High-dose Therapy In Multiple Myeloma Research Articles

Impact of cytogenetic classification on outcomes following early high-dose therapy in multiple myeloma.

Early high-dose therapy (HDT), consisting of high-dose melphalan and autologous stem cell transplantation following doublet or triplet novel agent induction, is a preferred management strategy for transplant-eligible myeloma patients. We set out to examine the utility of the current fluorescence in situ hybridization (FISH)-based risk stratification in a homogenously treated population of transplant-eligible myeloma patients receiving novel induction regimens and early HDT with or without posttransplant maintenance therapy. FISH was available in 409 patients at the time of diagnosis for patients receiving HDT within 12 months of diagnosis. We present comprehensive outcomes for chromosome 14 translocations and 17p abnormalities that both support and refute current risk stratification models. In contrast to its current classification as a marker of 'standard risk' (SR), t(11;14) was associated with inferior overall survival (OS) when compared with the classical SR cohort. The use of novel agent maintenance therapy (bortezomib or lenalidomide) following early HDT ameliorates the negative prognostic value of high-risk (HR) cytogenetic markers. HR patients who received maintenance following early HDT had similar OS compared with the SR cohort at 5 years.

Stem-cell collection before high-dose therapy for multiple myeloma: time has come to raise the standards!

Stem-cell collection before high-dose therapy for multiple myeloma: time has come to raise the standards!

International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100)

Multiple myeloma is the most common indication for high-dose chemotherapy with autologous stem cell support (ASCT) in North America today. Stem cell procurement for ASCT has most commonly been performed with stem cell mobilization using colony-stimulating factors with or without prior chemotherapy. The target CD34+ cell dose to be collected as well as the number of apheresis performed varies throughout the country, but a minimum of 2 million CD34+ cells/kg has been traditionally used for the support of one cycle of high-dose therapy. With the advent of plerixafor (AMD3100) (a novel stem cell mobilization agent), it is pertinent to review the current status of stem cell mobilization for myeloma as well as the role of autologous stem cell transplantation in this disease. On June 1, 2008, a panel of experts was convened by the International Myeloma Foundation to address issues regarding stem cell mobilization and autologous transplantation in myeloma in the context of new therapies. The panel was asked to discuss a variety of issues regarding stem cell collection and transplantation in myeloma especially with the arrival of plerixafor. Herein, is a summary of their deliberations and conclusions.

Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma

There are a number of reports in literature data on the long-term outcomes of patients with multiple myeloma treated with high-dose therapy and autologous stem cell transplantation (HDT/SCT). While in general these data support the association between maximal tumor response and overall survival or progression-free survival after HDT/SCT, some trials have failed to find such correlation and there is no recent comprehensive literature analysis of this issue. We, therefore, performed a comprehensive literature review to identify prospective and retrospective studies on HDT/SCT in frontline multiple myeloma in which long-term outcomes were reported according to best tumor response observed. Following a prospectively defined search strategy we identified 21 studies (10 prospective and 11 retrospective studies) in which outcomes of 4,990 HDT/SCT patients according to their best tumor response were reported. The majority of these studies indicated a correlation between maximal response during or after HDT/SCT and long-term outcomes (overall survival and event-free/progression-free survival). The conclusions in individual studies report on the association between maximal response following induction therapy and long-term outcomes were more heterogeneous, possibly due to the low rate of complete response after standard induction therapy in each individual study. We, therefore, performed two types of meta-analyses, one based on the p-values reported for these associations in the individual studies, and one based on the primary response and outcome data provided in the individual studies. Both meta-analyses indicated highly significant associations between maximal response (complete response/near complete response/very good partial response) during or after HDT/SCT and long-term outcomes (overall survival and event-free/progression-free survival). Both meta-analyses also provided evidence of highly significant associations between maximal response following induction therapy and long-term outcomes (overall survival and event-free/progression-free survival).

Risk factors for relapse after complete remission with high-dose therapy for multiple myeloma

Complete remission (CR) is an important surrogate for long-term survival for patients with multiple myeloma. However, most patients achieving CR eventually relapse and die from their disease. To better define the predictors of relapse, we conducted a retrospective review of outcomes for patients who achieved CR after autografting at our institution. From January 1990 to December 2002, among >400 patients transplanted, 81 (54 males and 27 females) achieved CR. With a median follow up of 58 months for all surviving patients, the 5-year progression-free survival (PFS) was 33% [95% confidence interval (CI) = 23 – 44] and 5-year overall survival (OS) was 67% (95% CI = 54 – 77). Median PFS was 37 months and median OS has not yet been reached. On multivariate analysis, high tumor mass at diagnosis emerged as a predictor of poor outcome. We conclude that high tumor mass at diagnosis predicts a significantly shorter remission duration for myeloma patients undergoing autografting.

Intensive Versus Double Intensive Therapy in Untreated Multiple Myeloma: Final Analysis of the HOVON 24 Trial.

The benefit of high-dose therapy for multiple myeloma has been demonstrated in phase lI/lII studies. HOVON started a randomized multicenter trial to compare the efficacy of intensified treatment followed by myelo-ablative therapy with intensified treatment alone in newly diagnosed patients. We now report the results of the final analysis in 441 eligible patients with stage II (22%) and stage III (78%) disease. The median age was 55 years (range 31–65 ). Remission induction consisted of 3–4 cycles of VAD. 63 patients who had an HLA identical sibling were candidates for an allogeneic transplantation. After VAD, patients were randomized to receive melphalan 140 mg/m2 divided in 2 doses of 70 mg/m2 (IDM) without stem cell rescue (arm A) or the same regimen followed by myelo-ablative treatment with cyclophosphamide (120 mg/kg) and TBI with stem cell transplantation (ASCT, arm B). Peripheral stem cells were mobilized by cyclophosphamide (4 g/m2) and G-CSF after VAD. Interferon-a -2a was given as maintenance therapy in both arms.Of 441 registered patients, 303 were eligible for randomization. Patient characteristics with regard to sex, age, stage of disease, Ig isotype, and b2-M were not different between the two arms. The median follow-up from randomization was 56 months. 81% of patients received both cycles of IDM (79% in arm A and 83% in arm B) and 79% of patients actually received myeloablative therapy followed by ASCT in arm B. Median duration of Interferon-a-2a maintenance treatment was 12 months (arm A) vs 7 months (arm B). CR rate was significantly better in Arm B (28% vs 13%, p=0.002), while the overall response rate (PR + CR) was not different (90% vs 86%, p=0.23). Median event-free survival (EFS) from randomization was 22 months (arm B) vs 20 months (arm A) (logrank p=0.014). Median progression-free survival (PFS) was significantly better in patients treated with double intensification (24 vs 23 months, logrank p=0.032). Time to Progression (TTP) was significantly worse in arm A (median 25 vs 33 months, logrank p=0.001). The difference for EFS, PFS and TTP between the 2 treatment arms became only evident after 4 years of follow-up. Overall survival (OS) was not different between both treatments (median 55 months vs 50 months, logrank p=0.39). Multivariate analysis showed that treatment arm A, higher age, hemoglobin > 6.21 mmol/l, stage 3 and high serum LDH were significant adverse prognostic factors for EFS. Cytogenetic analysis in 151 patients was abnormal in 37% (45% del 13/13q-, 51% abnormal 1p/q, 33% del 6q, 89% complex abnormalities). Cox regression analysis showed that 1p/q was an independent unfavourable prognostic factor for OS, EFS, PFS and TTP (p<0.001), calculated from start VAD. Del 13/13q- was highly correlated with 1p/q abnormalities. By combining B2M > 3 mg/L with del13/13q- and 1p/q, prognostic groups were defined with a significant impact on OS (p<0.000002), EFS (p< 0.0002), PFS (p<.00006) and TTP (p<0.0000002).In conclusion, second intensification when added to intensified chemotherapy alone resulted in a superior EFS, PFS and TTP, but not OS. The latter difference is probably due to the high proportion of patients from the control arm who were treated with ASCT at first relapse. It is concluded that double intensive therapy leads to a higher CR rate and a longer PFS.

Cardiovascular toxicity is increased, but manageable, during high-dose chemotherapy and autologous peripheral blood stem cell transplantation for patients aged 60 years and older

High-dose therapy (HDT) for non-Hodgkins lymphoma (NHL) and multiple myeloma (MM) is considered a feasible option for patients aged ⩾60 years. This study compared the outcomes for all patients aged ⩾60 years treated with HDT at the center to a matched cohort group aged <60 years. Results for patients who were ⩾60 years at HDT between 1997 – 2002 were retrospectively analysed to assess efficacy and safety. Event-free (EFS) and overall survival (OS) rates were compared with a cohort group, matched by disease type, chemotherapy sensitivity, year of treatment and conditioning regimen. Patients with NHL were also matched by International Prognostic Index score. Forty patients aged ⩾60 years were identified. Median age was 65 (range 60 – 76) with 22 MM and 18 NHL; 50% had 1 or more co-morbidity; 35% had cardiovascular co-morbidity vs. 18% of controls (p = 0.075). Response rates (RR) following HDT for MM were: 4 (18%) complete responses (CR) and 18 (82%) partial responses (PR), giving an overall response rate (ORR) of 100%, vs. 77% for controls (p = 0.02). For NHL patients there were: 8 CR (44%) and 4 PR (22%), giving an ORR of 67%, vs. 83% for controls (p = 0.3). Transplant-related mortality was 8% compared to 5% in controls (p = 0.6). Toxicities were similar with the exception of cardiac toxicity, which was significantly higher in patients aged ⩾60 years vs. controls (50% ⩾grade 3 vs. 10%: p < 0.0001). Atrial fibrillation was the most frequent cardiovascular toxicity (9 patients). At a median follow-up of 33 months, there is no significant difference between older vs. younger patients in median EFS (24 vs. 38 months: p = 0.78) or OS (40 months vs. not reached: p = 0.23). HDT is feasible and effective in selected patients ⩾60 years with MM and NHL. Patients ⩾60 years are more susceptible to cardiovascular toxicities, particularly atrial fibrillation, but have similar or better response rates following HDT and similar long-term outcomes to younger patients.

High-dose therapy in multiple myeloma.

High-dose therapy in multiple myeloma.

High-dose therapy in multiple myeloma

High-dose therapy in multiple myeloma

High-dose therapy and innovative approaches to treatment of multiple myeloma

High-dose therapy in multiple myeloma (MM) appears to be superior in terms of event-free survival and overall survival compared with conventional therapy. Melphalan-based high-dose therapy increases complete remission rates from 5% to 50% and extends event-free survival beyond 3 years and overall survival beyond 6 years. Critical disease features associated with durable complete remission, event-free survival, and overall survival include the absence of chromosome 13 deletion, low β 2-microglobulin, and low C-reactive protein levels. Data on 1,000 patients enrolled in tandem high-dose trials show that chromosome 13 deletion is an important prognostic feature. The timely application of a second cycle of high-dose therapy extends event-free survival and overall survival markedly in MM patients with low β 2-microglobulin levels. Long-term results of the total therapy trial indicate that patients who do not have chromosome 13 deletions and present with low C-reactive protein and β 2-microglobulin levels have longer complete remissions than patients lacking these prognostic factors. Thalidomide shows clear evidence of antitumor activity possibly because of its antiangiogenic activity. Magnetic resonance imaging (MRI) indicates that bone marrow lesions become smaller or disappear while patients receive dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) consolidation chemotherapy and that patients who have a compete remission after diagnostic MRI have a superior event-free and overall survival than those who still have persistent MRI lesions. Prospective trials are underway to evaluate the effectiveness of consolidation therapy (total therapy II).

High-dose therapy in multiple myeloma.

Autologous transplantation in myeloma can prolong survival as compared with standard chemotherapy but cannot be considered curative, as the majority of patients relapse within 5 years. Contaminating myeloma cells can be detected in stem cell harvests in the majority of patients, and the possibility that these cells lead to relapse has prompted widespread current interest in the use of positive stem cell selection as a means of purging. Allogeneic bone marrow transplantation is associated with a high transplant-related mortality but a lower relapse risk. A graft-versus-myeloma effect has recently been proven by the demonstration of response to donor lymphocyte infusion in patients relapsing after allogeneic bone marrow transplantation.

Who benefits from high-dose therapy for multiple myeloma?

Who benefits from high-dose therapy for multiple myeloma?

Marrow transplantation for myeloma.

High-dose therapy with hemopoietic stem cell support in multiple myeloma (MM) has been used for 10 years. This approach is currently the most promising form of treatment for this disease. We review here its rationale and the results of clinical trials according to the source of hematopoietic stem cells [allogeneic or autologous, bone marrow or blood]. Finally, we discuss the ongoing uncertainties regarding the utility of this treatment and the future prospects for high-dose therapy in MM.

The Role of Autologous Blood Stem Cells in Support of High-dose Therapy for Multiple Myeloma

During the last few years, high-dose therapy with hemopoietic stem cell support has become a well-admitted therapeutic option for young patients with MM. The role of allogeneic or autologous graft and of blood rather than bone marrow as the source of hemopoietic stem cells must be further investigated. Autologous PBSC transplantation has, however, both practical and theoretic advantages over allogeneic and autologous BMT: (1) It can be applied to most patients, especially if blood stem cells are collected early in the course of therapy. (2) It usually induces relatively rapid hematologic reconstitution. (3) In comparison with autologous BMT, it appears to minimize the hazard of the reinfusion of malignant cells.