An Update of a Comparison of Nonmyeloablative Allografting with Autografting for Newly Diagnosed Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 482-482
Author(s):  
B. Bruno ◽  
R. Sorasio ◽  
F. Patriarca ◽  
N. Mordini ◽  
B. Allione ◽  
...  
Keyword(s):  
Statistical Power ◽  
Autologous Transplantation ◽  
New Drugs ◽  
High Dose ◽  
Newly Diagnosed ◽  
Cox Models ◽  
Intention To Treat ◽  
Hematological Cancers ◽  
Intent To Treat

Abstract The concept of genetic randomisation has been applied to assess clinical outcomes between patients with hematological cancers treated with allografting or other therapies. Though not universally accepted, the comparison by the intention-to-treat principle between patients with HLA-identical siblings, who can be assigned to allografting, and those without, who cannot receive an allograft, is used as a surrogate for an unbiased randomisation. We previously published the results of a study where the treatment assignment of 162 newly diagnosed patients younger than 65 years was based only on the presence/absence of an HLA-identical sibling (Bruno et al, N Engl J Med). First-line treatment plans included a cytoreductive autograft followed by a nonmyeloablative allograft (Tandem auto-allo) or a second melphalan-based autograft (Double-auto). Primary endpoints were overall (OS) and event-free (EFS) survivals by intention-to-treat analysis. The 80 patients with a sibling donor were offered a Tandem auto-allo and the 82 without a Double-auto after high (140–200 mg/m2) or intermediate dose melphalan (100 mg/m2). After a median follow up of 45 (range 21–90) months, OS and EFS were significantly longer in patients with donors: 80 versus 54 months (p=0.01) and 35 versus 29 months (p=0.02). Median OS was not reached in the 58 (out of 60 enrolled, 97%) patients who completed Tandem auto-allo and was 58 months in the 46 (out of 59 enrolled, 78%) who completed high-dose double-auto (p=0.03). Here, we report a update analysis. At a median follow up of 56 months, OS was not reached for the 80 patients with an HLA-identical sibling and was 56 months for those without (HR 0.53, CI 95% 0.33–0.86, p=0.009). EFS remained significantly longer in patients with HLA-identical siblings: 35 versus 29 months (HR: 0.61; 95% Cl: 0.42–0.88, p=0.008). Median OS was not reached in the 58 patients who completed Tandem auto-allo and was 63 months in the 46 who completed high-dose double-auto (HR 0.47, CI 95% 0.25–0.86, p=0.016). EFS was 43 and 33 months (HR 0.64, CI 95% 0.40–1.02, p=0.06). By multivariate analysis, the presence of HLA-identical siblings was significantly correlated with longer OS and EFS. We carried out a stratified analysis, on the intent-to-treat population, that defined a patient subgroup at high risk in the light of high b -2-microglobulin levels or presence of del(13). The adjusted HRs by Cox models were 0.34 for OS and 0.52 for EFS similar to those obtained in the whole series. Though this exploratory analysis has low statistical power, its results indicate that del(13) does not offset the advantage in OS and EFS for patients with an HLA-identical sibling, but do not exclude an impact of del(13) in those patients undergoing an allograft. Attal et al. (N Engl J Med) previously reported median OS and EFS of 58 and 30 months, respectively, after double autologous transplantation, consistent with our results (OS: 63 months; EFS: 33 months). However, the EFS after Tandem auto-allo also indicates that long-term disease control is an issue. Allografting and new drugs with molecular targets should not be viewed as mutually exclusive. Thus, it is imperative to thoroughly explore their roles in increasing the response rates and their duration in Tandem auto-allo.

Comparison of two chemotherapy regimens in Ewing sarcoma (ES): Overall and subgroup results of the Euro Ewing 2012 randomized trial (EE2012).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11500-11500
Author(s):  
Bernadette Brennan ◽  
Laura Kirton ◽  
Perrine Marec-Berard ◽  
Javier Martin -Broto ◽  
Hans Gelderblom ◽  
...  
Keyword(s):  
Tumour Volume ◽  
Primary Outcome Measure ◽  
Newly Diagnosed ◽  
Posterior Probabilities ◽  
Serious Adverse Events ◽  
Cox Models ◽  
Intention To Treat ◽  
The Usa ◽  
Credible Intervals

11500 Background: In 2010, different chemotherapy regimens were standard in Europe and the USA for newly diagnosed ES. In the absence of novel agents to investigate, comparison of these two strategies was considered worthwhile. Methods: Newly diagnosed localised or metastatic ES patients aged 5-50 were eligible. Patients were randomized to receive either the European regimen (Arm A) of VIDE (vincristine [V], ifosfamide [I], doxorubicin [D] and etoposide [E]) induction and VAI or VAC (V, actinomycin D and I or cyclophosphamide [C]) consolidation or the USA regimen (Arm B) of compressed VDC/IE induction and IE/VC consolidation. The primary outcome measure was event-free survival (EFS); secondary outcomes included overall survival (OS) and toxicity. The design was Bayesian with interpretation based on posterior probabilities (with non-informative priors) – i.e. probability that true hazard ratio (HR) < 1.0 given the data [Pr(HR<1.0|data)], with 95% credible intervals (CrI) reported. HRs were obtained from Cox models adjusted for baseline stratification parameters. Heterogeneity tests (HT) were used to investigate whether the treatment effect differed according to baseline parameters. Analysis was intention-to-treat. Results: Between December 2013 and May 2019, 640 patients were randomised (320 to each arm) from 10 European countries. Baseline stratification factors were: sex (58% male; 42% female); age (41% <14 years; 59% 14+ years); disease type (74% localised, 17% lung/pleural metastasis, 9% other metastasis); tumour volume (56% <200 ml, 44% >200 ml); country (37% UK, 31% France, 32% other). Median follow-up was 1.7 years. The HRs (95% CrI) were 0.70 (0.51, 0.95) for EFS and 0.64 (0.42, 0.96) for OS in favour of Arm B, with posterior probabilities of 98% for both that Arm B was better. Subgroup analyses showed no evidence that this benefit differed depending the baseline features, with no HT being close to significance (table). There were no major differences in acute toxicity: 68% of patients in Arm A experienced serious adverse events and 67% in Arm B. Conclusions: VDC/IE chemotherapy is superior to VIDE for both EFS and OS, with no excess toxicity. This benefit is consistent across all baseline stratification parameters. Clinical trial information: ISRCTN92192408 . [Table: see text]

scholarly journals Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma

Blood ◽  
2011 ◽  
Vol 117 (24) ◽  
pp. 6721-6727 ◽  
Author(s):  
Luisa Giaccone ◽  
Barry Storer ◽  
Francesca Patriarca ◽  
Marcello Rotta ◽  
Roberto Sorasio ◽  
...  
Keyword(s):  
Complete Remission ◽  
New Drugs ◽  
High Dose ◽  
Newly Diagnosed ◽  
Term Survival ◽  
Free Survival ◽  
Long Term Follow Up ◽  
High Dose Melphalan

Abstract Before the introduction of new drugs, we designed a trial where treatment of newly diagnosed myeloma patients was based on the presence or absence of HLA-identical siblings. First-line treatments included a cytoreductive autograft followed by a nonmyeloablative allograft or a second melphalan-based autograft. Here, we report long-term clinical outcomes and discuss them in the light of the recent remarkable advancements in the treatment of myeloma. After a median follow-up of 7 years, median overall survival (OS) was not reached (P = .001) and event-free survival (EFS) was 2.8 years (P = .005) for 80 patients with HLA-identical siblings and 4.25 and 2.4 years for 82 without, respectively. Median OS was not reached (P = .02) and EFS was 39 months (P = .02) in the 58 patients who received a nonmyeloablative allograft whereas OS was 5.3 years and EFS 33 months in the 46 who received 2 high-dose melphalan autografts. Among patients who reached complete remission in these 2 cohorts, 53% and 19% are in continuous complete remission. Among relapsed patients rescued with “new drugs,” median OS from the start of salvage therapy was not reached and was 1.7 (P = .01) years, respectively. Allografting conferred a long-term survival and disease-free advantage over standard autografting in this comparative study.

Six Years of Experience and Outcome with Maintenance Therapy with Very Low Dose Thalidomide after Auto-SCT in Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5208-5208
Author(s):  
Vincenzo Mettivier ◽  
Luca Pezzullo ◽  
Stefano Rocco ◽  
Olimpia Finizio ◽  
Pellegrino Musto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Maintenance Therapy ◽  
Low Dose ◽  
Autologous Transplantation ◽  
Haematological Toxicity ◽  
New Drugs ◽  
Cell Leukaemia ◽  
High Dose

Abstract New drugs and high dose therapy with auto-transplantation (auto-SCT) has improved prognosis of multiple myeloma (MM). New drugs are promising in upfront therapy while the role of maintenance is still debated. Thalidomide (thal) is an active drug in the treatment of myeloma, and is been investigated as first line therapy, the limit of this drug is the toxicity dependent dose and this determines a poor compliance. It could be useful in the control of minimal residual disease. We used low dose of thal as maintenance after autologous transplantation in patient with MM from January 2002 and here we bring our experience after six years of observation. From January 2002 to August 2008 17 patients (8 males and 9 females) with MM have been treated in our institution. Median age was 59,5 years (range 48–72). 10 were IgG, 3 IgA, 3 light chains and 1 plasma-cell leukaemia. Treatment was 4 cycles of VAD regimen followed by auto-SCT. 4/17 performed double auto-SCT. Three months after SCT these patients has begun the maintenance with thal 50 mg/die, to start thal maintenance 9 patients were in CR, 5 in PR and 3 in resistant disease and the median somministration of thal has been of 12 months (range 3–24 months). Median follow up from the beginning of maintenance therapy was 40 months (range 4–76) with 11/17 (64%) patients in CR or stable disease, with progression free survival (PFS) and overall survival (OS) projected at 75 months respectively of 53% and 51% from to start thal. In our experience we have observed a neurological toxicity (grade I–III) in the 65% of the patients but only 4 have had to suspend the treatment; a haematological toxicity of grade I in the 55% of the patients that have not behaved interruption of the treatment and finally in any case we have documented thrombotic episodes. Finally we have compared this group of patients with another group (18 patients) with the same clinical characteristics that we have observed in the same period but that have not effected maintenance with thal. In this last group 13/18 patients (72%) relapsed with median follow-up of 36 months (range 14–75) and median PFS and OS of 16 and 30 months respectively. The difference between the 2 groups is statistically significant for PFS (p: 0.003) and OS (p: 0.04). The median overall survival observed after progression, in the two groups, has been of 13 months in thal group and 17 months in the group of patients that have not effected the maintenance, this difference is not statistically different (p:0.06). In conclusion in 6 years of observation our experience has shown, even if the number of the patients is small, that maintenance with low doses of thal, after auto-transplantation, it not only has a good compliance but it improves the PFS and OS in this cohort and it doesn’t worsen the OS from the relapse.

Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) plus lenalidomide maintenance or no maintenance in newly diagnosed multiple myeloma (MM) patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8509-8509 ◽  
Author(s):  
Mario Boccadoro ◽  
Federica Cavallo ◽  
Francesca Maria Gay ◽  
Francesco Di Raimondo ◽  
Arnon Nagler ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Autologous Transplantation ◽  
Previous Treatment ◽  
New Drugs ◽  
High Dose ◽  
Risk Of Progression ◽  
Treatment Paradigm ◽  
High Dose Melphalan ◽  
To Receive

8509 Background: The incorporation of new drugs into induction, consolidation, and maintenance therapy is changing the treatment paradigm of MM. Methods: At diagnosis, 402 pts (< 65 years) were randomly assigned to receive six MPR cycles (N=202) or tandem MEL200 (N=200). After MPR or MEL200, pts were further randomized, within each group, for no maintenance (N=204) or lenalidomide maintenance (N=198). A 2x2 factorial randomized trial was designed. The primary end point was PFS. An enrolment of 170 pts/arm was required to demonstrate a 15% improvement of PFS at 2 years (2-sides a = 0.05, 1- β 80%). Results: After a median follow-up of 45 mos from diagnosis, the median PFS was 25 mos with MPR and 39 mos with MEL200 (p=.0002). Median PFS were 37.5 mos for maintenance and 25.7 mos for no maintenance (p=.0008). The 4-year OS from diagnosis was 71% with MPR and 72% with MEL200 (p=0.71), 76% for maintenance and 68% for no maintenance (p=.08). After a median follow-up of 32 mos from start of maintenance, the median PFS was for 41 mos for maintenance and 18 mos for no maintenance (p<.0001). The 3-year OS from start of maintenance was 81% for maintenance and 72% for no maintenance (p=.04). Conclusions: MEL200 significantly prolonged PFS in comparison with MPR. Lenalidomide maintenance significantly reduced the risk of progression independently from the previous treatment. OS is similar between MPR and MEL200, with a trend for an improved OS in pts receiving lenalidomide as maintenance therapy. Clinical trial information: NCT00551928. [Table: see text]

Total Therapy With Tandem Transplants for Newly Diagnosed Multiple Myeloma

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 55-65 ◽  
Author(s):  
B. Barlogie ◽  
S. Jagannath ◽  
K.R. Desikan ◽  
S. Mattox ◽  
D. Vesole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Remission Induction ◽  
Comprehensive Treatment ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Total Therapy ◽  
Macrophage Colony ◽  
Intent To Treat

Abstract Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum β-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy (“Total Therapy”). Remission induction utilized non–cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low β-2-microglobulin at diagnosis. CR duration was significantly longer with early onset of CR and favorable karyotypes. Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly, independent of cytogenetics and β-2-microglobulin. Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients, using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This observation is particularly important because CR is a sine qua non for long-term disease control and, eventually, cure.

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.

Up-Front Thalidomide-Dexamethasone (THAL) and Double Autologous Transplantation (Double TX) for Multiple Myeloma: Comparison with Double TX without Added Thalidomide and Prognostic Implications of Chromosome 13 Deletion and Translocation t(4;14).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3081-3081 ◽  
Author(s):  
Michele Cavo ◽  
Nicoletta Testoni ◽  
Carolina Terragna ◽  
Elena Zamagni ◽  
Paola Tacchetti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Autologous Transplantation ◽  
Lower Probability ◽  
Fish Analysis ◽  
Primary Therapy ◽  
Cytogenetic Abnormalities ◽  
Chromosome 13 ◽  
Prognostic Implications ◽  
Intent To Treat

Abstract Aim of the present sudy was to evaluate the benefit of novel agents combined with conventional therapies in multiple myeloma (MM), with particular emphasis on patients (pts) carrying adverse cytogenetic abnormalities. For this purpose, we analyzed a series of 142 pts who received thalidomide-dexamethasone (thal-dex) and double autologous transplantation (double Tx). By study design, thal-dex was administered from the outset until the second autologous Tx. On an intent-to-treat basis, stringently defined (immumofixation negative) complete remission (CR) rate following double Tx and thal-dex was 54%. This value was significantly higher (P=0.0009) compared to the 33% observed in a comparable series of 129 pts who received double Tx without thal-dex. In comparison with these latter patients, addition of thal-dex to double Tx significantly prolonged PFS (median: 31 vs 42 months; P=0.04) and did not adversely affect survival after post-transplant relapse (P=0.7). All 142 pts included in the study were investigated at baseline for the presence of chromosome 13 deletion [del(13)] by FISH analysis and of t(4;14) using a RT-PCR assay. An analysis on an intent-to-treat basis performed according to the presence or absence of these cytogenetic abnormalities revealed that the probability to respond (more than 90% reduction in M protein concentration) to primary therapy with thal-dex for 94 pts who carried both del(13) and t(4;14) was significantly lower compared to that of 69 pts with del(13) alone (12% vs 41%, respectively; P=0.012) and of 18 pts with t(4;14) alone (12% vs 50%, respectively; P=0.006). The lower probability of response to first-line thal-dex therapy conferred by the presence of both del(13) and t(4;14) was completely offset by subsequent application of double Tx and thal-dex. Indeed, on an intent-to-treat basis, the probability to attain a very good partial response or CR for pts with both del(13) and t(4;14) positivity was 68% compared to 80% for pts with both del(13) and t(4;14) negativity (P=0.1). With a median follow-up of 24 months, the 3-year projected probabilities of OS and PFS were 80% and 59%, respectively (intent-to-treat). The presence or absence of t(4;14) had no significant impact on the 3-year projected probability of OS (80.12% vs 80.42%, respectively; P=0.3). Furthermore, an analysis of pts who actually received thal-dex and double Tx showed that curves of OS and EFS were almost superimposable among pts who carried or lacked both del(13) and t(4;14). Indeed, the 3-year projected probability of OS for pts with both these cytogenetic abnormalities was 92% compared to 88% for pts who were negative for both del(13) and t(4;14); (P=0.7); the corresponding figures for EFS were 70% vs 77%, respectively (P=0.9). These results suggest that thal-dex combined with double Tx may overcome the unfavourable prognosis conferred by del(13) and t(4;14). A longer follow-up is required before definite conclusions can be drawn.

Rituximab Plus Hypercvad Alternating with High Dose Methotrexate and Cytarabine for Patients with Newly Diagnosed Mantle Cell Lymphoma. A Multicenter Trial from GISL

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3050-3050 ◽  
Author(s):  
Francesco Merli ◽  
Stefano Luminari ◽  
Fiorella Ilariucci ◽  
Caterina Stelitano ◽  
Mario Petrini ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Hematological Toxicity ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Dose Methotrexate ◽  
Mantle Cell

Abstract BACKGROUND. Rituximab plus HyperCVAD alternating with High Dose Methotrexate and Cytarabine (R-HCVAD) has been tested in patients with newly diagnosed Mantle Cell Lymphoma (MCL) with promising results (Romaguera et al. JCO 2005). In 2005 the Gruppo Italiano Studio Linfomi (GISL) started a phase II multicenter study investigating clinical activity and toxicity of R-HCVAD in a similar group of patients. PATIENTS AND METHODS. To be included in the trial patients must have histologically confirmed diagnosis of MCL, be younger than 70 years, have adequate organ function. Chemotherapy consisted of rituximab plus fractionated cyclophosphamide, vincristine, doxorubicine, and dexamethasone(considered one cycle) alternating every 21 days with rituximab plus high dose methotrexate-cytarabine (considered one cycle) for a total of eight cycles per the MD Anderson protocol. Patients with baseline PCR positivity for t(11;14) on bone marrow (BM) had to perform PCR assessment of BM at evaluation of response and during follow-up. Only patients achieving partial response (PR) were to be addressed to HDC followed by ASCT. RESULTS. Thirty-two patients were enrolled. There were 23 males and 9 females; median age was 54 yrs (29 to 66), 80% were in stage IV, 50% and 71% had Gastrointestinal (GI) and BM involvement, respectively; PCR for t(11;14) was positive on BM in 51% of cases. Seven patients did not complete treatment due to toxicity; of these, two patients died (one with septic shock at cycle 1, one with pulmonary aspergillosis at cycle 4), one patient had thrombosis of central line extended to right atrium at cycle 1, one had grade IV skin reaction at cycle 3, one had a severe pneumonia at cycle 1, two had persistent grade IV hematological toxicity after cycle 1 and 5, respectively. All patients had grade III–IV hematological toxicity. Response was assessed in 17 patients with 16 CR and 1 PR. PCR for t(11;14) negativity on BM was achieved in 4/9 patients after cycle 4 and in 8/9 after cycle 8. After a median follow-up of 24 months 1 patient progressed at 6 months and 1 patient relapsed after 26 months of follow-up. Two-year Failure Free Survival (FFS) was 75% (IC95% 53 to 87) and 2 year Disease Free Survival was 93%(IC95% 59–99). CONCLUSIONS. Though longer follow-up is needed R-HCVAD regimen used in our multicenter setting confirmed high efficacy in terms of response (both clinical and molecular) and FFS. However the regimen was associated to a severe toxicity profile that caused treatment discontinuation in several patients and that may limit its use in the clinical setting.

Superiority of Lenalidomide-Dexamethasone Versus Thalidomide-Dexamethasone as Initial Therapy for Newly Diagnosed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3884-3884
Author(s):  
Francesca Gay ◽  
Suzanne Hayman ◽  
Martha Q. Lacy ◽  
Francis Buadi ◽  
Morie A Gertz ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Initial Therapy ◽  
High Dose ◽  
Toxicity Profile ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Intention To Treat ◽  
High Dose Dexamethasone ◽  
Grade 3

Abstract Abstract 3884 Poster Board III-820 Background and Objective Thalidomide/dexamethasone (thal/dex) combination has shown high activity in newly diagnosed multiple myeloma (MM) (Rajkumar SV. at al, J Clin Oncol 2006;24:431-436). In newly diagnosed patients, lenalidomide/dexamethasone (len/dex) has demonstrated superiority compared with high-dose dexamethasone alone (Zonder JA et al, Blood 2007;110:77). Although both thal/dex and len/dex are active in newly diagnosed MM, no randomized trial has been reported comparing these two regimens, and unfortunately none are ongoing or planned. We compared the efficacy and the toxicity of thal/dex and len/dex as primary therapy in 411 newly diagnosed MM patients treated at the Mayo Clinic. Patients and methods 411 consecutive patients seen at Mayo Clinic between 2001 and 2008, who received induction with thal/dex (n=183) or len/dex (n=288) were retrospectively studied. Thalidomide was given at a dose ranging from 100 mg/day to 400 mg/day continuously; the lenalidomide dose was 25 mg/day, days 1-21 on a 28-day cycle. All patients received dexamethasone, either at high-dose (40 mg orally on days 1-4, 9-12, and 17-20) or at low-dose (40 mg orally day 1, 8, 15, 22); each cycle was repeated every 4 weeks. In addition, a case-matched subgroup analysis that adjusted for age, gender and transplantation status was performed among patients who received high-dose dexamethasone comparing the thal/dex (n=72) and len/dex (n=72) groups. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and all comparisons were determined by the log-rank test and by the Cox proportional hazards model. Results On intention-to-treat analysis, of 411 patients, 80.3% versus 61.2% patients, respectively in the len/dex group and in the thal/dex group (p < 0.001), achieved at least a partial response. A significant difference between the 2 groups was found in terms of both very good partial response or better (34.2% vs 12.0%, p < 0.001) and complete response rate (13.6% vs 3.3%, p < 0.001). Duration of therapy was significantly longer in len/dex patients as compared to thal/dex patients: 36.7% vs 12.6% of patients who did not stop treatment to receive SCT were still receiving therapy at 1 year (p < 0.001).Time-to-progression was significantly better in the len/dex group than in patients receiving thal/dex (median 27.4 vs 17.2 months, HR 0.64; 95% CI 0.44-0.93; p = 0.019). Similarly, progression-free-survival was significantly higher in len/dex patients (median 26.7 vs 17.1 months, HR 0.69; 95% CI 0.48-0.98; p = 0.036). This translated into an increase in overall survival (OS) (median not reached for len/dex group compared to 57.2 months in thal/dex patients, HR 0.60; 95% CI 0.40-0.92; p = 0.018). Survival advantages were evident in patients presenting with International Staging System Stage (ISS) I/II (HR 0.57; 95% CI 0.32-1.00; p = 0.052) at diagnosis but not in patients with ISS stage III in subgroup analysis. There was a trend toward better OS in len/dex group compared to thal/dex group both for patients who underwent transplant and for patients who did not. A similar rate of patients experienced at least one grade 3 or higher adverse event (57.5% vs 54.6% in len/dex and thal/dex groups, respectively, p = 0.568). However, the toxicity profile was different in the two groups: major grade 3-4 toxicities of len/dex were hematological, in particular neutropenia (14% with len/dex vs 0.6% with thal/dex, p<0.001) while the most common toxicities in thal/dex were venous thromboembolism (15.3% vs 9.2%, p = 0.058) and peripheral neuropathy (10.4% vs 0.9%, p < 0.001). The data on efficacy and safety shown above were also confirmed in the subgroup case-matched analysis which included only high-dose dexamethasone patients. Conclusions This cohort study shows the superiority of len/dex in terms of response rates and survival, compared to thal/dex. The toxicity profile of the 2 regimens is different and len/dex treatment, although more active, was not associated with increased toxicity (grade 3-4 AEs). These data need to be carefully evaluated and randomized prospective phase III studies are necessary to confirm these results and determine the optimal initial therapy for MM. Disclosures: Off Label Use: research drugs in combination to standard care. Lacy:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Bergsagel:amgen: Membership on an entity's Board of Directors or advisory committees; genetech: Membership on an entity's Board of Directors or advisory committees; merck: Research Funding; celgene: Membership on an entity's Board of Directors or advisory committees. Witzig:celgene: Research Funding. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Greipp:celgene: Research Funding.

Achievement of Complete Response Is a Strong Prognostic Factor In Elderly Newly Diagnosed Myeloma: Retrospective Analysis of 1175 Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1949-1949
Author(s):  
Francesca Gay ◽  
Alessandra Larocca ◽  
P.W. Wijermans ◽  
Sara Bringhen ◽  
Tommasina Guglielmelli ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Complete Response ◽  
New Drugs ◽  
Response To Treatment ◽  
Maximal Response ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Best Response ◽  
The Impact

Abstract Abstract 1949 Introduction: There is extensive evidence from numerous studies in the transplant setting that achievement of complete response (CR) or at least very good partial response (VGPR) is significantly associated with prolonged progression-free survival (PFS) and overall survival (OS). In elderly myeloma patients CR was a rare event since new drugs has been added to standard melphalan-prednisone (MP). After the introduction of novel agents, CR represents an achievable goal, also outside of the transplant setting. Aims: to assess the impact of response to treatment on time-to-event parameters (PFS and OS) in elderly myeloma patients. Methods: We retrospectively analysed newly diagnosed myeloma patients, older than 65 years old, or younger but not eligible for high-dose chemotherapy and transplant. Patients were enrolled in 3 multicentre randomized European trials of the GIMEMA and Hovon groups, and were treated with MP (n=332), MP plus thalidomide (MPT, n=332), MP plus bortezomib (VMP, n=257) or MP plus bortezomib-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT, n=254). PFS, OS and duration of CR were analysed by the Cox proportional hazards model, comparing the two arms by the Wald test and calculating 95% confidence interval (CI). Univariate and multivariate analyses were performed for the following variables: age at diagnosis (>75 vs. ≤75 yrs), International Staging System (ISS) stages, type of chemotherapy and best response achieved. Best response was treated as a time-dependent variable. Results: A total of 1,175 patients, enrolled from November, 2001 to January, 2009, were retrospectively analysed. The best response to treatment was available in 1,136 patients: CR was reported in 195, VGPR in 212, PR in 397. Baseline characteristics according to best response achieved in patients who obtained CR, VGPR or PR were similar. Since response rates vary according to treatment regimens the proportion of patients who received MP, MPT, VMP, and VMPT-VT was different in the different response categories. After a median follow-up of 29 months, PFS was significantly higher in patients who achieved CR compared to those who obtained VGPR (HR 0.16; 95% CI 0.10–0.24; p<0.001) or PR (HR 0.07; 95% CI 0.04–0.13; p<0.001). The advantage in PFS translated into an advantage in OS: patients obtaining CR have a significantly prolonged OS than patients who achieved VGPR (HR 0.15; 95% CI 0.08–0.28; p<0.001) or PR (HR 0.08; 95% CI 0.04–0.16, p<0.001), (table). In multivariate analysis CR achievement was as an independent predictor of longer PFS and OS, regardless of age, ISS stage, and treatment administered. In patients > 75 years, both PFS and OS were shorter as compared to younger patients. Despite these differences, the impact of CR on outcome was identical. In the subgroup of patients > 75 years, PFS was significantly prolonged in patients who achieved CR, compared with those who obtained VGPR (HR 0.26; 95% CI 0.12–0.58, p = 0.001) or PR (HR 0.20; 95% CI 0.10–0.41, p < 0.001). Accordingly, OS was significantly higher in patients who achieved CR, compared with those who obtained VGPR (HR 0.13; 95% IC 0.03–0.58; p = 0.007), or PR (HR 0.12; 95% IC 0.03–0.51, p = 0.004), (table). No significant PFS differences between patients obtaining CR during the first 6 months of treatment or later were seen (HR 1.06; 95% IC 0.49–2.27; p=0.878). Similarly, no OS differences between these two groups were detected (p = 0.676). Duration of CR was comparable in patients who obtained CR during or after the first 6 months of treatment (HR 0.66; 95% CI 0.30–1.45; p = 0.305). Patients whose CR lasted more than 18 months have a significant OS benefit compared to patients who did not (p=0.006). Conclusions: These finding highlight the importance of CR, also outside of the transplant setting, regardless of age, ISS and treatment administered, and support the use of new drugs, also in patients older than 75 years, to achieve and maintain maximal response. Disclosures: Gay: Celgene: Honoraria. Bringhen:Calgene: Honoraria; Janssen-Cilag: Honoraria. Guglielmelli:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson : Membership on an entity's Board of Directors or advisory committees. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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