Lenalidomide and Low Dose Dexamethasone in Previously Treated Multiple Myeloma Patients with Impaired Renal Function: Efficacy Analysis of PrE1003, a Precog Study

Abstract Introduction: Lenalidomide (Len) and dexamethasone (dex) has proven to be a highly effective treatment for multiple myeloma (MM) and serves as the basis of other combinations in relapsed disease. However, nearly 1/3 of myeloma patients have renal insufficiency, and the optimal use of Len in this population is not well known. We undertook this study in 3 cohorts of pts: Group A had creatinine clearance (CrCl) of 30-60 ml/min, Group B with CrCl < 30 ml/min, and Group C, with CrCl < 30 ml/min and requiring dialysis. The Phase I component of the trial has been previously reported (ASCO 2014) demonstrating that full dose Len (25mg daily 21/28 days) can be given to all patients despite renal insufficiency, even when on dialysis. We now present data on response to treatment. Methods: In the Phase 2 component accrual was slow and the trial was terminated. However, prior to termination a modified exploratory analysis plan was established, including all 34 patients treated at the recommended phase 2 dose. This plan would declare the treatment worthy of further study if 18 or more of the 34 patients responded to treatment. This design had 84% power to distinguish a response rate of 60% from a null rate of 40%, using a 1-sided test with 10% type I error. Results: The Phase 2 efficacy cohort accrued 34 patients, consisting of 20 patients from Group A, 9 patients from Group B, and 5 patients from Group C. Response of PR or greater was seen in 17 patients, resulting in a 50% overall response rate (CI 37-63%). Treatment was well tolerated with expected adverse events; the most common adverse events were anemia, diarrhea, and fatigue. Eleven episodes of Grade 3 and one Grade 4 pneumonia were reported for 10 patients across all cohorts and dose levels; 3 were considered possibly related to treatment. Seventeen patients have remained on treatment for more than 12 cycles. In the exploratory analyses, median PFS was 7.5 months (95% CI, 3.6 - 19.7 months) and median OS was 19.7 months (95% CI, 10.4 - 42.5 months). Conclusions: Len Dex can be safely administered to patients with impaired renal function at full dose of 25mg daily 21/28 days, and is associated with a 50% response rate. Further investigation into other combinations with Len Dex in patients with renal impairment should be considered. Table Table. Disclosures Mikhael: Onyx: Research Funding; Sanofi: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Lonial:Merck: Consultancy; Novartis: Consultancy; Onyx: Consultancy; BMS: Consultancy; Onyx: Consultancy; Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Janssen: Consultancy. Weiss:Novartis: Consultancy.

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A Phase I/II Study of the Tolerability of Lenalidomide and Low Dose Dexamethasone in Previously Treated Multiple Myeloma Patients with Impaired Renal Function: Pre1003, a Precog LLC Study

Blood ◽

10.1182/blood.v120.21.1856.1856 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1856-1856

Author(s):

Joseph R. Mikhael ◽

Judith Manola ◽

Amylou Constance Dueck ◽

Suzanne R Hayman ◽

Kurt Oettel ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Renal Function ◽

Renal Insufficiency ◽

Impaired Renal Function ◽

Response Rate ◽

Progression Free Survival ◽

Free Survival ◽

Previously Treated ◽

Grade 3

Abstract Abstract 1856 Background: Lenalidomide has proven to be a highly effective treatment in relapsed multiple myeloma (MM), particularly when used in combination with dexamethasone. However, over 30% of patients with myeloma have renal insufficiency and as lenalidomide is renally excreted, little information is available about its use in myeloma patients with impaired kidney function. Defining a safe and effective dose of lenalidomide in this context is critical. Objective: We undertook this study to establish the maximum tolerated dose of lenalidomide in three cohorts of patients with different levels of impaired renal function: Group A - patients with creatinine clearance (CrCl) between 30 and 60 mL/min, Group B - patients with CrCl <30 mL/min not on dialysis, and Group C - patients with CrCl < 30mL/min who are on dialysis. Secondary endpoints included response rate, progression free survival and overall survival. Methods: Eligible patients had previously treated MM with renal impairment defined as creatinine clearance < 60 mL/min measured within 21 days prior to registration. Patients previously treated with lenalidomide were required to demonstrate clinical response (any duration) or stable disease with progression-free interval of > 6 months from start of that therapy. All patients received dexamethasone 40 mg orally on days 1, 8, 15 and 22 of a 28-day cycle. Prophylactic anticoagulation consisted of either 81 mg or 325 mg per day of aspirin. Patients also received lenalidomide orally every 1 or 2 days on days 1 through 21 of a 28-day cycle, as described below (Table 1). Starting doses were as in US Product Insert. Dose escalation follows a standard 3+3 design. Results: There have been 23 patients enrolled into groups and cohorts as shown in Table 1. Median age was 73 (range 49–89) and 13 (57%) were women. ISS stage was advanced in all patients, 0 in stage 1, 4 (18%) in stage 2 and 19 (82%) in stage 3. The regimen was well tolerated. Indeed, the MTD has not been reached in any of the groups, as no DLTs have occurred to date. The most commonly reported clinical adverse events (all grades, independent of attribution) across all patients included infections, hyperglycemia, constipation, dizziness, hyponatremia, hypocalcemia and tremor. Hematological toxicities (grade 3–4) occurred in 13 out of 21 pts (62%), mostly neutropenia and thrombocytopenia. Grade 3–4 events at least possibly related to the regimen occurred in 70% and included pneumonia (26%) and otitis media (9%). Response was seen in 14 patients, resulting in an overall response rate of 61%. CR was seen in 1 patient (4%), VGPR in 2 patients (9%), PR in 11 patients (43%), and SD for 9 patients. With median follow-up of 15.5 months, median progression-free survival is 9.8 months and median overall survival is 22 months. Conclusion: Lenalidomide and dexamethasone is a safe and effective regimen in patients with multiple myeloma and renal insufficiency. It is also very well tolerated, although cytopenias are common but manageable. MTD has yet to be reached in each group, allowing for higher doses to be given than previously thought, including 25mg daily (for 21/28 days) in patients with CrCl 30–60 mL/min, 25 mg every other day (for 21/28 days) in patients with CrCl < 30 mL/min not on dialysis, and 10mg daily (for 21/28 days) in patients with CrCl < 30 mL/min on dialysis. These results will provide needed, clinically relevant dosing for lenalidomide in MM patients with renal insufficiency. Disclosures: Kaufman: Millenium: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Novartis: Consultancy.

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Reversibility of Renal Failure in Newly Diagnosed Patients with Multiple Myeloma and the Role of Novel Agents.

Blood ◽

10.1182/blood.v114.22.955.955 ◽

2009 ◽

Vol 114 (22) ◽

pp. 955-955 ◽

Cited By ~ 1

Author(s):

Maria Roussou ◽

Efstathios Kastritis ◽

Dimitrios Christoulas ◽

Magdalini Migkou ◽

Maria Gavriatopoulou ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Function ◽

Renal Impairment ◽

High Dose ◽

Newly Diagnosed ◽

Agent Based ◽

Renal Response ◽

Group A ◽

Group B ◽

Novel Agent

Abstract Abstract 955 Renal impairment (RI) is a common complication of multiple myeloma (MM) and is associated with increased mortality. High dose dexamethasone-based regimens have been extensively used for the initial management of patients with MM presenting with RI. Recently, novel agent-based regimens have been introduced in the frontline management of MM. The purpose of our analysis was to assess the effect of novel agent-based regimens on the rate of RI improvement and compare their efficacy with conventional chemotherapy (CC) plus dexamethasone (Dexa) in newly diagnosed MM patients. Over the last decade, 82 patients with newly diagnosed MM and RI, defined as creatinine clearance (CrCI) <50ml/min, received frontline treatment in our Center. Patients were divided into three groups: group A: 28 patients who received CC plus Dexa-based regimens (VAD, VAD-like regimens, melphalan plus Dexa); group B: 38 patients who received IMiDs-based regimens (thalidomide or lenalidomide with high dose Dexa and/or cyclophosphamide or melphalan) and group C: 16 patients who received bortezomib-based regimens with Dexa. Renal complete response (RCR) was defined as a sustained increase of baseline CrCI to >60ml/min. Renal partial response (RPR) was defined as an increase of CrCI from<15 to 30-50ml/min. Renal minor response (RMR) was defined as sustained improvement of baseline CrCI of<15ml/min to 15-29 ml/min, or, if baseline CrCI was 15-29 ml/min, improvement to 30-59 ml/min. Patients in group B were older than those of groups A and C (p=0.01) while more patient in group C had light chain only MM than in groups A and B (p=0.04). There were no significant differences in the severity of RI, Bence Jones proteinuria, hypercalcemia or ISS stage among the three groups. Improvement of renal function, recorded as RMR or better, was achieved more frequently in patients treated with novel agents (group B: 87% and in group C: 94%) than in patients treated with CC plus Dexa-based regimens (64%, p=0.024). Among 9 patients who required renal dialysis 3 became independent of this procedure after treatment. We subsequently focused our analysis in major renal responses (RPR or RCR), because this endpoint is clinically more relevant. RCR was achieved in 43% of patients in group A, in 50% in group B and in 69% of patients in group C (p=0.2) and RCR+RPR rates were 50% and 57% and 81% for groups A, B and C respectively (p=0.1). Creatinine clearance <30 ml/min was associated with a significantly lower probability of RCR or RPR only in patients treated with CC plus Dexa- or with IMiDs-based regimens (p<0.01), but not in patients treated with bortezomib (p=0.529). The probability of RPR+RCR was similar for patients treated with IMiDs compared to CC plus Dexa-based regimens (p=0.619). In multivariate analysis bortezomib–based regimens (p=0.02, OR: 7, 95% CI 1.5-25) and CrCl>30 ml/min (p=0.002, OR: 6.1, 95% CI 2.5-22.5) were independently associated with a higher probability of RCR+RPR. The median time to RPR was similar for patients treated with IMiDs compared to CC plus Dexa-based regimens (2.2 months for Group A, 1.5 months for Group B, p=0.587) but it was significantly shorter for Group C (0.7 months, p=0.017). Other factors associated with a shorter time to ≥RPR included CrCl>30 ml/min (p=0.039) and age<75 (p=0.089). In multivariate analysis bortezomib–based regimens (p=0.004, OR: 3 95% CI 1.6-6.7) and CrCl>30 ml/min (p=0.006, OR: 2.5 95% CI 1.3-4.5) were independently associated with a shorter time to ≥RPR. In landmark analysis (time was one month in order to reduce bias due to early deaths), rapid improvement of renal function (≤1 month) was associated with a trend for a longer survival compared to patients who achieved renal response later (>1 month) (47 vs. 21 months, p=0.19). Myeloma response to treatment was 58%, 68% and 79% for the three treatment groups respectively and was associated with renal response (p=0.024), though less strongly with a major renal response (p=0.061). Our data indicate that novel agent-based regimens can improve renal function in most patients; furthermore bortezomib-based regimens improve renal function to a higher degree and significantly more rapidly than CC plus Dexa-based or IMiD-based regimens even in patients with severe renal impairment. We conclude that bortezomib-based regimens may be the preferred treatment for newly diagnosed myeloma patients who present with renal impairment. Disclosures: Dimopoulos: JANSSEN-CILAG: Honoraria; CELGENE: Honoraria.

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Reversal of Renal Function and Its Prognostic Impact in Patients with Multiple Myeloma in the Era of Novel Agents

Blood ◽

10.1182/blood.v126.23.3056.3056 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3056-3056

Author(s):

Kentaro Narita ◽

Yoshiaki Usui ◽

Yasuhito Suehara ◽

Kota Fukumoto ◽

Manabu Fujisawa ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Function ◽

Mortality Rate ◽

Light Chain ◽

Reduction Rate ◽

Prognostic Impact ◽

Median Serum ◽

Before And After ◽

Group A ◽

Group B

Abstract Aim and Background: Renal impairment (RI) is common feature in patients with multiple myeloma (MM) and is considered as a poor prognostic factor. Improvement of renal function can lead to the improved survival in patients with MM, however little is known on the prognostic impact of reversal of RI compared to that of the patients without RI at diagnosis in the novel agent era. To address this issue, we retrospectively analyzed the impact of RI on survival of newly diagnosed multiple myeloma (NDMM) patients with or without RI seen at our Department over the past 15 years. Patients and Methods: The study population included all patients diagnosed as MM and treated during May 2000 to March 2015 at Kameda Medical Center, Kamogawa-shi, Japan. We reviewed and retrospectively analyzed the medical records of the Department of Hematology/Oncology. All statistical analyses were performed with EZR, which is a graphical user interface for R ver. 3.2.1. Results: We identified 258 patients with NDMM during this period. RI was defined as eGFR<50ml/min/1.73m2. The median age of patients at diagnosis was 72 years (range 42-90), and 144 patients (55.6%) were male. The median follow-up period for the entire group was 37 months, median serum creatinine at diagnosis was 2.01mg/dL (range 0.4-15) and median eGFR was 52.4ml/min/1.73m2 (range: 2.11-136). RI was observed 122 patients (47.2%). Median serum creatinine of patients with and without RI at diagnosis was 2.07 mg/dL (range: 0.80-4.2) and 0.75mg/mL (range: 0.4-1.1), respectively (p<0.001). Patients with RI had significantly higher proportion of light-chain only disease (39.3% vs 12.5%, p<0.001), International Staging System (ISS) stage 3 (76.2%, vs 31.6%, p=0.001), and lower hemoglobin concentration (Hb<8.5mg/dL: 44.2% vs 21.3%, p<0.001). Bortezomib use, high risk cytogenetics, sex, serum LDH, age at diagnosis, amount of involved immunoglobulin, light chain subtype, and urine albumin at diagnosis were not different between patients with and without RI. Median overall survival (OS) for patients with (n=122) and without (n= 136) RI were 39 months and 57 months, respectively (p=0.16). The median OS for patients with or without RI before and after December 2006, when bortezomib became available in Japan, were 28 months and 41 months (p= 0.66), and 46 months and 71 months (p=0.01), respectively. To evaluate the prognostic impact of renal improvement on survival, patients were divided into 3 groups according to the eGFR and subsequent renal response: Group A; eGFR ≥ 50ml/min/1.73m2 at diagnosis, Group B; eGFR < 50 ml/min/1.73m2 at diagnosis but improved to >50ml/min/1.73m2, Group C; eGFR < 50 ml/min/1.73m2 at diagnosis, and remained <50 ml/min/1.73m2. Median OS of patients with Group A, B, and C was 57 months (n=136), 41 months (n=73), and 25 months (n=49), respectively (p=0.02) (Figure 1). When patients were analysed before and after 2006, the median OS of patients with group A, B, and C before 2006 were 41months (n=59), 38months (n=25) and 19months (n=15) (p=0.02), and those of after 2006 were 71 months (n=77), 46 months (n=48) and not reached (n=34) (p=0.03), respectively. On landmark analysis, median OS at 6 months in each group (Group A, B, and C) were 66 months (n=122), 43 months (n=42), 62 months (n=54), respectively (p= 0.74). Early mortality rate (within 6 months from diagnosis) was significantly higher in patients with group C (16%) compared to other groups (8.5% for group A and 8% for group B, respectively, p=0.03). Patients with group C has significantly higher proportion of mortality rate of infectious disease (26.9%) compared to other groups (7.6% for group A and 11.5% for group B, respectively, p=0.04). Reversal of RI was associated with free light chain (FLC) reduction rate >95% at day 21, age<70years, and treatment response ≥VGPR on univariate analysis, but only FLC reduction rate>95% at day 21 retained its significance on multivariate analysis Conclusions: Patients with MM with RI showed poor prognosis compared to those without RI. FLC reduction > 95% at day 21 was the independent prognostic predictor for reversal of RI. The higher mortality rate within 6 month of diagnosis observed in patients with RI without renal recovery might attribute to the inferior survival in patients with RI. Although patients with RI with improved renal function had superior survival compared to those without, it remains inferior to the patients without RI at diagnosis Figure 1. mOS of group A, B, and C Figure 1. mOS of group A, B, and C Disclosures No relevant conflicts of interest to declare.

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Carfilzomib: High Single Agent Response Rate with Minimal Neuropathy Even In High-Risk Patients

Blood ◽

10.1182/blood.v116.21.1938.1938 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1938-1938 ◽

Cited By ~ 2

Author(s):

Ravi Vij ◽

Jonathan L. Kaufman ◽

Andrzej J Jakubowiak ◽

A. Keith Stewart ◽

Sundar Jagannath ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Impaired Renal Function ◽

Response Rate ◽

Single Agent ◽

Advisory Committees ◽

High Risk Disease ◽

All Treatment

Abstract Abstract 1938 Background: Carfilzomib (CFZ), a selective, epoxyketone proteasome inhibitor, produces potent, sustained proteasome inhibition and lacks many of the off-target activities associated with bortezomib (BTZ). Durable single-agent activity with CFZ has been observed in patients (pts) with relapsed/refractory multiple myeloma (R/R MM) who have received multiple prior therapies as well as in pts with advanced stage disease or significant comorbidities (Jagannath et al. ASCO 2009 Meeting. Abstract 8504). PX-171-004, is an ongoing Phase 2 study of single-agent CFZ in pts with relapsed or refractory MM following 1–3 prior therapies. Here we present updated data on the BTZ-naïve pts and report on activity observed in pts with significant comorbidities or poor-risk cytogenetic or FISH markers for myeloma. Methods: Enrolled pts received either 20 mg/m2 for all treatment cycles, or a stepped-up, dose-escalating regimen of 20 mg/m2 for Cycle 1 and 27 mg/m2 for all treatment cycles thereafter. CFZ was administered on Days 1, 2, 8, 9, 15 and 16 every 28 days (one cycle), for a maximum of 12 cycles. Dexamethasone, 4mg, was administered prior to CFZ in Cycle 1 only. For the present analyses, pts were stratified according to several baseline criteria including ECOG performance score, cytogenetic or FISH markers of high-risk disease per mSMART criteria [del17p, t(4;14), t(14;16), del13 by karyotype and hypodiploidy] and serum ß2-microglobulin. The primary endpoint was overall response rate (ORR) per International Uniform Response Criteria for Multiple Myeloma. Results: Data are available for 110 BTZ-naïve pts. Baseline pt characteristics included: 60% of ECOG PS ≥1; 53% baseline neuropathy Grade 1/2; 30% moderately impaired renal function (CrCl <60 mL/min), and 17% diabetes. Approximately 13% of pts had cytogenetic or FISH markers of poor prognosis. The ORR for the entire BTZ-naïve population was 48%; the ORR for BTZ-naïve pts receiving 20–27 mg/m2 was 54%. The ORRs stratified according to dose and baseline measurements are detailed in the following table. The most common treatment-emergent AEs, regardless of relationship to study drug, were fatigue (61%), nausea (43%), anemia (39%), dyspnea (36%), cough (34%), headache (31%), thrombocytopenia and upper respiratory infections (30% each) and were primarily ≤ Grade 2 in severity. Grade 3/4 AEs occurring in >5% of pts included lymphopenia, neutropenia, pneumonia, thrombocytopenia, anemia and fatigue. Of note, there were no discontinuations for peripheral neuropathy and only 1 pt with impaired renal function at baseline was discontinued for creatinine increases. Twenty-four pts remain on study and 23% have completed the protocol-specified 12 cycles of therapy. Seventeen pts (20%) elected to continue CFZ on an extended treatment protocol (PX-171-010); no cumulative toxicities have been noted. Conclusions: Single-agent CFZ achieves high response rates in BTZ-naïve pts with relapsed myeloma, with minimal neuropathy, even in the setting of high-risk disease. In addition, single-agent CFZ continues to demonstrate long-term tolerability even in pts with comorbid conditions, including renal insufficiency and diabetes, who may benefit from a steroid-sparing treatment regimen. The data from this ongoing trial show that CFZ is a promising new treatment for multiple myeloma in the relapsed or refractory setting. Disclosures: Vij: Onyx: Honoraria. Kaufman:Celgene: Consultancy, Research Funding; Millenium: Consultancy; Merck: Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotec: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Gabrail:Millenium: Research Funding. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Speakers Bureau. Le:Onyx Pharmaceuticals: Employment. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding.

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Elotuzumab In Combination with Lenalidomide and Dexamethasone In Patients with Relapsed Multiple Myeloma: Interim Results of a Phase 2 Study

Blood ◽

10.1182/blood.v116.21.986.986 ◽

2010 ◽

Vol 116 (21) ◽

pp. 986-986 ◽

Cited By ~ 2

Author(s):

Paul G. Richardson ◽

Philippe Moreau ◽

Andrzej J Jakubowiak ◽

Thierry Facon ◽

Sundar Jagannath ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Phase 1 ◽

Phase 2 ◽

Phase 1 Study ◽

Advisory Committees ◽

Phase 2 Study ◽

Infusion Reactions

Abstract Abstract 986 Introduction: Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, an antigen highly and uniformly expressed on multiple myeloma (MM) cells but with restricted expression on normal cells. Elotuzumab exhibits significant antimyeloma activity in vitro and against MM xenografts, and its antitumor activity is enhanced independently by both lenalidomide and dexamethasone. In a dose-escalation phase 1 study that evaluated the combination of elotuzumab (5, 10, and 20 mg/kg), lenalidomide, and dexamethasone, the maximum tolerated dose was not reached, and the combination showed encouraging clinical activity (82% response rate) in patients with advanced MM. The most frequent infusion-related adverse events (AEs) were headache (21%), nausea (21%), and dizziness (11%), with 7% (2/28) of patients experiencing 3 serious infusion-related AEs during cycle 1 (1 with a grade 4 hypersensitivity reaction and 1 with 2 grade 3 stridor events). Key objectives of this dose randomized, open-label, multicenter, phase 2 study in patients with relapsed MM were to select the optimum dose of elotuzumab and to evaluate an enhanced premedication regimen to minimize the occurrence of infusion reactions. Methods: Patients with confirmed relapsed and/or refractory MM who had received 1–3 prior therapies were enrolled; prior lenalidomide therapy was excluded. Patients were randomized 1:1 to receive elotuzumab either 10 or 20 mg/kg (IV infusion on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles and then days 1 and 15 of subsequent cycles), along with lenalidomide 25 mg PO daily on days 1 to 21 and dexamethasone 40 mg PO weekly. Patients were treated until disease progression or unacceptable toxicity, if earlier. To control potential infusion reactions, patients received methylprednisolone (50 mg IV), diphenhydramine (25–50 mg PO or IV) or equivalent, ranitidine (50 mg IV) or equivalent, and acetaminophen (650–1000 mg PO) 30 to 60 minutes prior to each elotuzumab infusion. Objective responses (OR) were assessed according to the International Myeloma Working Group (IMWG) criteria. Results: As of July 8, 2010, a total of 59 patients were randomized (intent to treat population); 47 patients received at least 1 dose of study medication (safety population); and 26 patients completed or progressed prior to completing 2 cycles of treatment (efficacy population). Median age was 64 years; 36 (61%) had received ≥2 prior therapies; 28 (48%) and 31 (53%) had received bortezomib or thalidomide, respectively, and 40 (68%) had undergone transplantation. Among efficacy evaluable patients, 22/26 (85%) had a confirmed or an unconfirmed response (≥ PR) including 31% VGPR/CR. The remaining 4/26 (15%) had stable disease (Table). Treatment-emergent AEs were reported in 36/47 patients (77%); the most common events were fatigue (26%) and nausea (21%). Serious treatment-emergent AEs were reported in 22% of patients; 2 events, nausea and febrile neutropenia with thrombocytopenia, were considered to be related to elotuzumab and lenalidomide. The most common infusion-related AEs within 24 hours of elotuzumab infusion were dizziness (15%), nausea (15%), and headache (9%). These decreased in frequency after the first treatment cycle. There were no severe AEs associated with infusion reactions. Conclusion: The combination of elotuzumab, lenalidomide, and dexamethasone resulted in a high response rate in patients with advanced MM and was generally well tolerated. These results are consistent with the results previously reported from the phase 1 study. The revised premedication regimen appeared to be more effective in controlling infusion reactions, which were generally mild to moderate with no severe infusion reactions reported to date. Updated response and safety data on all patients by dose level will be presented at the meeting. Disclosures: Richardson: Millennium, Celgene, Johnson & Johnson, Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide. Moreau:Celgene, Facet, Bristol-Myers Squibb: Honoraria. Jakubowiak:Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson Ortho-Centocor: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor-Ortho Biotech: Speakers Bureau. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Millennium, Takeda Pharm, Janssen: Honoraria. Vij:Bristol-Myers Squibb: Honoraria; Celgene: Research Funding; Celgene, Bristol-Myers Squibb: Speakers Bureau. Reece:Celgene: Honoraria, Research Funding. Rossi:Sanofi-Aventis, Celgene: Consultancy, Honoraria. Tsao:Facet Biotech: Employment. Fry:Facet Biotech: Employment. Berman:Bristol-Myers Squibb: Employment. Singhal:Facet Biotech: Employment. Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding.

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Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lymphoproliferative Malignancies: Phase 1 Results.

Blood ◽

10.1182/blood.v114.22.1674.1674 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1674-1674 ◽

Cited By ~ 4

Author(s):

Steven M. Horwitz ◽

Julie M. Vose ◽

Ranjana Advani ◽

Kamalesh Sankhala ◽

Swaminathan Padmanabhan ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

B Cell Lymphoma ◽

Phase 2 ◽

Large B Cell Lymphoma ◽

Group A ◽

Refractory Lymphoma ◽

Group B

Abstract Abstract 1674 Poster Board I-700 Background Pralatrexate is a new anti-folate with increased affinity for the reduced folate carrier 1 (RFC-1) and longer intracellular retention in tumor cells due to efficient polyglutamation by folylpolyglutamyl synthetase (FPGS). Pralatrexate and gemcitabine each have activity as monotherapy in patients with relapsed or refractory lymphoma. Preclinical data reported synergy for the combination in NHL cell lines and xenografts that was schedule dependent (pralatrexate followed by gemcitabine) (Clin Cancer Res 2006;12:924-932). We initiated a multi-center Phase 1/2a study (PDX-009; NCT00481871) to evaluate this treatment combination. The primary objective of the Phase 1 portion was to determine the maximum tolerated dose (MTD) and optimal Phase 2 dose and schedule for the combination of pralatrexate and gemcitabine in patients with relapsed or refractory lymphoma. Methods Eligibility criteria included histologically confirmed lymphoma, progressive disease after ≥1 prior treatment and ECOG performance score 0-2. Patients in group A (n=7) received pralatrexate on day 1 and gemcitabine on day 2, once weekly for 3/4 wks. Patients in group B (n=10) also received pralatrexate and gemcitabine on sequential days, but were treated only every 2 wks (q2w). Patients in group C (n=17) received pralatrexate followed 1h later by gemcitabine on the same day q2w. All patients received vitamin B12 and folic acid supplementation. Prior gemcitabine exposure was permitted. Results As of May 2009, 34 patients were treated in Phase 1, including 24 men (71%), and median age was 63 years (range, 19-81). Histology included 13 patients with B-cell lymphoma, 11 with T/NK-cell lymphoma, 7 with Hodgkin's lymphoma, and 3 with “other” lymphoma. Patients had received a median of 3.5 prior regimens (range 1-11). All patients with once-weekly sequential-day dosing (pralatrexate 10-15 mg/m2 and gemcitabine 300-400 mg/m2) in Group A had dose-limiting toxicities (DLTs) of thrombocytopenia and/or neutropenia; therefore accrual to this schedule was halted and subsequent cohorts received pralatrexate with gemcitabine on the q2w schedule (groups B and C). The MTD with the q2w dosing schedule was pralatrexate/gemcitabine 10/400 mg/m2 when given on sequential days (group B) and 15/600 mg/m2 when given on the same day (group C). The DLTs for group B were cellulitis, pulmonary embolus, thrombocytopenia, and febrile neutropenia and the DLTs for Group C were fatigue, hypoxia, mucositis, and thrombocytopenia. Across all groups, the most frequently reported Gr 3-4 pralatrexate-related adverse events were neutropenia (41%), thrombocytopenia (35%), anemia (29%), and leukopenia (12%). Of 33 patients who were evaluable for response, 7 (21%) showed partial response, including patients with Hodgkin's lymphoma (4), diffuse large B-cell lymphoma (1), angioimmunoblastic T-cell lymphoma (1), and composite diffuse large B-cell lymphoma and T-cell lymphoma (1). Responses were seen in patients treated on the same day as well as the sequential day schedules. Conclusion Treatment with pralatrexate and gemcitabine is feasible, with acceptable toxicity, when administered on a q2w schedule. However, the MTD of each drug is 50% greater when given on the same day as compared to treating on sequential days. Preliminary results show activity of the combination of pralatrexate and gemcitabine in lymphoid malignancies with a 21% response rate in this heavily pretreated population. Phase 2 expansions at the MTD will explore both sequential-day dosing (10/400 mg/m2) and same-day dosing (15/600 mg/m2) in a q2w schedule. Disclosures Horwitz: Allos Therapeutics, Inc: Consultancy, Research Funding. Advani:Allos Therapeutics, Inc: Research Funding. Fruchtman:Allos Therapeutics, Inc.: Employment.

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Combined Bendamustine, Prednisone and Bortezomib (BPV) in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.1855.1855 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1855-1855

Author(s):

Wolfram Poenisch ◽

Malvina Bourgeois ◽

Barbara Moll ◽

Simone Heyn ◽

Nadja Jäkel ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Research Funding ◽

Median Number ◽

Maximum Response ◽

Myeloma Protein ◽

Group A ◽

Bone Marrow Function ◽

Grade 3 ◽

Group B

Abstract Abstract 1855 Introduction: Bortezomib and bendamustine have turned out to be effective, rapid action drugs in the treatment of multiple myeloma (MM). Bortezomib is a proteasome inhibitor that has shown important clinical efficacy either as a single agent or in combination with other cytostatic agents in MM. Bendamustine is a bifunctional alkylating agent with low toxicity that produces both single- and double-strand breaks in DNA, and shows only partial cross resistance with other alkylating drugs. The combination of bendamustine and prednisone with bortezomib (BPV) was assessed to determine the efficacy and toxicity of this regimen in patients with relapsed or refractory MM. Methods: Between January 2005 and December 2011, 78 patients (median age 62; range 31–81 years) with relapsed or refractory MM were treated with bendamustine 60 (–120) mg/qm on day 1 and 2, bortezomib 1.3 mg/qm on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11. Cycles were repeated every 21 days until maximum response or progressive disease. Maximum response was achieved if three weeks of therapy did not further reduce myeloma protein by more than 10 %. The median number of prior therapies was 2 (range 1–9). Previous therapies included 31 × thalidomide, 10 × lenalidomide, 14 × bortezomib, 24 × autologous PBSCT, and 19 × autologous-allogeneic PBSCT. In contrast to other clinical studies, patients with pronounced pancytopenia due to stem-cell toxic pre-treatment or advanced disease were also included. Patients were divided into two groups: group A (n = 45) comprised patients with normal bone marrow function and group B (n = 33) patients with pre-existing restricted bone marrow function and pronounced pancytopenia (CTC-Criteria grade III and IV). Patients were excluded from this retrospective analysis if they had other secondary malignancies. To exclude myelodysplastic syndroma or secondary acute myeloid leukemia cytological and cytogenetic examination of bone marrow was performed in patients with pre-existent severe pancytopenia. Response was assessed using EBMT criteria modified to include near complete remission (nCR) and very good partial remission (VGPR). Results: The median number of BPV-treatment cycles was 2 (1–7). 54 patients (69 %) responded after at least one cycle of chemotherapy with 3 CR, 10 nCR, 10 VGPR, and 31 PR. Nine patients had MR, 9 patient's stable disease and 6 patients underwent progression. A follow up of surviving patients at a median of 34 months revealed median PFS and OS for patients without preexisting severe haematological toxicities (group A) of 11 months and 50 months respectively. Outcome was significantly better than that of patients with pre-existing severe haematological toxicities (group B) who had a median PFS, and OS of 3 months and 5 months, respectively (p < 0.001). The regimen was well-tolerated with few significant side effects in patients without preexisting severe haematological toxicities. New cytopenias occured infrequently with thrombocytopenia grade 3 in 11 patients, grade 4 in 8 patients and neutropenia grade 3 in 7 patients. Six patients experienced a moderate new polyneuropathy (grade 2). Summary: BPV therapy was well tolerated in patients with relapsed/refractory MM, with a response rate of approximately 70 %. The high efficacy and the favourable toxicity profile of BPV warrant further evaluation in clinical trials. Disclosures: Poenisch: Mundipharma: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

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Use of Lenalidomide in DEL(5q) MDS. a National AIFA (Agenzia Italiana del Farmaco) Registry Study

Blood ◽

10.1182/blood.v126.23.1693.1693 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1693-1693

Author(s):

Francesco Arcioni ◽

Andrea Roncadori ◽

Valeria Di Battista ◽

Giuliana Alimena ◽

Fabrizio Pane ◽

...

Keyword(s):

Partial Response ◽

Disease Progression ◽

Real World ◽

Research Funding ◽

Response Rate ◽

Cytogenetic Response ◽

Real World Setting ◽

Group A ◽

Grade 3 ◽

Group B

Abstract In Italy the use of lenalidomide (LEN) in MDS with del(5q) is ruled by a national agency (AIFA, Agenzia Italiana del Farmaco) Registry since 2008. We conducted an observational, non-interventional, multi-centre, retrospective/prospective cohort study, registered as MORE (ClinicalTrials.gov NCT01347944), to investigate the use LEN in the context of a "real world setting". Registry eligibility: IPSS low or intermediate-1 risk MDS with transfusion-dependent anemia and 5q31 deletion. MORE integration: retrospective collection of clinical, hematological and cytogenetic data at pre-registry time, at enrollment, after 4-6 cycles and 8-12 cycles of LEN, and at the last available follow-up and/or end of treatment. Hematological and cytogenetic response was assessed according to Cheson et al (Blood 2006). Statistical analysis used PL / SQL Developer and R open source software. 190 patients (M:F 60: 130) were included in this study (Table 1). GROUP A, (149 patients, median age 75 years) with complete data sets, and GROUP B (41 patients, median age 71 years), investigated only by FISH were analyzed separately. By integration of Registry with MORE forms, including disease history and/or treatment preceding inclusion in the Registry, information was recruited over a median time of 44 months (range 0.5-237). The complete erythroid response rate was 74.6% in group A and 78.6% in group B after 4-6 cycles treatment, and 85.8% and 88.9%, respectively after 8-12 cycles. The partial response rate was 11.5% in group A and 10.7% in group B at 4-6 months cycles. The complete cytogenetic response rate (only group A ) after 4-6 cycles was 7.8%. The partial response rate was 2.3 %. After 8-12 cycles complete response increased to 13% , partial response to 9.6 %. Leukemic evolution was observed in 18 cases (9.5%). Disease progression to a higher risk MDS was found in 12 cases (6.3%). Neutropenia (grade 3-4; 59%) and thrombocytopenia (grade 3-4; 21%) were predominant in the first 6 months of treatment. Infections (21%) mostly affected the upper respiratory tract. As far as we know this is the first report on LEN administration within a national registry. Despite being a retrospective study solid information on real life management of del(5q)-MDS were obtained. The known efficacy on erythropoiesis was strongly confirmed (FIG.1A). Notably, we also found a good response in low/int-1 IPSS cases with non-isolated 5q- (70.6%), suggesting that IPSS score plays a role in the successful response. The low rate of cytogenetic response possibly reflected the high level of variations in timing and dosage of LEN as well as heterogeneity of analyses in a non-centralized study. Nevertheless, results after 8-12 cycles (22.6%; FIG.1B) were similar to the 25% found with 5mg LEN in the European cooperative MDS004 study (Fenaux P et al, Blood 2011). AML evolution was found in 18/190 cases (9.6%) after a median of 7.5 LEN cycles (range 1-30). Moreover twelve additional cases (6.3%) showed progression to RAEB1 or RAEB2 after a median of 19.5 LEN cycles (range 4-56). In the MDS004 study a similar analysis gave 25.4 % of leukemic evolution and 2.9% of disease progression. This large series of MDS with del(5q) allowed us to confirm the efficacy of LEN in a "real world setting". Biological and clinical features seem to be critical for the success of this personalized therapy. Table 1. Table 1. Figure 1. Clinical-hematological features of 190 cases (MORE Study). Figure 1. Clinical-hematological features of 190 cases (MORE Study). Disclosures Roncadori: Celgene: Research Funding. Rossi:Celgene: Research Funding. D'Emilio:Celgene: Research Funding. Di Renzo:Celgene: Research Funding. Leoni:Celgene: Research Funding. Rambaldi:Roche: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene: Research Funding; Pierre Fabre: Honoraria. Avanzini:Celgene: Research Funding. Visani:Celgene: Research Funding. Tura:Celgene: Research Funding. Covezzoli:Celgene: Research Funding. Mecucci:Celgene: Research Funding.

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Serum Copeptin, NLPR3, and suPAR Levels among Patients with Autosomal-Dominant Polycystic Kidney Disease with and without Impaired Renal Function

Cardiorenal Medicine ◽

10.1159/000510834 ◽

2020 ◽

Vol 10 (6) ◽

pp. 440-451

Author(s):

Vasileios Raptis ◽

Charalampos Loutradis ◽

Afroditi K. Boutou ◽

Danai Faitatzidou ◽

Athanasios Sioulis ◽

...

Keyword(s):

Renal Function ◽

Endothelial Dysfunction ◽

Kidney Disease ◽

Impaired Renal Function ◽

Autosomal Dominant ◽

Polycystic Kidney ◽

Group A ◽

Autosomal Dominant Polycystic Kidney ◽

Group B ◽

Age And Sex

Background: The pathophysiology of renal disease progression in autosomal-dominant polycystic kidney disease (ADPKD) involves not only cystogenesis but also endothelial dysfunction, leading to the activation of inflammatory and fibrotic pathways. This study evaluated the levels of biomarkers related to osmoregulation, immune system activation, and tubular injury in ADPKD patients with impaired or preserved renal function. Methods: This study included 26 ADPKD patients with modestly impaired renal function (estimated glomerular filtration rate [eGFR] 45–70 mL/min/1.73 m2; Group A), 26 age- and sex-matched ADPKD patients with relatively preserved renal function (eGFR >70 mL/min/1.73 m2; Group B), and 26 age- and sex-matched controls (Group C). Serum levels of copeptin, the inflammasome nucleotide-binding and oligomerization domain-like receptors pyrin domain-containing protein 3 (NLRP3), and soluble urokinase-type plasminogen activator receptor (suPAR) were measured with ELISA techniques. Results: Patients in Group A had higher levels of copeptin (median [interquartile range]: 50.44 [334.85] pg/mL), NLRP3 (5.86 [3.89] ng/mL), and suPAR (390.05 [476.53] pg/mL) compared to patients in Group B (32.38 [58.33], p = 0.042; 2.42 [1.96], p < 0.001; and 313.78 [178.85], p = 0.035, respectively) and Group C (6.75 [6.43]; 1.09 [0.56]; and 198.30 [28.53], respectively; p < 0.001 for all comparisons). Levels of all studied markers were also significantly higher in Group B patients compared to controls (p < 0.001), despite having similar eGFR. In patients with ADPKD, all studied biomarkers were correlated positively with asymmetric-dimethylarginine (ADMA) and endocan levels, and negatively with eGFR. ADMA and endocan levels were the only parameters independently associated with increased copeptin levels. Conclusions: This study showed that ADPKD patients with impaired and preserved renal function had higher copeptin, NLRP3, and suPAR levels than controls. Such findings support that cystogenesis and inflammation are associated with endothelial dysfunction, even in the early stages of ADKPD.

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POS0527 ACUTE KIDNEY INJURY (AKI) IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA)

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1786 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 497-497

Author(s):

A. Nakashima ◽

K. Suzuki ◽

H. Fujii ◽

Y. Fujisawa ◽

I. Mizushima ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Acute Kidney Injury ◽

Renal Function ◽

Impaired Renal Function ◽

Filtration Rate ◽

Estimated Glomerular Filtration Rate ◽

Kidney Injury ◽

Lower Egfr ◽

Group A ◽

Group B

Background:Methotrexate has been an anchor drug for patients with rheumatoid arthritis (RA). However, it is strictly prohibited to prescribe MTX to patients with severely decreased renal function because it can induce a fatal adverse event such as pancytopenia in these patients. On the other hand, since the average age of RA patients is gradually increasing, and many of them already have mildly to moderately impaired renal function, their renal function can easily decrease to below the critical level of the estimated glomerular filtration rate. Therefore, new development of acute kidney injury (AKI) during MTX administration might induce a fatal adverse event, making the identification of patients susceptible to AKI very important.Objectives:To clarify the frequency of AKI and the factors involved in it in RA patients.Methods:Two hundred and fifty-two RA patients (211 females, 41 males, mean age 62.3 ± 12.5 years, disease duration 11.0 ± 9.5 years) diagnosed more than 3 years earlier and followed for more than 5 years, and also, others diagnosed ≥3 years earlier but followed for ≤5 years were enrolled. We measured BUN, Cr, RF and aCCP in patient serum, urinary proteins, urinary blood, and urinary casts and evaluated CDAI, SDAI, disease activity score (DAS) 28-CRP and DAS28-ESR. Steinbrocker functional classification and radiological grading were evaluated. History of diabetes mellitus, hypertension and hyperlipidemia was determined from the medical records. Medications for RA, including non-steroid anti-inflammatory drugs (NSAIDs), prednisolone, csDMARD (MTX, Tacrolimus, etc.), bDMARDs and tsDMARDs were evaluated. Estimated glomerular filtration rate (eGFR) was calculated by the new Japanese coefficient-modified Modification of Diet in Renal disease (MDRD) study equation. The criteria of AKI were that serum Cr increased by 0.3 mg /dl or increased by 1.5-fold between consecutive visits according to the KIDIGO criteria 1) and the report of Leither et al2).Results:Twenty (7.9%) patients developed AKI, 22 times. The causes of AKI were 10 infections, 6 dehydrations, 2 enteritis, 1 urticaria, 2 hypercalcemia due to VitD administration, and 1 ureteral stone. We divided our patients into group A (with AKI) and group B (without AKI). Group A was older (69.9±10.1 vs 61.7±12.6 years), had greater physician VAS (29.5±27.7 vs 15.7±18.3 mm), higher serum creatinine (0.79±0.19 vs 0.60±0.16 mg/dl), higher BUN (18.4±5.7 vs 15.1±4.4 mg/dl), lower eGFR(65.5±23.3 vs 86.4±22.4 ml/min), more frequent prednisolone administration (75.0% vs 41.9%), more frequent hyperlipidemia (50.0% vs 19.2%) and more frequent hypertension (60.0% vs 30.6%) than Group B by univariate analysis significantly (p<0.01). We then performed multifactorial analysis using logistic regression analysis. Greater physician VAS (OR 1.02, 1.00-1.04), lower eGFR (OR 1.04, 1.01-1.08) and prednisolone administration (OR 3.29, 1.02-10.63) were found as independent relevant factors for group A.Conclusion:Our study indicated that AKI developed in RA patients and suggested that renal function decline and prednisolone administration may be implicated. RA patients with impaired renal function and prednisolone administration need to be treated with special attention to the onset of AKI.References:[1]Kidney Disease: Improving Global Outcomes (KDIGO) Practice Guideline for Acute Kidney Injury. Kidney Int Suppl 2: 1-138, 2012[2]Leither MD, Murphy DP, Bicknese L et al. The impact of outpatient acute kidney injury on mortality and chronic kidney disease: a retrospective cohort study. Nephrol Dial Transplant. 34:493-501, 2019Disclosure of Interests:None declared

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