Zhinuan Yu
CELGENE, Molecular & Cellular Biology, Department Member
Background: There is ongoing debate about what would be considered an acceptable response to therapy in patients with relapsed/refractory multiple myeloma (MM). Lenalidomide (Len) is an immunomodulatory compound. Two recent phase III... more
Background: There is ongoing debate about what would be considered an acceptable response to therapy in patients with relapsed/refractory multiple myeloma (MM). Lenalidomide (Len) is an immunomodulatory compound. Two recent phase III randomised trials (MM-009 and MM-010) showed Len in combination with Dexamethasone (Dex) provided significantly better overall response (OR), complete response (CR), overall survival (OS) and time to progression (TTP) compared with Dex alone in patients with relapsed/refractory MM. Approximately 60% of patients achieved an OR (61% in MM-009 and 60% in MM-010), including a CR in 15% (14% and 16%, respectively), Median OS was ≥29.5 months (29.5 and not yet reached) and median TTP was ≥11.1 months (11.1 months and 11.3 months, respectively). Here, we compare outcomes in patients with a CR or near CR (nCR) vs those with a partial response (PR). Methods: Data for patients who received Len/Dex in the MM-009 or MM-010 studies were pooled for this analysis. Pat...
Research Interests:
Background: Historically, patients with IgA multiple myeloma (MM) respond poorly to treatment. In 2 recent phase III trials, Lenalidomide (Len) in combination with Dexamethasone (Dex) led to an overall response (OR) rate of approximately... more
Background: Historically, patients with IgA multiple myeloma (MM) respond poorly to treatment. In 2 recent phase III trials, Lenalidomide (Len) in combination with Dexamethasone (Dex) led to an overall response (OR) rate of approximately 60% (61% in MM-009 and 60% in MM-010), a complete response (CR) rate of about 15% (14% and 16%, respectively), an overall survival (OS) of at least 29.5 months (29.5 and not yet reached), and a median time to progression (TTP) of at least 11.1 months (11.1 months and 11.3 months, respectively) in patients with relapsed/refractory MM. In both studies, OR, CR, OS and TTP were significantly better with Len/Dex than with Dex alone. Here, we assess the impact of IgA disease on the efficacy and tolerability of treatment with Len/Dex versus Dex alone. Methods: Data were pooled from the MM-009 and MM-010 studies. Patients were randomized to receive Len (25 mg/day on days 1–21 of each 28-day cycle) or placebo. Both groups received Dex 40mg PO q.d. on days 1–...
Research Interests:
613 Background: Lenalidomide (Revlimid®) is an oral immunomodulatory agent with clinical efficacy in patients with multiple myeloma (MM). In patients with relapsed/refractory MM, lenalidomide plus dexamethasone improved time to... more
613 Background: Lenalidomide (Revlimid®) is an oral immunomodulatory agent with clinical efficacy in patients with multiple myeloma (MM). In patients with relapsed/refractory MM, lenalidomide plus dexamethasone improved time to progression (TTP) and overall survival (OS) in comparison with dexamethasone alone. In newly diagnosed MM patients, the current study compares the efficacy and safety of melphalan, prednisone and lenalidomide (MPR) with that of MP alone. Methods: Key inclusion criteria were: ≥65 years of age, newly diagnosed and symptomatic MM. 459 patients were randomly assigned to receive MPR followed by lenalidomide maintenance therapy or MPR followed by placebo maintenance therapy or MP followed by placebo maintenance therapy (Figure 1). The study induction and maintenance phases were followed by an open label lenalidomide extension and a follow-up phase. All patients received aspirin 100 mg/day as thrombo-prophylaxis. The primary endpoint of the study is progression free...
Research Interests:
A Phase 3 Study Evaluating the Efficacy and Safety of Lenalidomide (Len) Combined with Melphalan and Prednisone Followed by Continuous Lenalidomide Maintenance (MPR-R) in Patients (Pts) ≥ 65 Years (Yrs) with Newly Diagnosed Multiple Myeloma (NDMM): Updated Results for Pts Aged 65–75 Yrs Enrolled ...more
475FN2 Background: An IMiDs® immunomodulatory agent, Len has a dual mechanism of action: its tumoricidal effect directly leads to tumor cell death, and its immunomodulatory effect may keep the tumor in remission. A phase 3, randomized,... more
475FN2 Background: An IMiDs® immunomodulatory agent, Len has a dual mechanism of action: its tumoricidal effect directly leads to tumor cell death, and its immunomodulatory effect may keep the tumor in remission. A phase 3, randomized, placebo (Pbo)-controlled trial, MM-015 compares MPR-R with fixed-duration MPR and MP induction in transplant-ineligible NDMM pts. Interim results showed unprecedented reduction in disease progression risk with MPR-R (Palumbo et al, IMW 2011); this analysis focuses on pts aged 65–75 yrs in whom the greatest benefit was observed. Methods: A total of 459 pts aged ≥ 65 yrs with NDMM were enrolled. Induction consisted of nine 28-day cycles of melphalan 0.18 mg/kg (D1-4), prednisone 2 mg/kg (D1-4), and Len 10 mg (D1-21) (MPR-R and MPR) or melphalan and prednisone with Pbo (MP). After induction, MPR-R pts received Len 10 mg (D1-21) maintenance until progression; MPR and MP pts received Pbo. Pts with progressive disease (PD) could enroll in an open-label exte...
Research Interests:
8001Background: Several studies demonstrate that LEN MNTC post ASCT reduces the risk of disease progression or death in patients (pts) with MM by ≈ 50% (Attal NEJM 2012; McCarthy NEJM 2012; Palumbo NEJM 2014). However, these studies were... more
8001Background: Several studies demonstrate that LEN MNTC post ASCT reduces the risk of disease progression or death in patients (pts) with MM by ≈ 50% (Attal NEJM 2012; McCarthy NEJM 2012; Palumbo NEJM 2014). However, these studies were not powered for OS. To assess the effect of LEN MNTC post ASCT on OS, an MA was conducted. Methods: A prospectively planned MA assessed the OS of LEN vs placebo/no MNTC (control; CTL) after ASCT. A search identified 17 randomized controlled trials (RCTs) using LEN post ASCT. 3 RCTs (IFM 2005-02, CALGB 100104 [Alliance], GIMEMA RV-209) met prespecified inclusion criteria (had pt-level data, a CTL arm, and achieved database lock for primary efficacy analysis of NDMM pts receiving LEN post ASCT). A March 2015 cutoff of the 3 RCTs enabled sufficient OS events to test treatment effect (HR = 0.78). Results: In the 3 RCTs, 1209 pts were randomized from 2005 to 2009 to receive LEN (n = 605) 10 mg/day on days 1-21/28 (GIMEMA) or 1-28/28 (IFM and CALGB) or CTL (n = 604). With a med...
Research Interests:
8007 Background: MM pts have an 8-10 fold higher risk of developing acute myeloid leukemia (AML) than the general population. MM-015 compared MPR-R vs fixed-duration MP or MPR in transplant-ineligible pts ≥65 yrs. This analysis evaluated... more
8007 Background: MM pts have an 8-10 fold higher risk of developing acute myeloid leukemia (AML) than the general population. MM-015 compared MPR-R vs fixed-duration MP or MPR in transplant-ineligible pts ≥65 yrs. This analysis evaluated SPM incidence rates (IRs) and standardized incidence ratios (SIR). METHODS IRs were calculated for AML and solid tumor (ST) malignancies. Expected IRs used to calculate SIR were derived from 23,838 MM pts identified in the Surveillance, Epidemiology, and End Results (SEER) Cancer Registries between 1973-2000 (Dores 2006). RESULTS As of May 2010 cut-off, total cases of SPM were 4/150 in MPR-R (IR=1.40), 6/152 in MPR (IR=2.05) and 2/153 in MP (IR=0.67), including 2 myelodysplastic syndromes cases in MPR-R and 2 AML cases in each of MPR-R and MPR. 11 pts with complex cytogenetics were randomized to MPR-R/MPR and none randomized to MP. Of these, 3 developed AML; 2 MDS. ST were of heterogeneous tumor types. No B-cell malignancies were reported. Median progression-free survival (PFS) of MPR-R vs MP was 31 vs 13 mos (P < .001; median follow-up: 25 months), with a reduced risk of progression of 60% (hazard ratio [HR] = 0.395). When SPM were added as additional events for PFS, results remained unchanged (HR = 0.408; P <.001). CONCLUSIONS An imbalance of AML incidence was observed in MPR/MPR-R vs MP, but incidence was low (0.7% vs 0%) and associated with complex baseline cytogenetics. ST IRs were low and similar for all arms. At present, the SPM risk is similar to that reported in other studies. Longer follow-up is needed to definitively assess the risk of SPM in NDMM pts receiving lenalidomide and alkylating agents. Evaluation will continue with updated data at the meeting. [Table: see text].
Research Interests:
795 appears in Blood, Volume 108, issue 11, November 16, 2006 Abstracts of Clinical Interest Tuesday, December 12, 2006 8:30 AM Simultaneous Session: Induction Therapy for Newly Diagnosed Myeloma (8:00 AM-10:00 AM)
Research Interests:
MPR-R elicited higher and more rapid responses resulting in prolonged PFS. Additionally, lenalidomide taken continuously versus a fixed number of cycles significantly extended PFS with incidence of AEs comparable to placebo during the... more
MPR-R elicited higher and more rapid responses resulting in prolonged PFS. Additionally, lenalidomide taken continuously versus a fixed number of cycles significantly extended PFS with incidence of AEs comparable to placebo during the continuous therapy period. These data suggest that continuous use of lenalidomide is superior to regimens of limited duration and provides sustained disease control to patients with NDMM.
Research Interests:
Background: There are limited treatment options for multiple myeloma (MM) patients who have a disease progression after CAR-T therapy. ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, inhibiting exportin 1. US... more
Background: There are limited treatment options for multiple myeloma (MM) patients who have a disease progression after CAR-T therapy. ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, inhibiting exportin 1. US FDA has approved selinexor plus low dose dexamethasone (Sd) to treat patients (pts) with penta-refractory MM. MARCH study, a single arm, Phase 2, registrational study evaluating Sd in Chinese RRMM pts, achieved an overall response rate (ORR) of 29.3% (95% CI: 19.7, 40.4), rejecting the null hypothesis of the study. Given its unique and novel mechanism of action, Sd preserves anti-tumor activity regardless of specific prior therapies. In the MARCH study, encouraging activity was demonstrated in a small group of Chinese RRMM pts previously exposed to CAR-T therapy. Methods: The study enrolled 82 pts previously exposed and refractory to a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and last line of therapy. Among them, 10 had received l...
Research Interests:
Background: ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, which blocks exportin 1. US FDA has approved selinexor plus low dose dexamethasone (Sd) to treat patients (pts) with penta-refractory MM based on the... more
Background: ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, which blocks exportin 1. US FDA has approved selinexor plus low dose dexamethasone (Sd) to treat patients (pts) with penta-refractory MM based on the STORM study. MARCH is a single arm, Phase 2, registrational study to assess efficacy and safety of Sd in Chinese pts with RRMM. Methods: Enrolled Chinese pts were previously refractory to PI, IMiD, and last line of therapy. ATG-010 (80mg) plus dexamethasone (20mg) was administered twice weekly. The primary endpoint was overall response rate (ORR) per independent review committee. The planned 82 pts would provide ~80% power to test against null hypothesis (H 0) of 15% ORR at one-sided α of 0.025 at the primary analysis, which is presented here. Results: As of 6 th May 2021, 9 (11%) of the 82 pts were still on treatment. Median follow-up was 10.6 months (mo) (range: 2.3-19.6). Median age was 60 years (39% ≥ 65yrs). Median duration from MM initial diag...
Research Interests:
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk... more
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Wholegenome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R= 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R of 34.3% for PFS and 46.5% for OS. A hig...
High-dose dexamethasone (Dex) remains a standard therapy for relapsed or refractory MM. Lenalidomide is a novel, orally administered, immunomodulatory drug (IMiD) that has single-agent activity against MM and additive effects when... more
High-dose dexamethasone (Dex) remains a standard therapy for relapsed or refractory MM. Lenalidomide is a novel, orally administered, immunomodulatory drug (IMiD) that has single-agent activity against MM and additive effects when combined with Dex. In this phase 3, multicenter, randomized, double-blind trial, 351 patients with relapsed or refractory MM were enrolled from clinical centers in Europe, Israel, and Australia. Patients were treated with Dex 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, the dose intensity of Dex was reduced to 40 mg daily on days 1–4 only every 28 days. Patients resistant to Dex were excluded. 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). A pre-planned interim analysis of time to progression (TTP; primary e...
Research Interests:
INTRODUCTION: Lenalidomide (REVLIMID®; CC-5013) is a novel, orally active immunomodulatory drug under investigation for the treatment of multiple myeloma (MM). Phase 1 dose-escalation studies in patients (pts) with relapsed and refractory... more
INTRODUCTION: Lenalidomide (REVLIMID®; CC-5013) is a novel, orally active immunomodulatory drug under investigation for the treatment of multiple myeloma (MM). Phase 1 dose-escalation studies in patients (pts) with relapsed and refractory MM determined that the maximum tolerated dose (MTD) of lenalidomide was 25 mg/day, based upon myelosuppression encountered beyond 28 days, which was manageable with growth factor support and dose reduction. In a multicenter phase 2 study to determine optimal dose and schedule, 102 pts with relapsed or refractory MM were randomized to receive lenalidomide at either 15 mg bid (n=34) or 30 mg qd (n=68), for 21 days every 4 wks. Both treatment arms showed significant activity with manageable toxicity. An increased incidence of cytopenia was noted in the 15-mg bid group and thus the 30 mg qd schedule was taken forward. METHODS: The objective of this multicenter, phase 2, open-label study (CC-5013-MM-014) was to further evaluate the effectiveness and saf...
Research Interests:
8544 Background: The MM-015 pivotal phase III trial showed significant PFS benefit for MPR-R (31 mos) vs. MPR (14 mos) or MP (13 mos; both p < 0.001) followed by placebo in NDMM pts aged ≥ 65 years. As NDMM pts with RI have poor... more
8544 Background: The MM-015 pivotal phase III trial showed significant PFS benefit for MPR-R (31 mos) vs. MPR (14 mos) or MP (13 mos; both p < 0.001) followed by placebo in NDMM pts aged ≥ 65 years. As NDMM pts with RI have poor prognosis, this retrospective analysis studied the efficacy and safety of MPR-R in pts with creatinine clearance (CrCl) < 60 mL/min. Methods: LEN starting dose for induction/maintenance was 10 mg/day (D1–21 of a 28-day cycle). Dose adjustments were not recommended for pts with RI. CrCl was calculated using the Cockcroft-Gault equation. Pts with severe RI (serum Cr > 2.5 mg/dL [221 μmol/L]) were excluded from the trial. Results: Pts with CrCl < 60 mL/min (median 47, interquartile range [IQR] 38–55) were included in this analysis: 51% MPR-R, 45% MPR, and 49% MP. Median PFS was significantly higher with MPR-R (26 mos [95% CI 14–48]) vs. MPR (13 mos [95% CI 12–15]) or MP (14 mos [95% CI 12–16]; both p < 0.001). In a Cox proportional model of PFS, ...
Research Interests:
8583 Background: Poor prognosis and therapy exhaustion have been associated with reduced QOL in RRMM. In MM-003, a randomized, multicenter, open-label phase 3 trial, POM + LoDEX (n = 302) significantly improved progression-free and... more
8583 Background: Poor prognosis and therapy exhaustion have been associated with reduced QOL in RRMM. In MM-003, a randomized, multicenter, open-label phase 3 trial, POM + LoDEX (n = 302) significantly improved progression-free and overall survival vs. high-dose dexamethasone (HiDEX; n = 153) in pts who failed lenalidomide (LEN) and bortezomib (BORT) and progressed on their last therapy. This analysis evaluated QOL changes in these pts. Methods: To assess pt-reported outcomes, cross-sectional and longitudinal analyses were performed. Minimal important differences for 5 clinically relevant EORTC QLQ-C30 domains (Global Health Status, Physical Functioning, Fatigue, Emotional Functioning, and Pain) were calculated as meaningful change thresholds (1 standard error of measurement) from baseline through cycle (C) 5. Time to QOL worsening was compared between arms using the Kaplan-Meier method. Results: Favorable trends were observed for POM + LoDEX vs. HiDEX in each of the 5 relevant doma...
Research Interests:
Introduction: Lenalidomide (Len), an analog of thalidomide (Thal) is a novel, oral, immunomodulatory agent that is effective against multiple myeloma (MM). In 2 prospective, randomized, double-blind, placebo-controlled phase III trials,... more
Introduction: Lenalidomide (Len), an analog of thalidomide (Thal) is a novel, oral, immunomodulatory agent that is effective against multiple myeloma (MM). In 2 prospective, randomized, double-blind, placebo-controlled phase III trials, Len with dexamethasone (Dex) induced a significantly higher overall response (OR) rate and complete remission (CR) rate, as well as longer time-to-progression (TTP) in comparison with Dex alone. Here, we investigate the long-term overall survival (OS) with Len/Dex. Methods: We evaluated the pooled results from both randomized trials (MM-009, MM-010) of 704 patients who had relapsed or refractory MM, without prior resistance to Dex, who received either Len (25 mg daily for 3 weeks every 4 weeks), or placebo. Dex was given at 40 mg on days 1–4, 9–12, 17–20 every 4 weeks for 4 cycles. From cycle 5 onwards, Dex was given at 40 mg on days 1–4 only. Response rate and TTP are based on data obtained before unblinding (June 2005 [MM-009] and August 2005 [MM-0...
Research Interests:
Background: The use of low-dose dexamethasone (Dex) in combination with lenalidomide (Len), an immunomodulatory compound, improves overall survival (OS) compared with high-dose Dex plus Len in patients (pts) with newly diagnosed multiple... more
Background: The use of low-dose dexamethasone (Dex) in combination with lenalidomide (Len), an immunomodulatory compound, improves overall survival (OS) compared with high-dose Dex plus Len in patients (pts) with newly diagnosed multiple myeloma (MM) (Rajkumar et al. 2007). Two phase III randomised trials of pts with relapsed/refractory MM showed that Len/Dex had significantly better overall response (OR), complete response (CR), OS and time to progression (TTP) than Dex alone. Dex dose reductions were permitted in relation to severity of adverse events (AEs). We investigated the effect of Dex dose reductions on efficacy and tolerability of Len/Dex in relapsed/refractory MM. Methods: Data were pooled from the MM-009/010 studies for pts treated in the Len/Dex group who had an unchanged Len dose (n=233). Pts were treated with Len (25mg/day on day 1–21 of each 28-day cycle) and Dex 40mg on day 1–4, 9–12, and 17–20 (for the first four cycles). After four cycles, Dex 40mg/day was adminis...
Research Interests:
622 Background: Lenalidomide is an oral IMiD® compound with a dual mechanism of action, namely tumoricidal and immunomodulatory activity, and has proven efficacy in patients with MM. The current study (MM-015) is a prospective, randomized... more
622 Background: Lenalidomide is an oral IMiD® compound with a dual mechanism of action, namely tumoricidal and immunomodulatory activity, and has proven efficacy in patients with MM. The current study (MM-015) is a prospective, randomized phase 3 trial designed to evaluate the efficacy and safety of continuous lenalidomide treatment (MPR-R: melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance) vs fixed-duration regimens of melphalan and prednisone (MP) or melphalan, prednisone, and lenalidomide (MPR) in transplant-ineligible patients with NDMM. Methods: 459 patients aged ≥ 65 years with NDMM, stratified by age and International Staging System (ISS) stage were randomized to receive MPR-R, MPR, or MP. During double-blind treatment, patients received melphalan 0.18 mg/kg (D1-4), prednisone 2 mg/kg (D1-4), with or without lenalidomide 10 mg/day (D1-21) for nine 28-day cycles. Following 9 cycles of MPR, patients received maintenance lenalidomide (10 mg/d...
Research Interests:
Introduction: Treatment of elderly pts (age >65 years) with rel/ref MM remains a challenge due to concurrent comorbid conditions and poor tolerability to chemotherapy limiting therapeutic options. Recently, 2 phase III randomized... more
Introduction: Treatment of elderly pts (age >65 years) with rel/ref MM remains a challenge due to concurrent comorbid conditions and poor tolerability to chemotherapy limiting therapeutic options. Recently, 2 phase III randomized clinical trials (MM-090 and MM-010) demonstrated superiority of the LD combination over D alone in previously treated MM pts. We examined the clinical benefit of LD combination in elderly pts enrolled in these 2 clinical trials. Methods: This is a retrospective data analysis of pts enrolled on the MM-090 and MM-010. All elderly pts (>65 years) were identified and parameters of clinical outcome (overall response, OR; time to progression, TTP; overall survival, OS) recorded. To determine the clinical benefit of L in elderly pt population, we compared the group of elderly pts who received LD combination with those who received D + placebo as well as with the group of younger pts who received the LD combination in these studies. Results: Collectively, 704...
Research Interests:
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... more
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 nu...
Research Interests:
Introduction In a phase 3 trial of transplant non-eligible elderly (≥ 65 yrs) patients (pts) with NDMM, the combination of melphalan-prednisone-lenalidomide (LEN) followed by LEN maintenance (MPR-R) reduced the risk of progression by 60%... more
Introduction In a phase 3 trial of transplant non-eligible elderly (≥ 65 yrs) patients (pts) with NDMM, the combination of melphalan-prednisone-lenalidomide (LEN) followed by LEN maintenance (MPR-R) reduced the risk of progression by 60% compared with 9 cycles of MP (HR=0.40; P < 0.001) and by 51% compared with 9 cycles of MPR (HR=0.49; P < 0.001) (Palumbo, NEJM. 2012). The progression-free survival (PFS) benefit was seen in all patient types. With a median follow-up of 53 mos, the median overall survival (OS) was similar across the 3 treatment (Tx) groups (54 mos for MPR-R vs. 52 mos for MPR vs. 55 mos for MP) (Dimopoulos, ASH 2012; abstract 944). The similar OS benefit seen across the 3 arms could be due in part to the availability of more effective Tx options in subsequent lines of therapy. Assessment of PFS2, defined as the time from initial randomization to time of objective disease progression (PD) after next-line of therapy or death from any cause, has recently been pro...
Research Interests:
Deletions of chromosome 17p (del17p) that span the TP53 gene are associated with poor outcome in multiple myeloma (MM), but the prognostic value of del17p cancer clonal fraction (CCF) remains unclear. We applied uniform cytogenetic... more
Deletions of chromosome 17p (del17p) that span the TP53 gene are associated with poor outcome in multiple myeloma (MM), but the prognostic value of del17p cancer clonal fraction (CCF) remains unclear. We applied uniform cytogenetic assessments in a large cohort of newly diagnosed MM (NDMM) patients carrying varying levels of del17p. Incremental CCF change was associated with shorter survival, and a robust CCF threshold of 0.55 was established in discovery and replication data sets. After stratification on the 0.55-CCF threshold, high-risk patients had statistically significantly poorer outcomes compared with low-risk patients (median progression-free survival [PFS] and overall survival [OS], 14 and 32 vs 23.1 and 76.2 months, respectively). Analyses of a third data set comprising whole-exome sequencing data from NDMM patients identified presence of TP53 deletions/mutations as a necessary requirement for high-risk stratification in addition to exceeding the del17p CCF threshold. Meta...
Research Interests:
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk... more
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R of 34.3% for PFS and 46.5% for OS. A h...
Research Interests:
Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in... more
Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1,273 newly diagnosed patients with multiple myeloma we identify 63 driver genes, some of which are novel including , , , , and Oncogene mutations are significantly more clonal than tumor suppressor mutations, indicating they may exert a bigger selective pressure. Patients with more mutations in driver genes are associated with a worse outcome, as are those with identified mechanisms of genomic instability. Oncogenic dependencies were identified between mutations in driver genes, common regions of copy number change, and primary translocation and hyperdiploidy events. These dependencies included associations with t(4;14) and mutations in , and ; t(11;14) with mutations in and ; t(14;16) with mutations in ...
Research Interests:
Purpose Lenalidomide maintenance therapy after autologous stem-cell transplantation (ASCT) demonstrated prolonged progression-free survival (PFS) versus placebo or observation in several randomized controlled trials (RCTs) of patients... more
Purpose Lenalidomide maintenance therapy after autologous stem-cell transplantation (ASCT) demonstrated prolonged progression-free survival (PFS) versus placebo or observation in several randomized controlled trials (RCTs) of patients with newly diagnosed multiple myeloma (NDMM). All studies had PFS as the primary end point, and none were powered for overall survival (OS) as a primary end point. Thus, a meta-analysis was conducted to better understand the impact of lenalidomide maintenance in this setting. Patients and Methods The meta-analysis was conducted using primary-source patient-level data and documentation from three RCTs (Cancer and Leukemia Group B 100104, Gruppo Italiano Malattie Ematologiche dell'Adulto RV-MM-PI-209, and Intergroupe Francophone du Myélome 2005-02) that met the following prespecified inclusion criteria: an RCT in patients with NDMM receiving ASCT followed by lenalidomide maintenance versus placebo or observation with patient-level data available and ...
Research Interests: Oncology, Medicine, Stem Cell Transplantation, Humans, Internal Medicine, and 15 moreFemale, Multiple Myeloma, Male, Clinical oncology, Risk factors, Aged, Middle Aged, Adult, Disease Progression, Risk Factors, Thalidomide, Randomized Controlled Trials as Topic, lenalidomide, Disease Free Survival, and Angiogenesis inhibitors
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy... more
Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopeni...
Research Interests:
Research Interests:
Research Interests:
Research Interests: Medicine, England, Dexamethasone, Humans, Female, and 15 moreMultiple Myeloma, Male, North America, Aged, Middle Aged, Adult, New England, Adverse Event, Combination drug therapy, Disease Progression, New England Journalof Medicine, Overall Survival, Glucocorticoids, lenalidomide, and Medical and Health Sciences
Introduction Segmenting multiple myeloma (MM) into subgroups with distinct pathogenesis and clinical behavior is important in order to move forward with advancements in therapy and implement a targeted therapy approach. Current... more
Introduction Segmenting multiple myeloma (MM) into subgroups with distinct pathogenesis and clinical behavior is important in order to move forward with advancements in therapy and implement a targeted therapy approach. Current technologies have elucidated five major translocation groups, which have a varying effect on prognosis: t(4;14), t(6;14), t(11;14), t(14;16) and t(14;20) along with recurrent copy number changes including deletion of CDKN2C (1p32.3) and TP53 (17p13.1) as well as gain or amplification of 1q21. However, minor translocation and mutational groups are poorly described because sample numbers are limited in small datasets. The availability of multiple sets of high quality mutation data associated with clinical outcomes has provided a unique opportunity in MM whereby clustering mutational data with chromosomal aberrations in the context of gene expression we can develop a molecular classification system to segment the disease into therapeutically meaningful subgroups...
Research Interests:
This analysis assessed the efficacy and safety of lenalidomide + dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. Of 704 patients, 39% were thalidomide exposed.... more
This analysis assessed the efficacy and safety of lenalidomide + dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. Of 704 patients, 39% were thalidomide exposed. Thalidomide-exposed patients had more prior lines of therapy and longer duration of myeloma than thalidomide-naive patients. Lenalidomide + dexamethasone led to higher overall response rate (ORR), longer time to progression (TTP), and progression-free survival (PFS) versus placebo + dexamethasone despite prior thalidomide exposure. Among lenalidomide + dexamethasone-treated patients, ORR was higher in thalidomide-naive versus thalidomide-exposed patients (P = .04), with longer median TTP (P = .04) and PFS (P = .02). Likewise for dexamethasone alone-treated patients (P = .03 for ORR, P = .03 for TTP, P = .06 for PFS). Prior thalidomide did not affect survival in lenalidomide + dexamethasone-treated patients (36.1 vs 33.3 months, P > .05). Thalidomide-naive and...
Research Interests: Survival Analysis, Treatment Outcome, Dexamethasone, Humans, Blood, and 13 moreMultiple Myeloma, Placebos, Recurrence, Clinical Sciences, Middle Aged, Retrospective Studies, Venous thromboembolism, Overall Survival, Thalidomide, Progression Free Survival, Randomized Controlled Trials as Topic, Cardiovascular medicine and haematology, and Paediatrics and reproductive medicine
Research Interests:
Key Points Pomalidomide plus low-dose dexamethasone significantly improved PFS vs pomalidomide alone in relapsed and refractory multiple myeloma. Pomalidomide plus low-dose dexamethasone is an important new treatment option for RRMM... more
Key Points Pomalidomide plus low-dose dexamethasone significantly improved PFS vs pomalidomide alone in relapsed and refractory multiple myeloma. Pomalidomide plus low-dose dexamethasone is an important new treatment option for RRMM patients who have received multiple prior therapies.
Research Interests:
Continuous therapy (CT) prolongs progression-free survival 1 (PFS1; time from random assignment until the first progression or death), but chemotherapy-resistant relapse may negatively impact overall survival (OS). Progression-free... more
Continuous therapy (CT) prolongs progression-free survival 1 (PFS1; time from random assignment until the first progression or death), but chemotherapy-resistant relapse may negatively impact overall survival (OS). Progression-free survival 2 (PFS2; time from random assignment until the second progression or death) may represent an additional tool to estimate outcome. This study evaluates the benefit of novel agent-based CT versus fixed duration of therapy (FDT) in patients with newly diagnosed myeloma. We included patients enrolled onto three phase III trials that randomly assigned patients to novel agent-based CT versus FDT. Primary analyses were restricted to the intent-to-treat population eligible for CT (patients progression free and alive at 1 year after random assignment). Primary end points were PFS1, PFS2, and OS. All hazard ratios (HRs) and 95% CIs were adjusted for several potential confounders using Cox models. In the pooled analysis of the three trials, 604 patients wer...
Research Interests:
Asian countries adjacent to the Golden Triangle and their neighbors have witnessed an evolution in &quot;drug abuse&quot; from traditional opium smoking to heroin eating, smoking, and finally heroin injection. A recent study of... more
Asian countries adjacent to the Golden Triangle and their neighbors have witnessed an evolution in &quot;drug abuse&quot; from traditional opium smoking to heroin eating, smoking, and finally heroin injection. A recent study of 630 heroin users was conducted in China&#39;s Yunnan Province, located close to the Golden Triangle. Data collected between August 1997 and February 1998 indicate injecting heroin users, in comparison to noninjectors, were more likely to have used drugs for a longer period of time, and to use drugs more frequently everyday. Other major differences existed between urban and rural subjects, especially highlighting differences between men and women. Women comprised a much higher proportion of urban subjects than rural subjects. Rural injectors were much more likely to be male, but urban injectors were almost evenly split between men and women. The emerging epidemic of heroin use in China and the continuing substance abuse problem in the United States provide an opportunity for collaborative research of mutual benefit.
Research Interests:
Research Interests:
Research Interests:
Research Interests: Pain, Adolescent, Chronic illness, Fatigue, Ovarian Cancer, and 20 moreHumans, Functional Capacity, Female, Male, Functional Assessment, Young Adult, Cancer Chemotherapy, Sample Size, Aged, Middle Aged, Cognitive impairment, Adult, Adverse Event, Cognitive Function, Neoplasms, Randomized Clinical Trial, Treatment Response, Methylphenidate, Antineoplastic Agents, and Dexmethylphenidate
This study examined the effects of migratory stream patterns on the amount of exposure to HIV prevention. It was hypothesized that fewer number of moves, a homebase in Collier County, Florida, greater number of years lived in Collier... more
This study examined the effects of migratory stream patterns on the amount of exposure to HIV prevention. It was hypothesized that fewer number of moves, a homebase in Collier County, Florida, greater number of years lived in Collier County, and having field-related jobs increase the potential for exposure to HIV prevention. Rural drug users and their sex partners were recruited
Research Interests:
Research Interests: Cancer, Dexamethasone, Humans, Female, Multiple Myeloma, and 6 moreRenal Function, Recurrence, Aged, Middle Aged, Adult, and Thalidomide
... Edward A. Stadtmauer 1 ,; Donna M. Weber 2 ,; Ruben Niesvizky 3 ,; Andrew Belch 4 ,; Miles H. Prince 5 ,; Jesús F. San Miguel 6 ,; Thierry Facon 7 ... Correspondence: Dr Edward A ... Combination therapy with lenalidomide plus... more
... Edward A. Stadtmauer 1 ,; Donna M. Weber 2 ,; Ruben Niesvizky 3 ,; Andrew Belch 4 ,; Miles H. Prince 5 ,; Jesús F. San Miguel 6 ,; Thierry Facon 7 ... Correspondence: Dr Edward A ... Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma ...