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

Bortezomib Continues Demonstrates Superior Efficacy Compared with High-Dose Dexamethasone in Relapsed Multiple Myeloma: Updated Results of the APEX Trail.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2547-2547 ◽  
Author(s):  
Paul Richardson ◽  
P. Sonneveld ◽  
M. Schuster ◽  
D. Irwin ◽  
E. Stadtmauer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Response Rate ◽  
Single Agent ◽  
Response Rates ◽  
High Dose ◽  
High Dose Dexamethasone ◽  
Duration Of Response ◽  
Clinical Benefits ◽  
Grade 3

Abstract Introduction: In the international, multicenter phase 3 APEX trial, 669 patients (pts) with multiple myeloma (MM) who had relapsed after 1–3 prior therapies were randomized to receive 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 dexamethasone (Dex) 40 mg PO d 1–4, 9–12, 17–20 q5wk for 4 cycles followed by 5 cycles on d 1–4 q4wk. Pts refractory to Dex were excluded, and those with progressive disease on Dex were eligible to cross over to bortezomib. Pts receiving bortezomib achieved significant improvement in time to progression (TTP, primary end point), response rate (CR + PR using EBMT criteria), and survival (Richardson. NEJM.2005;352:2487), which resulted in early closure of the trial. The duration of response (DOR) was longer with bortezomib, and infections ≥ grade 3, time to skeletal events, grade 4 adverse events (AE), serious AE, and discontinuations due to AE were similar in the 2 treatment arms. Methods: In this analysis, updated response rates, time to response (TTR), DOR, survival, and TTP are presented after extended follow-up. A matched-pairs analysis comparing survival and TTP of pts on bortezomib in APEX with those in another trial of MM pts who received bortezomib after Dex will also be presented. Results: 669 pts received a median of 7 cycles of therapy. Based on a median follow-up of 15.8 months, the median TTP, 1-year and overall survival (OS), response rates, median TTR, and median DOR for pts receiving bortezomib are shown in the table. Median duration of therapy for responders (CR + PR) was 7.2 months. Improved response with longer therapy (after cycle 6) was observed in 76 pts (56% of responders) in the bortezomib arm (20 pts improved from MR or PR to CR, and 56 pts improved from MR to PR). Furthermore, 28 of 135 responders (21%) achieved first response (CR/PR) after cycle 4, including 18 pts (13%) on or after cycle 6, and 10 pts (7%) on or after cycle 8. OS increased substantially with more follow-up. Median TTR was more rapid, and median DOR was longer in pts achieving CR and near CR than in those with PR. Conclusion: Updated TTP, response rates, survival, TTR, and DOR for the bortezomib group continue to support the findings of the original analysis. Thus, the clinical benefits of single-agent bortezomib in pts with relapsed MM remain robust after extended follow-up, supporting its early use in relapsed MM and its further study in the treatment of newly diagnosed disease. Efficacy Bortezomib (n = 333) Median TTP, mo 6.2 1-year survival, % 80 Median OS, mo 25.4 Response rate, % (n/N) 43 (135/315) CR 9 (27/315) PR 34 (108/315) -near CR 7 (21/315) Median TTR, mo (range) 1.4 (0.5–6.0) CR 0.8 (0.5–4.0) PR 1.4 (0.5–6.0) -near CR 0.8 (0.6–2.4) Median DOR, mo 7.8 CR 9.9 PR 7.6 -near CR 11.5

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]

Bortezomib in Combination with High-Dose Dexamethasone and Continuous Low-Dose Oral Cyclophosphamide for Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2549-2549 ◽  
Author(s):  
Martin Kropff ◽  
Guido Bisping ◽  
Peter Liebisch ◽  
Orhan Sezer ◽  
Hermann Einsele ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Low Dose ◽  
Response Rate ◽  
Single Agent ◽  
Median Number ◽  
High Dose ◽  
Oral Cyclophosphamide ◽  
Minor Response ◽  
Chromosome 13 ◽  
Dose Oral

Abstract Single agent bortezomib treatment yields ≥ partial responses (PR) in 24% of patients with relapsed, refractory multiple myeloma (MM) and 38% of patients who had received 1 – 3 previous therapies. Dexamethasone (DEX) adds to anti-myeloma activity of bortezomib. The present phase II trial was intitiated to study bortezomib combined with DEX and continuous low-dose oral cyclophosphamide (CY). 50 patients with advanced MM were scheduled to receive bortezomib 1.3 mg/m2 IV days 1, 4, 8, and 11 q 3 weeks for 8 cycles in combination with DEX 20 mg PO on the day of bortezomib injection and the day thereafter, and CY 50 mg PO daily; followed by 3 cycles bortezomib 1.3 mg/m2 IV days 1, 8, 15, and 22 q 5 weeks in combination with corresponding DEX and CY schedules. Patient characteristics included median age 63 years; B2M &gt; 3,0 mg/L, 64%; CRP &gt; 3,0 mg/L, 25%; deletion of chromosome 13, 46%; median number of prior regimens, 2 (range 1 – 9), and prior standard therapy &gt; 12 mo, 94 %. 78% of patients had relapsed after high-dose melphalan. The EBMT criteria were used for definition of response. Five patients (10%) achieved a complete response, 33 (66%) a PR, and 6 (12%) a minor response (MR) resulting in an overall response rate (≥MR) of 88%. On an intention-to-treat basis, median event-free survival (EFS) with this combination was 10 months. After a median follow-up of 10 months, median overall survival has not been reached. Notably, chromosome 13 deletion was predictive of a favorable outcome (higher response rate, longer EFS) in this setting. The median number or treatment cycles given was 6. 56% of the patients terminated study treatment prematurely, mainly for disease progression (10%) or adverse events (34%). Grade 4 neutropenia during at least one treatment cycle occurred in one patient (2%), grade 4 thrombocytopenia in 17%; one thrombocytopenic bleeding. Grade 3/4 non-hematologic toxicities requiring dose or schedule modifications included infections (26%), peripheral neuropathy (25%), fatigue (15%), herpes zoster (13%), and cardiovascular events (11%). One patient succumbed to infection without predisposing neutropenia. Bortezomib in combination with DEX and CY appears to be a highly active regimen without increased toxicity compared to a single agent treatment with bortezomib. Maintenance treatment might be required for prolonged EFS.

Relationship between Quality of Response to Bortezomib (btz) and Clinical Benefit in Multiple Myeloma (MM) in the APEX and SUMMIT Studies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3529-3529 ◽  
Author(s):  
Ruben Niesvizky ◽  
P.G. Richardson ◽  
P. Sonneveld ◽  
M.W. Schuster ◽  
M. Coleman ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Response Rate ◽  
Alternative Therapy ◽  
Single Agent ◽  
Initial Response ◽  
High Dose ◽  
Mass Reduction ◽  
Tumor Mass ◽  
High Dose Dexamethasone

Abstract BACKGROUND: The phase 2 SUMMIT trial of patients (pts) with relapsed and refractory MM showed that btz (VELCADE®) is active, with a response rate of 27% (CR/PR) as a single agent, median TTP of 7 months, and median OS of 17 months. The phase 3 APEX trial in pts with relapsed MM following 1–3 prior therapies showed btz to be superior to high-dose dexamethasone (dex) in terms of response rate, TTP, and OS. Updated APEX data show a CR/PR rate of 43%, median TTP of 6.2 months, and median OS of 29.8 months. This analysis evaluated the relationship between quality of response to btz (CR/nCR versus PR; PR does not include nCR in this analysis) in these trials and clinical benefit, as defined by treatment-free interval and time-to-alternative-therapy (TFI and TTAT; time from last and first dose of btz, respectively, to first dose of alternative antineoplastic therapy), OS, and TTP. METHODS: In SUMMIT, 202 pts received btz 1.3mg/m2 on days 1, 4, 8, and 11 for up to eight 21-day cycles (median # of cycles: 6). Dex 20mg was added on the day of and day after each btz dose in pts with suboptimal responses to btz alone. In one arm of APEX, 333 pts received btz 1.3mg/m2 on days 1, 4, 8, and 11 for eight 3-week cycles and then on days 1, 8, 15, and 22 for three 5-week maintenance cycles (median # of cycles: 6). Responses in both trials were assessed according to EBMT criteria (modified to include nCR, a CR with positive immunofixation test). RESULTS: Data are shown in the Table. Median TFI appeared longer in pts with CR/nCR vs PR (SUMMIT, 9.8 vs 3.1 months; APEX, 17.5 vs 6.7 months). Similarly, TTAT appeared longer in pts with CR/nCR vs PR (SUMMIT, 15.4 vs 8.5; APEX, 21.2 vs 14.0). Median OS in all response groups has not yet been reached after a median follow-up of 22 months. TTP tended to be longer with CR/nCR vs PR in both studies (SUMMIT, 16.4 vs 9.2; APEX, 12.2 vs 8.3). CONCLUSIONS: Increasing quality of response to btz is associated with greater clinical benefit assessed by extended TFI ,TTAT, and TTP. Long un-maintained remissions can be attained with btz by achieving maximum tumor mass reduction (CR/nCR), even in pts with relapsed/refractory MM. Updated APEX data show that despite rapid initial response, many pts showed continued improvement in terms of M-protein reduction, and an increasing proportion of pts achieved CR with continued therapy. These data, together with the findings of this analysis, support maximizing tumor mass reduction to CR/nCR with btz to achieve greater clinical benefit. Clinical benefit of btz by response Kaplan-Meier median (95% CI) CR/nCR PR* *PR does not include nCR in this analysis; †Includes 8 cycles of protocol-specified therapy plus maintenance cycles SUMMIT, n 19 34 TFI, mo 9.8 (2.7,14.3) 3.1 (2.0,8.7) TTAT, mo 15.4 (7.9,17.6) 8.5 (7.3,14.0) TTP, mo 16.4 (10.6,NE) 9.2 (7.2,NE) Median cycles, n 8 8 APEX, n 48 87 TFI, mo 17.5 (6.7,24.1) 6.7(4.4,10.0) TTAT, mo 21.2 (14.0,27.1) 14.0 (12.6,16.1) TTP, mo 12.2 (8.8,NE) 8.3 (7.6,10.3) Median cycles,† n 9 10

Bortezomib and Vorinostat Therapy as Maintenance Therapy after Autologous Transplant for Multiple Myeloma

2019 ◽  
Vol 143 (2) ◽  
pp. 146-154
Author(s):  
Leona A. Holmberg ◽  
Damian Green ◽  
Edward Libby ◽  
P.S. Becker
Keyword(s):  
Multiple Myeloma ◽  
Randomized Study ◽  
Single Agent ◽  
Survival Rates ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
High Dose Melphalan ◽  
Additional Therapy

Background: In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional therapy has been added post-ASCT. In a nontransplant relapse setting, the combination of intravenous bortezomib and oral vorinostat (BV) was studied and showed efficacy. Therefore, it was reasonable to study this combination therapy post-ASCT. Patients and Methods: We report on BV given post-ASCT. All 30 patients underwent conditioning for ASCT with high-dose melphalan. After recovery from the acute transplant-related toxicity, BV therapy was started and given for a total of 12 (28-day) cycles. Results: The most common toxicities were hematological, gastrointestinal (diarrhea and nausea), fatigue, and peripheral neuropathy. The median follow-up for BV patients is 7.8 (range: 6.12–9.03) years. After BV therapy, 18 patients (60%) are alive, and 9 (30%) are alive without disease progression. Conclusions: BV can be given post-ASCT with an acceptable toxicity profile and produces reasonable disease-free and overall survival rates. A randomized study comparing the BV regimen to single-agent lenalidomide or bortezomib is needed.

scholarly journals A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma

Blood ◽  
2012 ◽  
Vol 120 (14) ◽  
pp. 2817-2825 ◽  
Author(s):  
David S. Siegel ◽  
Thomas Martin ◽  
Michael Wang ◽  
Ravi Vij ◽  
Andrzej J. Jakubowiak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Clinical Benefit ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Phase 2 ◽  
Refractory Multiple Myeloma ◽  
Phase 2 Study ◽  
Duration Of Response

Abstract Carfilzomib is a next-generation, selective proteasome inhibitor being evaluated for the treatment of relapsed and refractory multiple myeloma. In this open-label, single-arm phase 2 study (PX-171-003-A1), patients received single-agent carfilzomib 20 mg/m2 intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m2 for ≤ 12 cycles. The primary endpoint was overall response rate (≥ partial response). Secondary endpoints included clinical benefit response rate (≥ minimal response), duration of response, progression-free survival, overall survival, and safety. A total of 266 patients were evaluable for safety, 257 for efficacy; 95% were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients had median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. Overall response rate was 23.7% with median duration of response of 7.8 months. Median overall survival was 15.6 months. Adverse events (AEs) were manageable without cumulative toxicities. Common AEs were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral neuropathy, primarily grades 1 or 2. Thirty-three patients (12.4%) withdrew because of an AE. Durable responses and an acceptable tolerability profile in this heavily pretreated population demonstrate the potential of carfilzomib to offer meaningful clinical benefit. This trial was registered at www.clinicaltrials.gov as #NCT00511238.

Clarithromycin (Biaxin)-Lenalidomide-Low-Dose Dexamethasone (BiRd) Versus Lenalidomide-Low-Dose Dexamethasone (Rd) as Initial Therapy for Newly Diagnosed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2868-2868 ◽  
Author(s):  
Francesca Gay ◽  
S. Vincent Rajkumar ◽  
David S Jayabalan ◽  
Shaji Kumar ◽  
Tomer Mark ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Low Dose ◽  
Response Rate ◽  
Initial Therapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Intention To Treat ◽  
High Dose Dexamethasone ◽  
Bird Group

Abstract Abstract 2868 Poster Board II-844 Background and Objective: In newly diagnosed multiple myeloma (MM), the combination of lenalidomide plus high-dose dexamethasone (RD) is superior to high-dose dexamethasone (Zonder JA et al, Blood 2007;110:77). Preliminary results show that lenalidomide plus low-dose dexamethasone (Rd) has better 2-year overall survival (OS) compared with RD (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The addition of clarithromycin (Biaxin) to lenalidomide and low-dose dexamethasone (BiRd) has been investigated in a phase II study, demonstrating a high response rate and 2-year OS (Niesvizky R at al, Blood 2008;111:1101-1109). However, the additive value of clarithromycin is not known. No randomized trials have compared Rd versus BiRd, none are planned. The objective of this case–matched study was to compare the efficacy and the toxicity of BiRd vs Rd as initial therapy for newly diagnosed MM. Patients and methods: Data from 72 newly diagnosed MM patients treated at the New York Presbyterian Hospital–Cornell Medical Center, from December 2004 to December 2006, with BiRD, were analyzed. For comparison, an equal number of pair mates were selected among newly diagnosed patients seen at the Mayo Clinic who received Rd, from March 2005 to December 2008. Case matching was performed with respect to age, gender, and transplant status. Patients treated with BiRd received oral lenalidomide (25 mg/day, days 3-21 of cycle 1; days 1-21 of subsequent cycles); dexamethasone (40 mg days 1, 2, 3, 8, 15, 22 of cycle 1; days 1, 8, 15, and 22 of each subsequent cycle); clarithromycin (500 mg twice daily, from day 2 of cycle 1). Patients treated with Rd received oral lenalidomide (25 mg/day, days 1-21) plus low-dose dexamethasone (40 mg days 1, 8, 15, 22). In both groups patients were allowed to discontinue treatment to pursue transplant, but treatment until progression, relapse or unacceptable toxicity was permitted at the physician's discretion. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method; comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: Median duration of treatment was 11.8 months in the BiRd group vs 6 months in the Rd group. On intention-to-treat analysis, complete response was significantly higher with BiRd compared to Rd (45.8% vs 13.9%, respectively, p<0.001); similarly very good partial response (VGPR) or better was higher with BiRd (73.6% vs 33.3%, p<0.001). Rates of VGPR or better, after 6 months and 1 year of therapy, were significantly higher in BiRd patients. Both time-to-progression (TTP) (median 48.3 months vs 27.5 months; HR 0.51; 95% CI 0.25-1.06; p=0.071) and PFS (median 48.3 months vs 27.5 months, HR 0.50; 95% CI 0.25-0.98; p=0.044) were higher with BiRd. Median time to next treatment (TTNT) was not reached in BiRd group compared to 29.9 months in Rd patients (HR 0.37 95% CI 0.20-0.66, p<0.001). There was a trend toward better OS with BiRd, (3-year OS: 89.7% vs 73.0%), but the difference was not statistically significant (HR 0.48; 95% CI 0.17-1.37; p=0.170). Thirty-two patients in each group received transplant; median time to transplant was longer in BiRd group (13.5 vs 5.9 months). Results of survival, for patients who received transplant and patients who did not, were similar to those of the total population. On subset analysis, among patients presenting with International Staging System (ISS) stage I/II at diagnosis, TTP, PFS and TTNT were significantly longer in BiRd patients; no significant differences were found among patients with ISS stage III. Main grade 3-4 toxicities of BiRd were hematological, in particular thrombocytopenia (23.6% vs 8.3%, p=0.012); rate of neutropenia was similar between the 2 groups (19.4% vs 16.7%, p=0.665). Infections (16.7% vs 9.7%, p=0.218) and dermatological toxicity (12.5% vs 4.2%, p=0.129) were higher in patients who received Rd. Rate of venous thromboembolism was similar in the 2 groups (9.7% vs 12.5%, respectively in Rd and BiRd patients, p=0.596). Conclusion: Results of this case-control analysis suggest superiority of BiRd in terms of response rate and survival, compared with Rd, and suggest that there may be a significant additive value when clarithromycin is added to Rd. These data indicate the need for randomized prospective phase III studies to evaluate BiRd versus Rd in the treatment of MM. Disclosures: Off Label Use: research drug in combination to standard of care. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; novartis: Research Funding; genzyme: Research Funding. Mark:celgene: Research Funding. Dispenzieri:celgene: Research Funding. Gertz:celgene: Honoraria; genzime: Honoraria; millenium: Honoraria; amgen: Honoraria. Leonard:celgene: Consultancy. Lacy:celgene: Research Funding. Witzig:celgene: Research Funding. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Greipp:celgene: Research Funding. Niesvizky:celgene: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Proteolix: Research Funding, data monitoring committee.

Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3557-3560 ◽  
Author(s):  
Paul G. Richardson ◽  
Pieter Sonneveld ◽  
Michael Schuster ◽  
David Irwin ◽  
Edward Stadtmauer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Response Duration ◽  
Proteasome Inhibition ◽  
Initial Response ◽  
Complete Response ◽  
High Dose ◽  
High Dose Dexamethasone ◽  
Protein Reduction

AbstractInitial analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of relapsed multiple myeloma patients showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib versus high-dose dexamethasone. In this updated analysis (median follow-up: 22 months), survival was assessed in both arms, and efficacy updated for the bortezomib arm. Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone, a 6-month benefit, despite substantial crossover from dexamethasone to bortezomib. Overall and complete response rates with bortezomib were 43% and 9%, respectively; among responding patients, 56% improved response with longer therapy beyond initial response, leading to continued improvement in overall quality of response. Higher response quality (100% M-protein reduction) was associated with longer response duration; response duration was not associated with time to response. These data confirm the activity of bortezomib and support extended treatment in relapsed multiple myeloma patients tolerating therapy. This study is registered at http://clinicaltrials.gov (Study ID NCT00048230).

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