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.

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 >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.

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%

scholarly journals VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1835-1835 ◽  
Author(s):  
Katrina M Piedra ◽  
Hani Hassoun ◽  
Larry W. Buie ◽  
Sean M. Devlin ◽  
Jessica Flynn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cancer Trial ◽  
Oncology Research ◽  
Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

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.

Aprepitant, Granisetron, and Dexamethasone for Prevention of Chemotherapy-Induced Nausea and Vomiting After High-Dose Melphalan in Autologous Transplantation for Multiple Myeloma: Results of a Randomized, Placebo-Controlled Phase III Trial

2014 ◽  
Vol 32 (30) ◽  
pp. 3413-3420 ◽  
Author(s):  
Thomas Schmitt ◽  
Hartmut Goldschmidt ◽  
Kai Neben ◽  
Anja Freiberger ◽  
Johannes Hüsing ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Multiple Myeloma ◽  
Rescue Therapy ◽  
Autologous Transplantation ◽  
Nausea And Vomiting ◽  
Phase Iii ◽  
High Dose ◽  
Phase Iii Trial ◽  
End Point

Purpose The optimal regimen to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing high-dose chemotherapy and autologous stem-cell transplantation (ASCT) is unclear. To evaluate the effect of aprepitant in addition to a standard regimen, we conducted this randomized, placebo-controlled phase III trial. Patients and Methods Patients with multiple myeloma were randomly assigned at a one-to-one ratio to receive either aprepitant (125 mg orally on day 1 and 80 mg orally on days 2 to 4), granisetron (2 mg orally on days 1 to 4), and dexamethasone (4 mg orally on day 1 and 2 mg orally on days 2 to 3) or matching placebo, granisetron (2 mg orally on days 1 to 4), and dexamethasone (8 mg orally on day 1 and 4 mg orally on days 2 to 3). Melphalan 100 mg/m2 was administered intravenously on days 1 to 2. ASCT was performed on day 4. The primary end point (complete response) was defined as no emesis and no rescue therapy within 120 hours of melphalan administration. Quality of life was assessed by modified Functional Living Index–Emesis (FLIE) questionnaire on days −1 and 6. Results Overall, 362 patients were available for the efficacy analysis (181 in each treatment arm). Significantly more patients receiving aprepitant reached the primary end point (58% v 41%; odds ratio [OR], 1.92; 95% CI, 1.23 to 3.00; P = .0042). Absence of major nausea (94% v 88%; OR, 2.37; 95% CI, 1.09 to 5.15; P = .026) and emesis (78% v 65%; OR, 1.99; 95% CI, 1.25 to 3.18; P = .0036) within 120 hours was increased by aprepitant. Mean total FLIE score (± standard deviation) was 114 ± 18 for aprepitant and 106 ± 26 for placebo (P < .001). Conclusion The addition of aprepitant resulted in significantly less CINV and had a positive effect on quality of life.

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.

Sign in / Sign up

Export Citation Format

Share Document