular lymphoma, diffuse large cell lymphoma, chronic lymphocytic leukemia and multiple myeloma is discussed. Due to a 1-year transplant-related mortality of 30-40% and complications caused by GVHD, conventional, myeloablative, allogeneic transplantation is a high-risk option for low-grade lymphoproliferative disorders. Novel applications of allogeneic HSCT are described that take advantage of a GVT effect while reducing the risk of GVHD. Minimally myelotoxic pretransplant conditioning regimens allow host antigen-presenting cells to persist, enabling presentation of host minor histocompatibility antigens to donor T cells, causing a GVT response. Although complications may arise due to GVHD, non-myeloablative HSCT can be offered to patients previously ineligible for conventional high-dose treatment. A protocol developed in Seattle using a low-dose total body irradiation (TBI)-based conditioning regimen with immunosuppression using mycophenolate mofetil in combination with cyclosporin has been used in a multicenter trial. To overcome the problem of graft rejection fludarabine was later added to the protocol. A second protocol from a smaller trial used a preparative, conventional-dose regimen of fludarabine, given with cyclophosphamide. Rituximab was also given to provide synergistic action with the chemotherapy to enhance tumor control in the early post-transplant period to allow time for the establishment of the GVT effect. Following transplantation, GVHD prophylaxis was given using tacrolimus with methotrexate. A trial of a further variation of allogeneic HSCT, tandem auto/allo transplants, is described. First, high-dose therapy with autologous PBSC rescue was used to cytoreduce the disease. This was followed by a reduced-intensity or non-myeloablative allogeneic graft. This procedure was devised to take advantage of high-dose therapy and allogeneic HSCT. Results for non-myeloablative allogeneic HSCT are particularly promising in low-grade NHL and the GVT effect may augment response and delay or prevent relapse. However, for aggressive disease, non-myeloablative regimens are only indicated for patients with minimal disease, as the non-myeloablative regimens are unable to control the tumor before the generation of a GVT effect, and/or lack the ability to control rapidly proliferating disease. Patients with relapsed disease may require a higher-dose regimen or tandem transplant approach.     

Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow autotransplants in newly diagnosed multiple myeloma.

There is controversy whether high-dose therapy and a bone marrow autotransplant or conventional chemotherapy is a better treatment for newly diagnosed multiple myeloma. Data from 1 comparative study and 1 randomized trial provide insufficient subject-level data to advise specific people whether to have an autotransplant. We analyzed appropriate use of high-dose therapy and bone marrow autotransplants in people with newly diagnosed, multiple myeloma using a modified Delphi-panel group judgment process. The panel consisted of 9 myeloma experts from diverse geographic sites and practice settings who reviewed Boolean MEDLINE searches of multiple myeloma and chemotherapy or autotransplants. The panel rated a metric of 64 clinical setting developed by permuting age, performance score, disease-stage and disease-related prognostic variables and response to initial therapy. Each panelist rated appropriateness of high-dose therapy and an autotransplant versus conventional-dose chemotherapy on a 9-point ordinal scale (1, most inappropriate, 9, most appropriate). An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Autotransplants were rated appropriate in persons <55 years old with stage 3 disease and a complete or partial response or stable disease after initial chemotherapy, inappropriate in persons with stage 1 or 2 disease, a performance score <70% and a complete or partial response or stable disease after initial chemotherapy and uncertain in all other settings.     

Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma

BACKGROUND: Most patients undergoing high-dose therapy and autologous transplant for multiple myeloma eventually develop a disease recurrence. However, to the authors' knowledge, the optimal salvage treatment for these patients is not well defined. Both autologous and allogeneic hematopoietic stem cell transplantations have been used for salvage therapy. The outcomes of salvage autologous or allogeneic transplants were analyzed retrospectively in patients relapsing after an autograft. METHODS: Fourteen patients (median age, 52 yrs) received a second autograft for salvage, whereas 26 patients (median age, 51 yrs) underwent a reduced-intensity allogeneic transplantation (related in 18 patients and unrelated in 8 patients). The median interval between the first and the second transplant was 25 months in the autologous group and 17 months in the allogeneic group. The two groups were evenly matched with regard to other disease characteristics. RESULTS: After a median follow-up of 18 months for the autologous group and 30 months for the allogeneic group, the median progression-free survival (PFS) and overall survival (OS) in the 2 groups were 6.8 months versus 7.3 months and 29 months versus 13 months, respectively. Acute and chronic graft versus host disease (15%) was the most common cause of non-recurrence mortality in the allogeneic group and infections (14%) in the autologous group. On univariate analysis, an interval of > 1 year between the first and the salvage transplant predicted a better OS in the allogeneic group. CONCLUSIONS: Both autografting and allografting are feasible as salvage therapy for myeloma patients who develop disease recurrence after the first autograft, although disease progression remains the major cause of failure. Better approaches are needed for salvage therapy in patients developing disease recurrence after an autograft.     

Multiple myeloma: what's new

With conventional therapy, only 5% of multiple myeloma patients achieve complete response. But in recent clinical trials of high-dose therapy with autologous hematopoietic stem cell transplant, complete remission rates of 25-30% can be affected with median survival exceeding 5 years. Newer approaches in clinical trials, including more potent induction regimens utilizing thalidomide, alone or in combination with dexamethasone, are improving treatment outcomes. The authors suggest that potential for a cure now appears to be within reach.     

Role of Proteasome Inhibitors in Relapsed and/or Refractory Multiple Myeloma

Proteasome inhibition is an established treatment strategy for patients with multiple myeloma as proteasome inhibitors (PIs) selectively target and disrupt the protein metabolism of aberrant plasma cells. Since the introduction of the first-in-class PIs bortezomib, the therapeutic landscape for multiple myeloma has shifted with the development of next-generation PIs (carfilzomib and ixazomib) and new classes of agents. Treatment with modern combination therapies has been shown to result in deep responses and improved outcomes, and these potent regimens are increasingly used as frontline therapy. As patients continue to live longer with modern frontline therapy, there will be an increased need for effective regimens after initial treatment failure. Several recent studies have shown that treatment with combination therapy incorporating PIs induces deep and durable responses in patients with relapsed and/or refractory multiple myeloma. In this review, we review pivotal data and discuss the role of PIs-based doublet and triplet regimens for the management of relapsed/refractory multiple myeloma in the era of modern combination therapy.     

Management Strategies for Relapsed Multiple Myeloma

Multiple myeloma is the second most common hematologic malignancy after non-Hodgkin lymphoma. Numerous treatments for this disease are available, but despite high overall response rates, relapse occurs in almost all patients, and survival has typically been no more than 5 years. Treatment options for relapsed patients include pulsed dexamethasone; cyclophosphamide-based therapy; doxorubicin-based regimens; melphalan and prednisone; thalidomide with or without dexamethasone; bortezomib; and high-dose chemotherapy supported by autologous or allogeneic stem cell transplantation. Relapsed disease is more difficult to treat, and patients characteristically become resistant to therapy. As a result of the numerous potential complications of multiple myeloma, including fatigue, bone pain, renal dysfunction, increased susceptibility to infection, and spinal cord compression, quality of life has a significant role in the choice of therapy. New strategies in the treatment of relapsed disease are focusing on therapy that is targeted to various cell-signaling pathways and microenvironmental interactions involved in the pathogenesis of multiple myeloma. As they become available, these strategies are showing promise in the treatment of both relapsed and refractory disease, the most recent being the potent thalidomide analog lenalidomide. Research efforts are also concentrated on improving front-line therapy to reduce the rate of relapse so that, ultimately, survival may be extended and patient outcome improved.     

Comparison of regimen-related toxicity between high-dose melphalan and ICE as a preparatory regimen for autologous stem cell transplantation

Chemotherapy-susceptive multiple myeloma (MM) has an indication for high-dose melphalan (HDM) followed by autologous stem cell transplantation (auto-SCT). HDM was a most simple and convenient regimen among various preparatory regimens, because of rapid infusion divided over 2 days. In order to assess the potential of auto-SCT by HDM in a outpatient setting, we evaluated the toxicities of HDM compared with the ICE regimen generally applied to patients with refractory or relapsed lymphoma. We reviewed 27 cases of auto-SCT from April 2003 to December 2004. The preparatory regimen was HDM (melphalan 200 mg/m(2)) for 18 cases of multiple myeloma and ICE therapy (ifosfamide 12 g/m (2), carboplatin 1,200 mg/m(2), etoposide 800 mg/m2) for 9 malignant lymphomas. Gastrointestinal (GI) adverse events for a patient per hospital day were 0.93 for myeloma and 0.95 for lymphoma (no significant differences), with GI toxicity of more than grade 3, 0.08 and 0.12, respectively (p=0.07). Hematological toxicity was not significantly different between the 2 therapies. The clinical toxicity of HDM was milder compared to ICE, especially regarding the speculated GI-associated nutritional disorders. We thus concluded that outpatient auto-SCT could be validated first in myeloma patients treated by HDM with careful supportive treatments, thereby avoiding regimen-related severe adverse events.     

Immunochemotherapy with in vivo purging and autotransplant induces long clinical and molecular remission in advanced relapsed and refractory follicular lymphoma

BackgroundTo evaluate the clinical outcome of patients with relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and high-dose therapy with autotransplant.Patients and methodsSixty-four patients were enrolled in the trial. Primary end point was progression-free survival (PFS). Secondary end points were the in vivo purging effect on stem-cell harvest and the impact of molecular response on the outcome.ResultsAt enrollment, 59% of patients were PCR+ for bcl-2 rearrangement in bone marrow (PCR-informative). After the immunochemotherapy, before mobilization, 97% obtained complete response or partial response and 87% of patients informative for bcl-2 were molecularly negative. Sixty-one patients proceeded to in vivo purging and peripheral blood stem cell (PBSC) mobilization with rituximab and high-dose AraC. The median number of CD34+ cells collected was 16.6 × 10⁶/kg. Of 33 PCR-informative patients, the harvests resulted in PCR- in all. Fifty-eight patients received high-dose therapy and autotransplant of in vivo purged PBSC. After a median follow-up of 3.5 years, 41 patients are in complete remission. Five-year PFS is 59%.ConclusionThis study demonstrates that patients with advanced relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and autotransplant may obtain long-lasting PFS. In bcl-2-positive patients, in vivo purging allows the harvest of lymphoma-free PBSC. Absence of the bcl-2 rearrangement after autotransplant is associated with persistent clinical remission.     

Autotransplants for Hodgkin's disease in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry.

PURPOSE: Hodgkin's disease patients who never achieve complete remission with conventional chemotherapy (i.e., those with primary induction failure) have a poor prognosis. Some subjects who receive high-dose therapy with autologous hematopoietic progenitor-cell infusion experience prolonged progression-free survival. PATIENTS AND METHODS: Detailed records from the Autologous Blood and Marrow Transplant Registry (ABMTR) on 122 Hodgkin's disease patients who failed to achieve complete remission after one or more conventional therapy regimens and subsequently received an autotransplant between 1989 and 1995 were reviewed. RESULTS: Median age was 27 years (range, 7 to 57 years). Median time from diagnosis to transplantation was 14 months (range, 5 to 38 months). Most patients received high-dose chemotherapy without radiation for pretransplantation conditioning (n = 107). The regimen most frequently used was cyclophosphamide, carmustine, and etoposide (n = 47). Fifteen patients received total-body irradiation (n = 15). The graft consisted of bone marrow (n = 86), blood stem cells (n = 25), or both (n = 11). The 100-day mortality was 12% (95% confidence interval, 7% to 19%). Sixty patients (50%) were considered to have achieved complete remission after autotransplantation; 37 of these had negative imaging studies, whereas scan abnormalities of unknown significance persisted in 23 patients. Twenty-seven patients (22%) had no response or progressive disease after transplantation. Probabilities of progression-free and overall survival at 3 years were 38% (95% confidence interval, 28% to 48%) and 50% (95% confidence interval, 39% to 60%), respectively. In multivariate analysis, "B" symptoms at diagnosis and poor performance score at transplantation were adverse prognostic factors for outcome. CONCLUSION: Autotransplants should be considered for patients with Hodgkin's disease who do not achieve complete remission with conventional therapy.     

High-dose melphalan in patients with multiple myeloma

Since 1983 an increasing number of clinical trials have used high-dose melphalan with or without autologous stem cell support in patients with multiple myeloma. It has been shown that high-dose therapy including high-dose melphalan may be considered as the treatment of choice in newly diagnosed patients. The purpose of this report is to review and summarize the clinical information on IV high-dose melphalan in patients with multiple myeloma and to examine potential areas of future investigation.     

Clinical impact of bortezomib in frontline regimens for patients with multiple myeloma

Standard frontline therapy for multiple myeloma comprises cytoreductive therapy with or without consolidative high-dose therapy plus stem cell transplantation (HDT-SCT). Despite therapeutic advances, the disease remains incurable; most patients relapse following frontline treatment and die within 5 years of diagnosis. New options are required to enhance and prolong response, and improve survival, particularly for elderly patients and those with renal dysfunction. Preclinical studies have demonstrated the ability of bortezomib to enhance the activity of commonly used myeloma agents, an observation validated through clinical studies in both the relapsed and frontline settings. This review focuses on the growing body of clinical evidence showing the effectiveness of bortezomib and bortezomib-based combinations in newly diagnosed patients, characterized by high overall response rates and consistently high rates of complete response. A number of studies incorporating bortezomib as part of induction therapy have demonstrated no adverse impact of bortezomib on stem cell harvest and engraftment in patients proceeding to transplantation. The higher rates of complete response typically associated with bortezomib treatment may potentially improve clinical outcomes in this setting. Final results from ongoing phase III studies of bortezomib-based combinations versus standard regimens will help define the optimal use of bortezomib as a standard component of frontline therapy for multiple myeloma. Disclosure of potential conflicts of interest is found at the end of this article.     

Multiples Myelom: Hochdosistherapie und Stammzelltransplantation

High-dose therapy and autologous stem cell transplantation is the treatment of choice in patients aged ≤70 years with advanced multiple myeloma. Based on documented survival benefit after high-dose therapy in several randomized and case-control studies in comparison to conventional chemotherapy, multiple myeloma has become one of the main indications for performing high-dose therapy with stem cell transplantation. New forms of allogeneic stem cell transplantation has rendered this treatment method also safer for patients with multiple myeloma and has resulted in high response rates and rates of complete remission never before obtained. Particularly in patients fulfilling high-risk criteria, i.e., with chromosomal aberrations (e.g., 13q deletion), studies currently underway are employing allogeneic stem cell transplantation.     

An update on the role of high-dose therapy with autologous or allogeneic stem cell transplantation in mantle cell lymphoma

PURPOSE OF REVIEW: Early trials of high-dose therapy with autologous stem cell transplantation in mantle cell lymphoma were discouraging, with no clear survival advantage attributable to the procedure. Most early series were plagued by small numbers, retrospective designs, and short follow-up. Also, until recently, allogeneic stem cell transplantation was not an option for most mantle cell lymphoma patients who were too old or infirm to tolerate standard conditioning regimens. RECENT FINDINGS: New advances in allogeneic transplantation, particularly reduced-intensity conditioning regimens, have increased the availability of this procedure to patients with mantle cell lymphoma. New evidence has emerged during the last several years that suggests autologous stem cell transplantation in first complete remission may provide a survival advantage over conventional chemotherapy in patients with mantle cell lymphoma. Additionally, investigational strategies such as in vivo purging with rituximab and the use of radioimmunotherapy in conditioning regimens may further increase response rates and, hopefully, survival in mantle cell lymphoma patients. Finally, recent studies suggest the existence of a graft-versus-lymphoma effect in mantle cell lymphoma providing strong scientific rationale for the possible curative potential of allogeneic stem cell transplantation in this disease. SUMMARY: This review focuses on recent advances in allogeneic and autologous transplantation for mantle cell lymphoma. Particular emphasis is placed on the role of autologous transplantation in first complete remission, the role of in vivo purging with rituximab, the utility of radioimmunotherapy and, finally, the evolving strategy of reduced-intensity allogeneic stem cell transplantation.     

适合移植的多发性骨髓瘤患者治疗研究进展

适合移植的多发性骨髓瘤（MM）患者的治疗通常采用三药方案诱导治疗后行造血干细胞采集.对于适合移植患者的标准预处理方案是大剂量美法仑方案.移植后行巩固治疗可提高缓解率.为了获得长期的疾病控制和改善总生存期,用硼替佐米或来那度胺（极高危患者二者联合）进行维持治疗是较合理的选择.随着新药在MM治疗中的应用,患者预后将会得到改善并获得长期的疾病控制.     

Role of allogeneic stem cell transplantation in multiple myeloma

Multiple myeloma remains incurable despite the use of high-dose therapy and autologous stem cell transplantation and the introduction of novel agents with high response rates. The use of an uncontaminated stem cell graft and the presence of a graft-versus-myeloma effect led to the use of allogeneic stem cell transplantation in myeloma, and it has been part of the therapeutic armamentarium for more than a decade. Early results were discouraging due to high transplantation-related mortality and high rates of graft-versus-host disease. More recently, better supportive care, increasing experience with this modality and its complications, use of reduced-intensity conditioning regimens, and its use earlier in the course of disease have led to improved outcomes. Patients with high-risk genetic and biochemical features do poorly with conventional therapies, and allogeneic transplantation offers the potential for long-term disease control.     

High-dose melphalan versus busulfan, cyclophosphamide, and etoposide as preparative regimens for autologous stem cell transplantation in patients with multiple myeloma

High-dose chemotherapy (HDC) with autologous stem cell transplant (ASCT) has improved response rates and survival for patients with multiple myeloma (MM). We report a single-institution experience using two conditioning regimens, busulfan, cyclophosphamide, and etoposide (BCV) or high-dose melphalan (HDM). Between July 1992 and August 2003, 110 patients with MM (median age=56.1) underwent HDC with ASCT using either BCV (n=62) or HDM (n=48) in sequential cohorts as the preparative regimen. Overall response rates, progression-free survival, and median overall survival were similar. BCV and HDM confer similar long-term outcomes with similar toxicity profiles as conditioning regimens prior to autologous stem cell transplant in patients with MM.     

Radiotherapy in the management of plasma cell tumors

Most patients with plasma cell tumors receive radiation therapy at some time during the course of their disease. Plasma cell tumors are radio-responsive, but the systemic nature of the disease in most patients limits the application of localized irradiation. In patients with solitary plasmacytomas (osseous and non-osseous), radiation therapy is the primary treatment modality. It provides excellent local control that may translate into a long remission and even cure. Adequate dose and careful anatomic planning are essential. In patients with multiple myeloma, effective palliation of pain can be achieved with relatively small fields and low doses of radiation. Hemibody irradiation has been shown to provide cost-effective palliation but is associated with toxicity and has failed to contribute to a more definitive therapeutic approach. Hemibody irradiation is rarely used today. Total-body irradiation is often employed in conditioning regimens prior to autologous or allogeneic stem-cell transplantation for multiple myeloma. However, the magnitude of its contribution to the efficacy of high-dose programs in multiple myeloma remains to be studied. This article explores the rationale for and various aspects of providing effective radiotherapy in patients with plasma cell tumors.     

Oral mucositis and outcomes of autologous hematopoietic stem-cell transplantation following high-dose melphalan conditioning for multiple myeloma

The purpose of this study was to assess the relationship between oral mucositis (OM) and adverse clinical and economic outcomes of autologous hematopoietic stem-cell transplantation (HSCT) following high-dose melphalan (Alkeran) conditioning in patients with multiple myeloma. A retrospective study of 115 consecutive autologous HSCT recipients with multiple myeloma who received high-dose melphalan conditioning before transplantation was undertaken at a single academic center. OM severity was assessed twice weekly using a validated scale beginning 3-4 days following conditioning and continuing until hospital discharge or day 28, whichever occurred first. OM was graded, based on presence/extent of erythema/ulceration across eight oropharyngeal sites, as follows: 0 = no erythema or ulceration; I = erythema but no ulceration; II = ulceration, 1 site; III = ulceration, 2 sites; IV = ulceration, 3 sites; and V = ulceration, > or = 4 sites. Analyses examined the relationship between worst OM grade and selected clinical and economic outcomes, including days with fever, days of total parenteral nutrition (TPN),days of parenteral narcotic therapy, incidence of significant infection, and inpatient days and charges. The mean age of study subjects was 54 years; 19 patients (17%) received total-body irradiation, and 55 patients (48%) experienced OM grade > or = II (ie, ulceration). The worst OM grade was significantly (P < 0.05) associated with numbers of days of TPN and parenteral narcotic therapy, length of hospitalization, and total inpatient charges. Worst OM grade was not associated with the number of febrile days or the risk of significant infection. OM is associated with worse clinical and economic outcomes in multiple myeloma patients undergoing autologous HSCT following high-dose melphalan conditioning.     

High-dose therapy for follicular lymphoma

Most patients with advanced-stage follicular non-Hodgkin's lymphoma (NHL) are not cured with conventional therapy. The use of high-dose therapy and autologous stem-cell transplantation in patients with relapsed follicular NHL has received increasing attention. Several large studies suggest a disease-free survival rate of approximately 40% among patients transplanted during sensitive relapse, although the role of autologous transplantation in first remission remains controversial. Patients with histologic transformation from low-grade to diffuse large B-cell lymphoma whose disease remains sensitive to conventional therapy have a similar disease-free survival rate. Allogeneic transplantation has achieved relapse, overall survival, and treatment-related death rates of approximately 15%, 50%, and 40%, respectively, in patients with follicular NHL. Studies of minimal residual disease suggest that the presence of lymphoma cells in the autologous graft and within the patient before clinically apparent relapse is predictive of later recurrence. Therefore, treatment of minimal residual disease may improve the outcome of high-dose therapy. Use of a tumor-free stem-cell product through improved purging or allogeneic stem cells is one approach, although the morbidity and mortality of allogeneic transplantation remain high. Immunomodulatory strategies with monoclonal antibodies, vaccines, or adoptive immunotherapy may be particularly well suited to patients at high risk for relapse following high-dose therapy.