Double Autologous Transplant Versus Tandem Autologus - Non Myeloablative Allogeneic Transplant for Newly Diagnosed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 46-46 ◽  
Author(s):  
B. Bruno ◽  
M. Rotta ◽  
F. Patriarca ◽  
N. Mordini ◽  
B. Allione ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Low Dose ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Allogeneic Hct ◽  
Autologous Transplant ◽  
Autologous Hct ◽  
Beta 2 Microglobulin

Abstract Allogeneic approaches employing low dose TBI nonmyeloablative conditionings reported a dramatic reduction of transplant-related mortality (TRM) compared to conventional high dose regimens in newly diagnosed multiple myeloma (MM) (Maloney et al, Blood, 2003). The role of allografting, however, compared to autologous HCT remains to be determined. From September 1999 to July 2004, 241 consecutive MM patients, up to the age of 65, were diagnosed at five academic Italian Institutions. Overall, 194/241 had natural siblings (Table 1): 158/194 (81%) were HLA typed, while 36/194 (19%) were not typed for the following reasons: patients not eligible for high dose chemotherapy (n. 14); siblings not eligible for peripheral hematopoietic cell (PHC) donation (n.11); patient refusal to high dose chemotherapy (n. 9), unknown (n.2). Seventy-six/158 (48%) with a matched donor were offered a tandem autologous- nonmyeloablative allogeneic HCT approach. Eventually, 56/76 (73%), the “auto-allo group”, were enrolled while 20 did not enter the tandem program as 5 siblings (5/76, 7%) were not eligible for PHC donation, 5 patients refused an allogeneic HCT, and 10 patients preferred allografting as a possible salvage treatment. Of 102 patients without matched donors or after refusal to allografting, 73, “double-auto group”, underwent a standard double autologous transplant while 29 received less intense treatments because of clinical conditions or patient preference. Table 1 Newly diagnosed pts 241 With sibs/without sibs 194 /47 (total 241) HLA typed /not HLA typed 158 /36 (total 194) Matched sibs /No matched sibs 76 /82 (total 158) Auto-Allo”/“Double Auto”/Other”“ 56 /73 /29 (total 158) After induction chemotherapy, patients of both groups underwent G-CSF mobilised autografting with high dose melphalan (200 mg/m2). In the “auto-allo” group, the autologous HCT was followed, 2-4 months later, by low dose (2.0 Gy) TBI, allogeneic PHC infusion, and post transplant mycophenolate mofetil and cyclosporin. In the “double-auto group”, patients received a second autologous HCT. Patients characteristics were as follows: age: 54 (range 34–65) vs 53 (range 33–64) (p=ns); stage III myeloma: 77% vs 64% (p=0.03); beta 2 microglobulin > 2,5 mg/dl: 75% vs 59% (p=0.005), for the “auto-allo group” and for “the double-auto group”, respectively. At the time of this analysis, 56/56 of the “auto-allo group” and 55/73 of “the double-auto group” had completed the transplant programs. After median follow up of 3 years (range 11–80 months), TRM was 11% vs 4% (p=0.09); complete remission rates, defined as the disappearance of the monoclonal paraprotein by immunofixation, were 46% vs 16% (p=0.0001); overall survivals were 84% versus 62% (p=0.003); progression free survivals were 75% vs 41% (p=0.00008); event free survivals were 61% (34/56)% vs 38% (30/73) (p=0.006) in the “auto-allo group” and in the “double-auto” group, respectively. Longer follow up is needed, however data suggest that the “auto- non myeloablative allo” approach is not inferior to “double autologous” HCT in newly diagnosed MM.

Long-Term Follow-Up of a Randomized Phase III Multicenter Study Comparing a Standard Versus an Intensified Conditioning Regimen for High-Dose Chemotherapy in Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 945-945
Author(s):  
Roland Fenk ◽  
Peter Schneider ◽  
Martin Kropff ◽  
Ali-Nuri Huenerlituerkoglu ◽  
Ulrich Steidl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Conditioning Regimen ◽  
High Dose Chemotherapy ◽  
Phase Iii ◽  
Study Endpoint ◽  
Primary Study ◽  
High Dose ◽  
Significant Difference

Abstract High-dose chemotherapy (HDT) improves the outcome of patients with multiple myeloma (MM) in comparison to conventional chemotherapy. Dose-escalating strategies including tandem HDT are currently evaluated to further improve remission rates and survival of patients. Therefore we conducted a randomized multicenter trial to compare an intensified conditioning regimen with the current standard high-dose melphalan. The primary study endpoint was response rate, with overall survival (OS), event-free survival (EFS) and toxicity analysed as secondary endpoints. Between 1997 and 1999 a total of 56 patients with stage II and III disease, who were matched for age (median 56 years), number of previous therapies (median time from diagnosis to transplant 7 months) and different risk factors (beta2-microglobulin, LDH, CRP, cytogentic abnormalities, chemoresistant disease, IgA-subtype, renal impairment), were randomized. All patients received 2 courses of oral idarubicine/dexamethasone and 2 courses of intravenous cyclophosphamide/adriamycine in combination with G-CSF followed by peripheral stem cell collection. Thirty patients were treated with melphalan 200mg/m2 (HD-M) whereas 26 patients received idarubicine 42mg/m2, melphalan 200mg/m2 and cyclophosphamide 120mg/kg (HD-IMC) followed by autologous blood stem cell transplantation. Acute toxicity was higher with HD-IMC, including 5 (20%) treatment-related deaths due to infections versus none (0%) in the HD-M group. This lead to early termination of the study. Severity of mucositis (grade III-IV 19 vs. 8 pts., p=0.001), CRP (20 vs. 7 mg/dl, p<0.001), days of fever (11 vs. 3, p<0.001), days with iv-antibiotics (13 vs. 4, p<0.001), number of erythrocyte-transfusions (6 vs. 2, p<0.001), number of platelet-transfusions (16 vs. 4, p<0.001) and days to granulocyte engraftment (18 vs. 11, p=0.007) were significantly higher after HD-IMC. After a follow-up of 5 years analysis restricted to patients surviving the first 30 days after HDT showed a trend to higher response rates (CR+vgPR: 47% (95%CI 24–72%) vs. 35% (95%CI 18–56%), PR 37% (95%CI 17–63%) vs. 48% (95%CI 29–68%) and time-to-progression (median 31 vs. 15 months, p=0.1) in the HD-IMC treatment arm in comparison to HD-M, but there was no significant difference in EFS and OS (median 22 vs. 30, p= 0.31 and 66 vs. 66 months, p=0.8, respectively). Univariate analysis demonstrated that LDH levels > 200 U/L (p=0.04) and chemoresistant disease (p=0.05) were a bad prognostic factor for EFS. Beta2-Microglobulin levels > 5mg/dl (p=0.01), abnormal conventional cytogenetics (p=0.02) and LDH levels > 200 U/L (p=0.03) were predictive for an inferior OS. In conclusion intensified conditioning for HDT had an intolerable high treatment-related mortality and did not improve EFS and OS in patients with multiple myeloma.

Bendamustine, Bortezomib and Dexamethasone (BBD) As First-Line Treatment of Patients with Multiple Myeloma Who Are Not Candidates for High Dose Chemotherapy: Toxicity Comparison of Two Dose Schedules

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4047-4047 ◽  
Author(s):  
Jesus G. Berdeja ◽  
Michael R. Savona ◽  
James Essell ◽  
Patrick Murphy ◽  
Luis Chu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Herpes Zoster ◽  
Research Funding ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Off Label Use ◽  
First Line ◽  
Off Label ◽  
Grade 3

Abstract Abstract 4047 Background: Despite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in patients (pts) who are ineligible for high dose chemotherapy. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as a single agent and in various combinations for the treatment of relapsed/refractory MM (Poenisch et al, 2007, Fenk et al, 2007). In this study, the combination of bendamustine, bortezomib and dexamethasone (BBD) was evaluated as a first-line therapy for patients with MM. Methods: Patients with newly diagnosed active multiple myeloma who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. The original treatment schema (schema A) consisted of: bendamustine 80 mg/m2 IV on days 1, 4; bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11; and dexamethasone 40 mg on days 1, 2, 3, 4 with cycles repeating every 28 days. Patients had the option to continue on maintenance bortezomib. An interim analysis found this combination to be efficacious but relatively toxic. As a result the treatment schema was amended to the following (schema B): bendamustine 80 mg/m2 IV on days 1, 2; bortezomib 1.3 mg/m2 IV on days 1, 8, 15; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Again, patients had the option to continue maintenance bortezamib. Acyclovir or equivalent viral prophylaxis was recommended on schema A and became required on schema B. Responses were assessed using the IMWG criteria. AEs were assessed using the CTCAE Version 4.0. We report the results of an interim safety assessment of the amended BBD combination and compare the results to those seen with the original regimen. Results: Treatment schema A accrued 18 patients between 5/2010 and 2/2011. Ten patients were accrued from 10/2011 and 4/2012 and treated on treatment schema B. The median ages of treatment schemas A and B were 75 and 72.5 respectively, with all other characteristics within expected distributions and no major differences between the groups. No grades 4 hematologic Adverse Events (AEs) were seen. Grade 3 hematologic AEs were similar in both arms seen in 33% of patients on treatment schema A and 40% of patients on treatment schema B. Grade 3/4 non-hematologic AEs were seen in 72% of patients on treatment schema A and 60% of patients on treatment schema B. Although the preliminary Serious Adverse Events (SAEs) were similar with 39% of patients on treatment schema A compared to 30% of patients on treatment schema B, a large proportion of patients on treatment schema A (39%) were unable to complete the study due to toxicity or related issues. The incidence and severity of neuropathy and herpes zoster infections were significantly different between the two schemas. Schema A had 72% of patients with any grade neuropathy, with 56% being grade 2 or worse while schema B had 40% of the patients with any grade neuropathy, all but one grade 1. Likewise, 44% of patients on the original treatment reported herpes zoster while there were no cases of herpes zoster reported for patients on the revised treatment schema. Thus far, the early response rates appear similar. Schema A had an ORR of 78% (56% >vgPR) while schema B had an ORR of 90% (40% >vgPR). Conclusions: The combination of bendamustine, bortezomib and dexamethasone is feasible and efficacious in an elderly patient population. Using the revised schema, we were able to lower treatment toxicity without adversely impacting initial efficacy. Updated results will be presented at the meeting. Disclosures: Off Label Use: Off-label use of Bendamustine in the treatment of Multiple Myeloma. Chu:Millennium: Research Funding; Cephalon: Research Funding.

Multiple Myeloma Profile In Latin America: Clinical and Epidemiological Observational Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5327-5327
Author(s):  
Vania T M Hungria ◽  
Angelo Maiolino ◽  
Gracia Aparecida Martinez ◽  
Carmino A De Souza ◽  
Rosane Bittencourt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Latin America ◽  
Clinical Features ◽  
Median Overall Survival ◽  
High Dose Chemotherapy ◽  
Patterns Of Care ◽  
Disease Stage ◽  
High Dose

Abstract Introduction Little is known about the incidence and clinical features of Multiple Myeloma (MM) in Latin America. A clinical registry of Latin American (LA) patients with MM represents an opportunity to gain insight into the prevalence of the disease in this region, the patterns of care and the current treatment status in different LA countries. Objective To characterize the demographic and clinical features of patients with multiple myeloma from five LA countries (Brazil, Argentina, Chile, Mexico and Peru) and to create a LA database on MM; in addition to investigating the patterns of care for MM patients in Latin America. Patients and Methods This is an observational, non-intervention study, with a prospective evaluation of data. Eligible patients were diagnosed with multiple myeloma, between January 1, 2005, and December 31, 2007, at any one of the participating centers, regardless of disease stage or treatment modality. The follow-up period extended to at least 5 years for each patient (December 31, 2012). Results Eight hundred and seventy six patients were included. The median age was 60 years old (25-97), 53.4% male and 46.6% female. The median follow-up was 31.4 months, and the median overall survival was 57 months. The median overall survival to patients who received high-dose chemotherapy was 77 months and for patients who received conventional chemotherapy was 48 months (p<0.001). The multivariate prognostic model included patient baseline variables that were associated with mortality in the Kaplan-Meier univariate analyses. Only hypercalcemia, DSS II and III, ISS stage III andnon- high-dose chemotherapy were independent predictors of mortality. Conclusion This current study, which is the largest case series of MM patients in Latin America, recognizes the feasibility of large, collaborative, observational studies among various tertiary-care hematology centers in Latin America. Note We will present more details related to the demographic and most frequently used treatments in Latin America for newly diagnosed and relapsed patients in these LA countries. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma: long-term follow-up results

1998 ◽  
Vol 102 (2) ◽  
pp. 495-502 ◽  
Author(s):  
Dadvid Cunningham ◽  
Ray Powles ◽  
James Malpas ◽  
Noopur Raje ◽  
Sarah Milan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Randomized Trial ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Long Term Follow Up

Influence of First-Line Regimens on the Outcomes of High-Dose Chemotherapy with Autologous Hematopoietic Stem-Cell Transplantation for Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 931-931 ◽  
Author(s):  
Bimalangshu R. Dey ◽  
Benjamin Cox ◽  
A. Jo Chien ◽  
Martin Caron ◽  
Steven L. McAfee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
First Line ◽  
Conventional Chemotherapy ◽  
Hematopoietic Stem ◽  
Group 2 ◽  
Group 1

Abstract Randomized trials that incorporated high-dose chemotherapy (HDC) plus autologous hematopoietic stem-cell transplantation (Au-HSCT) into the early treatment of patients with newly diagnosed multiple myeloma demonstrated superior overall and event-free survival (EFS) in patients 65 years of age or younger, who received Au-HSCT, as compared with patients who received conventional chemotherapy. Based on these encouraging results, Au-HSCT is recommended for patients with myeloma as part of their initial treatment, and today, myeloma is the most common indication for HSCT in the world. All patients in these trials received four to six months of conventional chemotherapy prior to HDC and Au-HSCT. In practice, however, both in the community as well as in academic hospitals, patients are undergoing Au-HSCT after being treated with various first-line regimens, including chemotherapeutics, high-dose dexamethasone (HDex), immunomodulatory drugs such as thalidomide and recently, proteasome inhibitors. In this retrospective study, we examined the impact of first-line therapy on the outcomes following Au-HSCT. Our objective was to compare two treatment groups - chemotherapy versus non-chemotherapy, prior to Au-HSCT - with respect to survival after Au-HSCT. Between 1997 and 2004, 37 previously untreated evaluable patients with myeloma, received either chemotherapy (group 1, n=25; vincristine, adriamycin and dexamethasone (VAD), n=24; melphalan and prednisone (MP), n=1) or non-chemotherapy regimens (group 2, n=12; HDex, n=9; thalidomide plus HDex, n=3), then received HDC followed by cyclophosphamide plus granulocyte colony stimulating factor-mobilized HSCT. The median age of patients in group 1 was 58 (range, 44–73) years and in group 2 was 55 (range, 41–67) years; 22 patients in group 1 (88%) and 10 patients in group 2 (83%) had stage III disease; the median times from diagnosis to HSCT were 6 (range, 5–16) and 8 (range, 5–25) months, respectively, in groups 1 and 2. The rates of complete and near-complete response were 44% in group 1 and 42% in group 2; the rates of partial responses were also similar: 48% and 42% respectively. The median duration of EFS was 31 (range, 7–89) months, and the median overall survival (OS) was 55 (range, 12–98) months in group 1, as compared with group 2 where EFS and OS were 21 (range, 12–40) and 31 (range, 16–76) months, respectively. The EFS at 3 years was 44% in group 1 and 25% in group 2, and OS at 5 years was 32% in group 1 and 8% in group 2 (statistically not significant). In conclusion, patients with newly diagnosed myeloma, when treated with chemotherapy prior to Au-HSCT, may have long-term overall and EFS advantages, as compared with patients who are treated with first-line non-chemotherapy regimens. The reasons for the longer duration of response in the chemotherapy group despite similar response rates in the two groups are unknown, but may be due to more effective suppression of residual disease or non-specific damage to the marrow microenvironment, which is necessary for the growth of myeloma cells. Although, the difference in survival outcomes following Au-HSCT between the two groups did not achieve statistical significance, our results raise an important question regarding the “adequacy” of different first-line regimens prior to Au-HSCT, and therefore, justify the need for prospective randomized studies to evaluate optimal pre-AuHSCT induction therapy.

Baseline Thrombophilic Alterations and Risk of Venous Thromboembolism in 266 Multiple Myeloma Patients Primarily Treated with Thalidomide and High-Dose Dexamethasone.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3997-3997
Author(s):  
Elena Zamagni ◽  
Lelia Valdre ◽  
Michela Cini ◽  
Cristina Legnani ◽  
Patrizia Tosi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Protein C ◽  
Low Dose ◽  
Autologous Transplantation ◽  
Phase Iii ◽  
High Dose ◽  
Induction Phase ◽  
Newly Diagnosed ◽  
Dose Warfarin

Abstract Venous thromboembolism (VTE) has emerged as a major adverse event of primary induction therapy with thalidomide (thal) and dexamethasone (dex) for newly diagnosed multiple myeloma (MM). Aim of the present study was to investigate the relationship between thrombophilic alterations and the risk of VTE in 266 patients who received four months of therapy with thal (200 mg/d) and pulsed high-dose dex in preparation for double autologous transplantation. The rate of VTE in the whole group of patients was 11.6%. The risk of VTE was 26.3% (86.2% patient-years) among the first 19 patients who entered the study and did not received any prophylaxis against thrombosis. The corresponding value among the remaining 247 patients who received thromboprophylaxis with fixed low-dose (1.25 mg/d) warfarin during the four months of thal-dex therapy was 10.6% (35.5% patient-years) (P=0.04). Episodes of VTE occurred at a median of 53 days from the start of thal therapy and, with the exception of 3 patients, were observed after at least a partial response to thal-dex was documented. No VTE events were recorded during the first two months after the end of the induction phase. After VTE occurrence, the majority of patients went on with thal treatment plus full anticoagulation, without evidence of progression of thrombosis. One hundred and ninety patients were evaluated for the presence of thrombophilic alterations at baseline and at the end of thal-dex therapy. The prevalence of factor V Leiden (3.2%) or g20210A prothrombin (2.1%) polymorphism in patients with MM was similar to that observed in 183 healthy controls (3.3%, P= 0.81; 3.8%, P= 0.50, respectively). The relative risk of VTE for patients carrying one of these thrombophilic alterations was 20% compared with 9.4% for patients who lacked both of them (P= 0.58). Reduced protein C and S activities or acquired activated protein C resistance (aAPCR) were recorded at baseline in 11% and 7.4% of MM patients, respectively. Abnormal values at baseline normalized almost completely at the end of treatment. Carriers of aAPCR and/or of reduced levels of natural anticoagulants at baseline did not have a significantly higher risk of VTE compared with normal patients (15.2% vs 9.3%; P=0.49). In conclusion, no significant relationship was found between baseline thrombophilic alterations, including aAPCR, and the risk of thal-related VTE. Prophylaxis with fixed low-dose warfarin was associated with an apparent decrease in the rate of VTE in comparison with a subgroup of patients who did not receive any thromboprophylaxis. A prospective phase III study comparing low molecular weight heparin with fixed low-dose warfarin with aspirin is currently ongoing in Italy to evaluate the best prophylaxis against the risk of thal-related VTE for patients with newly diagnosed MM.

Phase 2 Clinical Trial of Oral Lenalidomide, Cyclophosphamide, and Prednisone (RCP) for Newly Diagnosed Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2882-2882 ◽  
Author(s):  
Attaya Suvannasankha ◽  
Sherif Farag ◽  
Robin A O'Bryant ◽  
Lisa L Wood ◽  
Rafat Abonour
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Treatment Protocol ◽  
Median Number ◽  
High Dose Chemotherapy ◽  
M Protein ◽  
Hematological Toxicity ◽  
High Dose ◽  
Newly Diagnosed ◽  
Intent To Treat

Abstract Abstract 2882 Poster Board II-858 Background: Effective and convenient regimen is appealing for Multiple Myeloma (MM) therapy. Lenalidomide and dexamethasone combination is highly effective in MM. However, at the FDA approved dose, dexamethasone related toxicity remains problematic. We previously reported that oral cyclophosphamide and prednisone, when combined with thalidomide, was active and well tolerated in relapsed MM (Oncologist Jan, 2007). Using the similar approach, we now explore the efficacy of all oral, dexamethasone-sparing combination of lenalidomide, cyclophosphamide and prednisone in newly diagnosed MM. Methods: The treatment protocol consisted of lenalidomide given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle, cyclophosphamide at a dose of 50 mg b.i.d. days 1–21 of a 28-day cycle, and prednisone 50 mg q.o.d. Patients also received an aspirin once daily as thromboprophylaxis. Response was defined as a decrease in serum monoclonal (M) protein by 50% or higher and a decrease in urine M protein by at least 90% or to a level less than 200 mg/24 hours. Responses were assessed on intent to treat basis. Results: Twenty-one patients were enrolled from October 2007 to July 2009. The median age was 67 years (range, 41-76). 7 patients (33%) had ISS stage II and 3 (14%) had stage III disease. The median number of cycles was 6 (range: 1 – 6). The response is not evaluable in 4 patients who are still undergoing the first cycle of therapy. Among the remaining 17 patients, the over all response rate was 94%. The best response based on intent to treat basis was 83%, including CR: 1 (6%), nCR: 1 (6%), VGPR: 3 (18%), PR: 11 (65%) and less than PR: 1 (6%). Overall, 14 of the 21 enrolled patients have discontinued study treatment. Reasons for treatment discontinuation are: completed study per protocol (10), disease progression (1), and adverse event (1) and alternate treatment (1). Hematologic toxicities were the most common with grade 3 neutropenia seen in 10 patients. Infections were seen in 10 patients (5, febrile neutropenia and 5, with normal ANC). Non hematologic toxicities were fatigue, gastrointestinal side effects, neuropathy and mood swings. Specifically, neuropathy was reported in 5 patients. All were grade I. Five patients had grade 4 metabolic abnormalities (2 renal failure attributed to dehydration and tumor lysis, 2 hyperglycemia. and 1 hypokalemia). Five patients had dose adjustments, most commonly due to hematological toxicity attributed to lenalidomide or cyclophosphamide. Seven patients had stem cell collection. In all, sufficient numbers of stem cells were collected for the transplantation use. To date, five have undergone high dose chemotherapy and stem cell transplantation. Three patients with PR on RCP achieved VGPR. Response is not yet evaluable in the 2 remaining patients. Conclusions: The combination of lenalidomide, cyclophosphamide, and prednisone (RCP) has excellent activity in the setting of newly diagnosed myeloma. Overall toxicities were manageable. Myelosuppression was a significant toxicity and attenuated with dose reductions. The study is still ongoing with the total accrual goal of up to 48 patients. The updated data for response and toxicities will be presented at the ASH Annual Meeting. Disclosures: Abonour: Celgene: Honoraria; Millennium: Honoraria.

A Phase II Trial of Combined Bendamustine, Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma (MM) Patients Who Are Not Candidates for High-Dose Chemotherapy: Results of a Planned Interim Safety Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2943-2943 ◽  
Author(s):  
Jesus G. Berdeja ◽  
Daniel R. Couriel ◽  
Patrick Murphy ◽  
Ralph V. Boccia ◽  
Victor Priego ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Interim Analysis ◽  
Sensory Neuropathy ◽  
Response Rates ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Grade 3

Abstract Abstract 2943 Background Despite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in patients (pts) who are ineligible for high dose chemotherapy. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as single agent and in combination with steroids, thalidomide and bortezomib for the treatment of MM. Pönisch et al reported an overall response of 61% and CR of 15% in pts with relapsed/refractory MM using the combination of bendamustine, bortezomib and prednisone. In this study, the combination of bendamustine, bortezomib and dexamethasone (BVD) was tested for efficacy and safety in newly diagnosed pts with active MM who are not candidates for high-dose chemotherapy. Methods Patients with newly diagnosed active multiple myeloma who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. Pts were treated with bendamustine 80 mg/m2 on days 1, 4, bortezomib 1.3 mg/m2 on days 1, 4, 8, 11 and dexamethasone 40 mg on days 1, 2, 3, 4 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Responses were assessed using the IMWG criteria. We report on the preliminary efficacy and safety results of a planned interim analysis of the BVD combination. Results Between May 2010 and February 2011, 18 pts were enrolled, all evaluable for toxicity. The median age was 75 (range 56–82); nine (50%) pts were DS stage III; seven (39%) pts had a B2M ≥ 5mg/L. Cytogenetics and FISH analysis for 13 del, t4;14, t14;16, and 17p del were available for all but 1 pt; 8 (44%) pts had at least 1 chromosomal abnormality, while 9 (50%) pts had none. At the time of data cut off, pts completed a median of 5.5 cycles (range 1–8); with 11 (61 %) receiving at least 4 cycles; and 5 (28%) receiving 8 cycles. Seven (39%) pts remain on study and 10 have discontinued therapy (1 disease progression and 3 deaths on study [2 cardiac arrest, 1 pulmonary emboli; all 3 determined to be unrelated to treatment], 1 MD discretion, 1 non-compliance, 1 pt request, 2 poor tolerance, 1 intercurrent illness) and 1 completed treatment. The most common grade 3/4 adverse events, occurring in more than 10% of pts, were leucopenia (17%), neutropenia (11%), myalgia (17%) and sensory neuropathy (11%). Twelve pts had treatment emergent sensory neuropathy: 5 (28%) grade 1, 5 (28%) grade 2 and 2 (11%) grade 3. Of the 17 patients evaluable for response, 15 had at least a PR for an ORR of 88% (9 (53%) VGPR, 6 (35%) PR, 2 (12%) SD). The presence of cytogenetic abnormalities did not seem to have a strong impact on response rates, with 88% of pts with 1 or more abnormalities responding compared to 88% with none. The median time to best response was 9 weeks. Conclusions In this planned interim analysis, the combination of BVD produced a high ORR, however the current schedule is relatively toxic in this pt population. The majority of the non-hematological toxicities appear to be related to bortezomib and dexamethasone. For this reason, the protocol was amended where bortezomib and dexamethasone are now dosed weekly (days 1, 8, and 15). The amended trial is currently accruing. Disclosures: Off Label Use: Bendamustine in myeloma. Flinn:Cephalon and Millenium: Research Funding.

Lenalidomide and Dexamethasone Alone Is Equivalent To Lenalidomide and Dexamethasone With Autologous Stem Cell Transplant In Newly Diagnosed Multiple Myeloma: Interim Study Results Of a Randomized Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3180-3180 ◽  
Author(s):  
Jordan M. Schecter ◽  
Kristen Kipps ◽  
Amy O'Sullivan ◽  
Kent A. Griffith ◽  
Daniel Normolle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Interim Analysis ◽  
Research Funding ◽  
Low Dose ◽  
Secondary Malignancy ◽  
Similar Response ◽  
Newly Diagnosed

Abstract The current standard of care for patients with newly diagnosed multiple myeloma (MM) aged less than 65 years is high-dose chemotherapy combined with autologous stem cell transplantation (ASCT) based on improved progression free survival (PFS) and overall survival (OS) compared with conventional chemotherapy. The introduction of novel agents, for example lenalidomide and bortezomib over the last decade, has substantially improved MM outcomes providing similar response rates to ASCT. As a consequence, the role of upfront ASCT has become more controversial. Therefore, this randomized clinical trial aims to determine the role of upfront ASCT in patients with newly diagnosed MM patients receiving lenalidomide and low-dose dexamethasone as induction therapy. Patients enrolled into the study were aged ≥18 years with newly diagnosed MM, transplant eligible, and meeting CRAB criteria. Patients were randomized to receive 4 cycles of lenalidomide (25 mg days 1–21) plus low-dose dexamethasone (40 mg days 1, 8, 15, 22) followed by ASCT conditioned with 200 mg/m2 melphalan (Arm A; LD+ASCT) or 8 cycles of lenalidomide plus low-dose dexamethasone (Arm B; LD alone). Both groups received lenalidomide maintenance therapy 10-15 mg for up to 2 years. Patients in both treatment arms received stem cell collection after 4 cycles of lenalidomide plus dexamethasone if at least a partial response was achieved. Patients with stable disease or progressive disease (PD) went off study. The primary objective was to compare the best response between patients treated with lenalidomide plus dexamethasone followed by ASCT and patients treated with lenalidomide plus dexamethasone alone. Secondary objectives were to compare the duration of response (DOR), PFS, and OS between the two treatment arms and to evaluate the secondary malignancies in both arms. Fifty patients with newly diagnosed MM were randomized between February 2008 and May 2013, and 47 patients were eligible for evaluation in this interim analysis; 25 patients randomized to Arm A (LD+ASCT) and 22 patients randomized to Arm B (LD alone). Overall, patients had a median age of 61.6 years (range 48–75), 60% were male, 34% ISS Stage I, 49% ISS Stage II, 17% ISS Stage III. The data were analyzed according to the IMWG response criteria (Blood. 2011 May 5;117(18):4691-5). In an intention-to-treat analysis, there was a trend towards improved overall response rate (ORR) in patients receiving LD+ASCT (96%) compared with patients receiving LD alone (77%; p=0.08) (Table 1). After a median follow-up of 36.8 months (range 1.1–62.7), the median DOR was 13.9 months (95% confidence interval [CI] 4.0–34.1) in the LD+ASCT group compared with 21.2 months (95% CI 11.0–22.9) in the LD group. Overall, 18 patients have PD (10 patients in the LD+ASCT arm and 8 patients in LD arm), and 8 patients have died (4 patents in the LD+ASCT arm and 4 patients in the LD arm). Median PFS for LD+ASCT versus LD was 17.0 months (95% CI 15.5–not estimable) versus 25.2 months (95% CI 9.0–not estimable; p=0.94). Median OS for LD+ASCT versus LD was 57.6 months (95% CI 48.0–not estimable) versus not reached (p=0.94). Two patients in the LD alone arm developed a secondary malignancy, including 1 patient with myelodysplastic syndrome (MDS) 13 months after the start of therapy. This interim analysis of an ongoing randomized clinical study comparing lenalidomide plus low-dose dexamethasone induction with and without upfront ASCT in patients with newly diagnosed MM suggests that addition of ASCT resulted in a trend towards improved ORR. This did not result in a significant difference in terms of PFS or OS between the two treatment arms. In contrast there was a trend of better DOR in the LD alone arm. The data show that LD alone can achieve similar results as LD+ASCT, however careful interpretation is required due to the low patient number and relatively short follow-up. The incidence of secondary malignancy was low, including the development of 1 MDS. Disclosures: Schecter: Celgene: Honoraria, Speakers Bureau. Mapara:Celgene: Research Funding, RO1 Other. Lentzsch:Celgene: Research Funding.

A Phase 2 Study of High-Dose Melphalan Plus Bortezomib (Mel/Vel) Conditioning Followed By Autologous Hematopoietic Cell Transplantation in Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3987-3987
Author(s):  
Taiga Nishihori ◽  
Jose L Ochoa-Bayona ◽  
Rachid Baz ◽  
Kenneth H. Shain ◽  
Christine Simonelli ◽  
...  
Keyword(s):  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
High Dose ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Autologous Hct ◽  
High Dose Melphalan ◽  
Autologous Hematopoietic Cell Transplantation

Abstract Background: High-dose melphalan followed by autologous hematopoietic cell transplantation (HCT) remains the integral component of multiple myeloma (MM) therapy in the era of novel agents. We published our prior study with the use of high-dose melphalan + bortezomib (Mel/Vel) conditioning regimen for tandem transplants in refractory MM patients (Nishihori, et al. Br J Haematol 2012). We designed a phase 2 trial using MelVel conditioning followed by autologous HCT in patients with newly diagnosed chemosensitive MM (NCT 00948922). Methods: Sixty seven newly diagnosed MM patients who achieved ≥ partial response (PR) to induction therapy with ≤grade 1 peripheral neuropathy (PN) were enrolled from 12/2009 to 06/2014. Patients received high-dose melphalan at 100 mg/m2 IV for 2 days, immediately followed by 1 dose of bortezomib at 1.3 mg/m2 (Mel/Vel conditioning). Maintenance therapy was not prescribed by design. The protocol later was modified to include maintenance bortezomib subcutaneously (started at 3 months after HCT) at 1.3 mg/m2 weekly x4, every 8 weeks, for a total of 6 cycles. Progression-free and overall survival (PFS and OS) estimates were calculated using Kaplan-Meier method. Results: A total of 67 patients received autologous HCT. The median age was 58 (25 - 73) years with the following disease characteristics: Durie-Salmon stage, 3A (72%) and 3B (10%); IgG (55%), IgA (21%), IgD (1%), and light chain (22%). High-risk cytogenetics/FISH were seen in 28% of patients. The median beta-2 microglobulin was 3.3 (range, 1.3 – 34.8). Induction regimens were bortezomib-based in 39%, lenalidomide-based in 19% and, both bortezomib and lenalidomide in 42%. Median time from initiation of induction to HCT was 204 days (range, 101 - 664). Responses prior to HCT were stringent CR (sCR) 21%, CR 12%, very good partial response (VGPR) 34%, and PR 33%. Neutrophil engraftment was achieved after a median of 11 days (range, 10 – 14) and platelet engraftment occurred after a median of 15 days (range, 11 – 22). Median CD34 cell dose was 3.8 x 106/kg (range, 2 – 20.08). Responses at 3 months after HCT (in 64 evaluable patients) were sCR 47%, CR 14%, VGPR 20%, PR 16% and progressive disease 3%. Bortezomib maintenance was prescribed to 31 patients (46%). Prevalence of grade 1 PN before (n=67) and at 3 months (n=64) after HCT were 37% and 38%, respectively. Two patients withdrew consent to initiate maintenance and 1 patient was unable to initiate maintenance due to grade 1 PN (baseline PN of 0). At the time of review, a median number of maintenance delivered was 4 (range, 1-6) and only one patient required dose reduction. The 2-year PFS and OS estimates are 62% (95% CI 0.47 – 0.75) and 90% (95% CI 0.80 – 0.97) with a median follow-up of 21 months (range, 2 – 54). The 1-year PFS estimates were 85% (95% CI 0.65 – 0.97) for bortezomib maintenance vs. 81% (95% CI 0.66 – 0.92) for no maintenance (p=0.6). There were no significant differences in PFS or OS stratified by cytogenetic/FISH risk status. There was no transplant related mortality. Conclusions: The combination of bortezomib and high-dose melphalan (Mel/Vel) as conditioning regimen for autologous HCT is well tolerated and appears to improve responses after HCT. Weekly x4 post HCT bortezomib maintenance given every 8 weeks appears to be well tolerated and is a promising strategy for eligible patients. Longer follow up is required to assess the benefit of post HCT maintenance strategy. Disclosures Baz: Millennium: Research Funding. Alsina:Millennium: Consultancy, Research Funding.

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