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.

Lenalidomide plus high-dose dexamethasone provides improved overall survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma (MM): Results of a North American phase III study (MM-009)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7521-7521 ◽  
Author(s):  
D. M. Weber ◽  
C. Chen ◽  
R. Niesvizky ◽  
M. Wang ◽  
A. Belch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Response Rate ◽  
Phase Iii ◽  
High Dose ◽  
Cell Transplant ◽  
Time To Progression ◽  
Prognostic Features ◽  
High Dose Dexamethasone ◽  
Grade 3

7521 Background: Lenalidomide is a novel, orally administered, immunomodulatory drug (IMiD) that has single-agent activity against MM and additive effects when combined with dexamethasone (Dex). Methods: In this phase 3, multicenter, double-blind trial, 354 patients (pts)with relapsed or refractory MM were treated with Dex 40 mg daily on days 1–4, 9–12, 17–20 every 28 days and were randomized to receive either lenalidomide (Len) 25 mg daily orally on days 1–21 every 28 days or placebo. Beginning with cycle 5, Dex was reduced to 40 mg daily on days 1–4 only, every 28 days. Patients were 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). The treatment arms were well balanced for prognostic features. Results: The overall response rate was greater with Len-Dex than with Dex-placebo (59.4% vs. 21.1%; p < 0.001). Complete responses were achieved in 12.9% of pts treated with Len-Dex and 0.6% of pts treated with Dex-placebo. The median time to progression (TTP) for pts treated with Len-Dex was 11.1 months compared to 4.7 months for pts treated with Dex-placebo (p < 0.000001). Median overall survival was higher with Len-Dex (not reached) compared to Dex-placebo (24 months) (hazard ratio 1.76, p = .0125). Grade 3–4 neutropenia was more frequent with combination therapy than with Dex-placebo (24% vs. 3.5%), however ≥ grade 3 infections were similar in both groups. Thromboembolic events occurred in 15% of pts treated with Len-Dex and in 3.5% of pts treated with Dex-placebo. Atrial fibrillation occurred in 8 pts and CHF developed in 4 pts treated with Len-Dex. Conclusions: Considering the ease of oral administration, higher response rate, longer time to progression and overall survival benefit, the combination of lenalidomide-dexamethasone may very well represent the treatment of choice for early refractory or relapsing multiple myeloma. The relatively infrequent side effects should not detract from these improvements, but the use of prophylactic antithrombotic therapy should be considered for patients treated with the combination of lenalidomide and dexamethasone. [Table: see text]

Survival Effect of Venous Thromboembolism in Patients With Multiple Myeloma Treated With Lenalidomide and High-Dose Dexamethasone

2010 ◽  
Vol 28 (1) ◽  
pp. 132-135 ◽  
Author(s):  
Maurizio Zangari ◽  
Guido Tricot ◽  
Latha Polavaram ◽  
Fenghuang Zhan ◽  
Ashlie Finlayson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Venous Thromboembolism ◽  
Retrospective Analysis ◽  
The United States ◽  
Phase Iii ◽  
High Dose ◽  
Time To Progression ◽  
High Dose Dexamethasone ◽  
Survival Effect

Purpose We conducted a retrospective analysis of the survival effect of venous thromboembolism (VTE) development in patients with multiple myeloma (MM). Methods Two identically designed, multicenter, double-blind, phase III clinical trials (MM-009 and MM-010) were conducted in Europe and the United States to assess the effect of lenalidomide in combination with dexamethasone versus dexamethasone plus placebo in patients with relapsed or refractory MM, after failing at least one prior line of treatment. In this retrospective analysis, we evaluated incidence and survival effect of thromboembolism in 353 patients randomly assigned to receive 25 mg of lenalidomide on days 1 through 21 of a 28-day cycle, plus 40 mg of oral dexamethasone on days 1 through 4, 9 through 12, and 17 through 20 for the first four cycles; after the fourth cycle, 40 mg of dexamethasone was administered on days 1 through 4 only. Results Seventeen percent of patients experienced a thromboembolic episode. The development of VTE did not significantly affect overall survival (P = .90) or time to progression (P = .34). No significant survival impact was observed in a subgroup of patients who received prophylactic anticoagulation (overall survival P = .7, time to progression P = .1). Conclusion Patients with MM treated with lenalidomide and high-dose dexamethasone who developed a VTE did not experience shorter overall survival or time to progression.

Renal Impairment in Patients With Multiple Myeloma: A Consensus Statement on Behalf of the International Myeloma Working Group

2010 ◽  
Vol 28 (33) ◽  
pp. 4976-4984 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Evangelos Terpos ◽  
Asher Chanan-Khan ◽  
Nelson Leung ◽  
Heinz Ludwig ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Renal Impairment ◽  
Light Chain ◽  
Renal Injury ◽  
High Dose ◽  
Acute Renal Injury ◽  
High Dose Dexamethasone ◽  
Cast Nephropathy ◽  
High Dose Melphalan

Renal impairment is a common complication of multiple myeloma (MM). The estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula is the recommended method for the assessment of renal function in patients with MM with stabilized serum creatinine. In acute renal injury, the RIFLE (risk, injury, failure, loss and end-stage kidney disease) and Acute Renal Injury Network criteria seem to be appropriate to define the severity of renal impairment. Novel criteria based on eGFR measurements are recommended for the definition of the reversibility of renal impairment. Rapid intervention to reverse renal dysfunction is critical for the management of these patients, especially for those with light chain cast nephropathy. Bortezomib with high-dose dexamethasone is considered as the treatment of choice for such patients. There is limited experience with thalidomide in patients with myeloma with renal impairment. Thus, thalidomide can be carefully administered, mainly in the context of well-designed clinical trials, to evaluate if it can improve the rapidity and probability of response that is produced by the combination with bortezomib and high-dose dexamethasone. Lenalidomide is effective in this setting and can reverse renal insufficiency in a significant subset of patients, when it is given at reduced doses, according to renal function. The role of plasma exchange in patients with suspected light chain cast nephropathy and renal impairment is controversial. High-dose melphalan (140 mg/m2) and autologous stem-cell transplantation should be limited to younger patients with chemosensitive disease.

Achievement of CR and nCR Before and After First High-Dose Therapy Followed by Autologous Stem Cell Transplantation Is a Major Marker for Long-Term Survival in Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3400-3400
Author(s):  
Hartmut Goldschmidt ◽  
Gerlinde Egerer ◽  
Ute Hegenbart ◽  
Markus Munder ◽  
Thomas Hielscher ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Progression Free Survival ◽  
High Dose ◽  
Significant Prognostic Factor ◽  
High Dose Therapy ◽  
Free Survival ◽  
Before And After ◽  
Duration Of Response

Abstract Abstract 3400 Poster Board III-288 To analyse the impact of complete response (CR), near CR (nCR) and very good partial response (VGPR) before and after first high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) on overall survival (OS) and progression-free survival (PFS), we evaluated all patients with multiple myeloma (MM) who underwent an ASCT in frontline treatment at our centre. The transplantations were performed between June 1992 and February 2009 giving a minimum follow up of 5 months after ASCT. The retrospective analysis included a total of 994 patients (579 males and 415 females) with a median age of 58 years at time of first ASCT (range 25 - 76 years). Median follow-up after first ASCT was 5.8 years. All patients suffered from symptomatic MM. Before induction treatment 48%, 31% and 21% of patients were in ISS-stage I, II and III, respectively. The following induction regimes were applied prior to HDT: VAD (n=683), TAD (n=74), PAD (n=64), and other regimes (n= 173). The patients were treated with HDT once (n= 460), twice (n=437) or thrice (n=97). 91 patients received an allogeneic SCT, 30 of these before first progression after ASCT. These were censored for PFS at time of allogeneic SCT. Maintenance therapy (interferon n=332, thalidomide n=203, bortezomib n=48 or others n=13) was administered in 596 patients. Overall survival and progression-free survival were calculated from the time of first ASCT. The median OS time was 5.7 years and the median PFS was 2.2 years. Log-rank test, univariate and multivariate Cox PH regression as well as landmark analyses were utilized to assess the prognostic impact of response. We analysed the effect of achievement of CR, of nCR or CR and of VGPR or CR or nCR before and after HDT, respectively. Achieving CR or nCR is a highly significant prognostic factor for PFS and OS before (p<0.001 and p=0.01, respectively) and after first HDT (both p<0.001). The group including VGPR showed superior outcome when assessed after HDT, driven by the effect of CR/nCR. When adjusting for the effect of age, beta-2 microglobulin before ASCT, albumin before ASCT, new drugs before ASCT (thalidomide and bortezomib; yes/no), second ASCT within 9 months (yes/no), maintenance therapy (yes/no), and date of first ASCT, achieving CR or nCR remained a significant prognostic factor (PFS after ASCT: HR=0.66 [0.54;0.80], p<0.001; OS after ASCT: HR=0.65 [0.51;0.83], p=0.001). In addition, we analyzed the effect of duration of response compared to response achievement per se. Patients who sustained their remission (overall response = PR and better) at 3 yrs after first ASCT had a favourable prognosis with respect to OS compared to patients losing remission. Conclusion: In our single-center cohort achieving CR or nCR before and after first HDT is highly prognostic for PFS and OS in MM. Sustained duration of response is also associated with an improved prognosis (3 years landmark analysis). At our centre we recommend that patients not achieving at least an nCR should be treated with a second cycle of HDT. Disclosures: No relevant conflicts of interest to declare.

A Phase I/II Study of the Tolerability of Lenalidomide and Low Dose Dexamethasone in Previously Treated Multiple Myeloma Patients with Impaired Renal Function: Pre1003, a Precog LLC Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1856-1856
Author(s):  
Joseph R. Mikhael ◽  
Judith Manola ◽  
Amylou Constance Dueck ◽  
Suzanne R Hayman ◽  
Kurt Oettel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Renal Function ◽  
Renal Insufficiency ◽  
Impaired Renal Function ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 1856 Background: Lenalidomide has proven to be a highly effective treatment in relapsed multiple myeloma (MM), particularly when used in combination with dexamethasone. However, over 30% of patients with myeloma have renal insufficiency and as lenalidomide is renally excreted, little information is available about its use in myeloma patients with impaired kidney function. Defining a safe and effective dose of lenalidomide in this context is critical. Objective: We undertook this study to establish the maximum tolerated dose of lenalidomide in three cohorts of patients with different levels of impaired renal function: Group A - patients with creatinine clearance (CrCl) between 30 and 60 mL/min, Group B - patients with CrCl <30 mL/min not on dialysis, and Group C - patients with CrCl < 30mL/min who are on dialysis. Secondary endpoints included response rate, progression free survival and overall survival. Methods: Eligible patients had previously treated MM with renal impairment defined as creatinine clearance < 60 mL/min measured within 21 days prior to registration. Patients previously treated with lenalidomide were required to demonstrate clinical response (any duration) or stable disease with progression-free interval of > 6 months from start of that therapy. All patients received dexamethasone 40 mg orally on days 1, 8, 15 and 22 of a 28-day cycle. Prophylactic anticoagulation consisted of either 81 mg or 325 mg per day of aspirin. Patients also received lenalidomide orally every 1 or 2 days on days 1 through 21 of a 28-day cycle, as described below (Table 1). Starting doses were as in US Product Insert. Dose escalation follows a standard 3+3 design. Results: There have been 23 patients enrolled into groups and cohorts as shown in Table 1. Median age was 73 (range 49–89) and 13 (57%) were women. ISS stage was advanced in all patients, 0 in stage 1, 4 (18%) in stage 2 and 19 (82%) in stage 3. The regimen was well tolerated. Indeed, the MTD has not been reached in any of the groups, as no DLTs have occurred to date. The most commonly reported clinical adverse events (all grades, independent of attribution) across all patients included infections, hyperglycemia, constipation, dizziness, hyponatremia, hypocalcemia and tremor. Hematological toxicities (grade 3–4) occurred in 13 out of 21 pts (62%), mostly neutropenia and thrombocytopenia. Grade 3–4 events at least possibly related to the regimen occurred in 70% and included pneumonia (26%) and otitis media (9%). Response was seen in 14 patients, resulting in an overall response rate of 61%. CR was seen in 1 patient (4%), VGPR in 2 patients (9%), PR in 11 patients (43%), and SD for 9 patients. With median follow-up of 15.5 months, median progression-free survival is 9.8 months and median overall survival is 22 months. Conclusion: Lenalidomide and dexamethasone is a safe and effective regimen in patients with multiple myeloma and renal insufficiency. It is also very well tolerated, although cytopenias are common but manageable. MTD has yet to be reached in each group, allowing for higher doses to be given than previously thought, including 25mg daily (for 21/28 days) in patients with CrCl 30–60 mL/min, 25 mg every other day (for 21/28 days) in patients with CrCl < 30 mL/min not on dialysis, and 10mg daily (for 21/28 days) in patients with CrCl < 30 mL/min on dialysis. These results will provide needed, clinically relevant dosing for lenalidomide in MM patients with renal insufficiency. Disclosures: Kaufman: Millenium: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Novartis: Consultancy.

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&lt;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.

Autotransplantation in Patients with Multiple Myeloma and Concurrent Renal Failure Is Safe and Feasible and Associated with Recovery of Renal Function in > 30% of Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5126-5126
Author(s):  
Gaurav C. Parikh ◽  
Rima M. Saliba ◽  
Amit Lahoti ◽  
Chitra Hosing ◽  
Floralyn Mendoza ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Renal Failure ◽  
Renal Function ◽  
Serum Creatinine ◽  
Hazard Ratio ◽  
P Value ◽  
High Dose ◽  
Post Transplant ◽  
Relapsed Disease

Abstract Background: About 20% of patients with multiple myeloma (MM) have renal impairment at diagnosis and 2–3% are dialysis-dependent (DD). These patients may potentially benefit from high-dose therapy (HDT) and autotransplants. Method: We analyzed the outcome in 48 patient who received an autotransplant for MM while in renal failure at our institution between 8/1991 and 9/2006. Renal failure was defined as serum creatinine ≥ 2 mg/dl sustained for > 1 month. 9 patients (18%) were DD. Median age was 56 (29–72) years. 26 patients (54%) had at least a PR to induction therapy, 16 had primary refractory disease (33%) and 6 patients (12%) had relapsed disease. Median serum Cr was 2.9 mg/dl (2.0 – 12.5) and creatinine clearance (CrCl) at transplant was 33 ml/min (8.7 – 63). A CrCl of <20 ml/min was seen in 15 patients (31%). PBSC mobilization was performed with G-CSF alone in 37 patients (77%) and chemotherapy + G-CSF in the rest. Median CD34 cell dose was 4.47 x 106 /kg (1.4 – 9.7). Forty-six patients received HD melphalan as preparative regimen, while 2 patients received a combination of thiotepa, busulfan and cyclophosphamide. Results: 9 patients achieved a CR (19%), with a total response rate (CR + PR) of 67% (32 patients). 2 patients (4%) died within 100 days of autotransplant. Median times to neutrophil and platelet engraftment were 10 (9–18) and 12 (8–81) days, respectively. Grade ≥ 1 mucositis was seen in 21 patients (43%), with 3 patients (6%) experiencing grade ≥3 mucositis. After a median follow up of 34 months, the estimated median PFS and OS were 21 and 87 months, respectively. Kaplan-Meier estimates of 5-year PFS and OS probabilities were 21% and 54%, respectively. Significant improvement in renal function, defined as an increase in Glomerular Filtration Rate by 25% above baseline by 1 year post-transplant, was seen in 17 patients (35%). None of the 9 DD patients became dialysis independent. A pre-transplant creatinine level of ≥ 3mg/dl was associated with a significantly shorter overall survival (p = 0.05, HR 2.8), but did not adversely impact the improvement in renal function (p = 0.6). Conclusion: Autotransplant after HDT is safe and feasible in patients with multiple myeloma and renal failure. Response rates and outcomes were similar to those observed in other patients. Approximately 35% of patients had a significant improvement in renal function post-transplant. Analysis Results Ref= Reference N Event Free Survival Overall Survival 48 Hazard Ratio at 3 years 95% CI p value Hazard ratio at 3 years 95% CI p value Age ≤ 55 23 Ref Ref > 55 25 1.2 0.6–2.7 0.6 1.2 0.4–3.1 0.8 Cytogenetics Abnormal 10 0.9 0.4–2.5 0.9 1.7 0.5–6.1 0.4 Normal 27 Ref Ref Pretransplant Dialysis Dependent Yes 9 1.1 0.4–3.4 0.8 1.1 0.4–4.7 0.6 No 39 Ref Ref Serum Creatinine ≥ 3 23 1.6 0.7–3.4 0.2 2.8 1–7.9 0.05 <3 25 Ref Ref

Bortezomib Demonstrates Superior Efficacy to High-Dose Dexamethasone in Relapsed Multiple Myeloma: Final Report of the APEX Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1479-1479 ◽  
Author(s):  
Paul Richardson ◽  
P. Sonneveld ◽  
M. Schuster ◽  
D. Irwin ◽  
E. Stadtmauer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Response Rate ◽  
Randomized Study ◽  
Single Agent ◽  
Hazard Ratio ◽  
High Dose ◽  
Final Report ◽  
High Dose Dexamethasone ◽  
Duration Of Response ◽  
Overall Survival Benefit

Abstract Introduction/Methods: This international phase 3 study conducted at 93 sites is the largest randomized study to date in relapsed multiple myeloma (MM). Patients (pts) had to have received 1–3 prior therapies and those with dexamethasone (Dex) refractory disease were excluded. Pts were randomized to bortezomib (VELCADE®) 1.3 mg/m2 IV d 1, 4, 8, 11 q3wk for 8 cycles followed by 3 cycles on d 1, 8, 15, 22 q5wk, or Dex 40 mg PO d 1–4, 9–12, 17–20 q5wk for 4 cycles followed by 5 cycles on d 1–4 every 28 d. The 1° endpoint was time to progression (TTP); 2° endpoints included survival, response rate (CR+PR) using EBMT criteria, duration of response, time to response (TTR), time to skeletal events, infections ≥gr 3 and safety; exploratory endpoints included pharmacogenomics and quality of life. Pts with progressive disease on Dex were eligible to crossover to bortezomib in a companion study. Results: 669 pts were randomized and baseline characteristics were balanced in both arms. Based on a median follow-up of 8.3 mo, bortezomib demonstrated a 78% improvement in median TTP (hazard ratio 0.55, P<0.0001) and a significant 1-y and overall survival benefit over Dex (hazard ratio 0.53, P=0.0005; hazard ratio 0.57, P=0.0013, respectively). The response rate (CR+PR) was significantly higher (P<0.0001) with CR/nCR rates of 13% for bortezomib vs 2% for Dex. 132 (40%) and 119 (35%) pts received bortezomib or Dex 2nd line, respectively. Importantly, in 2nd-line bortezomib vs Dex, median TTP was 7.0 v 5.6 mo, 1-y survival was 89% vs 72%, and CR+PR rate was 45% vs 26%, respectively. The incidence of ≥ gr 3 adverse events and the discontinuation rate were similar across treatments in all pts. Conclusion: This is the first and largest randomized study demonstrating a survival advantage in relapsed MM, with single-agent bortezomib proving superior to Dex based on TTP, survival, and response. Superiority was also observed in 2nd line and later salvage therapy. The safety profiles of bortezomib and Dex were predictable and toxicities were manageable. Efficacy Bortezomib Dex P (n=333) (n=336) NC = not calculated. Median TTP, mo 6.2 3.5 <0.0001 1 prior line 7.0 (n=132) 5.6 (n=119) 0.0021 > 1 prior line 4.9 (n=200) 2.9 (n=217) <0.0001 1-year survival, % 80 66 0.0005 1 prior line 89 72 0.0098 > 1 prior line 73 62 0.0109 CR, % (n/N) 6 (20/315) 1 (2/312) 0.0001 1 prior line 6 (8/128) 2 (2/110) 0.0842 > 1 prior line 6 (12/187) 0 (0/202) 0.0002 CR/PR, % (n/N) 38 (121/315) 18 (56/312) <0.0001 1 prior line 45 (57/128) 26 (29/110) 0.0035 > 1 prior line 34 (64/187) 13 (27/202) <0.0001 Median TTR (CR/PR), d 43 43 NC

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