CR As Major End-Point After Consolidation for Multiple Myeloma Patients Eligible to High Dose Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1858-1858
Author(s):  
Benjamin Hebraud ◽  
Murielle Roussel ◽  
Gaelle Dörr ◽  
Anne Huynh ◽  
Jill Corre ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Residual Disease ◽  
Progression Free Survival ◽  
High Dose ◽  
Consolidation Therapy ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
End Point ◽  
Depth Of Response ◽  
Almost All

Abstract Abstract 1858 Introduction: High dose therapy (HDT) with autologous stem cell transplantation (ASCT) is a standard treatment option for eligible frontline myeloma patients (pts). However, almost all patients ultimately relapse. Thus, new strategies are required to control the residual disease after HDT. Consolidation therapy, given early after HDT, could enhance the depth of response and further improve progression free survival (PFS) and overall survival (OS). We previously reported that either Thalidomide or Lenalidomide given after HDT was able to reduce this residual disease (IFM 99-02 and 2005-02 trials). During last EHA meeting (abstract #510)., Cavo M et al., updated results of their recently published phase 3 trial. Consolidation by Bortezomib-Thalidomide-Dexamethasone (VTD) after VTD induction and double ASCT improved response in 31 % of pts and 61 % of them achieved CR. This translated into a gain of PFS (62 % at 3 years) and a reduction of the relative risk of progression or death of 36 %. The aim of this study was to evaluate the efficacy of early consolidation therapy and its impact on PFS. Patients and Methods: In this prospective monocenter study, pts were eligible to receive early consolidation if they had the following: 1) at least partial response (PR) after HD melphalan (HDM), 2) no grade ≥ 2 peripheral neuropathy (PNY). The consolidation regimen was: vTD 61%, Lenalidomide 23%, Lenalidomide plus Dexamethasone 13% and Bortezomib-Lenalidomide-Dexamethasone (VRD) 3%. Consolidation had to be started within 3 months from HDM with no following maintenance. Response was assessed according to International Myeloma Working Group uniform response criteria 1 month after the last cycle of consolidation. The duration of PFS was calculated for all patients from time to HDT to time of progression, relapse, death from any cause or to last contact. PFS was analysed using Kaplan-Meier curves. Results: From February 2007 to December 2010, 100 frontline MM pts under 65 received HDM followed by ASCT. Seventy six pts were eligible for consolidation (conso group), 24 pts were not (no conso group). After HDT, response rates were: VGPR=29%, and CR=71% in the no conso group, vs PR=20%, VGPR=55%, and CR=25% in the conso group (p<0.001). Early consolidation upgraded response in 17% of pts with PR=11%, VGPR=49%, and CR=36%. Three pts had progressive disease after or during consolidation. Median follow up is similar for the 2 groups (20 months). Maybe due to unbalanced response repartition, there was no impact of consolidation on PFS (median 25 mos in the 2 groups). Nevertheless, estimated median PFS was not reached in pts achieving CR after consolidation vs 27 mos in pts in CR after HDT in the no conso group (ns). If we focus on response after consolidation, estimated median PFS was not reached in CR pts versus 20 mos in PR pts, and 21 mos in VGPR pts (p=·006; figure 1), irrespective of post HDT status (already in CR or not). Moreover, if we compare pts in VGPR after ASCT (42) we observe two groups: those who upgrade their response to CR (19%) and those who stay in VGPR. The first group achieve the same PFS than patients in CR post ASCT and staying in CR after consolidation (28 mos). Interestingly, those pts (pts upgrading their response) present a longer PFS than those staying in VGPR post consolidation 28 mos versus 20 mos (p=0,032). Conclusion: Our data suggest that achieving CR after consolidation therapy is a major end-point to improve PFS, maybe even in pts already in CR after HDT. So we could propose to treat pts with consolidation until they obtain CR, they achieve a plateau or they present toxicities. Disclosures: No relevant conflicts of interest to declare.

Maintenance Therapy for Myeloma: How Much, How Long, and at What Cost?

2012 ◽  
pp. 515-522 ◽  
Author(s):  
Michel Attal ◽  
Murielle Roussel
Keyword(s):  
Multiple Myeloma ◽  
Maintenance Therapy ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Second Primary ◽  
High Dose ◽  
High Dose Therapy ◽  
Dose Therapy

Overview: Maintenance therapy in multiple myeloma has been under investigation for more than 3 decades and has been without evidence of clear advantage in terms of progression-free survival (PFS) until the mid-2000s. Neither conventional chemotherapy, prednisone, nor interferon-based maintenance regimens offered any benefit after conventional or high-dose therapy. Thalidomide was the first drug, mainly given as maintenance after high dose therapy, to demonstrate clinical benefits in terms of PFS and, in some studies, of overall survival (OS). The role of other novel agents such as lenalidomide and bortezomib as maintenance therapy is emerging. Lenalidomide has been shown to reduce the risk of relapse with longer follow-up needed to see if this will translate into a survival benefit. At present, a number of key questions remain unanswered. What are the optimal dose and duration of those treatments? Is the risk of toxicity and second primary malignancies acceptable? Will the disease be more aggressive at time of relapse? Is the clinical benefit predicted by initial prognostic factors and response to previous therapy? Does maintenance therapy work by further eradication of minimal residual disease or by immunological control of the malignant clone? Ongoing randomized trials are evaluating lenalidomide and bortezomib, both in the transplant and nontransplant settings, to better define the role of these drugs as maintenance in multiple myeloma.

Autotransplants for Multiple Myeloma (MM) – An Update of the Arkansas Experience Since 1989 In Almost 4000 Patients with Special Emphasis on Third and Further Transplants.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1352-1352
Author(s):  
Bijay Nair ◽  
Elias J. Anaissie ◽  
Sarah Waheed ◽  
Yazan Alsayed ◽  
Rachael Sexton ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Outcome Data ◽  
Hematopoietic Progenitor Cell ◽  
High Dose ◽  
Front Line ◽  
High Dose Therapy ◽  
Free Survival ◽  
Treatment Groups ◽  
Dose Therapy ◽  
Previously Treated

Abstract Abstract 1352 Background: The Arkansas program has emphasized high hematopoietic progenitor cell (HPC) yields since its inception in 1989, in order to enable further high-dose therapy for relapse, rescue patients from hematopoietic compromise due to extensive cumulative genotoxic or novel agent dosing, and provide a fall-back option in the case MDS develops. Here we are examining the overall outcome data among 3888 patients undergoing HPC-supported therapy since 1989. Patients and Methods: Patients were grouped according to whether they received front-line Total Therapy (TT) protocols (TT-P, n=1452), non-TT protocols for previously treated MM (non-TT-P, n= 1155) or non-protocol therapies (non-P, n=1281). Overall survival (OS) and event free survival (EFS) were measured from the 1st high-dose therapy (Tx-1) intervention and examined in the context of baseline variables present prior to Tx-1, the aforementioned 3 treatment groups, and intervals between successive Tx interventions. Results: OS/EFS from Tx-1 was longest with TT-P (5-yr estimates, 67%/52%) followed by non-TT-P (5-yr estimates, 43%/30%) and non-P (5-yr estimates, 36%/27%) (p<0.0001, p<0.0001). Among all 3888 patients, 2773 (71%) received Tx-2 including 2385 (86%) within 6 months of Tx-1; 405 (10%) received Tx-3 including 140 (35%) within 2yr of Tx-2; 58 (1.5%) received Tx-4 including 44 (76%) within 2yr form Tx-3; 12 (0.3%) received Tx-5 all within 2yr from Tx-4; and 3 patients had Tx-6. When examined in the context of the 3 different treatment groups, 1157/1231 (94%) of the TT-P group had Tx-2 within 6mo, 51/169 (30%) had Tx-3 within 2yr of Tx-2, 51/169 (30%) had Tx-4 within 2yr of Tx-3, and 7/7 (100%) had a Tx-5 within 2 yr of Tx-4. Among 1155 non-TT-P patients, 646/822 (79%) had Tx-2 within 6mo of Tx-1, 37/129 (29%) had Tx-3 within 2yr of Tx-2, 14/18 (78%) had Tx-4 within 3yr of Tx-3, and all 4 (100%) receiving Tx-5 had done so within 2yr of Tx-4. Among 1281 non-P patients, 582/720 (81%) had received Tx-2 within 6mo of Tx-1, 52/107 (49%) had received Tx-3 within 2yr of Tx-2, 7/10 (70%) had received Tx-4 within 2yr of Tx-3, and 1 patient received Tx-5 within 2yr of Tx-4. KM plots from Tx-3 were similar among the 3 treatment groups with median OS of 16mo for TT-P, 14mo for non-TT-P and 11mo for non-P (p=0.13); median EFS were 7, 8, and 6 months (P=0.17). Timely application within 6mo resulted in superior OS and EFS from Tx-2 (OS: 79 v 23 months, EFS: 48 v 14 months; both P<0.0001). Multivariate Cox analyses examining post-Tx EFS and OS revealed TT-P superiority from Tx-1 and Tx-2 over non-TT-P and non-P; Tx-2 within 6mo of Tx-1 provided superior post-Tx-2 EFS and OS; while benefit from Tx-3 was not apparent until at least 2yr had elapsed since Tx-2. CA within 1 year of Tx-1 adversely affected EFS and OS from Tx-1, Tx-2 and Tx-3. Other adverse baseline parameters included low albumin for EFS and OS post-Tx-1; and B2M >=3.5mg/L for EFS and OS post-Tx-1 and post-Tx-2. Conclusions: We confirm that front-line TT-P provides superior clinical outcomes in comparison with back-up/salvage non-TT-P and non-P Tx, emphasizing the benefit from planned upfront protocol therapy. Timely application of Tx-2 within 6 months of Tx-1 extended both EFS and OS from Tx-2, validating our concept of maximum tumor cyto-reduction and avoiding MM re-growth. Tx-3 was useful when applied beyond 2yr from Tx-2, in support of the notion that longer disease control prior to relapse favorably impacts subsequent salvage Tx. Disclosures: No relevant conflicts of interest to declare.

Adding The KIT Inhibitor Dasatinib (DAS) To Standard Induction and Consolidation Therapy For Newly Diagnosed Patients (pts) With Core Binding Factor (CBF) Acute Myeloid Leukemia (AML): Initial Results Of The CALGB 10801 (Alliance) Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 357-357 ◽  
Author(s):  
Guido Marcucci ◽  
Susan Geyer ◽  
John Zhao ◽  
Andrew J Caroll ◽  
Donna Bucci ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Rapid Screening ◽  
Induction Treatment ◽  
High Dose ◽  
Protein Chain ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Early Results

Abstract Among the prognostic cytogenetic and molecular aberrations in AML, t(8;21)(q22;q22) and inv(16)(p13q22) and their corresponding molecular rearrangements RUNX1/RUNX1T1 and CBFB/MYH11 (each involving a gene encoding a protein chain of the key transctiption factor CBF), predict for a favorable outcome in pts receiving consolidation with high-dose cytarabine (HiDAC) after achievement of complete remission (CR). However, approximately 40% of these pts eventually relapse. Approximately 25% of CBF AML pts carry gain-of function mutations in the KIT gene. These mutations result in a constitutively active tyrosine kinase (TK) that contributes to aggressive leukemia growth, and is associated with unfavorable outcome. In addition, CBF AML pts with wild type KIT overexpress this protein, and this is also associated with an inferior outcome. Therefore, inhibiting KIT with DAS is a rational therapeutic strategy in CBF AML. We report here on a phase II trial that combined DAS with standard chemotherapy for CBF AML. Enrollment required molecular confirmation of CBF AML by the Alliance Molecular Pathology central lab using RT-PCR and Sanger sequencing-based assays. Overall, 779 patients were screened for CBF; 69 were found to be CBF-positive and 61 were subsequently enrolled. Newly diagnosed RUNX1/RUNX1T1 or CBFB/MYH11-positive pts received induction chemotherapy with cytarabine (C) 200 mg/m2/day continuous intravenous (IV) infusion on days 1-7, daunorubicin (DNR) 60 mg/m2/d IV bolus on days 1-3 and DAS 100 mg/d PO on days 8-21. Pts with residual disease (>5% blasts) on day 21 after first induction received a re-induction treatment with same doses of C on days 1-5, DNR on days 1-3 and DAS on days 6-19. Pts who achieved CR received consolidation therapy with HiDAC 3000 mg/m2 over 3 hours (if <60 yrs old) or 1000 m/m2 (if older) q12h on days 1,3,5 and DAS 100 mg/d PO on days 6-26 x 4 courses. Pts who remained in CR after consolidation treatments received continuation treatment with DAS 100mg/d PO x 12 months. The primary goal of this study was to insure that the CR rate and survival during induction were not inferior to historical outcomes. Between April 2011 and January 2013, we completed the planned accrual of 61 adult CBF AML pts. Median age was 51 years (yrs; range: 19.6 to 85 yrs), and 15 pts (24%) were older (>60 yrs). Half of pts were male (51%) and a majority were Caucasian (75%). Of all 61 pts, 65% were CBFB/MYH11-positive and 35% were RUNX1/RUNX1T1-positive. Treatment was started on average 4 days from molecular diagnosis (range: 0 to 11 days). To date, 51% of pts are still undergoing treatment; 4 pts died on treatment (2 older), 7 (4 older) had an adverse event requiring treatment interruption, and 6 refused to complete the treatment (mainly the continuation component). Observed toxicities were those expected with C and DNR (hematologic and non-hematologic) and with DAS (nausea, liver toxicity). 55 pts are currently evaluable for treatment-related toxicity. The most common grade 4 toxicities were sepsis (5), acute kidney injury (3), and respiratory failure (3). Grade 5 toxicities included respiratory failure (1) and sepsis (2). Two of these pts died during induction (respiratory failure, sepsis); both were older and CBFB/MYH11. One pt died from sepsis during consolidation in CR (CBFB/MYH11, 48 yrs). The 30-day survival rate was 97% (95% CI: 89% to 99.6%) overall (98% in younger and 93% in older pts). Of 59 pts currently evaluable for response, 54 (92% of all pts; 96% younger and 80% older) achieved CR. Of the 5 patients who failed to achieve CR, 2 had RUNX1/RUNX1T1 and 3 had CBFB/MYH11. Among the 54 CR pts, no younger pt has relapsed, while 2 older pts with CBFB/MYH11 have relapsed. The median follow-up (f/u) was 11.2 months (range: 1.2 to 23.2 mos.). The 1-yr DFS and OS rates were respectively 90% and 87% for all pts; 97% and 95% for younger pts, and 63% and 62% for older pts, respectively. Early results from this study show that 1) rapid screening for CBF AML is feasible within a cooperative group, 2) DAS plus chemotherapy in CBF AML pts is tolerable including in older pts, and 3) the initial clinical outcomes are at least comparable to those historically observed in this patient population. Patients continue to be followed for survival endpoints. Molecular characterization for KIT mutations and expression levels of marrow and blood blasts is ongoing and will be correlated with toxicity and clinical outcome. Disclosures: No relevant conflicts of interest to declare.

Minimal residual disease (MRD) status pre- and post- high-dose therapy/autologous stem (HDC/ASCT) cell transplantation for multiple myeloma (MM) in the era of novel agents.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8605-8605
Author(s):  
Adetola Kassim ◽  
Jeremy Scott McDuffie ◽  
Claudio A Mosse ◽  
Bipin N. Savani ◽  
John P. Greer ◽  
...  
Keyword(s):  
Residual Disease ◽  
Prognostic Significance ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Novel Agents ◽  
Disease Stage ◽  
High Dose ◽  
Free Survival ◽  
Depth Of Response ◽  
The Impact

8605 Background: MRD assayed by multi-parameter flow cytometer (MFC), has prognostic significance after HDT/ASCT for MM (Paiva et. al. 2008). The frequency of MRD negativity (-) after induction therapy using novel agents such as immunomodulatory drugs like lenalidomide (IMiDs), and proteasome inhibitors like bortezomib, is unknown. The impact of HDT/ASCT on MRD status in this patient group has not been studied. Methods: We performed a retrospective study of all MM patients undergoing HDT/ASCT (January 2010 - December 2012) in our institution. No restrictions on inclusion were made based on the International Myeloma Working Group response criteria. All patients had novel agents as part of their initial induction regimen. Statistical analysis was by SPSS software (V 12.0). MRD status was determined by MFC on bone marrow samples pre- HDC/ASCT [M1] and post- HDC/ASCT (D100 [M2] and I year [M3]). MFC was done with antibodies against CD45, CD19, CD138, CD38, CD20, CD56, and anti-k and l cytoplasmic antibodies. Results: MRD status was available on 91 patients pre-transplant. Of these patients, 80 had MFC recorded at M2 and 17 patients had MFC recorded at M3. Fifty-eight percent were male and 76% were Caucasian. Forty percent received IMiDs, while 60% got proteasome based therapies. Of the 91 patients with MRD pre-HDC/ASCT, 58% (53/91) were MRD (-), and of these patients 89% (41/46) remained MRD (-) at M2. 48 patients were MRD positive (+) pre-HDC/ASCT, 58% (20/34) became MRD (-) at M2. Age, cytogenetic risk, disease stage, number of chemotherapy cycles or immunofixation status had no impact on MRD status. There were only 6 relapses in the cohort, thus the impact of MRD status on progression-free survival could not be studied. Conclusions: Novel agents improve depth of response pre-transplant. HDC/ASCT increases MRD negativity post-transplant. MRD status could aid better timing of HDC/ASCT or adoption of a risk-adapted strategy for high-risk patients. MRD status validation in a prospective cohort is underway at our center (NCT01215344). With future follow-up, the impact of MRD on progression-free survival in the era of novel agents will be determined.

GDP (Gemcitabine, Dexamethasone, Cisplatin) Salvage Therapy Results in Superior Progression Free Survival Compared to Mini-Beam Prior to Autologous Stem Cell Transplantation for Relapsed or Refractory Hodgkin’s Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 905-905 ◽  
Author(s):  
John Kuruvilla ◽  
Tracy Nagy ◽  
Melania Pintilie ◽  
Armand Keating ◽  
Michael Crump
Keyword(s):  
Stem Cell ◽  
Salvage Therapy ◽  
Progression Free Survival ◽  
Salvage Chemotherapy ◽  
Hodgkin's Lymphoma ◽  
High Dose ◽  
High Dose Therapy ◽  
Free Survival ◽  
Dose Therapy ◽  
Cd34 Cells

Abstract Objectives: To compare the response rates and early progression free survival (PFS) after high-dose therapy and autologous stem cell support (ASCT), following salvage chemotherapy with either GDP (gemcitabine 1000 mg/m2 IV d1 & 8, dexamethasone 40 mg PO d1-4, cisplatin 75 mg/m2 day 1) q 3 weeks or mini-BEAM (MB: BCNU, etoposide, cytarabine, melphalan) q3-4 weeks in patients (pts) with relapsed or refractory Hodgkin’s lymphoma. Material and methods: Sixty-eight consecutive pts referred for salvage therapy (34 MB, 34 GDP) were retrospectively compared. All had received prior ABVD chemotherapy except for 3 GDP pts (one received MOPP, one Stanford V, one MOPP/ABV). MB administration required admission to hospital wherease GDP was given in the outpatient setting. Pts typically received 2 cycles of salvage therapy; responding patients had PBSCs mobilized with cyclophosphamide 2 g/m2 day 1, etoposide 200 mg/m2 days 1–3 and filgrastim 10μg/kg. PBSC collection commenced when the blood CD34 cell count was >5–10/μL. Target PBSC number was ≥5 x 106 CD34+ cells/kg and a minimum threshold of 2 x 106 CD34+ cells/kg was required to proceed to high dose therapy (etoposide 60 mg/kg day −4, melphalan160 mg/m2 day −3; PBSC infusion day 0). Pts with bulk disease at relapse > 5cm received involved field radiation (RT) post-ASCT (7/30 GDP pts and 7/28 MB pts). Results: The MB and GDP groups were similar in stage at relapse (limited stage 38% in each group) and disease status (primary refractory: MB 47%, GDP 53%). Ps receiving GDP were older (mean age 43y, range 19–64, vs. MB: mean 34, range 19–60), while more MB pts had previous RT (48% vs. 24%, p=0.03). There were slightly more male pts that received MB versus GDP (M:F MB 24:10, GDP 17:17). The response rate to GDP prior to ASCT (CR, CRu or PR) was 62% (95% CI: 45%–78%) vs. 68% for MB (95% CI: 52%–83%, p=0.61). Nine and 5 pts had stable disease, and 4 and 6 pts progressed on GDP and MB, respectively. 30/34 pts receiving GDP and 28/34 MB pts proceeded to PBSC mobilization. The proportion of pts who had PBSC collections > 2 x 106 CD34+ cells/kg was 97% after GDP vs. 82% after MB (p=0.07), and the proportion collected in a single apheresis procedure was 90% vs 57% (p=0.0043). The proportion of pts who reached the PBSC target of ≥ 5 x 106 CD34+ cells/kg was 97% after GDP and 57% after MB (p=0.0003), and was obtained in a single apheresis more often after GDP (73% vs 36%, p=0.004). Bone marrow harvest was needed in 1 GDP pt (3%) and 5 MB pts (18%, p=0.07). After a median follow up of 1.8 yrs post ASCT for all pts (GDP: 1.2 yrs, range 0.3 – 2.8 yrs; MB: 3 years, range 1.2 – 4.6 yrs), PFS is significantly better for pts receiving GDP compared to MB (74% vs. 35% at 1.5 years, p=0.005). Overall survival at 1.5 yrs is 91% for GDP pts and 82% for MB (p=0.23). Conclusions: Although this is a retrospective analysis, response to and early PFS post-ASCT after GDP compares favourably to MB salvage chemotherapy, our previous standard. Pts receiving GDP have higher PBSC yields, are more likely to have an optimal collection after a single leukapheresis and less likely to experience mobilization failure than pts receiving MB salvage. Based on these data, a phase III trial comparing GDP to MB or dexa-BEAM is warranted.

High-Dose Therapy Followed by Autologous HSCT in Patients with Multiple Myeloma. Results of a Retrospective Multicenter Analysis Conducted by The Polish Myeloma Group.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5108-5108
Author(s):  
Wanda M. Knopinska-Posluszny ◽  
Andrzej Hellmann ◽  
Michal Taszner ◽  
Anna Dmoszynska ◽  
Wiktor Jedrzejczak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progenitor Cells ◽  
Bone Structure ◽  
Bone Marrow Involvement ◽  
Progression Free Survival ◽  
Albumin Level ◽  
New Drugs ◽  
High Dose ◽  
High Dose Therapy ◽  
Dose Therapy

Abstract In recent years high-dose therapy with autoHSCT has become the treatment of choice for eligible patients with multiple myeloma. This disease is now one of the most common indications for autotransplantation. The aim of this study was the clinical assessment of patients who underwent autotransplantation of progenitor cells and an analysis of the results of conducted treatment. The Polish Myeloma Group collected results of auto HSCT from 12 transplantology centres in Poland conducted between 1995 and 2006. We analyzed retrospectively the prognostic influence of pre-transplant characteristics on response and survival in 498 patients. Virtually all the patients received peripheral blood stem cell support after conditioning with melphalan (95%). We evaluated the influence of age, type of myeloma, Durie-Salmon stage, presence of renal impairment, plasma cell infiltration, albumin and b2 microglobulin level at diagnosis, status prior to and post HSCT, time from diagnosis to HSCT on overall survival (OS) and progression-free survival (PFS) to define patients with better prognosis. 232 females and 266 males underwent auto HSCT, and these included 297 (59,6%) with IgG, 97 (19,5%) with IgA, 31 (6%) with B-J, 22 (4,4%) with non-secretory myeloma. Bone structure changes were ascertained in 355 patients (71%). Bone marrow involvement higher than 20% was found in 282 patients (56,6%) at diagnosis. A decreased level of albumin (<35g/l) was determined in 168 patients (33,7%), and b2microglobuline level above 3,5 mg/l in 124 patients (24,9%). Transplantation of progenitor cells was conducted as consolidation of first line treatment following chemotherapy according to VAD in the majority of patients (74,7%). This number increased to 246 (49,4%) following transplantation. Double transplantation was conducted in 132 patients (26,5%). Median OS and PFS obtained were 3272 (1391–4232) and 1158 (102–3767) days respectively. CR achieved before transplantation, normal renal function, albumin level above 35g/l, b2 mikroglobulin below 3,5mg/l and DS stage I, were associated with a longer OS and PFS (p<0,05). This retrospective, multicenter study confirms the efficacy and safety of autoHSCT in multiple myeloma patients. Additional confirmation is given of the increased rate of CR, and the significantly prolonged survival observed in complete responders. Taking the above into account the employment of new drugs, such as thalidomide or bortezomib, which allow the achievement of a higher percentage of remissions should in the future bring about an improvement of the efficacy of transplantation in multiple myeloma.

Consolidation with Bortezomib, Thalidomide and Dexamethasone After High Dose Therapy Is Feasible, Safe and Effective In De Novo Multiple Myeloma Patients Who Already Received New Drugs Containing-Induction Regimen

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3041-3041 ◽  
Author(s):  
Murielle Roussel ◽  
Gaëlle Dörr ◽  
Willy Vaillant ◽  
Anne Huynh ◽  
Michel Attal
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Residual Disease ◽  
Complete Response ◽  
New Drugs ◽  
High Dose ◽  
Consolidation Therapy ◽  
High Dose Therapy ◽  
Induction Regimen ◽  
Immunophenotypic Analysis

Abstract Abstract 3041 High dose therapy (HDT) with autologous stem cell transplantation (ASCT) is a standard treatment option for frontline myeloma patients (pts). However, after a single or a double transplantation, almost all pts ultimately relapse. Thus, new strategies are required to control the residual disease after HDT. Consolidation therapy, given early after HDT, could enhance the depth of response and further improve progression free survival (PFS) and overall survival (OS). The IFM (Intergroupe Francophone du Myélome) previously reported that either Thalidomide or Lenalidomide, administered after HDT, was able to reduce this residual disease (IFM 99-02 and 2005-02 trials, Attal M et al. Blood 2006 and ASCO 2010). Ladetto M et al. (JCO 2010) also reported a major shrinking of residual tumor cell burden in myeloma pts undergoing early consolidation with Bortezomib, Thalidomide and Dexamethasone (VTD) after ASCT. None of these pts had previously received treatment with Thalidomide and/or Bortezomib during induction. The aim of this study was to evaluate the feasibility, safety and efficacy of early consolidation therapy in pts who had received new drugs containing-induction therapies before ASCT. Patients and Methods: In this prospective monocenter study,patients were eligible if they had the following: 1) at least partial response (PR) after HD melphalan (HDM), 2) no grade ≥ 2 peripheral neuropathy (PNY). The consolidation therapy with vTD had to be started within 3 months from ASCT for a total of 2 cycles. Each 4-week cycle consisted of: a) Bortezomib: 1mg/m2 as an IV injection twice weekly (on days 1, 4, 8, 11); b) oral Thalidomide: 100 mg/day; c) oral Dexamethasone 40 mg/day once a week (on days 1, 8, 15 and 22). Pts did not receive maintenance therapy after vTD consolidation. A systematic prophylactic anticoagulation therapy was given either by aspirin or low molecular weight heparin. Pts also received systematic anti herpes zoster prophylaxis with valacyclovir. Toxicities were graded according to the CTAECv4 at each cycle. Response was assessed according to modified European group for Blood and Marrow Transplantion criteria including very good partial response (VGPR), 1 month after the last cycle of vTD. As no immunophenotypic analysis was available routinely in our institute, we did not evaluate stingent complete response. Results: From August 2008 to May 2010, 90 newly diagnosed multiple myeloma pts under 65 received HDM followed by ASCT in the Toulouse's hospital bone marrow transplant unit, FRANCE. Forty-six pts were eligible for this study and started on consolidation. Two pts are ongoing their treatment and 41 received the whole planned treatment. Two pts withdrawn thalidomide and 1 pt did not receive the second cycle of consolidation because of toxicities. Forty-four pts were excluded mainly because of PN (27%). Initial characteristics were: age=58 years (range,44-65); ISS: 1= 50%, 2= 23%, 3=18%, NA= 9%; DS stage: I=4,5%, II=4,5%, III=91%; median beta-2microglobulin=2,9 mg/l (1,3-11,3); FISH analysis: t(4-14) and/or del 17p= 4/29 evaluable pts. The induction regimen was: Bortezomib/Dexamethasone (82%), vTD (11%), or another regimen (7%). Before consolidation therapy, response rates were: PR=16%, VGPR=48%, near complete response (nCR)=14% and CR=23%. In an Intend to treat basis, 17 pts (39%) improved their responses after consolidation with vTD: 3 pts (7%) from PR to VGPR, 8 pts (18%) from VGPR to nCR, and 6 pts (14%) from VGPR to CR. Response improvement was also reported in the 5 pts who already received induction therapy with vTD; three pts (60%) improved their response: 1 pt from PR to VGPR and 2 pts from VGPR to nCR. As immunophenotypic analysis was not avalaible, response improvement might be underestimate for CR pts. Overall, consolidation therapy with 2 cycles of vTD was efficient; 16 pts (36%) acheived CR, 30 pts (68%) CR+nCR and 40 pts (91%) VGPR or better. Considering the safety profile, there was no toxic death or grade 3/4 hematological toxicity. Non-hematological toxicities reported were: fatigue=18%, PNY (all grades)= 9%, pneumonia=7%, vertigo= 7%, constipation= 6%, and deep-vein thrombosis= 4,5%. Conclusions: Early consolidation with vTD in pts who already received Thalidomide and/or Bortezomib as induction therapy is feasible, safe and effective. Response rates improved in almost 40% of pts. Disclosures: Roussel: Janssen: Consultancy, Research Funding, orator; celgene: Consultancy, Orator, Research Funding. Off Label Use: bortezomib and thalidomide as consolidation therapy after High Dose Melphalan. Attal:celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding.

Induction Therapy in Multiple Myeloma

Hematology ◽  
2008 ◽  
Vol 2008 (1) ◽  
pp. 306-312 ◽  
Author(s):  
Jean-Luc Harousseau
Keyword(s):  
Multiple Myeloma ◽  
Progression Free Survival ◽  
Hematologic Malignancies ◽  
Tumor Burden ◽  
Prolonged Treatment ◽  
Induction Treatment ◽  
High Dose ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
High Dose Melphalan

Abstract In most hematologic malignancies the role of induction treatment is to achieve complete remission (CR). In multiple myeloma this has been possible only with the introduction of high-dose therapy plus autologous stem-cell transplantation (ASCT). In the context of ASCT there is a statistical relationship between CR or very good partial remission (VGPR) achievement and progression-free survival or overall survival. High-dose therapy consists of 3 to 6 courses of a dexamethasone alone or combined with vincristine-adriamycin (VAD) to reduce the tumor burden and the plasma cell infiltration followed by 1 or 2 courses of high-dose melphalan plus ASCT. This treatment induces 20% to 40% CR and 40% to 55% CR/VGPR. The introduction of novel agents in the induction treatment is changing this scenario. The combinations of dexamethasone with thalidomide, bortezomib or lenalidomide increase the CR/VGPR rates compared to dexamethasone or VAD. Triple combinations are currently being evaluated, but preliminary results with not more than 3 or 4 cycles show post-ASCT CR/VGPR rates of 60% to 75% In elderly patients who are not candidates for ASCT, combinations of melphalan-prednisone with a novel agent (thalidomide, bortezomib or lenalidomide) yield CR/VGPR rates that are quite comparable to those achieved in younger patients with ASCT. Prolonged treatment with the combination of lenalidomide plus dexamethasone can be administered safely and appears to induce very high (up to 70%) CR/VGPR rates as well.

scholarly journals Prognostic Factors for Patients with Diffuse Large B Cell Lymphoma and Transformed Indolent Lymphoma Undergoing Autologous Stem Cell Transplantation in Denmark 2000-2012

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1983-1983
Author(s):  
Bente Arboe ◽  
Kristina Fruerlund Nielsen ◽  
Charlotte Madsen ◽  
Rasmus Heje Thomsen ◽  
Soeren Ramme Nielsen ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cell ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Refractory Disease ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Large B Cell

Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) is the largest subgroup of malignant lymphoma. Today more than 80% of the patients will achieve partial or complete remission. However more than 20 % will either relapse or present with refractory disease. The standard approach for patients without major comorbidity is salvage treatment followed by high dose therapy with autologous stem cell transplant (HDT). This potentially curative treatment is toxic with many side effects and procedure related mortality, and therefore identification of patients eligible for HDT is a difficult challenge. Objectives: Patients with relapse of de novo DLBCL and transformed indolent lymphoma (TIL) were included. The aim was to identify clinical prognostic markers that can identify patients who will not benefit from HDT. Methods: From the national lymphoma registry patients with relapse of B-cell lymphoma in Denmark in the period 2000-2012, who underwent HDT, were extracted. Medical records were reviewed for clinical, pathological, and treatment information, and outcome. Patients were followed until death or emigration or until February 1, 2015. The Kaplan-Meier method was used to estimate overall survival (OS) and progression free survival (PFS). Cox regression models were used to assess prognostic factors. Results: A total of 370 patients were included, 174 with de novo DLBCL, and 196 with TIL, 143 of the 196 had histologically confirmed transformation. Median age was 58 (22-73), and 59% of the patients were male. With a median follow-up of 82 months from HDT, the 5-year OS was 52% and the 5-year PFS was 44% (median PFS 3.2 years). For the DLBCL patients the 5-year OS was 43% and the 5-year PFS was 38%. For TIL patients the OS was 62% and the PFS 49% (figure 1). During the first 100 days, 29 patients (8%) were admitted to the intensive care unit (14 DLBCL), and only four of these patients were alive at six months. The non-relapse mortality (NRM) at day 100 was 6 % for both groups, after five years 25% for DLBCL and 15% for TIL. No significant difference in 5-year PFS was seen between sexes or age, but patients younger than 58 had better 5-year OS compared to patients aged 58 or above (p=0.047). There was no difference in relapse treatment (DHAP vs ICE). Smoking (ever vs. never) caused a significantly worse OS (p=0.034). All IPI-factors, except Ann Arbor stage, was of prognostic importance (PFS). Primary refractory disease was of poor prognostic importance (p=0.001), and in patients, for whom the time from last salvage treatment to reinfusion of stem cells was more than 2 months, had a worse outcome (p=0.006). Patients, with less than 20 days of hospital admission in the period from the date of relapse to start of HDT, had a significantly higher survival (OS and PFS) (p>0.001). In a multivariate analysis (PFS), LDH above upper normal reference, HR 1.4 (95% CI: 1.0;2.1), involvement of more than one extranodal site, HR 1.6 (1.1;2.3) primary refractory disease, HR 1.6 (1.1;2.3) and more than two earlier relapses, HR 1.9 (1.1;3.5) were all factors associated with adverse outcome. For OS, the multivariate analysis showed, that patients with TIL had a better outcome, HR 0.7 (0.5;0.9), compared to DLBCL. Age above 58, HR 1.5 (1.1;2.1), involvement of more than one extranodal site, HR 1.9 (1.4;2.8), and primary refractory disease, HR 1.6 (1.1;2.3) were factors associated with adverse outcome. Discussion: In this population based study we find a 5-year OS of 52% after HDT and a 5-year PFS of 44%. Patients with TIL have a significantly higher 5-year PS (49%) than patients with de novo DLBCL (38%) whereas NRM is identical for the two groups at day 100 (6%). However, NRM increases subsequently more for DLBCL than for TIL over time to 25% and 15 % respectively after five years. Furthermore we show that hospitalization days less than 20 and postponement of stem cell infusion beyond 2 month after harvest may be useful parameters that can identify patients that have better or worse outcome after HDT. This nationwide study cohort with the long follow-up period is applicable to a general population of patients, and this may explain the somewhat lower outcome compared to other published HDT cohorts. Figure 1. Progression Free Survival (PFS) curves for Diffuse Large B-Cell Lymphomas (DLBCL) and Transformed Indolent Lymphomas (TIL) after high dose therapy with autologous stem cell transplant Figure 1. Progression Free Survival (PFS) curves for Diffuse Large B-Cell Lymphomas (DLBCL) and Transformed Indolent Lymphomas (TIL) after high dose therapy with autologous stem cell transplant Disclosures Brown: Bayer: Consultancy; Roche: Consultancy, Speakers Bureau.

High-Dose Therapy Improves Progression-Free Survival and Survival in Relapsed Follicular Non-Hodgkin’s Lymphoma: Results From the Randomized European CUP Trial

2003 ◽  
Vol 21 (21) ◽  
pp. 3918-3927 ◽  
Author(s):  
Harry C. Schouten ◽  
Wendi Qian ◽  
Stein Kvaloy ◽  
Adolfo Porcellini ◽  
Hans Hagberg ◽  
...  
Keyword(s):  
Stem Cell ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Hodgkin's Lymphoma ◽  
High Dose ◽  
High Dose Therapy ◽  
Free Survival ◽  
Dose Therapy ◽  
Hazard Ratios ◽  
Non Hodgkin's Lymphoma

Purpose: To determine, in a randomized clinical trial, whether high-dose therapy (HDT) followed by autologous stem-cell transplantation is more effective than standard treatment with regard to progression-free survival (PFS) and overall survival (OS) in patients with relapsed follicular non-Hodgkin’s lymphoma; and to assess the additional value of B-cell purging of the stem-cell graft with regards to PFS and OS. Patients and Methods: Patients received three cycles of chemotherapy. Responding patients with limited bone marrow infiltration were eligible for random assignment to three further cycles of chemotherapy (C), unpurged HDT (U), or purged HDT (P). Results: Between August 1993 and April 1997, 140 patients were registered from 36 centers internationally, and 89 were randomly assigned. Reasons for not randomizing included patient refusal, early progression, or death on induction therapy. With a 69-month median follow-up, the log-rank P value for PFS and OS were .0037 and .079, respectively. For PFS, the hazard ratios (95% CIs) for U versus C, P versus C, and P versus U were 0.33 (0.16 to 0.70), 0.38 (0.19 to 0.79), and 1.02 (0.51 to 2.05), respectively. The hazard ratio (95% CI) for C versus U + P was 0.30 (0.15 to 0.61). Hazard ratios (95% CIs) for OS were 0.43 (0.18 to 1.06), 0.43 (0.18 to 1.02), and 0.72 (0.32 to 1.63). For C versus U + P, the hazard ratio (95% CI) was 0.40 (0.18 to 0.89). Kaplan-Meier estimates (95% CIs) of 2-year PFS for C, U, and P were 26% (8% to 44%), 58% (37% to 79%), and 55% (34% to 75%), respectively. OS at 4 years for C, U, and P are 46% (25% to 67%), 71% (52% to 91%), and 77% (60% to 95%) respectively. Conclusion: HDT significantly improves PFS and OS. There is no clear evidence of benefit through purging.

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