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

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

scholarly journals Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

2020 ◽  
pp. JCO.20.02259
Author(s):  
Paul G. Richardson ◽  
Albert Oriol ◽  
Alessandra Larocca ◽  
Joan Bladé ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

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]

Evaluation of Single Agent Lenalidomide in Patients with Newly Diagnosed Multiple Myeloma (NDMM).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3868-3868
Author(s):  
Rachid Baz ◽  
Mohamad Hussein ◽  
Daniel J. Lebovic ◽  
Elizabeth Finley-Oliver ◽  
Mehul P Patel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Time ◽  
Light Chain ◽  
Single Agent ◽  
Immunomodulatory Activity ◽  
High Dose ◽  
Newly Diagnosed ◽  
Antitumor Effects ◽  
Grade 3

Abstract Abstract 3868 Poster Board III-804 Introduction Lenalidomide (Len) is an immunomodulatory drug with antitumor effects mediated through activation of T and NK cells as well as modulation of tumor cytokine environment. Currently Len is approved in combination with dexamethasone (dex) for treatment of patients with relapsed myeloma. Interestingly, in NDMM, higher 1 and 2 year survival rates were observed when the dose of dex was reduced compared to standard high dose dexamethasone and Len (Rajkumar et al. 2008). The immune suppressive effects of dex can antagonize Len immunomodulatory activity and may explain this observation. To our knowledge, Len has not been evaluated as a single agent in NDMM. Patients and methods Records of patients with newly diagnosed symptomatic multiple myeloma treated with single agent Len at H. Lee Moffitt Cancer Center and Roswell Park Cancer Institute were reviewed (after IRB approval at both institutions). Data was collected on disease characteristics, demographics and treatment outcomes. Responses assessed as per the IMWG criteria. Results From March 2007 to July of 2009, 18 patients with NDMM have been treated with Len alone. The median age was 70 years (range 46-84), and 12/18 were males. Heavy chain was IgG in 12 and IgA in 4 patients with 2 patients with light chain myeloma. The involved light chain was kappa in half the patients. Clinical stage of patients included stage IIIA (n=13), IIA (n=4) and IA (n=1) using the DS system whereas as per the ISS system 10, 6 and 2 has stages I, II and III respectively. Cytogenetics were not available on most patients (11); and 4 of 7 patients with available cytogenetics had deletion 13q identified by FISH. The median b2m was 2.8 mg/L (range 2.1-10.7) with >3.5mg/L in 7/18 patients. All except one patient (with a creatinine clearance of 49 ml/min) were started on Len 25 mg daily for 21 days of a 28 days cycle. As of August 1st 2009, 3 patients are inevaluable for response due to short follow up. Among the remainder 15 patients, 3 achieved a CR (1 stringent CR), 2 VGPR, 3 PR, 4 had MR with SD in additional 3 patients. Thus MR or better response was noted in 80% of patients. The median time to first response was 55 days (range 28-98) and median time to best response was 73 days (range 31-591). After a median follow up of 7 months (range 1-26), 1 patient died of progressive disease (despite the addition of dexamethasone and subsequent bortezomib therapy), 4 patients required the addition of dexamethasone. Len was generally well tolerated and no grade 4 hematologic toxicity were noted, 1 patient had grade 3 neutropenia, 1 patients grade 3 anemia and 2 patient grade 3 thrombocytopenia. Four patients had Len dose reduced. Conclusion Single agent Len appears to be an effective therapy in newly diagnosed myeloma patients (MR and better in 80% of patients) and should be evaluated in a prospective fashion in an attempt to decrease corticosteroid toxicity in a group of vulnerable patients and potentially enhance the immunomodulatory activity of Len. Our experience suggests that single agent Len can be effectively employed as an initial step in sequencing anti-myeloma regimen(s) for treatment of NDMM. Disclosures: Baz: celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: lenalidomide as a single agent in newly diagnosed myeloma. Hussein:Celgene: Employment.

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).

scholarly journals Bortezomib Plus Melphalan and Prednisone Compared With Melphalan and Prednisone in Previously Untreated Multiple Myeloma: Updated Follow-Up and Impact of Subsequent Therapy in the Phase III VISTA Trial

2010 ◽  
Vol 28 (13) ◽  
pp. 2259-2266 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Paul G. Richardson ◽  
Rudolf Schlag ◽  
Nuriet K. Khuageva ◽  
Meletios A. Dimopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Response Rates ◽  
Phase Iii ◽  
High Dose ◽  
First Line ◽  
Agent Based ◽  
Risk Of Death ◽  
Clinical Benefits ◽  
The Impact

PurposeThe purpose of this study was to confirm overall survival (OS) and other clinical benefits with bortezomib, melphalan, and prednisone (VMP) versus melphalan and prednisone (MP) in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial after prolonged follow-up, and evaluate the impact of subsequent therapies.Patients and MethodsPreviously untreated symptomatic patients with myeloma ineligible for high-dose therapy received up to nine 6-week cycles of VMP (n = 344) or MP (n = 338).ResultsWith a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide- (41% v 53%) and lenalidomide-based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months.ConclusionVMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent antimyeloma therapy. First-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib- and other novel agent–based treatment until relapse.

Inducible T-cell co-stimulatory (ICOS) receptor agonist, feladilimab (fela), alone and in combination (combo) with pembrolizumab (P): Results from INDUCE-1 urothelial carcinoma (UC) expansion cohorts (ECs).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4519-4519
Author(s):  
Arjun Vasant Balar ◽  
Victor Moreno ◽  
Eric Angevin ◽  
Hui Kong Gan ◽  
Maria Vieito ◽  
...  
Keyword(s):  
T Cell ◽  
Single Agent ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Metastatic Setting ◽  
Duration Of Response ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Tumor Types

4519 Background: INDUCE-1 is a first-in-human trial evaluating fela, an IgG4 ICOS agonist non-T-cell depleting mAb, as monotherapy (mono) and in combo with P. ECs include tumor types, such as UC, with high ICOS expression and immunotherapy-favorable features. Fela induced IFNγ, increased PD-1/L1 expression, and enhanced antitumor activity in combo with PD-1 blockade nonclinically. We report preliminary efficacy, safety, and biomarker data of fela ± P in INDUCE-1 UC ECs. Methods: Eligible patients (pts) had recurrent/metastatic (R/M) UC of the upper or lower urinary tract, ≤6 prior systemic therapy lines in the advanced setting, measurable disease, and no active autoimmune disease. Pts received 0.3 or 1 mg/kg fela (mono EC; anti-PD-1/L1–experienced [exp] pts) or 0.3 mg/kg fela + 200 mg P (combo EC; anti-PD-1/L1–naïve pts) every 3 wks, up to 35 cycles until disease progression or unacceptable toxicity. Disease was assessed every 9 wks through wk 54, then every 12 wks. Archival and/or fresh biopsy tumor tissue was collected for biomarker analyses and safety assessed. Results: By Nov 6 2020, 13 anti-PD-1/L1–exp and 32 anti-PD-1/L1–naïve pts were evaluable in the mono and combo ECs, respectively. In the mono EC, median age was 69 yrs (range: 47–82), 92% of pts were male, and 85% received ≥2 prior therapy lines in the metastatic setting. In the combo EC, median age was 70 yrs (range: 42–84), 75% of pts were male, and 72% received ≥1 prior therapy line in the metastatic setting. In the mono EC, median duration of follow-up (mDoF) was 10.6 mo (range: 1.1–22.8); overall response rate (ORR) was 8% (1 partial response [PR]; 95% CI: 0.2, 36.0) with a duration of response (DoR) of 6.1 mo; disease control rate (DCR [response or stable disease for ≥9 wks]) was 23% (95% CI: 5.0, 53.8), and median overall survival (mOS) was 14.5 mo (95% CI: 2.8, NR), with 74% of pts alive at 6 mo. In the combo EC, mDoF was 9.6 mo (range: 0.9–28.3); ORR was 22% (7 PRs; 95% CI: 9.3, 40.0) with a median DoR of 8.3 months (range: 3.5–23.3+); DCR was 63% (95% CI: 43.7, 78.9), and mOS was 10.7 mo (95% CI: 5.2, 18.1), with 64% of pts alive at 6 mo. Grade ≥3 treatment-related AEs were reported for 0% and 9% of pts in the mono (N = 16) and combo (N = 44) safety populations, respectively. PD-L1 expression and ICOS-specific biomarkers are being evaluated, with promising trends observed in enrichment of clinical activity in preliminary analyses. Conclusions: Fela is the first ICOS agonist with reported single-agent activity in anti-PD-1/L1–exp relapsed/refractory UC. Fela + P in combo shows promising clinical activity and manageable safety in PD-1/L1–naïve R/M UC. Further study is warranted. Updated data to be presented. Funding: Study 204691 (NCT02723955) funded by GlaxoSmithKline in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA. Clinical trial information: NCT02723955.

scholarly journals A Phase 1/2 Trial of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4774-4774
Author(s):  
James R. Berenson ◽  
Laura V. Stampleman ◽  
Alberto Bessudo ◽  
Peter J. Rosen ◽  
Leonard M Klein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Phase 1 ◽  
Single Agent ◽  
Pegylated Liposomal Doxorubicin ◽  
Great Promise ◽  
Phase 2 ◽  
Grade 3

Abstract Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/ progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who have previously received POM treatment were ineligible. In the phase 1 portion, POM was administered at 2, 3 or 4 mg daily in three cohorts on days 1-21 of a 28-day cycle and DEX (40 mg) and PLD (5 mg/m2) were fixed and given intravenously on days 1, 4, 8, and 11. Results As of June 20th, 2014, 48 pts were enrolled in the trial and a total of 47 pts had received study drug. Pts had received a median of 4 prior treatments (range 1-18), with a median of 2 prior IMiD-containing regimens (range, 0-8). Fifty-three percent of the pts had received a prior PLD-containing regimen and 21% had received a prior IMiD and PLD combination treatment. Among all enrolled pts, 40 pts discontinued treatment and seven remain active. Pts completed a median of 3 cycles (range: 1-8), with a median follow-up time of 5.4 months (range: 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 36 pts enrolled in phase 2, 78% percent were refractory to LEN and steroids with or without other agents and 47% had previously received PLD. A median of 2 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Thirty-five pts were evaluable for response as one pt was active but had not yet had any post-baseline disease assessments. Among all pts enrolled in phase 2, the overall response rate (ORR) and clinical benefit rate (CBR) were 29% and 49%, respectively, with 6 pts (17%) showing stable disease and 12 pts (34%) demonstrating progressive disease. For all pts enrolled in phase 2, the median follow-up time was 4.7 months (range 0-12) and the median PFS was 5.3 months. ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (32% and 58%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (21 pts; 44.7%), lymphopenia (10 pts; 21.3%), and hyponatremia (4 pts; 8.5%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Consultancy, Honoraria. Vescio:Celgene: Honoraria.

Follow-Up Results of a Prospective, Multicenter, Open-Label Study of Oral Fludarabine Phosphate in Patients with Previously Untreated B-CLL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2128-2128
Author(s):  
Jean-Francois Rossi ◽  
A. Van Hoof ◽  
K. De Boeck ◽  
S. A. Johnson ◽  
D. Bron ◽  
...  
Keyword(s):  
Disease Progression ◽  
Median Time ◽  
Response Rate ◽  
Time To Progression ◽  
Open Label ◽  
Overall Response ◽  
Fludarabine Phosphate ◽  
Duration Of Response ◽  
Grade 3

Abstract The IV formulation of fludarabine phosphate is an effective treatment in patients with B-cell chronic lymphocytic leukemia (B-CLL), yielding overall response rates of 60% to 80%. An oral formulation of fludarabine phosphate has been developed. In a previously published multicenter, open-label, phase II clinical trial, 81 previously untreated B-CLL patients received 10-mg tablets of fludarabine phosphate (Fludara® oral) 40 mg/m2/day for 5 days, repeated every 4 weeks. The primary endpoint of the trial was response rate, and secondary endpoints included safety and quality of life assessments. Of 81 patients (mean age, 61.2 years; range, 30–75 years) with previously untreated B-CLL, 81.5% were classified as Binet stage B or C. The overall response rate (complete response [CR] + partial response [PR]) using National Cancer Institute (NCI) criteria was 80.2% (12.3% CR and 67.9% PR) and the median time to progression was 841 days (range, 28–1,146 days) (Rossi JF, et al. J Clin Oncol2004;22:1260–1267). The most frequently reported grade 3/4 adverse event was myelosuppression: WHO grade 3/4 hematologic toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). This analysis reports on the long-term follow-up of this cohort during the period from November 2001 to November 2004. Of the 74 patients eligible for the survival analysis, 61 were also assessed for duration of response using NCI criteria: 9 CR (14.8%) and 52 PR (82.2%). During the 3-year follow-up period, 22 (29.7%) patients did not progress. For those who progressed, median time to progression was 29.7 months, and median duration of response was 22.9 months. In 41 (80.4%) of these patients, an increase in circulating lymphocytes was reported as evidence of disease progression. In 23 patients (45.1%), an increase in the sum of the products of at least 2 lymph nodes and/or appearance of new palpable nodes was reported as evidence of disease progression. During the indicated follow-up period, 37 patients (50%) received subsequent treatment. Twelve patients (16.2%) died during the follow-up period: 7 patients (58.3%) due to disease progression, 3 patients (25.0%) due to adverse events, and 2 patients (16.7%) due to other causes. Results from this study suggest that oral fludarabine phosphate is clinically effective and well tolerated by patients with previously untreated B-CLL. Moreover, these data demonstrate that oral fludarabine phosphate achieves response rates and duration of response comparable to those achieved with first-line fludarabine phosphate IV therapy.

A Phase I/II Study of Bortezomib and Low Dose Intravenous Melphalan (BM) for Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2555-2555 ◽  
Author(s):  
Rakesh Popat ◽  
Heather E. Oakervee ◽  
Nicola Foot ◽  
Samir Agrawal ◽  
Patricia Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progressive Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Median Number ◽  
Overall Response ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Background: Bortezomib as a single agent has known efficacy in the treatment of relapsed multiple myeloma. The overall response rate (CR+PR+MR) was 35% in the SUMMIT study and 46% in the APEX study. In-vitro studies including our own have demonstrated potent synergy with other chemotherapeutic agents such as melphalan. It therefore follows that responses to bortezomib may be further improved by the combination of such drugs. Aims: The primary objectives of this Phase I/II study was to assess the safety, tolerability and response rates in patients with relapsed multiple myeloma; secondary objectives being time to progression (TTP) and overall surival (OS). Methods: This was a multi-centre, non-randomised trial for patients with relapsed myeloma. Patients received bortezomib 1.3mg/m2 on days 1,4,8 and 11 of each 28 day cycle with melphalan on day 2 at increasing dose levels. This was initially at 10mg/m2, but due to cytopenias subsequently at 2.5 and 5mg/m2 (levels 1a, 1 and 2) and we plan to escalate to 7.5mg/m2. Up to 8 cycles were given with dexamethasone added for stable or progressive disease after 4 or 2 cycles respectively. Responses were determined by EBMT criteria. Results: To date, 18 patients have been enrolled (12 male 6 female; median age 60 [range 44–73]; median number of prior therapies 3 [range 1–5] of which 17 have had at least one autologous stem cell procedure with high dose melphalan; 10 prior thalidomide and 2 prior bortezomib). 12 patients received melphalan at 10mg/m2 but due to unacceptable delays predominantly due to thrombocytopaenia, subsequent treatment levels commenced at 2.5mg/m2. The median number of cycles completed thus far is 4 (range 0–8) and of the 16 evaluable, the overall response rate (CR+PR+MR) across all treatment levels was 50% rising to 75% following the addition of dexamethasone as per protocol. At level 1a (melphalan 10mg/m2 ,N=12, median number of cycles completed =5) the best responses (with dexamethasone as indicated) were: 1CR, 1 VGPR, 5 PR, 2 MR; at level 1 (melphalan 2.5mg/m2, N=4) 1 PR, 2 MR (after 2 cycles only). The median time to any response was 1 cycle (range 1–3 ). Three patients have progressive disease, but the median TTP and OS have not yet been reached (median follow-up 3 months). Non-haematological toxicities have been modest with 7 SAEs reported of which only 1 was possibly drug related (myocardial infarction), and 4 episodes of Grade 3 neuropathy (2 resulting in study withdrawal). The commonest grade 3–4 haematological toxicity was thrombocytopaenia (N=10) complicated by bleeding in one patient, followed by neutropenia (N=6). Summary: The combination of bortezomib and intravenous melphalan can be given safely to patients with relapsed multiple myeloma and dose escalation is ongoing. Myelosupression was the commonest grade 3–4 adverse event. A response rate of 50% was seen, which was further improved to 75% with the addition of dexamethasone. This combination may therefore result in higher responses than single agent bortezomib in heavily pretreated patients.

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