Activity and Safety of Lenalidomide and Dexamethasone in Multiple Myeloma Patients with Advanced Renal Failure: a Spanish Multicenter Retrospective Study.

Abstract Abstract 1886 Poster Board I-909 Background: Approximately 30% of patients with multiple myeloma (MM) present with baseline renal impairement, with 1% to 13% having renal failure requiring dialysis support. The severity of renal impairment significantly affects the prognosis of patients with MM and has been associated with shorter survival or early death. Lenalidomide is an immunomodulating agent indicated for the treatment of MM patients after one prior therapy. Lenalidomide is primarily excreted unchanged by the kidney, adjustements to the starting dose are recommended in patients with moderate or severe renal impairement and in patients on dialysis. For patients with end stage renal disease (CLCr < 30 mL/min) requiring dialysis, the recommended starting dose is 5 mg/day. However, experience in patients with MM and dialysis support is limited. To further examine the safety and activity of lenalidomide-based therapy in these patients, we underwent a retrospective analysis in patients with MM who required dialysis at the time of lenalidomide administration. Methods: Fifteen patients (10 M/5 F; median age, 70 years, range 55–77) with relapsed MM from 10 Spanish hospitals received lenalidomide-based therapy between 2007 and 2009. All patients were on dialysis at the time of lenalidomide administration. Median (range) number of therapies previously administered was 2 (1–4) and median time between diagnosis and lenalidomide treatment was 14 months (range, 5–50). Eighty-seven percent of patients received lenalidomide at a dose of 15 mg/day three times weekly after dialysis given in combination with dexamethasone. Patients were given a median of seven 28-day cycles (range, 1–22 cycles) of lenalidomide treatment. Antithrombotic prophylaxis was administrated in fourteen patientes and consisted of low molecular weight heparin (five cases, 36%), oral anticoagulation (four cases, 29%), antiplatelet therapy (three cases, 21%), and combination of the above agents (two cases, 14%). Results: Overall, 13 (87%) patients experienced adverse events, with grade 3 neutropenia as the most common (8 patients). Seven patients (47%) developed grade 3–4 infectious complications (3 bacteremias, 1 infection of arterio-venous fistula, 1 septic arthritis, 1 central venous line infection, and two pneumonias in the remaining patient). No patient developed thromboembolic complications. Fourteen patients were evaluable for response: 4 had complete response (29%), 1 a very good partial response (7%), and 3 partial response (21%). In addition, 4 patients had stable disease (29%) and 2 (14%) did not respond. One patient became independent of dialysis following lenalidomide-based treatment. As of July 2009, seven (47%) patients have died, four due to infectious complications and three as a result of progressive disease. Eight patients are still alive, six of them continue on lenalidomide treatment and two discontinued therapy due to liver toxicity (1 case) and progressive disease (1 case). Conclusion>: These results suggest that lenalidomide-based regimens can be used in MM patients requiring dialysis, with a good response rate. The high incidence of neutropenia and infectious complications highlights the need of a close monitoring of these patients. Currently ongoing studies will more formally evaluate the impact of lenalidomide-based regimens in this patient population. Disclosures: No relevant conflicts of interest to declare.

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A Phase II Study of PS-341 for Patients with High Risk, Newly Diagnosed Multiple Myeloma: A Trial of the Eastern Cooperative Oncology Group (E2A02).

Blood ◽

10.1182/blood.v106.11.2546.2546 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2546-2546 ◽

Cited By ~ 2

Author(s):

Angela Dispenzieri ◽

Emily Blood ◽

David Vesole ◽

Rafael Fonseca ◽

Natalie Callander ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Peripheral Neuropathy ◽

High Risk ◽

Partial Response ◽

Progressive Disease ◽

Response Rate ◽

Cell Labeling ◽

Newly Diagnosed ◽

Grade 3

Abstract Background: Multiple myeloma (MM) is an incurable disease with a anticipated overall survival (OS) ranging from months to decades. Modest improvements in OS have been made with high-dose chemotherapy with peripheral blood stem cell transplant (PBSCT), but to date prognostic factors have a greater impact on OS than do individual therapies. Patients with adverse risk factors such as elevated beta-2 microglobulin (B2M), plasma cell labeling index, deletions of the long arm of chromosome 13 by metaphase cytogenetics (del 13q) require innovative new treatment strategies. Bortezomib has significant activity in patients with both newly diagnosed and relapsed/refractory MM, but its specific role in patients with adverse features has not yet been defined. Methods: Patients with newly diagnosed “high-risk” myeloma (B2M ≥ 5.5., PCLI ≥ 1, or del 13q) and adequate organ and functional status were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients were scheduled to receive bortezomib 1.3 mg/m2 every other week indefinitely. Elective peripheral stem cell mobilization (growth factor alone) was allowed after 4 cycles of bortezomib. Patients relapsing on maintenance schedule were to have the full induction schedule resumed. Responses were by the EBMT criteria but a very good partial response category was included. The primary end-point was the response rate in these high-risk patients (90% power to detect a response rate of 50% or higher). The study decision rule requires that 16 or more responses, among 39 eligible patients, are seen in order to declare this treatment effective. Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled on study. Among the 43 eligible patients, median age was 63; 51% were male. All patients had high risk disease: del 13q (6/41); plasma cell labeling index ≥1% (16/34); and B2M≥5.5 (34/43). Preliminary response data are available for 18 of the 44 cases enrolled, of which 7 had partial response, 1 had minimal response, 1 had no response, 2 had progressive disease, and 5 were unevaluable. Among those patients completing induction therapy and with response information, the median number of cycles of therapy administered is 5, range (0,8). The most common non-hematologic adverse events (AEs) of grade 3 or higher included hyponatremia (9 patients) and diarrhea (6 patients). Mild sensory peripheral neuropathy was common: grade 1, 16 patients; grade 2, 2 patients. Only 1 patient had grade 3 peripheral neuropathy. One patient died after receiving 2 doses bortezomib due to heart block and asystole. Two patients had a grade 4, 25 patients had grade 3, and 13 had grade 1 or 2 as the worst grade non-hematologic adverse event. Based on data received by August 1, 2005, 18 patients have gone off study: AEs (2); death (1); progressive disease (9); and other reasons (6). Updated results on the full study population along with FISH data for IgH translocations and deletions of 13q and 17p will be presented at the meeting. Conclusions: Preliminary results suggest that upfront bortezomib has activity in patients with high-risk MM, but further follow-up is required.

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Safety and Efficacy of Bortezomib (VELCADE™) in 104 Patients with Relapsed and/or Refractory Multiple Myeloma Who Have Received at Least Two Previous Lines of Therapy: Impact of Cytogenetics on Response from a Canadian Cohort.

Blood ◽

10.1182/blood.v108.11.5118.5118 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5118-5118

Author(s):

Joseph R. Mikhael ◽

Donna E. Reece ◽

Andrew Belch ◽

Nizar J. Bahlis ◽

Deepa Sharma

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Poor Prognosis ◽

Progressive Disease ◽

Karnofsky Performance Status ◽

Performance Status ◽

M Protein ◽

Cytogenetic Abnormalities ◽

Refractory Multiple Myeloma ◽

The Impact

Abstract Background: Bortezomib (VELCADE™) is a reversible proteasome inhibitor that has been shown to be safe and efficacious in patients (pts) with relapsed and/or refractory multiple myeloma (MM) using a dose of 1.3 mg/m2 on days 1, 4, 8 & 11 of a 21-day cycle. Certain cytogenetic abnormalities are associated with poor prognosis in MM, including deletion 13, t(4;14) and the p53 deletion.(Stewart et al, JCO2005; 23(26):6339–44). Bortezomib has demonstrated the ability to overcome the poor prognosis associated with deletion 13 (Jagannath, JCO2005; 23(16S) 6501). The impact of bortezomib on a broader range of cytogenetic abnormalities, such as t(4;14) has yet to be determined. Methods: In this multicentre, open-label, non-randomized, phase 3b study, pts with MM across 13 centres in Canada, who had received at least 2 previous lines of therapy and who were refractory to or had relapsed after their last therapy were enrolled. Pts received up to eight 3-week cycles of bortezomib on days 1, 4, 8 & 11. Dexamethasone 20 mg PO was administered on each day of and day after bortezomib administration if the pts either experienced progressive disease after receiving at least 2 treatment cycles of bortezomib or had no change in disease status from baseline after receiving at least 4 treatment cycles of bortezomib. Results: 104 pts were enrolled; the mean age in this cohort was 60.7 years, and 65 (62.5%) were male. Approximately 30% of pts had a Karnofsky performance status of 70 or less at baseline. 71 pts (68.3%) had received prior thalidomide therapy, 32 (30.8%) had received a prior autotransplant and 4 (3.8%) had received prior bortezomib treatment. 74 (71.2%) received 3 or more lines of prior MM therapy. During the study, mean number of bortezomib cycles completed was 4.6 (range, 0–11 cycles), and the number of pts that completed 8 cycles of therapy was 36 (34.6%). 15.2% of pts received dexamethasone at cycle 3 and 19.2% at cycle 5. Cytogenetic analysis was performed on approximately half of the pts. Response data for cycle 5 is currently available for 69/99 (69.7%) of evaluable pts (see Table 1). Overall, 76.9% of the pts experienced Grade 3 & 4 adverse events. Safety profile observed is similar to past trial results with bortezomib. Conclusion: In this large Canadian cohort of extensively pre-treated patients with mulitple myeloma, bortezomib demonstrated good response, consistent with previous studies. Analysis correlating cytogenetic profile and response rate is ongoing and will be available at the time of conference. In addition, a detailed safety analysis and impact of prior treatment on response will be analyzed and made available at the time of conference. Table 1. Response to Bortezomib Category of Response* No. of Patients (%) *Modified SWOG: CR 100% M-protein reduction; R 75–99%; PR 50–74%; MR 25–49%; SD<25%, PD increasing M-protein Any Response (CR + VGPR + PR + MR) 47 (68.1) ---Complete Response (CR) + Very Good Partial Response (VGPR) ---22 (31.9) ---Partial Response (PR) + Minimal Response (MR) ---25 (36.2) Stable Disease 10 (14.5) Progressive Disease 12 (17.4)

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Melphalan, Prednisone and Lenalidomide Followed by Lenalidomide Maintenance Displays Treatment Characteristics Favourable to Global Quality of Life in Newly Diagnosed Multiple Myeloma (NDMM) Patients ≥ 65 Years,

Blood ◽

10.1182/blood.v118.21.3988.3988 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3988-3988 ◽

Cited By ~ 2

Author(s):

Meletios Athanasios Dimopoulos ◽

Antonio Palumbo ◽

Roman Hajek ◽

Martin Kropff ◽

Maria Teresa Petrucci ◽

...

Keyword(s):

Quality Of Life ◽

Multiple Myeloma ◽

Partial Response ◽

Progressive Disease ◽

Newly Diagnosed ◽

Employment Equity ◽

Risk Of Disease ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 3988 Background: Melphalan, prednisone and lenalidomide followed by lenalidomide maintenance (MPR-R) demonstrated higher response rates (ORR; 77% vs. 50%, p <.001; VGPR or better: 32% vs. 12%, p <.001) and significantly reduced the risk of disease progression (hazard ratio [HR] = 0.423, p <.001) vs. MP alone [Palumbo, 2010]. Alongside efficacy considerations, analyses on health-related quality of life (HRQoL) may help more fully establish a regimen's overall treatment profile. HRQoL improvements with MPR-R were observed during MPR induction as well as lenalidomide maintenance, documenting a well-balanced profile in terms of efficacy, tolerability and HRQoL [Dimopoulos, 2011]. Alternative findings on novel NDMM treatment have shown efficacy of melphalan, prednisone and bortezomib (VMP) treatment to be associated with an intermittent deterioration in patients' HRQoL [Dhawan, 2009]. Methods: A mixed effects model was developed based on parameters pre-selected as potentially clinically relevant in impacting HRQoL. Models were run on six domains pre-selected based on clinical relevance: Global QoL, Physical Functioning, Fatigue and Pain (from EORTC QLQ-C30), and Disease Symptoms and Side Effects of Treatment (from EORTC MY20). Cycle 16 was determined as the last observation time point with a statistically meaningful sample size at time of follow-up (May 2010). Following explanatory variables were included: time-dependant covariates at individual HRQoL measurement time points (i.e. cycle 4, 7, 10, 13 and 16), treatment group (MPR-R vs. MP), gender (Female vs. Male), age, baseline QoL, Partial Response (PR) vs. Stable Disease (SD) and Very Good Partial Response or better (≥VGPR) vs. SD, Progressive Disease (PD) and Discontinuation (DC). Neutropenia and anemia, both Grade 3 or 4, were considered the clinically most relevant safety parameters. Main results for Global QoL are reported, with results from other domains found to be comparable. Results: Across all time-dependant covariates, a statistically significant reduction on Global QoL (−4.63; p=.004) was observed at Cycle 4. Being female vs. male significantly reduced Global QoL by -−.07 (p=.026). Each additional life year was found to lower Global QoL b− −0.40 points (p=.034). Baseline Global QoL was also significant, each additional score point leading to +0.30 (p <.001). A response level of ≥VGPR vs. SD increased Global QoL by 9.11 (p=.023); Progressive Disease (PD) reduced Global QoL by -−.34 score points (p <.001). All other pre-defined variables did not significantly impact Global QoL. Clinically meaningful changes for Global QoL in the underlying patient population have been determined to constitute at least a 7-point change [Dimopoulos, 2011]. Progressive disease (reducing Global QoL), respectively ≥VGPR (increasing Global QoL) exerted clinically meaningful changes, as did anemia grade 3–4, which had a clinically meaningful, but not statistically significant negative impact (−9.85; p=.057). Although no significant direct effect of MPR-R over MP on Global QoL was detected in the underlying model, MPR-R displays properties which favor an improved HRQoL profile, including a stronger delay in PD and higher % of VGPR vs. MP patients. Furthermore, certain properties more frequently observed with MPR-R than MP (neutropenia grade 3 or 4 and discontinuation, DC) were shown not to have a significant impact on HRQoL. Anemia grade 3 or 4, exerted a clinically meaningful negative effect but was not significantly more often observed with MPR-R compared to MP (24% vs. 17%, p= 0.091). Conclusions: More patients achieved ≥VGPR when receiving continuous MPR-R treatment than those receiving MP. In the above pooled analysis, ≥VGPR was shown to improve Global QoL in a clinically meaningful and statistically significant way. Furthermore, progression was also shown to negatively impact Global QoL (−8.34; p <.001), with MPR-R significantly reducing the risk of disease progression over MP. Delaying progression with continuous MPR-R therefore helps to maintain a high Global QoL. Disclosures: Dimopoulos: Celgene: Consultancy, Honoraria. Off Label Use: Lenalidomide in newly diagnosed multiple myeloma. Palumbo:Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Ortho-Biotech: Honoraria. Hajek:Celgene: Honoraria; Janssen-Cilag: Honoraria; Merck: Honoraria. Petrucci:Celgene: Honoraria. Lewis:Celgene: Employment, Equity Ownership. Millar:Celgene: Consultancy. Zhang:Celgene: Employment, Equity Ownership. Mei:Celgene: Employment, Equity Ownership. Delforge:Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Speakers Bureau.

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Efficacy and Safety of Bortezomib Based Regimens Retreatment in Relapsed Multiple Myeloma Patients: Results from a Retrospective Study.

Blood ◽

10.1182/blood.v126.23.5387.5387 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5387-5387

Author(s):

Wenjun Wu ◽

Gaofeng Zheng ◽

Xiaoyan Han ◽

Yi Zhao ◽

Donghua He ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Confidence Interval ◽

Incidence Rate ◽

Conflicts Of Interest ◽

Progression Free Survival ◽

Initial Therapy ◽

Efficacy And Safety ◽

Grade 3 ◽

Group 1

Abstract Objective: To evaluate the efficacy and safety of bortezomib retreatment in relapsed multiple myeloma (MM) patients, who previously responded to bortezomib. Methods: This retrospective observational study included data from 45 patients and evaluated the efficacy and safety of bortezomib based retreatment in these patients, who had achieved at least a partial response (PR) on initial bortezomib therapy in our hospital from May 2006 to May 2013. Results: The overall response rate (ORR) was 71.2%, among them 9% patients achieved CR, 11.1% patients achieved very good partial response (VGPR), 51.1% patients achieved PR. All patients were divided into 3 groups according to the response of initial bortezomib therapy, including CR group, VGPR group and PR group. After bortezomib retreatment, the ORR of the 3 groups was 76.9%, 75% and 62.5%, respectively. According to the response of bortezomib retreatment, the patients were divided into 2 groups: group 1 who at least achieved PR, group 2 who showed no response. The median progression-free survival (PFS) after bortezomib retreatment for group 1 and 2 was 9( 95% confidence interval 7.947~10.051) and 10 (95% confidence interval 8.381∼11.619) months, respectively (P>0.05), while the median overall survival (OS) after bortezomib retreatment was 71 (95% confidence interval 66.694∼75.306)) and 37 (95% confidence interval 1-28) months, respectively (P<0.05). In patients with bortezomib retreatment had different degrees of adverse events (AE) , the most AE for grade 1~2. The most common grade ≥3 AE was thrombocytopenia, neutropenia and anemia. The incidence rate of grade ≥3 AE peripheral neuropathy bortezomib was 15%. Conclusion: Bortezomib based regimens retreatment was effective and tolerable in relapsed MM patients, who had achieved at least a partial response (PR) on initial therapy. The incidence rate of AE was not significantly increased. Disclosures No relevant conflicts of interest to declare.

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Preliminary Safety and Efficacy Results from an International Phase 3b Study for Expanded Access to Bortezomib in 624 Patients with Relapsed and/or Refractory Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3530.3530 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3530-3530 ◽

Cited By ~ 1

Author(s):

Joseph R. Mikhael ◽

Andrew Belch ◽

Miles Prince ◽

Maria Nambo Lucio ◽

Angelo Maiolino ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Median Time ◽

Stable Disease ◽

Progressive Disease ◽

Karnofsky Performance Status ◽

M Protein ◽

Significant Activity ◽

Expanded Access ◽

Grade 3

Abstract Background: Bortezomib (VELCADE®) is a first-in-class, reversible proteasome inhibitor with activity in multiple myeloma (MM) and other malignancies. Bortezomib showed significant activity in previous phase 2 and 3 studies in patients (pts) with previously treated MM. This international multicenter open-label phase 3b study allowed expanded access to bortezomib therapy in pts with relapsed/refractory MM treated with ≥ 2 previous lines of therapy. Methods: Pts with MM were eligible if they had received ≥ 2 prior lines of therapy and required treatment due to relapsed or progressive disease. Pts with grade ≥ 2 peripheral neuropathy (PN) were excluded. Pts received 1.3 mg/m2 IV bolus bortezomib on days 1, 4, 8, and 11 of each 3-week cycle for up to 8 cycles; dexamethasone (20 mg/d PO on the day of and day after bortezomib dose) could be added after cycle 2 for progressive disease or after cycle 4 for stable disease. Adverse events (AEs) were assessed beginning at the start of treatment and continuing until 30–42 days after treatment and were graded based on NCI-CTC version 2.0. Efficacy assessment was performed based on changes in disease burden as measured by monoclonal (M)-protein concentration in serum and urine every 2 cycles (6 weeks). Response was assessed using modified SWOG criteria: complete response (CR) was a 100% reduction in M-protein; very good partial response (VGPR), 75–99% reduction; partial response (PR), 50–74% reduction; minimal response (MR), 25–49% reduction; and stable disease, < 25% reduction. Increasing M-protein levels indicated progressive disease. Results: 624 pts in 93 centers from 21 countries received at least 1 dose of treatment and were evaluable for safety (55.3% male; median age 62.7 years). 68% of pts received 3–11 lines of previous therapy. Karnofsky performance status was ≤70 in 25.6% of pts; 141 pts (22.6%) were ≥ 70 years of age. Pts completed a median of 5 cycles of therapy (range 0–13); 39.3% of pts completed all 8 planned cycles. Grade 3/4 treatment-emergent (related and unrelated) AEs were reported in 430 pts (68.9%), with thrombocytopenia (29.2%), neutropenia (13.3%), and anemia (11.7%) the most common hematologic AEs. Grade 3/4 PN was reported in 8.2% of pts. Overall, 165 pts (26.4%) discontinued therapy due to treatment-related AEs. Best responses among evaluable pts (n = 593) included 12.0% CR, 23.1% VGPR, 19.1% PR, and 16.5% MR, for an overall response rate of 70.7%. Median time to first response was 42 days (range 7–125), and median time to best response was 63 days (range 7–235). Conclusions: Bortezomib 1.3 mg/m2 administered biweekly q3 weeks was well tolerated with manageable toxicities in pts with relapsed and/or refractory MM. Response rates with bortezomib were high, even in heavily pretreated pts, inducing > 25% CR/VGPR. This study confirms results from initial clinical trials in a broader population.

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Combination Therapy Based on Bortezomib for Newly-Diagnosed Multiple Myeloma: a Chinese Experience

Blood ◽

10.1182/blood.v116.21.5036.5036 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5036-5036

Author(s):

Li Yang ◽

Jing-Song He ◽

WenJun Wu ◽

Xiujin Ye ◽

Jimin Shi ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Combination Therapy ◽

Combination Chemotherapy ◽

Chinese Population ◽

Conflicts Of Interest ◽

Malignant Neoplasm ◽

Chinese Patients ◽

Newly Diagnosed ◽

Grade 3

Abstract Abstract 5036 Multiple myeloma (MM) is a malignant neoplasm of plasma. With conventional chemotherapy, the rates of complete remission (CR) or very good partial remission (VGPR) are still low. Little has been reported on Bortezomib-based therapies specifically in the Chinese pateitns with MM. Here we report our results with combination therapy based on bortezomib in the Chinese population. We investigated the efficacy and safety of Bortezomib-based therapies in previously untreated MM patients. Methods: Between June 2006 and June 2010, 61 consecutive newly-diagnosed patients with symptomatic MM were treated with combination therapies based on Bortezomib. Forty-two patients were male and 19 were female. Median age was 59 years (range 37–86 years). Forty-four patients were stage 3 according to the International Staging System, 6 patients were stage 2 and 11 patients were stage 1. The conbinations included dexamethasone, dexamethasone plus subsequent thalidomide and dexamethasone plus cyclophosphamide. In detail, Bortezomib was at the dose of 1.3 mg per square meter IV on days 1, 4, 8, 11 and dexamethasone at 20 mg per square meter IV daily on the day of bortezomib and the day after, with or without daily oral thalidomide that was escalated from 100 mg to 200 mg (BD group or BDT group) or plus cyclophosphamide at 0.2 per square meter IV on days 1 to days 4 (BDC group). Thirty-four patients were in BDT group, 12 in BD group and 15 in BDC group. All patients received a median of three cycles of therapy (range 1–6). The IMWG criteria were used for response evaluation and toxicities were evluated according to the NCI Common Toxicity Criteria version 3. Results: The proportions of patients with very good partial response (VGPR) or better were 38% (13/34), 25% (3/12) and 60% (9/15) in BDT, BD and BDC group, respectively; 44% (15/34), 33% (4/12) and 33% (5/15) achieved partial response (PR). Therefore the overall response (VGPR plus PR) were 82% (28/34), 58% (7/12) and 93% (14/15). Three patients died with severe infection without disease progression. Grade 3–4 toxicities included fatigue (4/34, 1/12 and 4/15), thrombocytopenia (8/34, 3/12 and 5/15), diarrhea (4/34, 2/12 and 2/15) and infection (7/34,3/12,6/15) in BDT, BD and BDC group, respectively. Grade 1–2 neuropathy were occurred in 20 patients (59%), 6 patients (50%) and 9 patients (60%) and grade 3–4 were occurred in 6 (18%), 1 (8%) and 1 (7%) in BDT, BD and BDC group, respectively. Herpes zoster occurred in 6 patients (18%), 1 patients (8%) and 2 patients (13%) respectively. Routine anticoagulation or anti-thrombsis were not used. Only 1 patient suffered from DVT/PE but did well with treatment. Conclusions: Our preliminary experience in Chinese patients indicated that combination chemotherapy based on Bortezomib is highly effective in newly-diagnosed multiple myeloma and BDC or BDT regimens may be more superior than BD in Chinese population. There were relative lower rates of grade 3–4 neuropathy and DVT/PE in the Chinese patients with MM receved combination chemotherapy based on bortezomib. Disclosures: No relevant conflicts of interest to declare.

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Clinical Efficacy of a Bortezomib, Cyclophosphamide and Dexamethasone Compared with Bortezomib, Cyclophosphamide, Thalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.1868.1868 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1868-1868

Author(s):

Jae-Sook Ahn ◽

Deok-Hwan Yang ◽

Joon Ho Moon ◽

Sang Kyun Sohn ◽

Sung-Hoon Jung ◽

...

Keyword(s):

Multiple Myeloma ◽

Herpes Zoster ◽

Partial Response ◽

Adverse Events ◽

Conflicts Of Interest ◽

Sensory Neuropathy ◽

Salvage Regimen ◽

Refractory Multiple Myeloma ◽

Grade 3 ◽

Acyclovir Prophylaxis

Abstract Abstract 1868 Backgrounds & Aims: Salvage therapy such as bortezomib, cyclophosphamide, thalidomide and dexamethasone (Vel-CTD) showed an effective regimen in patients with relapsed or refractory multiple myeloma (MM). However, toxicities of this regimen due to combination bortezomib and thalidomide interrupt the consecutive treatments in a few patients. Therefore, we compared the clinical responses and toxicities between bortezomib, cyclophosphamide and dexamethasone (Vel-CD) and Vel-CTD in patients with relapsed or refractory MM patients, retrospectively. Methods: Eighty-six patients received at least 2 cycles of treatment with Vel-CTD (bortezomib 1.3 mg/m2 i.v. on D1, 4, 8 and 11; cyclophosphamide 150 mg/m2 orally on D1-4; thalidomide 50 mg/day orally every day; and dexamethasone 20 mg/m2 i.v. on D1, 4, 8 and 11 for every 3 weeks) and 67 patients with Vel-CD, which is the same regimen except thalidomide. Vel-CD group was only received low-dose acyclovir for prevention of herpes zoster. Results: 17/67 (25%) and 10/86 (12%) of light chain disease was enrolled in Vel-CD and Vel-CTD group respectively (p=0.027) and there was no statistical difference at baseline demographic and disease characteristics between two groups in the others. The median time from diagnosis to treatment in Vel-CD and Vel-CTD was 15.6 months (range, 2–250 months) and 15.7 months (range, 1–230 months), respectively (p=0.54). The median number of treatment cycles was 6 cycles (range, 2–18) in Vel-CD and 8 cycles (range, 2–24) in Vel CTD group, and the number of cycles delivered was 430 and 678, respectively. The overall response rates (≥PR) of Vel-CD and Vel-CTD group were 88% and 90% ( 49% and 48% of complete response, 9% and 14% of very good partial response, 30% and 28% of partial response), respectively (each, p>0.05). There was no difference in progression free survival (p=0.69) and overall survival (p=0.49). Grade 3 or more hematologic adverse events occurred in the same proportion of patients in the both group. In non hematologic toxicities profiles, Vel-CTD group (14%) showed the higher proportion of grade 3 or more sensory neuropathy compared with Vel-CD group (3%) (p=0.02). Dose adjustment of bortezomib in Vel-CD and Vel-CTD were 40% (27/67) and 41%(35/86), respectively (p=0.96). Two patients (3%) in Vel-CD group received acyclovir prophylaxis developed herpes zoster compared with 17 patients (20%) in Vel-CTD group they were not received acyclovir prophylaxis (p=0.002). Three patients showed thrombotic events (2: pulmonary thromboembolism, 1: acute myocardial infarction) in only Vel-CTD group despite aspirin prophylaxis (p=0.16). Conclusion: Vel-CD combination therapy in patients with relapsed or refractory MM is an effective and more tolerable salvage regimen compared with Vel-CTD in the aspect of comparable response rate, less non-hematologic toxicities especially thalidomide associated adverse events. Disclosures: No relevant conflicts of interest to declare.

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Combination Therapy Based on Bortezomib for Newly Diagnosed Multiple Myeloma Patients

Blood ◽

10.1182/blood.v120.21.5048.5048 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5048-5048

Author(s):

Jingsong He ◽

Li Yang ◽

Dian Jin ◽

Xuanru Lin ◽

Qianqian Yang ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Combination Therapy ◽

Conflicts Of Interest ◽

Complete Response ◽

Chinese Patients ◽

Newly Diagnosed ◽

Serious Adverse Events ◽

Novel Drugs ◽

Grade 3

Abstract Abstract 5048 Introduction: Novel drugs, such as bortezomib, have significantly improved the response rates in multiple myeloma (MM), but little has been reported on bortezomib-based therapies in Chinese patients. Methods: In the initial eight 28-day cycles, newly diagnosed ymptomatic patients were treated with combination therapy including bortezomib plus dexamethasone (PD) and the triplet combinations of PD with adriamycin (PAD), cyclophosphamide (PCD), thalidomide (PDT) between February 1, 2006 and May 31, 2012. Among the above regimens, bortezomib (1. 3 mg/m2) was given intravenously on days 1, 4, 8, 11, while dexamethasone (20 mg/m2/day) was given intravenously on days 1–2, 4–5, 8–9, 11–12, adriamycin (10 mg/m2) was given intravenously on days 1–4, cyclophosphamide (200 mg/m2) was given intravenously on days 1–4 and thalidomide (100 mg) was administered orally each day. Results: The overall response rate (¡Ý partial response, PR) of all the 151 eligible patients was 88. 7% (including 29. 8% very good partial response (VGPR) and 25. 8% complete response/near complete response (CR/nCR). The responses per IMWG criteria for patients are shown in Table 2. The median PFS was 20. 3 months (95% CI: 14. 8–25. 8 months) in the patients who received PDT, 24. 8 months (95% CI: 20. 0–30. 0 months) in the patients who received PCD, 22. 9 months (95% CI: 17. 6–28. 2 months) in patients who received PAD and 21. 8 months (95% CI: 15. 3–28. 3 months) in the patients who received PD with no significant differences between the groups. The median OS for PD arm was 42. 0(95% CI: 20. 1–63. 9 months) months while other arms were not reached, but the median OS for PDT, PCD and PAD was significant longer than PD (P=0. 042, 0. 039, 0. 010). PFS and OS for patients with favorable cytogenetics were significantly longer than those with unfavorable cytogenetics by FISH. The frequently observed hematologic toxicities (Grade 3/4) were: thrombocytopenia (17. 00%), neutropenia (15. 00%) and anemia (8. 61%). The most common non-hematologic toxicities included (all Grades) peripheral neuropathy(57. 61%), fatigue(27. 15%), infection(23. 84%), constipation(22. 52%), herpes zoster(17. 22%) and diarrhea(15. 23%). Conclusions: Our experience indicated that bortezomib-based regimens were active and well-tolerated for MM patients, and triplet combinations were superior to PD. Serious Adverse events were rare in the Chinese patients with MM who received bortezomib-based chemotherapy. Disclosures: No relevant conflicts of interest to declare.

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Lymphocytopenia Is Associated with an Increased Risk of Severe Infections in Patients with Multiple Myeloma Treated with Bortezomib-Based Regimens

Blood ◽

10.1182/blood.v120.21.5042.5042 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5042-5042 ◽

Cited By ~ 1

Author(s):

Sung-Hoon Jung ◽

Jae-Sook Ahn ◽

Seung-Ji Kang ◽

Deok-Hwan Yang ◽

Yeo-Kyeoung Kim ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

Conflicts Of Interest ◽

Severe Infection ◽

Infectious Complications ◽

P Value ◽

Factors Affecting ◽

Increased Risk ◽

Severe Infections ◽

Grade 3

Abstract Abstract 5042 Bortezomib is a proteasome inhibitor with potent antimyeloma activity in relapsed/refractory multiple myeloma (MM) patients. We evaluated the type and factors affecting the onset of infectious complications and mortality owing to infection in MM patients treated with bortezomib-based regimens. We reviewed 139 patients with MM treated with regimens containing bortezomib in order to assess the type and factors affecting the development of severe infections. Infections occurred in 56 (40. 3%) of 139 patients and 83 (7. 8%) cases of the 1, 069 evaluable cycles. Severe infections developed in 43 (30. 9%) patients and ten patients (7. 1%) died during bortezomib-based treatment. Multivariate analysis determined lymphocytopenia grade 3–4 (OR 3. 17, 95% CI 1. 38–7. 31, p = 0. 007) and number of cycle ° Â 8 cycles (OR 3. 91, 95% CI 1. 39–11. 02, p =0. 010) as risk factors associated with increased severe infection. This study showed that MM patients who received bortezomib-based regimens are at a higher risk of severe infections within eight cycles of treatment during especially severe lymphocytopenic period. MM patients treated with bortezomib-based regimens should be closely monitored for the development of infectious complications during lymphocytopenia. Table I. Multivariate analysis of factors affecting severe infection development Parameter OR (95% CI) p-Value Age (> 65) 1.78 (0.77–4.13) 0.180 Immunophenotype IgA 1.51 (0.60–3.77) 0.379 Lymphocytopenia (grade 3–4) 3.17 (1.38–7.31) 0.007 Neutropenia (grade 3–4) 1.25 (0.55–2.85) 0.600 Number of cycles (°Â 8 cycles) 3.91 (1.39–11.02) 0.010 Disclosures: No relevant conflicts of interest to declare.

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Model-based analysis to support dose selection of pevonedistat (PEV) combined with azacitidine (AZA) in patients (pts) with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7042 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 7042-7042

Author(s):

Xiaofei Zhou ◽

Diane R. Mould ◽

Dan Zhao ◽

Mikkael A. Sekeres ◽

Lionel Adès ◽

...

Keyword(s):

Clinical Benefit ◽

Phase 1 ◽

Performance Status ◽

Disease Type ◽

International Prognostic Scoring System ◽

Population Pharmacokinetic ◽

Starting Dose ◽

Grade 3 ◽

The Impact ◽

Dose Reductions

7042 Background: PEV+AZA has been studied in higher-risk MDS/CMML and AML, with encouraging efficacy and an acceptable safety profile without added myelosuppression. This pooled analysis was performed to evaluate the impact of PEV exposure on safety and efficacy. Methods: Data from three studies (NCT01814826, NCT02782468 and NCT02610777) were used in the PEV exposure–safety analyses, including ≥ grade 3 neutropenia (NEU3), febrile neutropenia (FN), ≥ grade 3 thrombocytopenia, ≥ grade 3 alanine aminotransferase elevation, ≥ grade 3 aspartate aminotransferase elevation and ≥ grade 3 treatment-emergent adverse event (TEAE3), in pts with higher-risk MDS/CMML and AML who received PEV+AZA. Data from NCT02610777 were used for exposure–efficacy analyses, including overall survival (OS), event-free survival (EFS), complete response (CR) and CR+partial response (PR), in pts with higher-risk MDS/CMML who received PEV+AZA. The exposure metrics for individual pts were derived from a previously developed population pharmacokinetic model with pooled data from eight phase 1/2 studies. PEV exposure–safety relationships for the toxicity endpoints, exposure–CR and exposure–CR+PR, were estimated by logistic regression. Age, sex, race, baseline Eastern Cooperate Oncology Group (ECOG) Performance Status score and disease type were evaluated as covariates. Cox proportional-hazards models were used to evaluate the PEV exposure–survival for higher-risk MDS/CMML, with age, sex, baseline ECOG PS score, Revised International Prognostic Scoring System score (IPSS-R) and disease type as potential covariates. Results: In total, 135 pts (median age, 74 years; male, 64%; Caucasian, 82%) and 41 pts (median age, 74 years; male, 76%; Caucasian, 90%; median IPSS-R, 5.5) were included in PEV exposure–safety and exposure–efficacy analyses, respectively. PEV exposure was significantly related to the incidence of NEU3 ( p = 0.003), FN ( p = 0.02) and TEAE3 ( p = 0.02), supporting PEV dose reductions for pts with treatment-related toxicities. Relationships between PEV exposures and CR, CR+PR, EFS or OS indicated consistent clinical benefit across ranges of PEV exposure following a starting dose of 20 mg/m2. Conclusions: The association between exposure and safety supports PEV dose reductions for pts with treatment-related toxicities. The exposure–efficacy analyses indicated consistent clinical benefit across ranges of PEV exposure following a starting dose of 20 mg/m2. These results support a favorable benefit–risk profile of the 20 mg/m2 PEV dose on days 1, 3 and 5 in combination with AZA 75 mg/m2 for 7 days in 28-day cycles. Clinical trial information: NCT01814826 , NCT02782468 , NCT02610777.

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