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.

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 (L) in Combination with Dexamethasone (D) Significantly Improves Time to Progression (TTP) in Non-Stem Cell Transplant Patients (pts) with Relapsed or Refractory (rel/ref) Multiple Myeloma (MM): Analysis from MM-009 and MM-010 Randomized Phase III Clinical Trials.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3554-3554 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Zhinuan Yu ◽  
Donna Weber ◽  
Christine Chen ◽  
Ruben Niesvizky ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Stem Cell ◽  
Stem Cell Transplant ◽  
Phase Iii ◽  
Cell Transplant ◽  
Time To Progression ◽  
Data Set ◽  
Pathologic Diagnosis ◽  
Grade 3

Abstract INTRODUCTION: Although autologous stem cell transplant (ASCT) has demonstrated high overall survival (OS) and progression free survival (PFS) in MM pts, for many pts this may not be an option due to comorbid conditions, advance age, aggressive refractory disease or personal preferences. Two phase III studies demonstrated superiority of the LD combination over D alone in rel/ref MM pts resulting in approval of L by the FDA. To evaluate the utility of LD combination in non-transplant pts we examined all pts who were enrolled on the MM-090 and MM-010 clinical trials and compared the efficacy and safety profile of LD combination among pts with no prior ASCT (NT) vs. those who had a prior ASCT (PT). METHODS: Data set from the 2 phase III trial was queried and pts with or without a previous ASCT identified. Clinical outcome (overall response rate, ORR; time to progression, TTP; overall survival, OS) was compared between the two groups. RESULTS: Of the 704 pts enrolled 353 (210 in the PT and 143 in the NT group) were randomized to receive LD. Patients demographic are summarized in Table 1. The median dose for L in both group was 25mg. Using the Blade criteria the ORR and CR rates in the PT vs. NT group were 63% (CR =13%) and 55% (CR=16%) p=0.12, while the median TTP was 44.1 and 61.4 (p=0.13), respectively. Toxicity: Although a higher incidence grade 3/4 neutropenia in the PT vs. NT group (38.1% vs. 27.3, p<.05) was noted the incidence of grade 3/4 thrombocytopenia were comparable (5.7% vs. 6.3%). The incidence for toxicity associated discontinuation of therapy in each arm was 12.9% and 19.6%. CONCLUSION: Our analysis showed no difference in ORR and CR rates in the 2 groups though there was a trend towards prolong TTP in NT pts. Although there was a slightly higher incidence of grade 3/4 neutropenia, overall there was no impact of prior ASCT on treatment outcome with LD. An interesting observation was that the median time from first pathologic diagnosis was the same for both groups; this observation is encouraging as they offer advantage to pts who may not have a chance to benefit from ASCT and supports the rationale to investigate L based therapies early on in the course of treatment. Characteristics of patients treated with LD combination. Prior Transplant Group (PT) No Prior Transplant (NPT) P value Median age (range) 59.5 (33–77) 69 (38–86) <0.001 Sex (%) M/F 62.4/37.6 55.2/44.8 0.187 Stage III (%) 60 70.6 0.184 B2M 3.1 4.1 <0.05 Time from first pathologic diagnosis in years (range) 3.4 (0.6–15.7) 2.9 (0.4–14.7) 0.098

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

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

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

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

Superiority of Lenalidomide (Len) Plus High-Dose Dexamethasone (HD) Compared to HD Alone as Treatment of Newly-Diagnosed Multiple Myeloma (NDMM): Results of the Randomized, Double-Blinded, Placebo-Controlled SWOG Trial S0232.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 77-77 ◽  
Author(s):  
Jeffrey A. Zonder ◽  
John Crowley ◽  
Mohamad A. Hussein ◽  
Vanessa Bolejack ◽  
Dennis F. Moore ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Response Rate ◽  
Controlled Trial ◽  
Performance Status ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Open Label ◽  
High Dose Dexamethasone ◽  
Double Blinded

Abstract Lenalidomide (Len) is an immunomodulatory drug approved for use with high-dose dexamethasone (HD) as therapy for relapsed-refractory multiple myeloma (RRMM). Preliminary data suggest Len+HD may be even more active versus newly-diagnosed myeloma (NDMM). SWOG conducted a randomized, double-blinded, placebo-controlled trial (S0232) comparing Len+HD to HD alone. Methods: Original study design: enrollment of 500 pts with NDMM (measurable disease, Cr ≤ 2.5 mg/dL, ineligible for/declining immediate autologous stem cell transplant), with interim analysis after accrual of 300 pts. The trial was closed after 198 pts were enrolled, due to external data affecting acceptability of HD as the control arm. Pts were randomized to Len 25 mg/d (28 of 35 days for 3 induction cycles, then 21 of 28 days as maintenance thereafter) plus HD (40 mg days 1–4, 9–12, 17–20 induction, then days 1–4, 15–18 maintenance) or HD (same induction and maintenance schedules) plus placebo. Therapy was unblinded for disease progression; pts on HD could crossover to Len+HD. After a high initial rate of thrombosis (TEE) was seen in pts on Len+HD, aspirin (ASA) 325 mg/d was mandated. Pts were stratified by ISS stage and SWOG performance status (PS). The primary endpoint is progression-free survival (PFS). Secondary endpoints reported here are overall response rate (ORR), major response rate (MRR), overall survival (OS), and toxicity. Results: Between Oct 2004 and Mar 2007, 100 pts were randomized to Len+HD (arm A) and 98 pts to HD plus placebo (arm B), with no differences in age (median 64.6 yrs overall), sex, race, PS, or stage distribution between arms. As of July 18, 2007, 61 pts on arm A and 72 pts on arm B were assessable for response. Estimated 1-yr PFS was 77% (arm A), vs 55% (arm B) (p=0.002). The ORR was 85.3% (≥ MR 79.4%, CR 22.1%) vs 51.3% (≥ MR 26.2%, CR 3.8%) on arms A and B, respectively (p = 0.001). OS was high in both arms (93% vs 91% at 1 yr; p=NS). Forty pts on arm B crossed over to arm A. Of these, 23 are assessable for response: ORR is 70.4% (14.8% CR). Grade 3–4 neutropenia was more frequent on arm A (13.5% vs 2.4%; p=0.010), as were infections (arm A: n=38, Gr 3–4=13, Gr 5=1; arm B: n=23, Gr 3–4=8, Gr 5=0; p= 0.003). There were 20 TEEs on arm A (14 on ASA prophylaxis) and 12 on arm B (all on ASA; 5 after crossover to Len+HD). Thus, 25 TEEs occurred during either blinded or open-label Len+HD vs 7 on HD alone (p=0.089). Discussion: In NDMM, Len+HD is superior in terms of ORR, MRR, and PFS compared to HD alone. The 1-yr OS in both arms of this study is among the highest reported. ASA at this dose may not be optimal thromboprophylaxis for pts with NDMM treated with Len+HD, although pt compliance with ASA on this study is not known. With recent evidence that dex intensity may affect TEE risk, this study was modified to include lower dose dex (40 mg q wk) with no change in TEE prophylaxis.

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

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 74-74 ◽  
Author(s):  
S. Vincent Rajkumar ◽  
Susanna Jacobus ◽  
Natalie Callander ◽  
Rafael Fonseca ◽  
David Vesole ◽  
...  
Keyword(s):  
Disease Progression ◽  
Low Dose ◽  
Response Rate ◽  
Phase Iii ◽  
High Dose ◽  
Type I ◽  
Newly Diagnosed ◽  
High Dose Dexamethasone ◽  
Grade 3 ◽  
One Year

Abstract Aim: A 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 primary endpoint was response rate at 4 months, with the null hypothesis being that the response rates in the two 2 arms are equivalent. Planned sample size was 196 eligible pts per arm with one-sided 0.10 Type I and 0.05 Type II error rate. All analysis were performed on an intent to treat basis. An independent DMC recommended release of study results. Results: 445 pts (median age, 65 yrs) were accrued; 223 randomized to RD, 222 to Rd. Median follow-up time is 17 months. Arms were well balanced for age, gender, stage, bone lesions, hemoglobin, beta-2 microglobulin, performance status, bone marrow plasma cells, and M protein levels at baseline. Major grade 3 or higher toxicities, including DVT/PE and infections, were significantly higher in the high dose dex arm (see Table). Overall survival (OS) at the second pre-planned interim analysis was significantly superior with lenalidomide plus low dose dex, P<0.001; one year survival 96% (Rd) versus 87% (RD). The 18 month survival rate is 91% versus 80%, respectively. OS differences in favor of the low dose dex arm were seen in pts <65 (P=0.022; one year rate 97% vs 92%) as well as pts 65 and older (P=0.002; one year rate 94% vs 83%), respectively. Sixty-one patients have died; 42 in the RD arm and 16 in Rd arm. The cause of death has been verified by detailed chart review in 38 patients. Of 29 verified deaths in the RD arm, 13 were due to disease progression, 6 thrombosis/embolism, 3 infection, 3 cardiac ischemia, 1 stroke, and 1 respiratory failure. Of 9 verified deaths in the Rd arm, 5 were due to disease progression, 2 infection, 1 thrombosis/embolism, and 1 cardiac arrest. Response rate data are expected to be available at the time of the meeting. Conclusions: Lenalidomide plus low-dose dexamethasone (Rd) is associated with superior OS compared to lenalidomide plus high-dose dexamethasone (RD) in newly diagnosed MM. The increased mortality in Arm A is due to disease progression (myeloma deaths) as well as increased toxicity. This study has major implications for the use of high-dose dexamethasone in the treatment of newly diagnosed MM. Major Grade 3 or Higher Adverse Events Toxicity Arm A % Arm B % P value Neutropenia 10 19 0.01 DVT/PE 25 9 <0.001 Infections 16 6 <0.001 Any grade 3 or higher non-hematologic 49 32 <0.001 Any grade 4 or higher non-hematologic 20 9 <0.001 Deaths in first 4 months 5 0.5 0.006

scholarly journals Phase 2 Trial of LDE225 and Lenalidomide Maintenance Post Autologous Stem Cell Transplant for Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1905-1905
Author(s):  
Francis K. Buadi ◽  
Martha Q. Lacy ◽  
Angela Dispenzieri ◽  
Gabriela Perez ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Grade 3

Background: Lenalidomide maintenance therapy post-autologous stem cell transplantation (ASCT) is associated with improved progression-free survival (PFS) and possibly overall survival in multiple myeloma (MM). However, almost all patients do relapse as a result of residual multiple myeloma cells that remain after the high-dose chemotherapy. In the myeloma setting it has been found that the hedgehog (Hh) pathway is essential for maintaining a subset of tumor causing stem cells. LDE 225 (Sonidegib) is a potent selective oral bioavailable antagonist of Smoothened (SMO), a component of the Hh signaling pathway. In in vitro experiments, LDE225 treatment of myeloma cell lines resulted in a modest inhibition of cell proliferation at increasing doses. When LDE225 was combined with lenalidomide, a more than additive effect was observed in terms of cell proliferation, an effect that was more pronounced in the context of myeloma cell lines growing in co-culture with marrow derived stromal cells. These findings form the basis of evaluation of LDE 225 as a strategy to enhance the activity of lenalidomide in the post-transplant maintenance setting. The minimal residual state post SCT provides the most optimal situation for evaluation of a drug that is likely to work by inhibiting the tumor cells that escaped high dose therapy. Methods: Multiple myeloma patients without evidence of progression, who were 60 - 120 days after a single autologous stem cell transplant (SCT), performed within 1 year of diagnosis were eligible for the study. Maintenance therapy was started approximately 3 months after SCT. Treatment consisted of lenalidomide 10 mg days 1-21 and LDE225 400 mg days 1-28 in 28-day cycles for a total of 18 cycles. The goal of the study was to assess toxicity of this combination, complete response rate (CR) progression free survival (PFS) at 1 and 2 year and overall survival (OS). CR and PFS were estimated using an exact binomial distribution and Kaplan Meier curves respectively. Results: A total of 28 patients were accrued from Jan 2014 to Aug 2016, 1 patient canceled prior to treatment and 1 patient was deemed ineligible resulting in 26 evaluable pts for CR and PFS. The median age of all pts (n=26) was 60 years (range 43-69) and 50% were males. Seventy-three percent of patients reported one treatment regimen prior to SCT, while 27% reported 2 or more prior regimens. The other characteristics of the patient are summarized in Table 1. Twenty seven pts received at least one cycle of treatment and are evaluable for toxicities (AE). Patients were treated for a median of 12.5 (range 1-18) cycles. While 10 pts (38.5%) completed protocol treatment (18 cycles), the remaining 16 pts went off treatment due to AEs (6, 23%), disease progression (3, 11.5%), refusal of further treatment (3, 11.5%) and other reasons (4, 15.4%). A grade 3 or higher AE at least possibly attributed to either drug was seen in 63%. Grade 3+ hematologic toxicities were noted in 30%, with 7% neutropenia and 4% thrombocytopenia. Notable grade 2+ non-hematologic toxicities with more than 5% incidence were dysgeusia 22%, alopecia 11%, and anorexia 7%. Grade 3+ non-hematologic toxicities were fatigue, myalgia and arthralgia each at 7%. The CR rate in evaluable patients was 46% (5 CRs and 7 sCRs) with a 95% CI of 27% - 66%. CR rate improved from 31% to 46%. VGPR or better improved from 42% to 85%. The 24-month PFS (time from SCT to progression or death due to any cause) was 73% (95% CI: 57.9 - 92.3%) with a median time to censoring of 38 months. Conclusion: Lenalidomide in combination with LDE225 as posttransplant maintenance therapy was associated with some toxicity but manageable. The combination improved the depth of response after autologous stem cell transplant. Long-term follow-up is needed to determine overall survival. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Spectrum: Honoraria, Research Funding; Janssen: Honoraria. Kapoor:Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Celgene: Honoraria; Sanofi: Consultancy, Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Russell:Imanis: Equity Ownership. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. OffLabel Disclosure: Sonidegib (LDE 225) is a selective oral bioavailable antagonist of Smoothened (SMO), a component of the hedgehog signaling pathway.

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.

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

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

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

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