High-Dose Cyclophosphamide: An Effective Non-Transplant Salvage Option in Relapsed/Refractory Multiple Myeloma.

Abstract Abstract 4947 Background Recent advances in the treatment of multiple myeloma (MM) have significantly improved overall survival. With MM patients living longer, there is a constant need to find better therapeutic options, especially when patients are refractory to conventional agents, and are not eligible for experimental therapeutics in clinical trials. We evaluated treatment with single-agent high-dose cyclophosphamide (HDCy) in a cohort of heavily pre-treated patients with relapsed/refractory MM. Methods All the patients were previously treated for active MM at the University of Southern California (USC), Los Angeles, CA. Cyclophosphamide was administered at 1.2 gm/m2 in D5W intravenous (IV) over 1 hour every 3 hours for a total of 4 doses. Mesna was given to prevent urinary adverse events from cyclophosphamide as 4 gm/m2 in 1000 ml D5W IV to run at 50 ml/hr for 20 hours, starting 15 minutes prior to the first dose of cyclophosphamide. Patients were given pre-medications with 5HT3 antagonists an steroids. Treatment was administered in the in-patient setting and patients were discharged after the last dose of cyclophosphamide. Treatment was repeated every 4 weeks, if well-tolerated and continued response. Growth factor support was provided to the patients, as needed. Response to treatment was assessed after each 4-week cycle according to the International Uniform Response Criteria for MM. Results Seven patients (4 females, 3 males) were treated on this regimen with a median age of 53 years (range 34-61 yrs). These patients included 3 Hispanics (43%), 2 Asians (29%), 1 Caucasian (14%) and 1 African-American (14%). MM subtype was IgG disease in 3, IgA in 2, and light-chain only in 2 patients. Advanced stage disease (>stage 1) at the time of diagnosis as per the Durie Salmon (DS) staging system was present in 71% of the patients, while 3 patients (43%) had advanced stage disease as per the International Staging System (ISS). Four patients (57%) had lytic bone disease at the time of diagnosis, while only 1 patient was a non-secretor. Five of these patients (71%) never received an autologous stem cell transplant (ASCT) as a part of their MM treatment. Median number of therapies in these patients was 5 (range 4-8), while median number of therapies prior to high-dose cyclophosphamide (HDCy) were 3 (range 2-7). Median number of cycles of HDCy administered to the patients was 2 (range 1-5). Overall Response Rate (ORR = CR+PR) was 29% (n=2) with 1 patient achieving CR and 1 patient achieving VGPR. Four patients (57%) had stable disease (SD) and 1 patient had progressive disease (PD). Thus, the overall clinical benefit (CR+PR+SD) was seen in 6 out of the 7 patients (86%). Median time to best response was 5 weeks (range 4-10 weeks). Median time to progression was 16 weeks (range 8-24 weeks). Most common adverse events were cytopenias and fatigue, but were easily manageable with supportive care on an out-patient basis. Conclusions Despite improvement in therapeutic regimens for MM, it remains an incurable disorder. There is a constant need to develop regimens for treatment of relapsed/refractory MM patients that are efficacious and well-tolerated. We report the use of single-agent HDCy in heavily pre-treated MM patients. Despite the small number of patients studied, we have noted meaningful clinical benefit with a manageable toxicity profile. This warrants further investigation into developing therapeutic regimens with high-dose cyclophosphamide. Disclosures No relevant conflicts of interest to declare.

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Bortezomib in Multiple Myeloma: Treatment and Retreatment. A Single Center Experience.

Blood ◽

10.1182/blood.v110.11.4819.4819 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4819-4819 ◽

Cited By ~ 1

Author(s):

Antonios G. Bilalis ◽

Konstantinos Papadimitriou ◽

Anastasia Pouli ◽

Konstantinos Papanastasiou ◽

Seraphem Tsakanikas ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Median Time ◽

Light Chain ◽

Staging System ◽

Median Number ◽

High Dose Chemotherapy ◽

Pulmonary Complications ◽

High Dose ◽

Time To Progression

Abstract Introduction: Although major advances have been done in the treatment of multiple myeloma (MM) patients (pts), it still remains incurable with conventional or high dose chemotherapy with autologous stem cell rescue (ASCT). A novel agent which takes standard place in the management of MM pts is bortezomib. Patients and methods: The aim of our study is to evaluate prospectively the response to bortezomib (1.3mg/m2 on days 1, 4, 8, 11 in a 21-day cycle for up to 8 cycles) in MM pts relapsed or refractory after standard therapy. We evaluate its re-administration (with the same schedule) in a number of pts who have relapsed after a complete course of bortezomib as well. We also present the pts who have received bortezomib as maintenance therapy (1.3mg/m2 on days 1 and 4 in a 28-day cycle). Results: From September 2004 until August 2007 36 MM pts have been included. The characteristics of the pts are as follows: 21 males, 15 females, median age at diagnosis 57 years (41–70). Eleven pts was IgGκ, 8 pts IgGλ, 8 IgAκ,3 IgAλ, 3 κ light chain and 3 λ light chain. According to the Durie-Salmon staging system 3 pts was IA, 13 IIA, 16 IIIA and 4 IIIB. The median number of prior therapies was 3 (1–7). Nineteen pts had received ASCT prior to bortezomib. Median time from diagnosis to the first dose of bortezomib was 47 months (5–156). Twenty eight pts received bortezomib for relapse and 8 for refractory disease. Median follow-up time since bortezomib administration was 12 months (1–30). The pts who achieved CR, VGPR or was in PD for two successive cycles discontinued treatment. The median number of cycles received was 5.5 (1–8). The response outcome, according to the International Myeloma Working Group response criteria, for the pts who received up to 4 cycles, was: 7 pts in CR, 5 pts in VGPR, 7 pts in PR, 7 pts in SD, 6 pts in PD, 3 pts died due to PD and 1 due to pulmonary complications. The response outcome for the pts who received up to 8 cycles was: 5 pts in CR, 4 pts in VGPR, 5 pts in PR, 4 pts in SD, 3 pts in PD. The median time to progression for responders was 8 months (1–26). The overall outcome was CR 22.3%, VGPR 16.7%, PR 11.1%, SD 19.4% and PD 30.5%. Ten pts who achieved CR, VGPR or PR continued maintenance therapy with bortezomib. The median time of maintenance therapy until relapse was 7 months (2–16). Six pts from the maintenance group who relapsed re-treated with bortezomib. Also 1 patient who relapsed without receiving bortezomib maintenance re-treated as well. After a median number of 6 cycles (1–8) of re-treatment, 1 patient is in VGPR, 1 in PR, 3 in SD and 2 in PD. Conclusions: We conclude that bortezomib offers an overall response rate of 50.1% (CR, VGPR, PR) in heavily pre-treated MM pts achieved even from the very first cycle. Probably the addition of bortezomib as maintenance therapy may prolong the time to progression in responding pts. Retreatment is also an attractive option, but we cannot extract safe conclusions due to our limited sample size.

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Bortezomib and Dexamethasone as Maintenance therapy in Relapse/Refractory multiple myeloma Patients

Blood ◽

10.1182/blood.v112.11.2771.2771 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2771-2771 ◽

Cited By ~ 1

Author(s):

Giulia Benevolo ◽

Alessandra Larocca ◽

Patrizia Pregno ◽

Francesca Gay ◽

Barbara Botto ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Median Time ◽

Salvage Therapy ◽

Univariate Analysis ◽

Single Agent ◽

Haemoglobin Concentration ◽

Progression Free Survival ◽

Median Number

Abstract Background: Despite the advances in the treatment for multiple myeloma (MM) in the past decade, it still remains an incurable haematological disease and the majority of patients still experience relapse. Bortezomib is a novel proteasome inhibitor approved for the treatment of MM patients. Several studies have demonstrated its efficacy as front-line therapy and in relapsed, advanced MM but no data are available as maintenance therapy (MT) in refractory/relapsed MM. Patients and methods: The aim of this study is to evaluate the safety and the efficacy of bortezomib/dexamethasone MT (1.3 mg/mq bortezomib on days 1 and 15; 20 mg dexamethasone on days 1–2 and 15–16 in a 28-day cycle for a total of 6 cycles) in patients with refractory/relapse MM who responded to salvage therapy. Results: From October 2004 until April 2008, 40 MM patients have been enrolled. The characteristics of the patients were as follows: 20 males and 20 females, median age was 70 years (IQR:66–75). Median haemoglobin value was 10.85 (IQR:10.175–12.225) and 7 (18%) patients had a renal failure. Skeletal disease was present in 27 (68%) patients. The median number of prior therapies was 2 (1–4). The salvage therapy included bortezomib as single agent or in combination with steroids and/or thalidomide in 12 patients (30%). Median time from diagnosis to the first dose of MT was 41 months (IQR:26–59). The median number of bortezomib infusion was 8 (1–18). After a median follow up of 13 months (IQR:6–31), 10 patients died for PD and 4 patients for infections. The MT improved the quality of response and converted in 1 CR and 4 VGPR the PR after salvage therapy in 5 patients; moreover, we observed a remarkable decreased of M component in 11 patients. The median time to progression was 23 months (95%CI: 8-not reached) with a progression free-survival at 1 year of 69% (95%CI: 50–82). The overall survival at 1 years was 63% and the cumulative incidence of death due to PD adjusted for competitive risk event was 25% (95%IC:10–41). In a univariate analysis the response rate to MT was not significantly affected by age, sex, number or type of previous therapy and haemoglobin concentration. Non-dose-limiting toxicities included neuropathy grade 1 (12 pts), herpes zoster reactivation (2 pts) and gastrointestinal affections (1 pts). Conclusion: The combination bortezomib/dexamethasone can be safely administered as a maintenance therapy in relapse/refractoy MM. These preliminary data suggest that bortezomib/dexametasone MT can improve remission duration and also quality of response with an acceptable toxicity.

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Effect of lenalidomide (LEN) on biochemical responses and clinical benefit (CB) as a single agent in chemotherapy-naive castration-resistant prostate cancer (CRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.128 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 128-128 ◽

Cited By ~ 1

Author(s):

Chadi Nabhan ◽

Anand Patel ◽

Dana Villines ◽

Kathy Tolzien ◽

Susan K. Kelby ◽

...

Keyword(s):

Adverse Events ◽

Clinical Benefit ◽

Single Agent ◽

Complete Response ◽

Median Number ◽

Castration Resistant Prostate Cancer ◽

Serious Adverse Events ◽

Biochemical Responses ◽

Grade 3 ◽

Dose Reductions

128 Background: LEN has anti-angiogenesis and immunomodulatory properties making it ideal to investigate in CRPC. We report on a phase II study investigating LEN in chemotherapy-naïve CRPC patients (pts) Methods: Eligible pts received LEN at 25 mg daily on days 1 – 21 every 28-days until progression. Daily aspirin or coumadin were required. Responses were assessed every 2 cycles. Toxicity was assessed every cycle. Primary end point: The CB of LEN [Sum of complete response (CR), partial response (PR) and stable disease (SD)]. Secondary end points: Toxicity, time to radiographic and PSA progression (TTP and TTP-PSA), time to next treatment (TTNT), overall survival (OS), and LEN’s impact on quality of life (QOL). Results: 31 pts were enrolled; 27 response-evaluable (1 withdrew consent, 3 off per choice after adverse events). Median age is 74 (range 58-89) with 24 (77%) having Gleason ≥ 7 disease. Median PSA is 66 (2.1-918.6). Six pts (19%) had liver/lung involvement. Fourteen pts (51%) showed biochemical response with 4 (15%) having >50% PSA drop. TTP-PSA is 4 months (2-11). No radiographic responses seen but 17 pts had SD for a median of 4 months (2-16) (CB=55%). Median number of LEN cycles was 3 (2-15). With a median follow-up of 18 months (5-38), 17 patients (55%) remain alive; median OS of 18 months. Grade 3/4 hematologic toxicities were most common (neutropenia 41%, leukopenia 12%, anemia 9%, thrombocytopenia 9%). Other grade 3/4 toxicities: venothromboembolism, atrial fibrillation, and dehydration (6% each). Serious adverse events (SAEs) were witnessed in 10 pts (32%) with only 1 (3%, rash) definitely related to LEN. Others were not related or possibly related. Of 27 pts, 7 (26%) had a dose reduction and 2 (7%) required two dose reductions. Dose reductions occurred after cycle 3. QOL scales suggested no adverse impact. Median TTNT is 2 months (9 pts received chemotherapy, 10 pts went onto studies, 3 pts received hormonal therapies, 4 pts received radiation, 3 pts had no therapy yet, and 2 pts remain on LEN). Conclusions: LEN is active as monotherapy in CRPC. Biochemical responses are witnessed and clinical benefit is observed. Myelosuppression is the most common toxicity.

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A Phase 1b Study of 30-Minute Infusion Carfilzomib 20/45 and 20/56 Mg/m2 Plus 40 Mg Weekly Dexamethasone in Patients with Relapsed and/or Refractory (R/R) Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.4036.4036 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4036-4036 ◽

Cited By ~ 4

Author(s):

Ashraf Z. Badros ◽

Kyriakos P Papadopoulos ◽

Naseem Zojwalla ◽

Ju RueyJiuan Lee ◽

David S. Siegel

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Single Agent ◽

Safety Data ◽

Median Number ◽

Combination Regimen ◽

Upper Respiratory Tract ◽

Advisory Boards ◽

Phase 1B ◽

Higher Doses

Abstract Abstract 4036 Background: Carfilzomib, a next-generation proteasome inhibitor, has shown a favorable efficacy and safety profile in phase 1 and 2 trials in patients with multiple myeloma (MM) with doses up to 27 mg/m2 administered intravenously (IV) over 2–10 minutes on 2 consecutive days for 3 weeks of a 4-week cycle. In patients with relapsed and/or refractory MM, durable responses were noted in 24% of patients from the pivotal trial PX-171-003-A1 (Siegel DS, et al. Blood. 2012) and in 48% of bortezomib-naïve patients from PX-171-004 (Vij R, et al. Blood. 2012). Based on preclinical safety data showing that a slower infusion rate of carfilzomib was better tolerated and permitted administration of higher doses than a 2- to 10-minute infusion, a phase 1b/2 study (PX-171-007, NCT00531284) was undertaken to evaluate a 30-minute infusion of escalated doses of carfilzomib. As previously reported, the MTD was 56 mg/m2 with an ORR of 60% and >50% of patients treated at this dose reporting fatigue, nausea, dyspnea, and pyrexia (Papadopoulos KP, et al. Blood. 2011). To assess the tolerability and efficacy of higher doses of carfilzomib in combination with dexamethasone 40 mg weekly, we expanded a MM cohort of the 007 study and administered carfilzomib at 45 mg/m2 (n=14) and 56 mg/m2 (n=8) as a 30-minute IV infusion. An interim analysis of the results is reported herein. Methods: Carfilzomib was administered as a 30-minute IV infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle 1, Day 1–2 doses were 20 mg/m2, followed by escalation to either 45 or 56 mg/m2. Dexamethasone 20 mg was administered prior to carfilzomib dosing on Days 1, 2, 8, 9, 15, and 16; 40 mg was administered on Day 22 during the carfilzomib “rest” week of the cycle. Safety assessments included incidence, severity, and duration of adverse events (AEs), which were evaluated according to the Common Terminology Criteria for Adverse Events v 3.0. Responses were determined according to International Myeloma Working Group Uniform Response Criteria. The response-evaluable population required 2 consecutive assessments made at any time before classification as relapse or disease progression. Results: A total of 22 patients were treated; the median age was 59.5 years (range 41 − 72); 17 were men and 7 were African American. The median number of prior chemotherapies was 4 lines (range 1−9), and median number of transplants was 2 (range 0−4); 96% of patients received prior bortezomib. As of May 2012, patients had received a median of 4 cycles (range 1−6), with no dose reductions reported. Thirty-minute infusion of carfilzomib at 45 mg/m2 or 56 mg/m2 in combination with dexamethasone was well tolerated. The most common AEs, irrespective of relationship to carfilzomib, were fatigue (36.4%), headache (36.4%), thrombocytopenia (36.4%), anemia (31.8%), cough (31.8%), dyspnea (31.8%), insomnia (27.3%), upper respiratory tract infection (27.3%), nausea (22.7%), and hypertension (18.2%). Non-hematologic AEs were mostly Grade 1 or 2. Grade 3 or higher AEs reported in >10% of patients were anemia (27.3%) and thrombocytopenia (27.3%). SAEs were reported in 4 (18.2%) patients, and there were no deaths on study. Seven patients discontinued therapy due to PD (n=6, all on 45 mg/m2) or SAE (n=1, on 56 mg/m2for Grade 4 increased aspartate aminotransferase). Preliminary responses in patients who completed at least 2 cycles (n=20) included VGPR (n=2) and PR (n=9), for an ORR of 55% with SD in 6 patients and PD in 3. The remaining 2 patients discontinued prior to cycle 2 (unrelated AE=1, patient decision=1). Conclusions: Thirty-minute infusion of carfilzomib combined with dexamethasone was well tolerated with a trend toward fewer AEs related to fatigue, nausea, dyspnea, and pyrexia relative to single-agent carfilzomib. In addition, preliminary reports of efficacy are compelling. This combination regimen with carfilzomib at 56 mg/m2 is currently being evaluated in the phase 3 trial ENDEAVOR comparing carfilzomib plus dexamethasone vs bortezomib plus dexamethasone in patients with relapsed MM (NCT01568866). Disclosures: Off Label Use: Carfilzomib for the treatment of Multiple Myeloma. Papadopoulos:Onyx Pharmaceuticals: Honoraria, Research Funding. Zojwalla:Onyx Pharmaceuticals: Employment. Lee:Onyx Pharmaceuticals: Employment. Siegel:Millennium: Advisory Boards, Advisory Boards Other, Honoraria, Speakers Bureau; Merck: Advisory Boards, Advisory Boards Other, Honoraria, Speakers Bureau; Celgene: Advisory Boards, Advisory Boards Other, Honoraria, Speakers Bureau; Onyx Pharmaceuticals: Advisory Boards Other, Honoraria, Speakers Bureau.

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Retrospective Analysis of the Efficacy and Safety of Modified Bortezomib-Lenalidomide-Dexamethasonelite (modified RVD-lite) Therapy for Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-112294 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1961-1961

Author(s):

Kiyoshi Okazuka ◽

Tadao Ishida ◽

Junichiro Nashimoto ◽

Takao Yogo ◽

Kanji Miyazaki ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Adverse Events ◽

Staging System ◽

Median Number ◽

Al Amyloidosis ◽

Fish Analysis ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Grade 3

Abstract [Background] Thecombination therapy consisting of bortezomib, lenalidomide and dexamethasone (RVD) for newly diagnosed multiple myeloma has been one of the standard induction therapies in recent years. However, 9-23 % of patients discontinued treatments because of severe adverse events in the previous reports (SWOG S077, IFM2009). Thus, it has not been clarified ifthe dosing schedule of RVD is appropriate. Here, we investigated the efficacy and safety of modified RVD-lite for 45 transplant eligible patients with newly diagnosed multiple myeloma (NDMM). [Patients and methods] We retrospectively analyzed 45 transplant eligible patients with NDMM who received modified RVD-lite for induction therapy between February 2016 and March 2018. The median age was 58 years old (range 36~66), and 6 (13.3%) patients were AL amyloidosisassociated with multiple myeloma. Patients received bortezomib 1.3 mg/m2once weekly subcutaneous (SC) on days 1, 8, 15, 22, lenalidomide 15 mg/day on days 2-7, 9-14, 16-21 and dexamethasone 40mg on days 1, 8, 15, 22. The Revised International Staging System (R-ISS) wereI in 13 (28.9%), II in 30 (66.7%) and III in 2 (4.4%). High-risk cytogenetics, defined as the presence of deletion 17, t(4;14) and t(14;16) by FISH analysis, were identified in 5 (11.1%) patients. After 4 cycles of modifiedVRd-lite, we evaluated the efficacy and adverse events. [Results] The overall response rate (ORR) after four 28-day cycles of modifiedRVD-lite was obtained in 41 (91.1%), including sCR in 6 (13.3%) and CR in 5 (11.1%). SD and PD were observed in 2 patients (4.4%) and 1 patient (2.2%), respectively. One patient was not evaluated efficacy, because a patient changed modifiedRVD-lite to ixazomib, lenalidomideand dexamethasone therapy for grade 3 peripheral neuropathy. Thirty-eight of 45 patients (84.4%) received autologous stem cell transplantation (ASCT) after at least 4 courses of modifiedVRd-lite. The median number of CD34+cells/kg collected was 4.83 x 106(range, 1.1-11.9). All patients received melphalan at doses of 200 mg/m2. In these patients, response after ASCT were sCR in 15(41.7%), CR in 2 (5.6%), VGPR in 8 (22.2%) and PR in 8 (22.2%). Three of seven patients who did not received ASCT will receive ASCT ina few months. Among other 4 patients who did not receive ASCT, 2 patients chose other therapies without ASCT, and 2 patients could not receiveASCT because they showed no improvement in cardiac AL amyloidosis. Grade 3 or higher adverse events (AEs) were observed in 17 (37.8%). Most frequent grade 3 or higher AE was neutropenia (grade 3:17.8%, grade 4:6.7%). Only one patient (2.2 %) discontinued modifiedRVD-lite because of grade 3 peripheral neuropathy. [Conclusions] The ORR after 4 cycles ofmodifiedRVD-lite was high (91.1%). These results might be related to low rate of discontinuation of treatment. Also, the ORR after ASCT was comparable to the results previously published (N Engl J Med .2017 Apr 6:376(14):1311). AEs in modified RVD-lite were feasible and manageable in most patients. Our results suggest that modifiedRVD-lite is very feasible and effective treatment for patients with transplant eligible NDMM. Disclosures Suzuki: Sanofi Aventis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ono: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; SRL.Inc: Employment.

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Bortezomib in Combination with High-Dose Dexamethasone and Continuous Low-Dose Oral Cyclophosphamide for Relapsed Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.2549.2549 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2549-2549 ◽

Cited By ~ 11

Author(s):

Martin Kropff ◽

Guido Bisping ◽

Peter Liebisch ◽

Orhan Sezer ◽

Hermann Einsele ◽

...

Keyword(s):

Multiple Myeloma ◽

Low Dose ◽

Response Rate ◽

Single Agent ◽

Median Number ◽

High Dose ◽

Oral Cyclophosphamide ◽

Minor Response ◽

Chromosome 13 ◽

Dose Oral

Abstract Single agent bortezomib treatment yields ≥ partial responses (PR) in 24% of patients with relapsed, refractory multiple myeloma (MM) and 38% of patients who had received 1 – 3 previous therapies. Dexamethasone (DEX) adds to anti-myeloma activity of bortezomib. The present phase II trial was intitiated to study bortezomib combined with DEX and continuous low-dose oral cyclophosphamide (CY). 50 patients with advanced MM were scheduled to receive bortezomib 1.3 mg/m2 IV days 1, 4, 8, and 11 q 3 weeks for 8 cycles in combination with DEX 20 mg PO on the day of bortezomib injection and the day thereafter, and CY 50 mg PO daily; followed by 3 cycles bortezomib 1.3 mg/m2 IV days 1, 8, 15, and 22 q 5 weeks in combination with corresponding DEX and CY schedules. Patient characteristics included median age 63 years; B2M > 3,0 mg/L, 64%; CRP > 3,0 mg/L, 25%; deletion of chromosome 13, 46%; median number of prior regimens, 2 (range 1 – 9), and prior standard therapy > 12 mo, 94 %. 78% of patients had relapsed after high-dose melphalan. The EBMT criteria were used for definition of response. Five patients (10%) achieved a complete response, 33 (66%) a PR, and 6 (12%) a minor response (MR) resulting in an overall response rate (≥MR) of 88%. On an intention-to-treat basis, median event-free survival (EFS) with this combination was 10 months. After a median follow-up of 10 months, median overall survival has not been reached. Notably, chromosome 13 deletion was predictive of a favorable outcome (higher response rate, longer EFS) in this setting. The median number or treatment cycles given was 6. 56% of the patients terminated study treatment prematurely, mainly for disease progression (10%) or adverse events (34%). Grade 4 neutropenia during at least one treatment cycle occurred in one patient (2%), grade 4 thrombocytopenia in 17%; one thrombocytopenic bleeding. Grade 3/4 non-hematologic toxicities requiring dose or schedule modifications included infections (26%), peripheral neuropathy (25%), fatigue (15%), herpes zoster (13%), and cardiovascular events (11%). One patient succumbed to infection without predisposing neutropenia. Bortezomib in combination with DEX and CY appears to be a highly active regimen without increased toxicity compared to a single agent treatment with bortezomib. Maintenance treatment might be required for prolonged EFS.

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Fotemustine (MUFORAN) in Combination with Once Weekly Bortezomib and Dexamethasone (B-MuD): Good Clinical Activity and Favourable Toxicity Profile for Treatment of Relapsed Multiple Myeloma Patients.

Blood ◽

10.1182/blood.v120.21.2957.2957 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2957-2957

Author(s):

Silvia Mangiacavalli ◽

Alessandra Pompa ◽

Lara Pochintesta ◽

Cristiana Pascutto ◽

Federica Cocito ◽

...

Keyword(s):

Multiple Myeloma ◽

Median Time ◽

Conflicts Of Interest ◽

Single Agent ◽

Gastrointestinal Symptoms ◽

Median Number ◽

Hematological Toxicity ◽

Clinical Activity ◽

Dose Escalation Study ◽

Advanced Phase

Abstract Abstract 2957 Fotemustine (Muphoran), a nitrosourea alkylating agent approved for metastatic melanoma, and recently used in alternative autotransplant condition regimen (FEAM) for lymphoma patients, has proven to be active as single agent in Multiple Myeloma (MM) refractory-relapsed patients. Given the importance of reaching high-quality response even beyond frontline setting, and the proven activity of the proteasome inhibitor bortezomib + dexamethasone therapy, we explored by means of a phase I-II dose escalation study the feasibility and the efficacy of the three drug combination bortezomib (B) + fotemustine (Mu) + dexamethasone (D) (B-MuD) in MM patients (pts) relapsed after at least one therapy. The study has been approved by our local ethical committee; all pts signed written informed consent. Fotemustine was administered at two dose levels (80–100 mg/m2 i.v.) on day 1. The original 21-day schedule was early amended due to extra-hematological toxicity and a 35-day schedule was adopted (Bortezomib 1,3 mg/ m2 i.v. on days 1, 8, 15, 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, 22) for a total of six courses. Twenty-four pts have been enrolled: M/F 13 (54%)/11(46%), median age 69 years (44–83), median number of previous therapies 2 (1–5). Previous treatments included autologous transplant in 13 pts (54%), bortezomib in 8 pts (33%), oral melphalan in 11 pts (46%) and thalidomide in 15 (63%). The MTD of Fotemustine was tested to be 100 mg/m2. Six pts dropped-out: 4 pts for extra-hematological toxicity, 2 for progression. The overall response rate was of 62% (CR 8%, VGPR 33%, PR 21%). Median time to first response was 36 days (range 21–83) with a median DOR of 19.4 months (95% CI 11.6–23.7 months). After a median follow-up of 24.3 months (range 1.6–32.8 months), the median OS was 28.5 months (95% CI 22.1-NR). The median TTP and the median PFS were 20.5 (95% CI 11.9–22.2 months) and 19.1 (95% CI 11.9–22.2) months respectively. Median time to next therapy (TNT) was 16.2 months (4–25.2). There was a correlation between response and PFS (p=0.0002). B-MuD resulted effective in patients previous exposed to bortezomib without difference in terms of response (p=0.25) and PFS (p=0.87) when compared to bortezomib-naive patients. As far as toxicity was concern, one-hundred and thirty-three AE of any grade were observed, 65 hematological (49%) and 68 (51%) non-hematological; Thrombocytopenia was the most common AE (32%) overall. Extra-hematological toxicity included neuropathy (23%), infections (14%), gastrointestinal symptoms (7%). Half of the events occurred during the first two cycles (49%), most were manageable, with 69% resolved or improved, 15% unchanged, 15% worsened. In conclusion B-MuD is effective and well tolerated in relapsed MM even in patients in advanced phase and previously exposed to several lines of therapies, including bortezomib. Disclosures: No relevant conflicts of interest to declare.

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A Novel High Dose Chemotherapy Strategy with Bendamustine In Adjunct to Etoposide, Cytarabine and Melphalan (BeEAM) Followed by Autologous Stem Cell Rescue Is Safe and Highly Effective for the Treatment of Resistant/Relapsed Lymphoma Patients: a Phase I-II Study on 44 Patients

Blood ◽

10.1182/blood.v116.21.31.31 ◽

2010 ◽

Vol 116 (21) ◽

pp. 31-31 ◽

Cited By ~ 4

Author(s):

Giuseppe Visani ◽

Lara Malerba ◽

Pietro Maria Stefani ◽

Saveria Capria ◽

Piero Galieni ◽

...

Keyword(s):

Stem Cell ◽

Complete Remission ◽

Adverse Events ◽

Phase I ◽

Median Time ◽

Conditioning Regimen ◽

Median Number ◽

High Dose ◽

Stem Cell Rescue ◽

Relapsed Lymphoma

Abstract Abstract 31 Background: BEAM (Carmustine, etoposide, cytarabine, and melphalan) regimen is the most used conditioning regimen before autologous stem cell transplant (ASCT) in lymphoma patients. However, patients receiving BEAM show a significant number of side effects, and relapse rate after transplant is still a matter of concern. Therefore, new regimens with a higher efficacy and a better toxicity profile in comparison to BEAM are highly needed. Aims: We designed a phase I-II study to evaluate the safety and the efficacy of increasing doses of Bendamustine for the conditioning regimen to ASCT for resistant/relapsed lymphoma patients. Methods: Forty-four patients (median age 47 years, range 18–70) with resistant/relapsed non-Hodgkin (29) or Hodgkin (15) lymphoma were consecutively enrolled in the study. The new conditioning regimen consisted of increasing doses of Bendamustine coupled with fixed doses of Etoposide (200mg/m2/day on days -5 to -2), Cytarabine (400mg/m2 on days -5 to -2) and Melphalan (140 mg/m2 on day -1) (BeEAM regimen). Three cohorts of 3 patients each were treated starting with Bendamustine 160 mg/m2/daily given on days -7 and -6. The dose of Bendamustine was then escalated according to the Fibonacci's increment rule until the onset of severe adverse events and/or the attainment of the expected MTD, but not higher than 200 mg/m2. Patients were carefully monitored for adverse events. The study was registered at EMEA with the EUDRACT no 2008–002736-15. Results: The administration of Bendamustine was safe in all the 3 cohorts of patients. The major side effect was a grade III-IV oral mucositis developed by 9 patients during neutropenia. We then fixed the dose of Bendamustine 200 mg/m2 as safe and effective for the Phase II study. A median number of 5.68×106CD34+/kg cells (range 2.4–15.5) collected from peripheral blood was reinfused to patients. All patients engrafted, with a median time to ANC>0.5×109/l of 10 days. Median times to achieve a platelet count >20×109/l and >50×109/l were 13 and 16 days respectively. Twenty-two out of 44 patients presented a fever of unknown origin (50%). The median number of days with fever was 2 (range: 0–7), with a median number of 9 days of intravenous antibiotics (range: 3–22). All patients received G-CSF after transplant for a median time of 9 days (range: 8–25). Two patients developed a viral infection (1 HSV-6, 1 CMV) early after transplant. Thirty-nine out of 44 patients are evaluable up to now for the response to treatment. All evaluable patients are alive. 32/39 are in complete remission whereas 4/39 are in partial response, after a median follow-up of 11 months from transplant. Three out of 39 patients relapsed after a median time of 3 months from transplant. It is of note that 4/39 patients achieved the first complete remission after receiving the high-dose therapy with autologous stem cell rescue. Conclusions: The new BeEAM regimen is safe and seems to have a high efficacy in heavily pretreated lymphoma patients. Basing on this experience, future studies incorporating Bendamustine in conditioning regimens pre-ASCT in lymphoma patients should use Bendamustine 200 mg/m2/day over 2 days. Acknowledgments: supported in part by AIL Pesaro Onlus. Disclosures: Malerba: celgene, Janssen-Cilag: Honoraria.

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Daratumumab Is an Effective and Safe Salvage Therapy in Relapsed/Refractory Patients with Multiple Myeloma after Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood.v128.22.3437.3437 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3437-3437 ◽

Cited By ~ 5

Author(s):

Evgeny Klyuchnikov ◽

Ute-Marie von Pein ◽

Francis A. Ayuk ◽

Maximilian Christopeit ◽

Raissa Adjalle ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibody ◽

Adverse Events ◽

Safety Profile ◽

Salvage Therapy ◽

Research Funding ◽

Single Agent ◽

Median Number ◽

Post Transplant ◽

Coronary Syndrome

Abstract Daratumumab is a human monoclonal antibody that targets CD38, a cell surface protein that is overexpressed on multiple myeloma cells. Some clinical studies have shown encouraging efficacy and acceptable safety profile of daratumumab, so that the drug became the first monoclonal antibody as single agent therapy approved by the FDA for the treatment of multiple myeloma. The role of allo-SCT in myeloma patients remains unclear; nevertheless, the registry study of European Society for Blood and Marrow Transplantation (EBMT) suggests an increasing rate of allografts in Europe in last years. Despite the potentially curative potential of this approach, the increased relapse rate and low PFS remain a central clinical problem. In this single center retrospective analysis, we report on our experience on the use of daratumumab in relapsed/refractory myeloma patients after allo-SCT. A total of 10 patients (male, n=5) with median age of 59 years (range, 37-69) relapsing after allo-SCTs that had been performed during a period 2008-2015 at the University of Hamburg and received daratumumab as single agent salvage therapy. Before allografting 8 patients received one and 2 patients ≥2 autografts, respectively. All but one patient received at least 1 salvage therapy line prior to the allo-SCT. The allografts were performed from unrelated donors (MUD, n=5; MMUD, n=3) or matched related donors (MRD, n=2). Five patients experienced early relapses (≤12 months) after allo-SCT. The median number of salvage lines post-transplant and prior to first daratumumab infusion was 3 (range, 1-4). The salvage regimens included bortezomib, lenalidomide, pomalidomide and carfilzomib. Daratumumab infusions were started at a median of 21 months (range, 2-30) after relapse/progress. The median number of infusions was 6 (range, 2-12). A total of 10 and 9 patients were available to safety and efficacy evaluation, respectively. The safety was assessed according to the Common Toxicity Criteria (CTC). A total of 14 adverse events were observed in 9 patients: dyspnea (CTC1, n=2; CTC2, n=1), bronchospasm (CTC2, n=1) shivering (CTC1, n=3), cough (CTC1, n=1; CTC2, n=1), musculoskeletal pain (CTC1, n=2), acute coronary syndrome (CTC3, n=1), skin rush (CTC2, n=1), pressure on eyes (n=1). There were no cases of hematologic toxicity. There were no cases of GvHD. The adverse events appeared in all patients after the first infusion, with improved tolerance of following infusions. There were no cases, where the therapy had to be stopped due to adverse events. Within a median follow-up of 25 months (range, 3-38) from the relapse/progression 9 of 10 patients remain alive. One patient died due to severe infection after progress of myeloma. A total of 5 of 9 evaluable patients responded (56%), of those 3 of 5 patients with early relapses (PR, n=2; vgPR, n=1). The responses (decrease of paraprotein and/or free light chains; reduction of extramedullary tumor in 1 patient) occurred at a median of 7 days (range, 7-22) after the first administration of daratumumab. The median response duration is 35 days (range, 7-84). All responding and 2 non-responding patients showed clinical improvement of constitutional symptoms. No patients required blood or platelets transfusions during and after the therapy. All responding patients maintain their responses 7, 14, 35, 54 and 84 days after the first administration of daratumumab. Daratumumab demonstrated encouraging efficacy in relapsed/refractory patients with myeloma after allo-SCT. The administrations of the drug in these heavily pre-treated patients were associated with good safety profile and development in majority of cases non-severe adverse events mostly after the first infusion. Further studies on the use of daratumumab in post-transplant setting are warranted. Disclosures Kröger: Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding.

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Repurposing Leflunomide for Relapsed/Refractory Multiple Myeloma: Final Analysis of a Phase 1 Study

Blood ◽

10.1182/blood-2018-99-120042 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2007-2007

Author(s):

Michael Rosenzweig ◽

Joycelynne Palmer ◽

Ni-Chun Tsai ◽

Ralf Buettner ◽

Lupe Duarte ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

Dose Escalation ◽

Clinical Benefit ◽

Phase 1 ◽

Single Agent ◽

Study Drug ◽

Median Number ◽

Maximum Tolerated Dose ◽

Phase 1 Study

Abstract Introduction: Despite significant progress in the treatment of multiple myeloma (MM), the disease remains incurable and typically follows a pattern of multiple responses and relapses. In the relapsed/refractory MM setting (RRMM), outcomes for patients may be particularly discouraging. New treatments that are safe and effective are therefore of urgent need for this population. Since its FDA approval in 1998 for the treatment of rheumatoid arthritis, leflunomide has been used in over 300,000 patients worldwide. Leflunomide is hepatically cleared and has a favorable toxicity profile even when given over long periods. Its primary mechanism of action is inhibition of pyrimidine synthesis by targeting dihydroorotate dehydrogenase, thus achieving anti-proliferative effects on B and T lymphocytes. The anti-neoplastic potential of this agent has been studied in a number of pre-clinical tumor models. Leflunomide's immunoregulatory action may be related to functional inhibition of CD4+ effector T cells, including Th17 cells as well as dysregulation of T regulatory cells (Tregs). We found that leflunomide-treated C57BL/KaLwRij mice engrafted with 5TGM1 cells had more robust expansion of CD8+ cytotoxic T cells and subsequent decrease of CD4+ Tregs compared to untreated mice. We have also noted that leflunomide impairs growth of MM cells at least partly through inhibition of PIM kinases and c-Myc signaling. We present here final results from a phase 1 study of leflunomide in patients with RRMM. Methods: This single center, single agent, phase 1 dose-escalation trial was designed to determine the maximum tolerated dose of leflunomide in patients with RRMM. The trial implemented a modified rolling six phase 1 dose escalation design. The primary objectives were as follows: 1) to determine the maximum tolerated dose and recommended phase 2 dose of leflunomide; 2) to assess the safety and tolerably of leflunomide at each dose level by evaluation of toxicities. Leflunomide was administered at a loading dose of 100 mg daily for the first three days, then daily in 28-day cycles. The starting dose of daily leflunomide was 20 mg daily, with dose escalation in increments of 20 mg/day, up to 60 mg/day. Dose de-escalation in decrements of 10mg/day was planned. Results: A total of 12 patients have been enrolled starting in December 2015 and treated. The median age is 68 (range 48 - 85), and the median number of prior therapies is 5 (range: 3 - 14). Nine patients had prior autologous stem cell transplant. Double refractory (lenalidomide/bortezomib) disease was noted in 9 patients. High-risk cytogenetics were observed in 5 patients including 2 patients with del17p. All 12 subjects were evaluable for toxicity. One subject was not evaluable for response because of non-compliance. Of the eleven patients evaluable for response, the median number of cycles was 3 (range 1- 15). The median follow up was 177 days (range: 42 - 602). Three patients were treated on DL 1 (20 mg) and three on DL3 (40 mg) without incidence of DLT. At DL5 (60 mg), one patient had a DLT with grade III elevation of alanine aminotransferase; an additional three patients were enrolled at this dose level without further DLTs. One out of 12 subjects remains on treatment, 8 patients were removed from study due to disease progression, two due to adverse events (bacteremia at 60 mg, possibly related to study drug and angioedema at 40 mg, not related to study drug) and one from noncompliance. The most common toxicities were hematologic. There were 4 patients with grade 1 or 2 neutropenia on the 20 and 40 mg dose levels and 1 patient with grade 4 lymphopenia on the 40 mg dose. Except for the DLT, all non-hematologic toxicities were ≤ grade 2. Response: Although not all patients were treated at the 60 mg dose, a clinical benefit rate of 90% has been seen, with 9/10 achieving stable disease (SD). The median duration of SD among 9 patients thus far is 56 days (range: 27-401). In the five evaluable patients with high risk cytogenetics, four of them achieved a clinical benefit. Two subjects had SD lasting nearly one year or longer. In this small cohort, no association between dose and benefit was observed. Conclusion: Leflunomide is a safe and well-tolerated oral option for patients with RRMM, with a clinical benefit from single agent dosing. On the basis of our preclinical work showing synergistic inhibition of MM using leflunomide, pomalidomide, and dexamethasone, we plan clinical testing of this drug combination. Disclosures Rosenzweig: Celgene: Speakers Bureau. Krishnan:Janssen: Consultancy, Speakers Bureau; Sutro: Speakers Bureau; Onyx: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Consultancy, Equity Ownership, Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

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