Treatment-emergent Neuropathy Research Articles

BOLD-100-001 (TRIO039): A phase 2 study of BOLD-100 in combination with FOLFOX in patients with advanced mCRC previously treated with FOLFOX/CAPOX—Efficacy and safety analysis.

143 Background: BOLD-100 is a first-in-class metallotherapeutic with a unique multimodal mechanism of action currently in phase 2 clinical development for the treatment of advanced gastrointestinal cancers. Standard treatment options for patients (pts) with metastatic colorectal cancer (mCRC) include FOLFOX or CAPOX in first or second line therapy. This study explored the benefit of BOLD-100 + FOLFOX in previously treated mCRC patients. Methods: This prospective, phase 2 study evaluates BOLD-100 + FOLFOX in pts with mCRC. All pts received prior standard treatment, including FOLFOX or CAPOX. Pts received 625 mg/m2 of BOLD-100 + FOLFOX on day 1 of each 14-day cycle and treated until progressive disease or unacceptable toxicity. The primary objective is to evaluate PFS, OS, and ORR in treated patients. Disease Control Rate (DCR) was also determined. Results: As of 31Aug2023, 36 pts with advanced mCRC were treated. Median age was 62 years (range 40-78), 56% were women, all pts were ECOG 0 (25%) or 1 (75%). Enrolled pts had a median of 4 prior systemic therapies, including FOLFOX/CAPOX. All but one patient had stage IV disease. On study, pts received a median of 6 cycles of BOLD-100 + FOLFOX [range 1-17]. Five pts remain on treatment with 19 in follow-up. Median PFS was 3.9 [2.7, 5.7] months, median OS 9.6 [6.0, 17] months, ORR 7% [1,20] and DCR 76% [58, 88] in the 29 evaluable pts. Two pts achieved a partial response, and 2 pts had target tumor lesion decreases between 20-29%. Study treatment was well tolerated. Of the 36 treated pts, 33 had 1 or more treatment-emergent adverse events (AEs), most common neutropenia (n=17, 47%), nausea (n=15, 42%), vomiting (n=8, 22%), fatigue (n=7, 19%), infusion related reaction (n=7, 19%), and pruritus (n=6, 17%). Most related AEs were grade (G) 1-2. 15 pts (42%) had G3/4 neutropenia. Despite previous oxaliplatin treatment, fewer than 6% of pts reported peripheral neuropathy or peripheral sensory neuropathy and all were G1/2. Conclusions: BOLD-100 + FOLFOX is an active and well-tolerated treatment in this heavily pre-treated Stage IV mCRC study population. There were no new safety signals. The mPFS, mOS, ORR and DCR data demonstrate significant clinical benefit and improvement over the currently available therapies, with minimal treatment emergent neuropathy or significant toxicities. This promising treatment combination should be further studied. Clinical trial information: NCT04421820 .

Weekly Dosing of Bortezomib in RVD Achieves Minimal Toxicity with No Reduction in Efficacy in a Diverse Cohort of Multiple Myeloma Patients

Introduction: Lenalidomide, bortezomib, and dexamethasone is a standard of care in the treatment of fit multiple myeloma patients due to high efficacy, with ORR exceeding 90% in the first-line setting (Richardson et al. 2010). The initial RVD regimen utilized a 21-day cycle with bortezomib administered IV 1.3 mg/m2 days 1, 4, 8, and 11; lenalidomide 25 mg administered days 1-14; and dexamethasone administered 160 to 320 mg per cycle. However, toxicity may be treatment-limiting, with bortezomib-induced neuropathy affecting up to 80% of patients. Modifications to RVD to optimize tolerance include reducing the bortezomib dose to a weekly schedule (1.6 mg/m2 IV or 1.3 mg/m2SC) and extending the cycle to 28 or 35 days (Broijl et al. 2016; O'Donnell et al. 2014). Notably, those regimens were studied in transplant-ineligible or relapsed/refractory patients. Based on regimens like CyBorD (which utilize weekly SC administration of bortezomib, are well-tolerated and are efficacious), we modified the standard 21-day RVD regimen to include 3 doses of weekly bortezomib in an attempt to preserve efficacy while minimizing toxicity. We present a retrospective analysis of both fit and transplant-ineligible patients treated at our institution using “Louisville RVD.”Methods: We identified the charts of patients who received RVD over a 21-day cycle at the following starting doses: lenalidomide 25 mg orally days 1-14; bortezomib 1.5 mg/m2 SC days 1, 8, and 15; and dexamethasone 40 mg days 1, 8, and 15. Autologous stem cell harvest took place after 4 cycles of lenalidomide-based therapy when feasible, in appropriate candidates. We noted demographic factors, ISS stage, performance status, cytogenetic risk stratification, line of therapy (initial, later-line, and consolidation), history of autologous transplant, degree of response (PD, SD, PR, VGPR, and CR based on International Myeloma Working Group criteria), EFS, OS, and toxicities.Results: We identified 23 patients who received Louisville RVD between 2009 and 2017. Median age was 59 years (range 37-77) at treatment start; 9 (39%) were 65 or older; 12 (52%) were male; 11 (48%) were African-American; ISS stages were I in 6 (26%), II in 7 (30%), III in 9 (39%), and missing in 1 patient; ECOG status was 0 in 7 (30%), 1 in 11 (48%), and 2 in 5 (21%). Line of therapy was 1 in 13 (56%) and 2 or later in 10 (44%); RVD was used as post-transplant consolidation in 4 (14%). Line of therapy ranged from 1 to 8. 16 patients (57%) were treated with intent to transplant. The median number of cycles given was 4 (range 1-64). Dose reductions and discontinuation occurred in 5 (22%) patients and 1 (4%) patient after 1 cycle, respectively. Response was assessable in 22 patients. 21 (95%) of patients achieved PR or better; 3 patients (14%) achieved CR, 7 (32%) VGPR; and 11 (50%) PR. OS and EFS at 1 year were 90% and 60%, respectively; median duration of follow-up was 15.5 months (range 1.2-95.1); follow-up time was limited for a significant fraction of our patients. There was no association of relapse with ISS stage (p=0.357), ECOG score (p=0.088), or cytogenetic risk (p=1.00). Treatment-related toxicities were reported for 11 patients. Treatment-emergent neuropathy was seen in 5 patients (22%); 4 patients experienced grade 1 neuropathy (17%), and 1 patient experienced grade 3 neuropathy (4%). 1 patient underwent dose-reduction of bortezomib to 1.3 mg/m2 after 18 cycles. 6 patients had treatment related cytopenias (26%), of which 1 (4%) was grade 3.Conclusions: Retrospective analysis of 21-day “Louisville RVD” with weekly subcutaneous bortezomib demonstrates efficacy comparable to previously published RVD regimens. Toxicity, especially peripheral neuropathy, favors the weekly SC administration schedule. Dose reductions were uncommon and treatment discontinuations were rare. Patients may ultimately achieve superior bortezomib dosing due to rarity of dose reductions. Our cohort was well-balanced with regard to ethnicity, gender, age, and performance status. Treatment was efficacious and well-tolerated in both transplant and non-transplant candidates. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outcomes with different administration schedules of bortezomib in bortezomib, lenalidomide and dexamethasone (VRd) as first‐line therapy in multiple myeloma

Induction therapy for multiple myeloma with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (d) (VRd) was traditionally administered as bortezomib given twice weekly on a 3 week cycle. A modified schedule of weekly bortezomib has been adopted over time to decrease treatment burden for patients and reduce treatment-emergent neuropathy. This study evaluates the response rates and outcomes with different schedules of bortezomib in VRd administered for first-line treatment for patients with newly diagnosed MM (NDMM). We retrospectively analyzed patients treated with upfront VRd from June 30th 2008 to December 31st 2018, for variations of bortezomib administration. Five hundred and fifty-five (555) NDMM patients met inclusion criteria; median age 63 years and 61% men. Bortezomib was administered twice weekly every 21 days in 43%, once weekly every 21 days in 41% and once weekly every 28 days in 16%. Though peripheral sensory neuropathy was more frequent with twice weekly dosing (P = .002), this group achieved shorter time to best response (P = .01). Weekly every 21-day treatment saw higher VGPR or better rates (P = .02). However, with median follow up time of 37 months (IQR 22-56), we found no difference in PFS or OS among the groups. While small differences in response rates were found among the varying administration schedules of bortezomib administration, there was no significant effect on PFS or OS. Given that VRd remains a first line standard of care option for newly diagnosed MM, in the absence of a large trial comparing bortezomib dosing schedule modifications, these results are helpful in supporting current practices of once weekly administration.

Carfilzomib Versus Bortezomib in Combination with Cyclophosphamide and Dexamethasone for Treatment of First Relapse or Primary Refractory Multiple Myeloma (MM): Outcomes Based on Genetic Risk and Long Term Follow up of the Phase 2 Muk Five Study

Carfilzomib Versus Bortezomib in Combination with Cyclophosphamide and Dexamethasone for Treatment of First Relapse or Primary Refractory Multiple Myeloma (MM): Outcomes Based on Genetic Risk and Long Term Follow up of the Phase 2 Muk Five Study

Carfilzomib, Cyclophosphamide and Dexamethasone (KCD) Versus Bortezomib, Cyclophosphamide and Dexamethasone (VCD) for Treatment of First Relapse or Primary Refractory Multiple Myeloma (MM): First Final Analysis of the Phase 2 Muk Five Study

Carfilzomib, Cyclophosphamide and Dexamethasone (KCD) Versus Bortezomib, Cyclophosphamide and Dexamethasone (VCD) for Treatment of First Relapse or Primary Refractory Multiple Myeloma (MM): First Final Analysis of the Phase 2 Muk Five Study

Pre-Treatment Small Fiber Neuropathy by Sympathetic Skin Response (SSR) Does Not Predict Treatment Emergent Neuropathy in Newly Diagnosed Multiple Myeloma (NDMM) Patients Receiving Bortezomib Based Induction Therapy

Pre-Treatment Small Fiber Neuropathy by Sympathetic Skin Response (SSR) Does Not Predict Treatment Emergent Neuropathy in Newly Diagnosed Multiple Myeloma (NDMM) Patients Receiving Bortezomib Based Induction Therapy

Carfilzomib, Cyclophosphamide and Dexamethasone Is Well Tolerated in Patients with Relapsed/Refractory Multiple Myeloma Who Have Received One Prior Regimen

Introduction. Carfilzomib-containing doublet and triplet regimens demonstrate high response rates both in the relapsed and frontline settings and will soon enter the treatment pathways for multiple myeloma (MM). While the phase 3 studies, ENDEAVOUR and ASPIRE provide information on combinations with dexamethasone with or without lenalidomide, there are limited data on other combinations, especially with alkylating agents.Aim. To describe the safety and toxicity of Carfilzomib, cyclophosphamide and dexamethasone in patients at first relapse of MM, based on an interim assessment of the MyelomaUKfive (MUKfive) study.Methods. MUKfive is a randomised phase 2 study comparing carfilzomib with bortezomib, in triplet combination with cyclophosphamide and dexamethasone for patients who require treatment after one prior regimen, in a 2:1 randomisation, target 300 patients. Patients receive 6 months of induction treatment with six 28-day cycles of carfilzomib (20/36 mg/m2 in stepped up dosing d1, 2, 8, 9, 15, 16 by IV infusion over 30 minutes), oral cyclophosphamide (500 mg d1, 8, 15) and oral dexamethasone (40mg d1, 8, 15, 22) or eight 21-day cycles of bortezomib (1.3mg/m2 SC d1, 4, 8, 11) by SC or IV, cyclophosphamide (500 mg d1, 8, 15) and dexamethasone (40mg d1, 8, 15). The primary endpoint for this part of the study is ≥VGPR rate. The study opened in 2013, and we have carried out an interim assessment of safety data on the first 69 patients randomised to the Carfilzomib arm, with toxicities graded by CTCAE V4.0.Results. Median age was 67.6 years (range 35-85), 62.3% were male, and ISS stage as follows: 32 patients ISS 1, 22 patients ISS 2, 15 patients ISS 3. Median GFR was 78ml/min (range 30-243) and ECOG performance status as follows: 43 patients PS 0, 20 patients PS 1, 5 patients PS 2, 1 patient missing PS. Sixty-seven patients received at least one dose of trial treatment and are evaluable for safety.In cycle 1, the commonest treatment-related toxicities of any grade (adverse reactions, ARs) were anaemia (89.6%), thrombocytopenia (67.2%) neutropenia (29.9%), nausea (14.9%), diarrhoea (11.9%), vomiting (10.6%), constipation (9%), infections (4.5%) and infusion reactions (4.5%). During induction treatment (all cycles), the most common ARs of all grades were anaemia (97%), thrombocytopenia (83.6%) neutropenia (58.2%), nausea (47.8%), diarrhoea (37.3%), infections (29.9%) vomiting (22.4%), constipation (22.4%), hypotension (4.5%) and infusion reactions (4.5%). Haematologic grade ≥3 ARs included anaemia (19.4%), neutropenia (12%), and thrombocytopenia (10.5%), while non-haematological grade ≥3 ARs were infections (20.9%), vomiting (4.5%), nausea (3%), diarrhoea (3%), infusion reactions (3%). Treatment emergent neuropathy was reported by 18 patients (26.9%), all G1 except for 1 patient (G2). Three patients had thromboembolic ARs: one each of pulmonary embolism (G3), thrombophlebitis (G2) and brachial vein thrombosis (G1).Serious AEs were reported in 29 patients (43.3%). A total of 47 SAEs were reported, of which 31 (66%) were treatment related (28 related to carfilzomib). Treatment related SAEs included 22 infections (noted above, of which 15 were respiratory infections), 2 gastrointestinal, 1 acute kidney injury (G2) and 1 worsening of renal function (G1), 2 endocrine (1 each of hypo- and hyperglycemia), and 1 hepatobiliary. Two G3 SUSARs were reported, one cardiomyopathy, one extensive pulmonary embolism. In 87.2% of SAEs, patients had recovered or were improving.In cycle 1, 19 patients (28.4%) had at least one dose modification; carfilzomib dose was modified in 14, cyclophosphamide in 7 and dexamethasone in 11. The majority of these were dose omissions. Across all cycles, 54 patients (80.6%) had dose modification/s, 47 to carfilzomib, 32 to cyclophosphamide and 40 to dexamethasone. Of carfilzomib modifications, 53.3% were omissions, while the rest were reductions (24.6%) or delays (22.1%). Of carfilzomib dose reductions, the majority (72.9%) were due to haematological toxicity. Five patients (7.2%) stopped treatment due to toxicity after a median of 3 (range 1-4) cycles. There were no treatment related deaths.Conclusion. The triplet regimen carfilzomib, cyclophosphamide and dexamethasone is well tolerated in this patient group, with toxicity profile that is as expected from published data on carfilzomib.Acknowledgments: This trial a Myeloma UK Clinical Trial Network study DisclosuresYong:Autolous: Consultancy; Novartis: Consultancy; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria; BMS: Honoraria. Off Label Use: Carfilzomib with cyclophosphamide and dexamethasone as therapy in relapsed myeloma. Ramasamy:Celgene: Honoraria; Amgen: Honoraria; Takeda Millenium: Honoraria. Cavenagh:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Owen:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Kaiser:Chugai: Consultancy; Janssen: Honoraria; BristolMyerSquibb: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. Williams:Amgen: Honoraria; Janssen: Honoraria.

Final Results of a Phase I/II Trial of the Combination of Concurrent Lenalidomide, Thalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Myeloma

AbstractAbstract 75 Background:The combination of lenalidomide (Len) and dexamethasone (Dex) has demonstrated overall response rates (ORR) of 60% in relapsed and/or refractory multiple myeloma (RRMM). Preclinical studies have demonstrated Len resistance is mediated via the Wnt/β-catenin pathway, which can be reversed by thalidomide (Thal). The concurrent administration of Len, Thal and Dex has not previously been evaluated in RRMM. Our hypothesis proposed that the concurrent administration of Len, Thal and Dex may overcome Len resistance and improve response rates in patients with relapsed and/or refractory myeloma. The aim of this study was to determine the maximum tolerated dose (MTD) of the combination of Len/Thal/Dex and evaluate efficacy of the combination. Methods:The primary objective of the phase 1 portion was to determine the MTD, and the primary objective of the phase 2 was to determine the overall response rate. Patients (pts) with relapsed and/or refractory myeloma with ≥1 line of therapy were eligible, and received dexamethasone in pulse dose fashion in cycles 1–2, and weekly Dex in cycles 3 and beyond. The protocol was amended to enroll an additional 10 patient cohort who were Len refractory and received Dex on days 1, 8, 15 and 22 starting with cycle 1. All patients received anticoagulation with warfarin or low molecular weight heparin. Phase 1 data has been previously presented, and herein we present the final data from the phase 1/2. Adverse events (AEs) were graded by NCI-CTCAE v4, and responses were assessed by the modified International Uniform Response Criteria. Results:64 patients were enrolled who had a median of 4 prior lines of therapy (range: 1–12), a median age of 65 (range: 36–86), and 40/64 (63%) were males. 60/64 patients had available cytogenetic data; and 52% (31/60) had high risk cytogenetics, including 40% (24/60) with deletion 13; 13% (8/60) with deletion 17p; 5% (3/60) with t(4:14); and 12% (7/60) with t(11:14). These patients were heavily pretreated, with 66% (42/64) having Len refractory disease; 56% (36/64) had prior Thal; and 77% (49/64) had prior autologous transplantation. The maximum tolerated dose used for phase 2 was Len 25 mg/Thal 100 mg/Dex 40 mg. Among the 64 patients, 59/64 patients were evaluable for efficacy, excluding 5 who withdrew consent during cycle 1. Among the 59 evaluable patients, 56% (34/59) had a partial remission (PR) or greater, and 73% (43/59) had at least a minor response (MR). 13% (8/60) achieved a complete remission (CR/near CR (nCR)), 7% (4/60) had a very good partial remission (VGPR), 37% (22/60) had a PR, 15% (9/60) had MR, 15% had stable disease (SD), and 12% (7/60) had progressive disease (PD).Among the 42 patients who were Len refractory, 38 were efficacy evaluable. The ORR (≥MR) was 63% (24/38) and ≥PR was 39% (15/38), and achieved at least a minor response. 2/38 had a CR/nCR, 1/38 a VGPR, 12/38 a PR, 9/38 a, MR, 8/38 had SD, and 6/38 had PD.Grade 1–4 AEs regardless of causality occurring in >20% of patients included anemia (26/56), thrombocytopenia (29/56), neutropenia (21/56), diarrhea (24/56), constipation (32/56), nausea (15/56), dizziness (32/56), memory changes (21/56), blurred vision (24/56), fatigue (41/56), elevated creatinine (16/56), dyspnea (32/56), transaminitis (11/56), pneumonia (14/56), upper respiratory infection (16/56), hyperglycemia (18/56), hypomagnesemia (23/56), hypokalemia (16/56), hyponatermia (14/56), and hypophosphatemia (15/56). Grade ≥3 AEs regardless of causality included anemia (10/56), thrombocytopenia (12/56), neutropenia (15/56), diarrhea (2/56), dizziness (5/56), fatigue (17/56), elevated creatinine (5/56), and pneumonia (10/56).One venous thromboembolic (VTE) event was observed. No treatment emergent G3/4 peripheral neuropathy was seen. 1 patient died on study with cardiac arrest at home. Conclusions:The recommended dose for this regimen is Len 25 mg/Thal 100 mg/Dex 40 mg. The combination is well tolerated with an expected side effect profile and, importantly, limited incidence of VTE and treatment emergent neuropathy. The ORR of 73% was higher than would be expected of the two-drug regimen of Len/Dex. The preserved activity in Len-refractory disease, with a response rate of 63%, supports the hypothesis that the combination of Len and Thal can overcome lenalidomide resistance, and provides a new treatment option for patients with Len-refractory disease. Disclosures:Shah:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: This presentation will include information about panobinostat, which is not yet approved for use in patients with multiple myeloma. Orlowski:Celgene: Honoraria, Research Funding. Thomas:celgene: Research Funding.

Comparison of the incidence of peripheral neuropathy (PN) with eribulin versus ixabepilone (IXA) in metastatic breast cancer (MBC) patients: A randomized phase II study.

121 Background: Eribulin mesylate is approved for patients (pts) with MBC who have previously received ≥2 chemotherapeutic regimens for metastatic disease including an anthracycline and taxane in either the adjuvant or metastatic setting. This study compared incidence and severity of neuropathy adverse events (AEs) in pts receiving eribulin or IXA. Methods: Pts (locally recurrent/MBC; prior taxane therapy; ≥1 prior chemotherapy for advanced disease; pre-existing neuropathy Grade 0 [n=51] or 1 [n=53]) were randomized to receive 1.4 mg/m2 eribulin mesylate (2–5-min intravenous (IV), Days 1 and 8 of a 21-day cycle) or 40 mg/m2IXA (3 h IV, Day 1 of a 21-day cycle). The primary objective was to compare incidence of neuropathy AEs by CTCAE grade. Secondary objectives: severity of neuropathy AEs by CTCAE grade, patient neurotoxicity questionnaire (PNQ), and vibration sensitivity using Vibration Perception Threshold (VPT); time to onset of treatment-emergent neuropathy (TEN); efficacy; safety and tolerability. Results: Incidences ofPN and TEN (all grades) with eribulin (n=51) versus (vs) IXA (n=50) were 31.3% vs 44.0%, p=0.1632 and 33.3% vs 48.0%, p=0.1284, respectively. Severity (grade ≥3) was numerically lower with eribulin than IXA (PN: 9.8% vs 20.0%; TEN: 9.8% vs 22.0%). No significant differences were seen in baseline to worst PNQ scores. Median worst post-baseline VPT scores were lower with eribulin than IXA (index finger: 2.3 vs 2.4 vibration units [vu]; great toe: 7.75 vs 8.6 vu). Median time to onset of TEN was earlier with IXA (11.6 weeks [wks]) than eribulin (35.9 wks). TEAEs were comparable. Median treatment duration was 15.0 wks (eribulin) and 10.5 wks (IXA). Reasons for discontinuation (eribulin vs IXA): TEN (3.9% vs 18.0%); any TEAE (11.8% vs 32.0%); progressive disease (68.6% vs 48.0%). Objective response and clinical benefit rates were 15.4% vs 5.8% and 26.9% vs 19.2% for eribulin and IXA, respectively. Conclusions: Although not statistically significant, neuropathy AEs were less common with eribulin than IXA. Eribulin was associated with longer time to onset of TEN and fewer discontinuations due to neuropathy and other toxicities.

P5-19-02: Comparison of the Incidence of Peripheral Neuropathy with Eribulin Mesylate Versus Ixabepilone in Metastatic Breast Cancer Patients: A Randomized Phase II Study.

Abstract Background Peripheral neuropathy (PN) is a common toxicity and treatment limiting factor in heavily pretreated patients (pts) with metastatic breast cancer (MBC). Consequently, tolerability is important when choosing treatment. Eribulin mesylate has recently been approved in the US for patients with MBC who have previously received at least two chemotherapeutic regimens for metastatic disease including an anthracycline and a taxane. Eribulin was associated with a 34.6% incidence of PN (7.8% grade 3; 0.4% grade 4), however, over half of pts experiencing grade 3/4 PN continued eribulin. Ixabepilone (IXA) is frequently used in late-line MBC pts and registration studies reported an overall PN incidence of 63% (14-21% grade 3/4). We sought to define incidence of PN of eribulin and IXA in a late-line setting since indirect comparisons suggest eribulin may have a more favorable neurotoxicity profile compared with IXA. Methods: This randomized, two-arm, multicenter, open-label, phase II study stratified pts by pre-existing neuropathy (grade 0 or 1) and number of prior chemotherapy (CT) regimens (≥3 or >3). 104 pts with locally recurrent or MBC, who had received at least one prior cytotoxic CT, including a taxane for MBC were randomized to receive eribulin mesylate (n=52; 1.4 mg/m2 2- to 5-min IV on Days 1 and 8 of a 21-day cycle) or IXA (n=52; 40 mg/m2 as a 3 h IV infusion on Day 1 of a 21-day cycle). The primary objective was to compare the incidence of neuropathic adverse events. Secondary objectives were: 1) to compare the severity of neuropathy using CTCAE grading, a patient-reported neurotoxicity questionnaire (SRNQ), and vibration sensitivity (VS); 2) to evaluate efficacy as measured by objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), and progression-free survival (PFS); and 3) to evaluate safety. Results: Of 51 eribulin and 50 IXA pts who received treatment, eribulin-treated pts experienced a trend towards less PN and treatment-emergent neuropathy (TEN) than IXA-treated pts (31.4% vs 44.0%, p=0.1632; and 33.3% vs 48.0%, p=0.1284, respectively). The incidence of grade ≥3 neuropathy was 9.8% and 22% for eribulin and IXA, respectively. Time to onset of severe neuropathy was earlier for IXA relative to eribulin (4.8 vs 9.9 weeks, respectively); by cycle 4, 44% of subjects receiving IXA experienced TEN compared with 24% on eribulin. SRNQ and VS results will be analyzed separately. Treatment-emergent adverse events (TEAEs) and serious TEAEs were comparable (98% and 96%; 37% and 34% in eribulin- and IXA-treated subjects, respectively). Eribulin-treated pts experienced less discontinuation of treatment due to neuropathy (3.9% vs 18%) or TEAEs in general (11.8% vs 32.0%) relative to IXA pts. The efficacy data for eribulin vs IXA was 15.4% vs 5.8% for ORR, 26.9% vs 19.2% for CBR, 67.3% vs 55.8% for DCR, and 104 days vs 95 days for median PFS, respectively. Conclusions: Although the difference in overall incidence of PN and TEN was not significant for eribulin vs IXA, eribulin tended to show less PN and TEN. Eribulin also had less severe and longer time to development of grade 3/4 PN and fewer discontinuations due to toxicity. Support: Eisai Inc. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-02.

Combined Autophagy and Proteasome Inhibition for Multiple Myeloma: Final Results of a Phase 1 Trial of Hydroxychloroquine and Standard Dose Bortezomib for Patients with Relapsed or Refractory Myeloma

Abstract 1869 BACKGROUND:The aggresome/autophagy pathway is the primary mechanism for disposal of ubiquitinated proteins for cells exposed to proteasome inhibition. Preclinical evidence shows that combining inhibition of the proteasome with bortezomib (Bz) and inhibition of autophagy with the anti-malarial drug hydroxychloroquine (HCQ) leads to enhanced cytotoxicity in myeloma cells. METHODS:Patients with relapsed or refractory myeloma enrolled on a standard 3+3 dose escalation design. Patients received 2-weeks of single-agent oral HCQ, followed by the addition of Bz on days 1, 4, 8, and 11 of 21-day cycles. HCQ and Bz doses were determined by dose level: (1) 200 mg qod / 1.0 mg/m2, (2) 200 qod / 1.3, (3) 200 qd / 1.3, (4) 200 bid / 1.3, (5) 400 bid / 1.3, (6) 600 bid / 1.3. Dose-limiting toxicity (DLT) was defined as grade ≥3 toxicity probably related to study therapy and occurring during the first 5 weeks, with the exception of any anemia or lymphopenia, neutropenia responsive to growth factor, platelets >10,000/mm3 not associated with bleeding, or gastrointestinal complaints relieved by symptomatic therapy. We used electron microscopy to characterize changes in autophagic vesicles in serial samples of peripheral blood mononuclear cells and CD138-selected bone marrow plasma cells. RESULTS:We enrolled 25 patients between 1/2008 and 2/2011, of which 21 patients completed at least 1 cycle of combined therapy and were evaluable for toxicity. The median duration of study participation was 14 weeks (range 1–77). Reasons for study discontinuation were side effects of therapy (6), lack of response (7), disease progression (11), and non-compliance (1). No protocol-defined dose limiting toxicities occurred, and the maximum tolerated dose was determined to be the top dose level of Bz 1.3 mg/m2 and HCQ 600 mg twice daily. Hematologic abnormalities were generally more attributable to disease progression than to treatment toxicity, but at the top dose level one patient had grade 3 thrombocytopenia and neutropenia after starting with a normal platelet count and ANC, without evidence of progression through therapy. At the top dose level, gastrointestinal toxicities predominated, including 5 out of 6 evaluable patients with some form of grade 3 GI toxicity. Treatment emergent neuropathy occurred in 7 patients but was restricted to grade 1 or 2 and was easily managed with dose reduction of the Velcade. Three patients came off study before receiving the combined regimen and were not evaluable for response. The best responses for the remaining 22 patients included 3 near complete responses (nCR), 3 minor responses (MR), 9 stable disease (SD), and 7 progression (PD). The 3 nCRs occurred in Bz-naïve patients receiving HCQ at 400 mg/d (1 pt) and 1200 mg/d (2 pts). Two patients who had previously progressed while receiving weekly maintenance Bz had MRs on study, including one who maintained a MR for over 7 months. Three additional Bz-refractory patients initially achieved stable disease during study treatment, with on study TTP of 8 weeks (at HCQ 1200 mg/d), 15 weeks (100 mg/d), and 17 weeks (200 mg/d). Preliminary analyses of vesicle counts at HCQ doses up to 800 mg/d identify individual patients with increases in autophagic vesicles in either peripheral blood or bone marrow plasma cells, but these are not consistent, nor is there any evident correlation with response. CONCLUSION:Combined Bz and HCQ is tolerable, with a phase 2 dose of Bz 1.3 mg/m2 and HCQ 1200 mg/d and likely hematologic and gastrointestinal DLTs. There is a suggestion of improved efficacy over Bz alone, with minor responses and long periods of stable disease in Bz-refractory patients. Final analysis of autophagy inhibition in correlative specimens, including the top dose cohort, will be available for the meeting. Disclosures:Vogl:Millennium Pharmaceuticals: Honoraria, Research Funding. Off Label Use: Hydroxychloroquine is FDA approved for treatment of malaria and rheumatoid arthritis. This paper discusses its use in treatment of myeloma. Carroll:Agios Pharmaceuticals: Research Funding; TetraLogic Pharmaceuticals: Research Funding; Sanofi Aventis Corporation: Research Funding; Glaxo Smith Kline, Inc.: Research Funding. Amaravadi:Millennium Pharmaceuticals: Honoraria, Research Funding.

Towards a better understanding of treatment-related peripheral neuropathy in multiple myeloma

In this issue of The Lancet Oncology, Annemeik Broyl and colleagues1 assessed the genetic susceptibility to treatment-emergent neuropathy in patients who were in a prospective, phase 3 trial of bortezomib-based therapy (bortezomib, doxorubicin, and dexamethasone) versus vincristine-based induction treatment (vincristine, doxorubicin, and dexamethasone). The comparison between vincristine-induced peripheral neuropathy and bortezomib-induced peripheral neuropathy using gene expression profiling suggests that the factors involved in the development of peripheral neuropathy are distinct and involve different molecular mechanisms.

Primary therapy with single agent bortezomib as induction, maintenance and re-induction in patients with high-risk myeloma: results of the ECOG E2A02 trial

Single agent bortezomib results in response rates of 51% in patients with newly diagnosed multiple myeloma (MM) and is touted to be especially effective in high-risk disease. We are the first to prospectively explore single agent bortezomib as primary therapy (response rate, maintenance and reinduction) without consolidative autologous stem cell transplant in a cohort selected to have high-risk MM. Patients received 8-cycles of induction followed by maintenance bortezomib every other week indefinitely. Patients relapsing on maintenance had full induction schedule resumed. On an intention to treat basis the response rate (>=PR) was 48%. Among 7 patients, who progressed on maintenance bortezomib and received reinduction, two responded. With a median follow-up of 48.2 months, 1- and 2-year OS probabilities were 88% (95%CI, 74–95%) and 76% (95%CI, 60–86%), respectively. Median PFS was 7.9 months (95%CI, 5.8–12.0). Twenty-three and 34 patients had >=grade 3 hematologic and non-hematologic toxicity, respectively with treatment emergent neuropathy in: 7%, motor grade 1–2; 56%, sensory grade 1–2 and 2%, grade 3; and 14%, neuropathic pain grade 1–2 in and 2%, grade 3. In high-risk patients, upfront bortezomib results in response rates comparable to those reported for unselected cohorts, but single agent bortezomib is not sufficient as primary therapy.

Single-Agent Bortezomib in Previously Untreated Multiple Myeloma: Efficacy, Characterization of Peripheral Neuropathy, and Molecular Correlations With Response and Neuropathy

PURPOSE To assess efficacy and safety of single-agent bortezomib in previously untreated patients with multiple myeloma, investigate prevalence of baseline and treatment-emergent polyneuropathy, and identify molecular markers associated with response and neuropathy. PATIENTS AND METHODS Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, for up to eight 21-day cycles. A subset of patients underwent neurophysiologic evaluation pre- and post-treatment. Bone marrow aspirates were performed at baseline for exploratory whole-genome analyses. Results Among 64 patients, 41% had partial response or better, including 9% complete/near-complete responses; median duration of response was 8.4 months. Response rates did not differ in the presence or absence of adverse cytogenetics. After median follow-up of 29 months, median time to progression was 17.3 months. Median overall survival had not been reached; estimated 1-year survival was 92%. Thirty-two patients successfully underwent optional stem-cell transplantation. Bortezomib treatment was generally well tolerated. At baseline, 20% of patients had sensory polyneuropathy. Sensory polyneuropathy developed during treatment in 64% of patients (grade 3 in 3%), but proved manageable and resolved in 85% within a median of 98 days. Neurologic examination, neurophysiologic testing, and measurements of epidermal nerve fiber densities in 35 patients confirmed pretreatment sensory neuropathy in 20% and new or worsening neuropathy in 63%. Pharmacogenomic analyses identified molecular markers of response and treatment-emergent neuropathy, which will require future study. CONCLUSION Single-agent bortezomib is effective in previously untreated myeloma. Baseline myeloma-associated neuropathy seems more common than previously reported, and bortezomib-associated neuropathy, although a common toxicity, is reversible in most patients.

Phase I Study of Bortezomib and 153Sm-Lexidronam Combination for Refractory and Relapsed Multiple Myeloma.

Background: Multiple myeloma (MM) is a highly radiosensitive B-cell malignancy and radiation therapy is an effective treatment for these patients. Recent preclinical studies have demonstrated that the bone-seeking radionuclide, Samarium Sm153 lexidronam (Sam) in combination with the proteasome inhibitor, bortezomib (Velcade [Vel]), can synergistically inhibit proliferation of myeloma cell lines in vitro and reduce MM growth in mice bearing murine MM without significant myelotoxicity. These results provide the basis for a new targeted therapeutic approach for refractory and relapsed MM patients involving combining Vel with Sam to improve the anti-MM effects of these agents without increasing their toxicity.Aims: The primary objective of this dose escalation Phase I study is to determine safety and tolerability as well as the response rate as determined by Blade criteria of Vel + Sam treatment for patients with relapsed or refractory MM.Methods: MM patients who had failed ≥2 prior treatments will be enrolled on this Phase I dose-escalation trial which involves six cohorts with three patients each. Previous treatment with Vel is allowed. Dose escalations in parallel arms are as follows:A complete treatment cycle is 8 weeks, and patients are to receive a maximum of 4 cycles. Vel is given on days 1, 4, 8 and 11 followed by a 45-day rest period. Sam is administered only on day 3. The cycle is repeated on Day 57 if disease is stable or improved and platelets and neutrophils recover to at least Grade 1 toxicity (may be delayed for up to four weeks). Dose limiting toxicity (DLT) is defined as cycle 1 Grade 4 hematologic or Grade ≥3 non-hematologic toxicity.Results: Eighteen patients have been enrolled to date in cohorts 1 through 5. Three patients have been treated in cohorts 1, 2, 4, and 5, and 6 patients have been entered in cohort 3. Fifteen patients are evaluable for response and the other 3 patients have not yet completed a treatment cycle. Of 15 evaluable patients, 3 patients including one Velcade-refractory patient have shown responses [immunofixation+ complete response {IF+ CR} (n=2) and minor response (n=1)], 3 have stable disease, and 9 patients showed progressive disease. One Velcade-refractory patient with progressive disease initially showed a transient IF+ CR. Two patients developed transient Grade 4 thrombocytopenia. One of these episodes occurred during Cycle 1 in a patient in cohort 3; and, as a result, cohort 3 has been expanded to a total of 6 patients. Four patients showed transient Grade 3 neutropenia. Only two patients showed treatment emergent neuropathy one of which resolved while on study. To date, seven patients remain on study and one patient has completed 4 cycles of therapy.Conclusions: Early results from this dose escalation Phase I trial evaluating the combination of Vel and Sam are encouraging and demonstrate responses in relapsed and refractory MM patients. The trial continues to enroll subjects. Updated results from this study will be presented at the meeting.Arm 1Arm 2SamVelSamVelCohort 10.25 mCi/kg1.0 mg/m2Cohort 40.25 mCi/kg1.3 mg/m2Cohort 20.5 mCi/kg1.0 mg/m2Cohort 50.5 mCi/kg1.3 mg/m2Cohort 31.0 mCi/kg1.0 mg/m2Cohort 61.0 mCi/kg1.3 mg/m2

Frequency, Characteristics, and Reversibility of Peripheral Neuropathy During Treatment of Advanced Multiple Myeloma With Bortezomib

To determine the frequency, characteristics, and reversibility of peripheral neuropathy from bortezomib treatment of advanced multiple myeloma. Peripheral neuropathy was assessed in two phase II studies in 256 patients with relapsed and/or refractory myeloma treated with bortezomib 1.0 or 1.3 mg/m2 intravenous bolus on days 1, 4, 8, and 11, every 21 days, for up to eight cycles. Peripheral neuropathy was evaluated at baseline, during the study, and after the study by patient-reported symptoms using the Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire and neurologic examination. During the study, peripheral neuropathy was also evaluated by investigator assessment. A subset of patients underwent nerve conduction studies (n = 13). Before treatment, 194 (81%) of 239 patients had peripheral neuropathy by FACT/GOG-Ntx questionnaire, and 203 (83%) of 244 patients had peripheral neuropathy by neurologic examination. Treatment-emergent neuropathy was reported in 35% of patients, including 37% (84 of 228 patients) receiving bortezomib 1.3 mg/m2 and 21% (six of 28 patients) receiving bortezomib 1.0 mg/m2. Grade 1 or 2, 3, and 4 neuropathy occurred in 22%, 13%, and 0.4% of patients, respectively. The incidence of grade > or = 3 neuropathy was higher among patients with baseline neuropathy by FACT/GOG-Ntx questionnaire compared with patients without baseline neuropathy (14% v 4%, respectively). In all 256 patients, neuropathy led to dose reduction in 12% and discontinuation in 5%. Of 35 patients with neuropathy > or = grade 3 and/or requiring discontinuation, resolution to baseline or improvement occurred in 71%. Bortezomib-associated peripheral neuropathy seemed reversible in the majority of patients after dose reduction or discontinuation. Although severe neuropathy was more frequent in the presence of baseline neuropathy, the overall occurrence was independent of baseline neuropathy or type of prior therapy.

Salvage non-myeloablative allogeneic transplantation after failure of an autologous transplantation in multiple myeloma

male (22), female (11), median age 56 years (range 39–70), Stage II (9), Stage III (24), IgG (22), IgA (9), free light chain (2). Median paraprotein at initiation of consolidation was 0 (range 0–3.6) (n 33), day 1 cycle 4 was 0.1 (range 0–2.1) (n 23), and at end of study was 0.35 (range 0–3.4) (n 20). With a median follow up of 14 months, disease progression has occurred in 5 patients with 1 death. Fourteen patients (42%) experienced reactivation of VZV, 2 patients had human herpes virus 6 reactivation, and 1 patient had oral herpes simplex virus reactivation, all requiring therapy. The median absolute lymphocyte count at the onset of viral reactivation was 1336/mcl (range 600–4800/mcl). A significant difference was seen in the mean CD8 count just prior to transplantation between those patients with viral reactivation (243, range 77–685) and the rest of the study population (392, range 87–1339) (P .03). The median time from enrollment to VZV reactivation was 189 days (range 25–375). Ten patients had grade 1/2 and none had grade 3/4 neuropathy at study enrollment. At initiation of post transplant bortezomib 21 (64%) had grade 1/2 neuropathy and 1 (3%) had grade 3/4 neuropathy. Treatment emergent neuropathy on once weekly bortezomib was seen in only 3 patients (9%), necessitating dose reduction (1 patient) or discontinuation of therapy (2 patients). No grade 3/4 thrombocytopenia or neutropenia was observed with consolidation bortezomib. We conclude that bortezomib when administered preand post HDCT in MM patients results in a very high rate of viral reactivation. This finding may be explained by a decrease in circulating CD8 T cells and has implications for future clinical trials of bortezomib in this setting.

Bortezomib (Velcade) When Given Pretransplant and Once Weekly as Consolidation Therapy Following High Dose Chemotherapy (HDCT) Leads to High Rates of Reactivation of Varicella Zoster Virus (VZV).

Bortezomib is a selective inhibitor of the 26S proteasome with proven efficacy in relapsed multiple myeloma (MM). Current trials are evaluating bortezomib both as single agent and combination therapy in a variety of clinical settings. No data exists on the tolerability of bortezomib in the immediate post transplant setting. We conducted a prospective pilot study of bortezomib administered to MM patients both prior to, and as consolidation therapy following HDCT. Patients received 2 cycles of bortezomib 1.3mg/m2 on days 1, 4, 8 and 11 of every 21 days, beginning 42 days prior to stem cell collection. HDCT comprised melphalan 100mg/m2/day x 2 days followed by reinfusion of peripheral blood stem cells 48 hours later. All patients received six cycles of consolidation bortezomib 1.3mg/m2 given once weekly (for ease of administration) for 4 of every 5 weeks, 90–120 days following transplantation. To date, 40 patients have been enrolled. 3 patients did not receive HDCT (medical complications unrelated to therapy 1, failure to mobilize sufficient stem cells 1, disease progression 1). 4 patients did not proceed to consolidation therapy after HDCT (disease progression 1, grade 3/4 neuropathy 3). 33 patients have received at least one post transplantation cycle of consolidation bortezomib. Patient and disease characteristics at diagnosis were as follows (no. of patients): male (22), female (11), median age 56 years (range 39–70), Stage II (9), Stage III (24), IgG (22), IgA (9), free light chain (2). Median paraprotein at initiation of consolidation was 0 (range 0–3.6)(n=33), Day 1 cycle 4 was 0.1 (range 0–2.1)(n=23) and at end of study was 0.35 (range 0–3.4)(n=20). With a median follow up of 14 months 5 patients have had disease progression and 1 has died from progressive disease. 13 of 33 patients (39%) experienced reactivation of varicella zoster virus (VZV), 2 patients had human herpes virus 6 reactivation and 1 patient had oral herpes simplex virus reactivation, all requiring therapy. The median absolute lymphocyte count (ALC) at the onset of viral reactivation was 1336/mcl (range=600–4800/mcl). No significant difference was seen in the median ALC at initiation of consolidation therapy between the study population (1400/mcl, range 700–3500/mcl) and those patients with viral reactivation (1300/mcl, range 800–3700/mcl). The median time from enrollment to VZV reactivation was 189 days (range 25–375). 10 of 33 patients had grade 1/2 and none had grade 3/4 neuropathy at study enrollment. At initiation of post transplant bortezomib 21 of 33 (64%) had grade 1/2 neuropathy and 1 of 33 (3%) had grade 3/4 neuropathy. Treatment emergent neuropathy on once weekly bortezomib was seen in only 3 of 33 (9%) patients, necessitating dose reduction in 1 and discontinuation of therapy in the other 2 individuals. No grade 3/4 thrombocytopenia or neutropenia was observed with once weekly bortezomib. In conclusion, we observed a very high rate of VZV reactivation in this prospective study. Elsewhere we report that bortezomib therapy results in a decrease in circulating CD8 T cell and CD56 natural killer cell counts. Alterations in proportions of T cell subsets may therefore explain this finding which has major implications for future clinical trials of bortezomib in the peritransplant setting.

Safety and Activity of KOS-953 in Patients with Relapsed Refractory Multiple Myeloma (MM): Interim Results of a Phase 1 Trial.

Background: Heat shock protein 90 supports the function of client proteins in multiple myeloma (MM) including IL-6 and IGF-R1. Inhibition of HSP90 leads to protein degradation and apoptosis of MM cells, including patient-derived cells resistant to bortezomib or immunomodulators. KOS-953, a new formulation of 17-AAG, is a potent HSP90 inhibitor in phase 1 and 2 trials that suppresses cell surface expression of IL-6, IGF-R1 and their downstream signaling molecules, including the PI-3K/Akt/IKK-a and Ras/Raf/MAPK pathways. In vivo, KOS-953 extends the survival of mice after MM cells are injected and home to the marrow (>250 days in KOS-953-treated mice vs 29 days in the control group; p=0.0001).Aims: To define the MTD, toxicity, PK and pharmacodynamics of KOS-953 in patients (pts) with relapsed and relapsed, refractory MM.Methods: Pts receive an IV infusion of KOS-953 twice weekly for 2 out of 3 weeks. PK and PD are performed following the 1st and 4th infusion. Parent drug and its active metabolite are quantified in plasma. PD is assessed in bone marrow aspirates (BM) with MM cells examined for apoptosis, proliferation, pAKT, and change in HSP, IL-6 and IGF-R1 expression. Peripheral blood lymphocytes (PBLs) are assayed for change in HSP70/90 levels. Response is assessed by EBMT criteria.Results: Twenty -two pts (6 F/16 M; median age 64 yrs; median number of prior regimens 4, range 2–19; 41% prior SCT, 100% prior thalidomide, 82% prior bortezomib) were enrolled in 4 dose levels (150, 220, 275 and 340 mg/m2). Two episodes of DLT have been observed (both G3–4 elevations in liver transaminases): one pt at 220 mg/m2 with hepatic infiltration with MM (who continued with G1-2 elevations following dose reduction) and 1/6 pts at 340 mg/m2. Assessment of 420 mg/m2 is planned. Overall, G ≥ 3 drug-related toxicity was rare, consisting of AST/ALT (n=3), anemia, vomiting, memory impairment and rash (n=1 in each case). Common G1-2 drug related toxicity included diarrhea (n=9), fatigue (n=6), elevated transaminases (n=5), myalgias (n=5), infusional reactions (n=5) and rash (n=4).Elimination half-life (parent) equaled 2.8±1.0 hrs (5.1+/−1.0 hrs for the metabolite). Clearance equaled 45.0±3.0 L/hr with Vss 137±43 L. No change in PK was observed comparing the 1st and 4th infusion. At 340 mg/m2: AUCtot and Cmax were 18997 ng/mL*hr and 9355 ng/mL (parent); 13121 ng/mL*hr and 1644 ng/mL (metabolite). For the parent, AUC and Cmax increased linearly with dose. Comparing BMs (screening and 4 hr following 1st dose), CD138+ cells showed decreased pAKT (p=0.04) and increased apoptosis (p=0.06). PBLs showed reactive induction of HSP70 following KOS-953. Responses include 1 MR (150 mg/m2); 1 PR (220 mg/m2); 1 PR (340 mg/m2 with confirmation pending). An additional 6 pts have stable disease (≥ 3 cycles).Conclusions: KOS-953 has been successfully dose escalated from 150 - 340 mg/m2 with manageable toxicity and without treatment-emergent neuropathy. PK studies show linear kinetics, supporting further dose escalation to define MTD. PD studies suggest activity in heavily pre-treated MM patients, with clinical benefit (PR/MR or SD) observed in 9/22 pts (41%).