Effect of Venous Thrombotic Events on Overall Survival in Multiple Myeloma: Analysis of Thrombotic Events Occurring in E4A03A Randomized Trial of Lenalidomide Plus High-Dose Dexamethasone (RD) Versus Lenalidomide Plus Low-Dose Dexamethasone (Rd) in Newly Diagnosed Multiple Myeloma, a Trial Coordinated by the Eastern Cooperative Oncology Group (ECOG).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1740-1740 ◽  
Author(s):  
Susanna Jacobus ◽  
Shaji Kumar ◽  
Natalie Scott Callander ◽  
Rafat Abonour ◽  
Rafael Fonseca ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Low Dose ◽  
Standard Dose ◽  
Eastern Cooperative Oncology Group ◽  
Phase Iii ◽  
High Dose ◽  
Newly Diagnosed ◽  
Serious Adverse Events ◽  
The Impact

Abstract Background: Venous thrombotic events (VTE) are a common complication of therapy with the lenalidomide plus dexamethasone regimen. The incidence of VTE with RD is approximately 20%, and can be lowered with the use of effective thromboprophylaxis, avoidance of erythropoietin, and the use of lower doses of dexamethasone. The goal of this study was to determine the impact of VTE on overall survival of patients with newly diagnosed myeloma by studying events occurring in ECOG E4A03 phase III trial of lenalidomide plus high (standard) dose dex (RD) versus lenalidomide plus low dose dex (Rd) in newly diagnosed myeloma (MM). Methods: Pts with untreated, symptomatic MM were eligible. Pts in the RD arm (Arm A) received lenalidomide 25 mg/day PO days 1–21 every 28 days plus dex 40 mg days 1–4, 9–12, and 17–20 PO every 28 days; pts in the Rd arm (Arm B) received lenalidomide at the same dose plus dex 40 mg days 1, 8, 15, and 22 PO every 28 days. The trial initially did not mandate routine thromboprophylaxis, but recommended that such treatment be considered. After the first 264 patients were enrolled the trial was amended to require mandatory thromboprophylaxis of aspirin for all patients, with a recommendation to use stronger thromboprophylaxis with either warfarin (target INR 2–3) or low molecular weight heparin among patients in the RD arm. Results: 445 pts (median age, 65 yrs) were accrued; 223 randomized to RD, 222 to Rd. Median follow-up time is 30 months. Overall VTE including deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 18.5% of patients; 25.6% in Arm A and 11.4% in Arm B. Rates for the first 4 cycles of treatment were 20.2% in Arm A and 8.2% in Arm B, P<0.01. Rates did not change substantially before and after the prophylaxis amendment. A partial response (PR) or higher was seen in 82.1% of pts who experienced VTE compared with 74.6% of pts who did not experience VTE, P=0.19. Overall VGPR rates also were not inferior. Pts who had VTE, however, had significantly higher other grade 3–5 toxicities such as hyperglycemia (14.6% vs 7.5%, P=0.051), cardiac ischemia (4.9% vs 0.8%, P=0.002), non-neuropathic weakness (13.4% vs 6.4%, P=0.039), infection/pneumonia (17.1% vs 11.1%, P=0.138) and fatigue (18.3% vs 10.5%, P=0.060). In a Cox PH model, VTE status as a time-varying covariate was marginally significant: HR 1.54 95%CI (0.96–2.47), P=0.074, suggesting patients that develop VTE have a higher hazard of death. Conclusions: The occurrence of VTE may adversely affect the survival of patients with newly diagnosed myeloma receiving Rev-Dex. VTE was associated with a higher frequency of other serious adverse events. Prevention of VTE events is a priority. Besides lowering the dose of dexamethasone, studies investigating optimum thromboprophylaxis are needed.

A Randomized Phase III Trial of Lenalidomide Plus High-Dose Dexamethasone Versus Lenalidomide Plus Low-Dose Dexamethasone in Newly Diagnosed Multiple Myeloma (E4A03): A Trial Coordinated by the Eastern Cooperative Oncology Group.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 799-799 ◽  
Author(s):  
S. Vincent Rajkumar ◽  
Susanna Jacobus ◽  
Natalie Callander ◽  
Rafael Fonseca ◽  
David Vesole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Low Dose ◽  
Eastern Cooperative Oncology Group ◽  
Phase Iii ◽  
M Protein ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Phase Iii Trial ◽  
High Dose Dexamethasone

Abstract Background: Lenalidomide has shown efficacy in patients with relapsed myeloma in phase II and III clinical trials, and is currently being investigated as initial therapy for the disease. We report results of a phase III trial comparing lenalidomide plus high-dose dexamethasone (Dex) versus lenalidomide plus low-dose Dex as first line therapy in newly diagnosed multiple myeloma (MM). Methods: Pts with newly diagnosed, untreated, symptomatic MM were eligible. Pts in both arms received lenalidomide 25 mg/day PO on days 1–21 every 28 days. In addition, patients in the high-dose Dex arm (Arm A) received Dex 40 mg on days 1–4, 9–12, and 17–20 PO every 28 days, while pts in the low-dose Dex arm (Arm B) received Dex 40 mg on days 1, 8, 15, and 22 PO every 28 days. The primary endpoint was best response at 4 months on intent to treat basis. At 4 months pts could go off study for stem cell transplant or elect to continue therapy until progression. Response was defined as a decrease in serum and urine monoclonal (M) protein by 50% or higher. If the serum M protein was unmeasurable, a 90% or higher decrease in urine M protein was required. Responses need to be confirmed at least 4 weeks apart. Patients with disease progression or not responding to lenalidomide within 4 months switched to thalidomide with the same dose of dexamethasone they were receiving (Arms C and D, respectively). An independent Data Monitoring Committee approved release of these results. Results: 445 pts were enrolled: 223 randomized to Arm A and 222 to Arm B. Median age was 65 yrs. Serious adverse event data based on expedited reporting (AdEERS) is available on all pts (see table). Common adverse events of Grade 3 or higher were thromboembolism (18.4% in arm A vs 5.4% in Arm B), infection/pneumonia (18.8% vs 9.0%) and hyperglycemia (5.8% vs 1.8%). Incidence of any grade 4 or higher toxicity was 22.0% in Arm A vs 12.6% in Arm B. Response data is being analyzed. Conclusions: Lenalidomide plus two different schedules of Dex was investigated in this phase III trial. Preliminary results suggest that toxicity rates are higher in the high-dose Dex arm. The differences in the response rates between the two arms will dictate future trials and clinical practice. Major Toxicties (AdEERS) Toxicity Arm A (n=223) Arm B (n=222) Cardiac ischemia (Grade >=3) 2.7% 0.5% Hyperglycemia (Grade >=3) 5.8% 1.8% Infection/Pneumonitis (Grade >=3) 18.8% 9.0% Neuropathy (Grade >=3) 0.9% 0.9% Thromboembolism (Grade >=3) 18.4% 5.4% Any non-Hem toxicity (Grade >=3) 53.4% 36.0% Any toxicity (Grade >=4) 22.0% 12.6% Death (Grade 5) 4.5% 1.4%

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.

scholarly journals Three Drug Regimens for Newly Diagnosed Multiple Myeloma Transplant-Ineligible Elderly Patients - a Systematic Review

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5574-5574
Author(s):  
Abdul Aziz Siddiqui ◽  
Kazi Najamus-saqib Khan ◽  
Arafat Ali Farooqui ◽  
Muhammad Saad Farooqi ◽  
Muhammad Junaid Tariq ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Elderly Patients ◽  
Phase Ii ◽  
Low Dose ◽  
Phase Ii Trial ◽  
Alkylating Agents ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Great Efficacy ◽  
Drug Regimens

Introduction: Patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT) tend to have comorbidities and/or advanced age that make this subset of patients difficult to manage with current drug regimens. Methods: A comprehensive literature search of PubMed, Embase, Clinicaltrials.gov and Web of Science was performed from inception and completed on 07/17/2019. Studies focusing on efficacy and tolerability of 3-drug regimens in patients with NDMM were included for the review. Results: Out of 3579 studies, a total of 10 (08 phase II and 03 phase III) clinical trials in last ten years (2010-2019) using 3-drug regimens in NDMM elderly pts (893M/807F) ineligible for ASCT (determined by investigators) were selected. A total of 1703/1740 NDMM pts were evaluated. Proteasome inhibitors (PIs) such as carfilzomib (C), bortezomib (V) and ixazomib (I) showed promising results in elderly transplant-ineligible NDMM pts. CLARION trial (phase III, n=955) compared two PIs (C and V) with melphalan (M) and prednisone. There was no statistically significant difference in progression-free survival (PFS) between two groups (median: 22.3 vs 22.1 months; HR: 0.91; 95% CI, 0.75-1.10, p = 0.159) as well as overall survival (OS) (HR: 1.08; 95% CI: 0.82-1.43). Difference in the least square means of the HR-QoL (Health related- quality of life) was 4.99 (p<.0001) favoring C-group. M may not be an ideal drug to combine with carfilzomib in this setting given more AEs.(Facon et al 2019). V as 3-drug regimen in combination with lenalidomide (L) in 242 pts achieved statistically significant prolonged PFS (median 43 mo) and OS (median 75 mo) with great efficacy and acceptable risk-benefit profile. (Durie et al 2017; phase III). Multinational phase II trial (n=70) by Dimopoulos et al (2019) evaluated I, with different fixed doses of cyclophosphamide (Cy). Median duration was 19 cycles, indicating the long-term tolerability of regimen. With favorable toxicity profile and maintained QoL scores, trial concluded that this therapy is tolerable in elderly transplant-ineligible NDMM pts. Tuchman et al (2017) in phase II trial (n=14) investigated (V-Cy-d) and achieved ORR of 64%, with ≥VGPR of 57%. Low dose V showed great efficacy with M yielding ORR of 86% and VGPR or better of 49% in phase II trial (n=101) that also evaluated Cy as 3-drug combination but results were more productive with M with longer PFS and OS which reduced when impact of frailty was examined on outcomes. Since toxicity was higher with M, trial suggested that 2-drug combination should be preferred in elderly frail patients. (Larocca et al 2015). Efficacy was quite promising when Bringhen et al (2014) trialed C with Cy-d; 87% OS and 76% PFS at 1 y in phase II trial (n=58) with much favorable safety profile. Monoclonal antibodies (mAb) such as elotuzumab (E) and pembrolizumab (Pe) are also tested in elderly. First study conducted on NDMM pts using humanized mAb; E, in phase II trial (n=40) by Takezako et al (2017) attained primary endpoint of the study (ORR) of (88%) and VGPR or better of 45% in Japanese pts with tolerable toxicities in elderly. No subjects on this study experienced severe peripheral neuropathy. KEYNOTE-185; a phase III multinational trial by Usmani et al (2019) evaluated Pe with Ld in 151 pts. FDA halted this study due to unfavorable benefit-risk profile; 19 deaths, 6 due to disease progression (PD), and 13 due to treatment-related AEs. Median PFS and median OS were not reached in either group. Immunomodulators such as L achieved one of the longest PFS reported in a trial of transplant ineligible patients (35 mo) by using LVd regimen in phase II multicenter trial (n=50). (O'Donnell et al 2018) Alkylating agents like bendamustine (ben) and M have been tested in different novel regimens. Decreasing intensity and increasing duration of ben resulted in better outcomes in phase II trial (n=59) by Berdeja et al (2016) and can be given as first line treatment. Ben yielded great results with low dose dexa as compared to high dose achieving 92% ORR. Original regimen was effective but relatively more toxic. Incidence of herpes and neuropathy decreased dramatically with the treatment modifications. Conclusion: Three-drug regimens having PIs, mABs, immunomodulators and alkylating agents have shown desirable results in NDMM transplant (ASCT)-ineligible elderly patients and are likely the emerging standard of care for NDMM. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Efficacy of Modified Vrd-Lite for Transplant Ineligible Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-4
Author(s):  
Mizuki Ogura ◽  
Tadao Ishida ◽  
Moe Nomura ◽  
Hirofumi Irita ◽  
Junichiro Nashimoto ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Multiple Myeloma ◽  
Cardiac Amyloidosis ◽  
Staging System ◽  
Treatment Interruption ◽  
Cardiac Complications ◽  
High Dose ◽  
Al Amyloidosis ◽  
Newly Diagnosed ◽  
The Impact

BACKGROUND: High dose chemotherapy followed by autologous peripheral blood stem cell transplantation is an effective treatment for multiple myeloma. However, many patients with newly diagnosed multiple myeloma are transplant-ineligible because of their age and complications, result in a poorer prognosis than transplant-eligible patients. Furthermore, many of them cannot complete normal chemotherapy because of low tolerability. Here, we investigated the efficacy and safety of modified bortezomib with lenalidomide and dexamethasone (mVRD-lite) for transplant-ineligible patients with newly diagnosed multiple myeloma. STUDY DESIGN: A retrospective observational analysis was performed on patients who received mVRd-lite for the first line chemotherapy between Jan. 2016 and Mar. 2020 in our hospital. Patients who received high dose dexamethasone to reduce tumor burden, and patients who received bortezomib with dexamethasone or lenalidomide with dexamethasone as a reduction regimen of mVRd-lite were also included. We evaluated ORR, OS, PFS and adverse effect. mVRD-lite at first was administered over a 28-day cycle. Bortezomib 1.3 mg/m2 weekly was administered subcutaneously on days 1, 8, 15 and 22. Lenalidomide 15 mg was given orally 18 days, omitted on days 1, 8, 15, which are the days of bortezomib administration. Dexamethasone 20 mg was given orally on days 1, 2, 8, 9, 15, 16, 22, which are the day of and day after bortezomib. We also reviewed patients background, especially complication of light-chain amyloidosis and considered the impact of cardiac amyloidosis on patient prognosis. This study was conducted with the permission of the Ethics Review Board in our hospital. RESULTS: The subjects analyzed totaled 40 transplant-ineligible patients. 11(27.5%) patients were AL amyloidosis associated with multiple myeloma and 8(20%) patients had cardiac amyloidosis. Median age at diagnosis was 73 (range 48-86) and Male:Female=1:1. Most of them were judged inadequate to transplantation due to their age, general condition, or complication. One patient was ruled unfit to transplantation, because of his refusion. The Revised International Staging System (R-ISS) were I in 5 (12.5%), II in 25 (62.5%) and III in 8 (20%). 5(25%) patients switched to maintenance therapy. 17(42.5%) patients discontinued treatment, because of adverse effect (cardiac failure 4 ; two of them combined with cardiac amyloidosis, rash 4, peripheral neuropathy 3, infection 3, etc). 2(5%) patients died during treatment by mVRd-lite, because of Grade 4 adverse effect, such as pneumonia. 11(27.5%) patients died during observation period and causes of death were primary disease and TRM. 1(2.5%) patient was died of heart failure associated with cardiac amyloidosis. The overall response rate(ORR) during treatment period of mVRd-lite was obtained in 34(85%), including sCR in 5 (12.5%), VGPR in 13 (32.5%) and PR in 14(30%). 2(5%) patients achieved MRD negative. SD were observed in 3(7.5%) patients. 3(7.5%) patients were not evaluated efficacy because of treatment interruption by adverse effect. Overall survival rate at two year is 64.3%, median OS was not reached, at a median follow-up of 20 months. CONCLUSIONS: Transplant-ineligible multiple myeloma patients are associated with poor prognosis. Modified RVD-lite is one of the appropriate therapeutic options, in the transplant-ineligible multiple myeloma patients. Twenty-five percent of patients with cardiac amyloidosis had treatment discontinued due to cardiac complications. Further study is needed for treatment of patients with multiple myeloma complicated with cardiac amyloidosis. Disclosures Ishida: Janssen: Speakers Bureau; Celgene: Speakers Bureau; Ono pharmaceutical co: Speakers Bureau; Takeda pharmaceutical co: Speakers Bureau. Nashimoto:Janssen: Speakers Bureau; Celgene: Speakers Bureau. Tsukada:Takeda pharmaceutical co: Speakers Bureau. Suzuki:Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria; Bristol-Myers Squibb, Celgene and Amgen: Research Funding.

Efficacy of Melphalan and Prednisone Plus Thalidomide in Patients Older Than 75 Years With Newly Diagnosed Multiple Myeloma: IFM 01/01 Trial

2009 ◽  
Vol 27 (22) ◽  
pp. 3664-3670 ◽  
Author(s):  
Cyrille Hulin ◽  
Thierry Facon ◽  
Philippe Rodon ◽  
Brigitte Pegourie ◽  
Lotfi Benboubker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Elderly Patients ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Standards Of Care ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
To Receive

Purpose Until recently, melphalan and prednisone were the standards of care in elderly patients with multiple myeloma. The addition of thalidomide to this combination demonstrated a survival benefit for patients age 65 to 75 years. This randomized, placebo-controlled, phase III trial investigated the efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed myeloma. Patients and Methods Between April 2002 and December 2006, 232 previously untreated patients with myeloma, age 75 years or older, were enrolled and 229 were randomly assigned to treatment. All patients received melphalan (0.2 mg/kg/d) plus prednisone (2 mg/kg/d) for 12 courses (day 1 to 4) every 6 weeks. Patients were randomly assigned to receive 100 mg/d of oral thalidomide (n = 113) or placebo (n = 116), continuously for 72 weeks. The primary end point was overall survival. Results After a median follow-up of 47.5 months, overall survival was significantly longer in patients who received melphalan and prednisone plus thalidomide compared with those who received melphalan and prednisone plus placebo (median, 44.0 v 29.1 months; P = .028). Progression-free survival was significantly prolonged in the melphalan and prednisone plus thalidomide group (median, 24.1 v 18.5 months; P = .001). Two adverse events were significantly increased in the melphalan and prednisone plus thalidomide group: grade 2 to 4 peripheral neuropathy (20% v 5% in the melphalan and prednisone plus placebo group; P < .001) and grade 3 to 4 neutropenia (23% v 9%; P = .003). Conclusion This trial confirms the superiority of the combination melphalan and prednisone plus thalidomide over melphalan and prednisone alone for prolonging survival in very elderly patients with newly diagnosed myeloma. Toxicity was acceptable.

Total Therapy 1 (TT1): Status Report of the First Tandem Autotransplant (TAT) Trial for Multiple Myeloma (MM) - 15 Years Later.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1151-1151
Author(s):  
Bart Barlogie ◽  
Guido Tricot ◽  
Athanasios Fassas ◽  
Raman Desikan ◽  
Elias Anaissie ◽  
...  
Keyword(s):  
Overall Survival ◽  
Standard Dose ◽  
Detailed Account ◽  
Status Report ◽  
High Dose ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Long Term Outcome ◽  
Free Survival ◽  
Dose Therapy

Abstract Background: Melphalan-based high-dose therapy (HDT) with autologous peripheral blood stem cell support has become the standard of care for newly diagnosed patients with MM, based on IMF90 and MRC7 trial results of single HDT vs. standard-dose therapy and on IMF94 data demonstrating superior EFS and OS with TAT over single HDT. The aim of this report is to provide a detailed account of the long-term outcome of all 231 patients originally enrolled in TT1 between 8/1990 and 6/1995 of whom 63 remain alive. Patients and Methods: Outcome data on TT1 have been reported previously (Blood93, 1999; 101, 2003). Here we give final account of patient status with a median follow-up of 12 years (range, 9–15). Results: Of 231 patients, 195 had received at least 1 and 165 the 2 scheduled transplants; 7 without insurance coverage were given intermediate dose melphalan 70mg/sqm. Of 87 (38%) initially achieving CR (median, 27 mo), 17 (20%) remain in uninterrupted 1st CR. The median EFS duration was 31mo, and 32 (14%) remain continuously event-free. The median OS duration is 68 mo with a 12-yr estimate of almost 30%. Of all 63 survivors, 19% had cytogenetic abnormalities (CA) prior to therapy, and 38% had CA intermittently. Of the 17 patients in continuous CR, 10 never had CA at any time, 4 developed CA subsequently with resolution in 3; of 3 with baseline CA, 2 normalized and 1 persisted. A detailed account of CA type and frequency as well as salvage therapies such as thalidomide, bortezomib and further auto- or allotransplants will be provided. Conclusion: TT1 was the first tandem autotransplant protocol applied to 231 newly diagnosed patients MM that yielded an unprecedented positive outcome with 12-yr rates of CCR, EFS and OS of 20%, 14%, and 30%, respectively. The Figure displays a 3-phasic relapse pattern: an initial steep slope spanning years 1-3, a more shallow slope between years 4 to 10, merging into a cure-consistent “hockey-stick”. Event-Free Survival- TT1 Patients Event-Free Survival- TT1 Patients Overall Survival- TT1 Patients Overall Survival- TT1 Patients

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.

Arsenic Trioxide with Ascorbic Acid and High-Dose Melphalan for Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3090-3090 ◽  
Author(s):  
Muzaffar H. Qazilbash ◽  
Rima M. Saliba ◽  
Marilyn S. Davis ◽  
Floralyn L. Mendoza ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Ascorbic Acid ◽  
Arsenic Trioxide ◽  
Cell Transplantation ◽  
Hematopoietic Progenitor Cell ◽  
High Dose ◽  
Significant Difference ◽  
Preparative Regimen ◽  
The Impact

Abstract Backround: Arsenic trioxide (ATO) has been shown to be synergistic with melphalan both in vitro and in vivo. We conducted a phase I/II trial to determine the safety and efficacy of a combination of arsenic trioxide, melphalan and ascorbic acid (AA) as preparative regimen in patients undergoing high-dose therapy (HDT) and autologous hematopoietic progenitor cell transplantation for multiple myeloma (MM). We also assessed the impact ATO levels on melphalan pharmacokinetics (PK), engraftment and toxicity. Methods: Forty-eight patients with secretory myeloma (23 females, 25 males; median age: 54, range: 3570) were treated between 4/04 and 8/05. All patient received melphalan 100 mg/m2 IV on days -4 and -3 and AA 1000 mg/day IV on days -9 to -3. Patients were randomized to 3 arms; no ATO (arm 1), ATO 0.15 mg/kg IV on days -9 to -3 (arm 2) and ATO 0.25 mg/kg IV on days -9 to -3 (arm 3). Twelve patients had disease progression or relapse after a prior autograft. Median CD34 cells dose infused was 4.5 x 106/kg (range 2.3–10.9). Results: Patients in all 3 arms were evenly matched. With a median F/U of 14.0 months (range 6–25) post autograft, no dose-limiting toxicity or non-relapse mortality was seen. Toxicity was limited to grade I or II nausea, vomiting and diarrhea. Median ATO levels on day 0 in arms 1, 2 and 3 were 0.2, 26.3 and 46.2 ng/ml, respectively. Melphalan PK was not altered by ATO pretreatment. Median time to neutrophil engraftment (ANC >500/ dl) was 9 days. There were no engraftment failures or delays in the ATO arms. CR rate for the entire group was 23%, and total response rate (CR + PR) was 75%. 1-year Progression-free survival (PFS) and overall survival (OS) were 75% and 95%, respectively. There was no significant difference in CR, RR, PFS or OS between the 3 arms (p = 0.9, 0.9, 0.4 and 0.6, respectively). A prior autologous transplant (p = 0.02) and abnormal cytogenetics at transplant (p = 0.04) were associated with a significantly shorter remission. Conclusions: ATO + melphalan + ascorbic acid is a safe, effective and well tolerated preparative regimen for patients with multiple myeloma undergoing an autotransplant. A longer follow up is needed to assess the impact of ATO on progression-free and overall survival.

Lenalidomide Plus High-Dose Dexamethasone Provides Improved Overall Survival Compared to High-Dose Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma (MM): Results of 2 Phase III Studies (MM-009, MM-010) and Subgroup Analysis of Patients with Impaired Renal Function.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3547-3547 ◽  
Author(s):  
Donna Weber ◽  
Michael Wang ◽  
Christine Chen ◽  
Andrew Belch ◽  
Edward A. Stadtmauer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Renal Function ◽  
Creatinine Clearance ◽  
Subgroup Analysis ◽  
Impaired Renal Function ◽  
Phase Iii ◽  
High Dose ◽  
High Dose Dexamethasone ◽  
Duration Of Response

Abstract Lenalidomide is a novel, orally administered immunomodulatory drug (IMiD) that has single-agent activity against multiple myeloma (MM) and additive effects when combined with dexamethasone. We have previously reported improved response (OR), time to progression (TTP) and overall survival (OS) with lenalidomide-dexamethasone (Len-Dex) compared to dexamethasone-placebo (Dex) based on the results of 2 phase III trials (MM-009, North American, 353 pts; MM-010, Europe, Australia, and Israel, 351 pts). In both trials patients with relapsed or refractory MM not resistant to dexamethasone, were treated with dexamethasone 40 mg daily on days 1–4, 9–12, and 17–20 every 28 days and were randomized to receive either lenalidomide 25 mg daily orally on days 1–21 every 28 days or placebo. Beginning at cycle 5, Dex was reduced to 40 mg daily on days 1–4 only, every 28 days. Patients were also stratified with respect to B2M (≤2.5 vs. > 2.5 mg/mL), prior stem cell transplant (none vs. ≥ 1), and number of prior regimens (1 vs > 1). At a median follow-up from randomization of 17.1 mos (MM-009) and 16.5 mos (MM-010), both studies continue to show significant improvement with Len-Dex compared to Dex in OR (MM-009: 61% vs 20.5%, p<.001; MM-010: 59.1% vs. 24%, p<.001, respectively), TTP (MM-009: 11.1mos vs. 4.7mos, p<.001; MM-010: 11.3mos vs. 4.7mos, p<.001, respectively), and OS (MM-009: 29.6mos vs. 20.5mos, p<.001; MM-010: not estimable vs 20.6mos, p<.001, respectively). Pooled data from both trials demonstrates a significant improvement in duration of response for pts achieving ≥ PR with 122/216 pts (56.5%) who received Len-Dex continuing in remission (med. duration of response not reached but > 68.1 wks) compared to only 22/76 pts (28.9%) treated with dexamethasone alone (med. duration of response 22.1 wks, p<.001). An additional subgroup analysis was performed on pts with impaired creatinine clearance (cr cl). No significant difference in response rate, TTP, or OS was noted for patients with cr cl above or below 50 ml/min who were treated with Len-Dex, but for 16 pts with cr cl <30ml/min, med. TTP and OS was shorter than for those with cr cl >30ml/min, but still significantly higher than for pts treated with Dex. Grade 3–4 thrombocytopenia was significantly higher in pts with impaired renal function (<50ml/min, 13.8%; >50ml/min 4.6%, p<.01; <30ml/min, 18.8%, >30 ml/min, 5.5%, p<.05), but there was no difference for G3–4 neutropenia at either cutoff. Phase I–II evaluation to establish appropriate dosing in pts with cr cl < 30ml/min, particularly with respect to thrombocytopenia is warranted, but should not underscore improved OR, TTP, and OS for pts treated with Len-Dex regardless of creatinine clearance.

A Phase III Study of Enoxaparin Versus Low-Dose Warfarin Versus Aspirin as Thromboprophylaxis for Patients with Newly Diagnosed Multiple Myeloma Treated up-Front with Thalidomide-Containing Regimens

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3017-3017 ◽  
Author(s):  
Michele Cavo ◽  
Antonio Palumbo ◽  
Sara Bringhen ◽  
Antonietta Falcone ◽  
Pellegrino Musto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Induction Therapy ◽  
Cardiovascular Events ◽  
Low Dose ◽  
Phase Iii ◽  
Bleeding Complications ◽  
Newly Diagnosed ◽  
P Values ◽  
Dose Warfarin ◽  
To Receive

Abstract Thalidomide-containing regimens are currently being used as standard initial therapy for both younger and elderly pts with multiple myeloma (MM), but are associated with an increased risk of venous thromboembolism (VTE) which necessitates routine thromboprophylaxis. Controversies exist concerning the best thromboprophylactic regimen to be used in these pts. To address this issue, the Italian Myeloma Network GIMEMA designed a phase III sub-study aimed at prospectively investigating the efficacy and safety of low molecular weight heparin (LMWH) or fixed low-dose warfarin (WAR) or low-dose aspirin (ASA) as prophylaxis against VTE in newly diagnosed MM pts who were randomized to receive primary induction therapy with thalidomide-containing regimens in the context of 2 phase III studies conducted by the same group. In one of these studies, pts with ≤65 years of age were randomly assigned to receive Velcade-Thalidomide-Dexamethasone (VTD) or Thalidomide-Dexamethasone (TD) before autologous transplantation. In the other study, Velcade-Melphalan-Prednisone (VMP) was compared with VMP plus thalidomide (VMPT) for elderly patients aged &gt;65 years. The daily dose of Thalidomide was 200 mg in both VTD and TD, and 50 mg in VMPT. Pts randomized to VTD or TD received a total Dexamethasone dose of 320 mg/cycle, while those assigned to VMP or VMPT were given a total Prednisone dose of 240 mg/m2/cycle. By sub-study design, pts treated on VTD or TD or VMPT were randomly assigned to receive thromboprophylaxis with LMWH (Enoxaparin, 40 mg/d) or WAR (1.25 mg/d) or ASA (100 mg/d) for the duration of induction therapy. At the opposite, pts randomized to VMP did not receive any prophylaxis and were used as controls. Sub-study end points included incidence of VTE, acute cardiovascular events, sudden death, bleeding and any other serious adverse events. At the time of the present analysis, 703 pts who received at least 3 cycles of induction therapy were evaluated. Of these pts, 164 treated on VMP were the control group, while the remaining 539 pts (of whom, 209 treated on VTD, 211 on TD and 119 on VMPT) were randomized to receive either LMWH (n=178) or WAR (n=180) or ASA (n=181). Baseline pts characteristics and risk factors for VTE were comparable in all sub-groups. Overall, the risk of VTE was 3.9% with WAR vs 4.5% with LMWH vs 5.5% with ASA (P values not significant for comparisons between different sub-groups), whereas it was 1.8% among the controls. Median times to onset of VTE for pts treated on LMWH or WAR or ASA were 2.66 vs 2.96 vs 2.10 months, respectively. Pts receiving Velcade-containing regimens (VTD or VMPT) had a VTE frequency in the range of approximately 3%, as compared to 5.8% for pts on TD (P value not significant). The rates of cardiovascular events were 0.6% in each of sub-groups including LMWH, WAR and controls, vs 1.1% for pts treated on ASA. No sudden deaths were reported. The incidence of all grades bleeding was 0.6% with LMWH vs 1.1% with WAR vs 3.3% with ASA (P values not significant for comparisons between different sub-groups), while it was 3.7% among the controls. In conclusion, results of the present analysis show that the overall risk of VTE among sub-groups of pts treated with different thalidomide-containing regimens was not superior to that expected during the natural course of MM. No significant relationship was found between the frequency of VTE and thromboprophylactic regimens, induction treatments (e.g. containing or not Velcade) and age of pts (e.g. young vs elderly). In comparison with LMWH and WAR, there was a higher, albeit marginal, risk of VTE and bleeding complications associated with ASA prophylaxis. Finally, a finding not previously well recognized, fixed low-dose WAR was not inferior to LMWH in reducing the risk of VTE among newly diagnosed MM pts receiving thalidomide-containing regimens. For these pts, LMWH, WAR and ASA are likely to be effective thromboprophylactic regimens.

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