Feasibility and Activity Of Bortezomib-Based Therapy In Patients With Relapsed/Refractory Multiple Myeloma Previously Treated With Carfilzomib

Abstract Introduction Carfilzomib (Car) is a proteasome inhibitor (PI) that was recently approved for the treatment of relapsed or refractory multiple myeloma. It is indicated for patients (pts) who previously received the proteasome inhibitor bortezomib (Bz) and an immunomodulatory drug (thalidomide or lenalidomide (len)) and had disease refractory to the last line of therapy. With the increasing number of therapeutic options, the optimal sequencing strategy of PIs to maximize clinical benefit and patient outcomes is unclear. The objective of our study was to therefore evaluate the activity of Bz after Car exposure. Methods Pts who enrolled and received Carfilzomib-based therapy on clinical trials at The University of Texas M. D. Anderson Cancer Center were screened for subsequent Bz therapy. Carfilzomib was administered as a single agent, or with len/dexamethasone (dex). We evaluated the overall response and tolerability of Bz pre- and post-Car, and to Car-based therapy. Results 16 pts were identified with a mean age of 67 (range 48-85), including 11 women and 5 men. ISS stage was I in 10 pts, stage II in 1, and stage III in 5. Median lines of therapy prior to Car were 3 (1-9), and 11 pts had prior stem cell transplant. Prior to Car-based therapy, 5 pts were Bz naïve, 7 were Bz sensitive, and 4 were Bz intolerant. Among the 16 patients treated with Car as a single agent, or Car in combination with dex (n=1), len/dex (n=12), panobinostat (n=2) and pomalidomide/dex (n=1) the overall response rate (ORR) to Car-based therapy on protocol (≥MR) was 75% (12/16). Among the 16 pts who subsequently received Bz after Car, 4 patients remained sensitive to Car (2/4 were Bz naïve), 5 were intolerant to Car, and 7 were Car refractory (3/7 were Bz naïve). Patients received Bz in combination with various other therapeutics, including cyclophosphamide/dex (n=5), melphalan/dex (n=2), modified-CVAD (n=3), len/dex (n=5), pegylated doxorubicin/dex (n=7) and bendamustine (n=3). The ORR to Bz-based therapy after Car was 81% (13/16). Among the 7 patients who were refractory to Car, 5/7 patients had ≥MR to Bz based therapy, while 2 patients were Bz intolerant due to rash and neutropenia. Among the 13 pts who responded to Bz after Car, 10 patients had received prior Bz. 3/5 pts who were Bz naïve had ≥MR. 4/4 patients who were intolerant to prior Bz had ≥MR, and 6/7 Bz sensitive patients had ≥MR. Discussion Bortezomib-based therapy is feasible after carfilzomib exposure in patients including those who were previously intolerant to bortezomib. The ORR(≥MR) in this patient population to Bz-based therapy was 81%. Disclosures: Thomas: Millenium: Research Funding; Novartis Pharmaceuticals: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Orlowski:Bristol-Myers Squibb: 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; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Shah:Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

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Phase II Study of Infusional Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.947.947 ◽

2012 ◽

Vol 120 (21) ◽

pp. 947-947 ◽

Cited By ~ 4

Author(s):

Nikoletta Lendvai ◽

Heather Landau ◽

Alexander Lesokhin ◽

Ioanna Tsakos ◽

Guenther Koehne ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Cell Transplant ◽

Phase 2 ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Higher Doses

Abstract Abstract 947 Background: Carfilzomib (CFZ) is a selective, irreversible epoxyketone inhibitor of the chymotrypsin-like activity of both the constitutive proteasome and the immunoproteasome. In patients with multiple myeloma single-agent CFZ is active and well tolerated at doses up to 27 mg/m2 when administered intravenously over 2–10 minutes. Based on preclinical safety data showing that a slower infusion was better tolerated and permitted administration of higher doses than a 2–10 minute infusion, the phase1b/2 PX-171-007 (NCT00531284) study evaluated the administration of CFZ as a 30-minute infusion. That study found the maximally tolerated dose of CFZ given as a 30 minutes infusion to be 56mg/m2. We designed a single institution, phase 2 study of high dose, infusional CFZ in patients with relapsed and/or refractory multiple myeloma. Methods: CFZ was given as a 30-minute IV infusion on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle1 Day1–2 doses were 20 mg/m2, followed by escalation to 56mg/m2. Dexamethasone 8 mg was given prior to infusion as premedication to mitigate infusion-related reactions. Patients who did not achieve a partial response (PR) after two cycles of CFZ or initially responded to single agent CFZ, but later showed evidence of progression of disease (POD) had dexamethasone (40mg/week) added to their regimen. Overall response rate (ORR; [sCR + CR + VGPR + PR]) was determined according to International Myeloma Working Group Uniform Response Criteria. Subjects were evaluated for adverse events according to the Common Terminology Criteria for Adverse Events v 4.0. Results: Thirty-four patients have been enrolled. Patients had received a median of 5 (range 1–11) prior treatment regimens and included 7 patients who relapsed following allogeneic stem cell transplant. Seventy eight percent of patients were bortezomib-refractory. ORR among patients who completed 4 cycles of therapy or experienced POD prior to completing 4 cycles of therapy was 58% with 1 CR, 7 VGPRs, and 6 PRs. ORR after 4 cycles of therapy was 57% in bortezomib-refractory patients. By intention to treat analysis the ORR in all comers was 50%. Median progression free survival was 4.6 months, median overall survival has not been reached with a median follow-up among survivors of 9.6 months (range: 0.3–14.3 months). The average time to best response was two cycles. Three out of the 11 patients that had dexamethasone 40mg/week added to their regimen obtained an improved response. Twelve patients (35%) were dose reduced. Treatment emergent, non-hematologic Grade 3/4 adverse events for which contribution of CFZ cannot be excluded were: HTN (n = 7), lung infection (n = 6), pulmonary edema (n = 3), reduced ejection fraction (n=1), sepsis (n=2), febrile neutropenia (n=1), bacteremia (n = 1), protothecosis (n = 1), fatigue (n=1), neuropathy (n=1), microangiopathic hemolytic anemia(n=1), nausea/vomiting/+/− diarrhea (n = 2), gastrointestinal bleed in the setting of Grade 4 thrombocytopenia (n = 1), hyperkalemia (n = 1). Conclusions: The 20/56 mg/m2 dose for CFZ administered as a 30-minute IV infusion was associated with 58% ORR, in a heavily pretreated patient population, including 21% of patients w/ prior allogeneic transplant, where the majority of patients were bortezomib-refractory. The ORR from this study is consistent with the one previously reported at the similar dose. Higher doses of carfilzomib continue to be explored in ongoing Phase 2 and Phase 3 studies. Disclosures: Landau: Onyx: Research Funding; Milleneum: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hassoun:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Giralt:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Milleneum: Membership on an entity's Board of Directors or advisory committees.

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Daratumumab, Pomalidomide, and Dexamethasone (DPd) for the Treatment of Relapsed/Refractory Multiple Myeloma: A Single Institution Experience

Blood ◽

10.1182/blood-2018-99-117497 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5642-5642 ◽

Cited By ~ 1

Author(s):

Al-Ola Abdallah ◽

Neil Dunavin ◽

Brian McClune ◽

Leyla Shune ◽

Ajoy L. Dias ◽

...

Keyword(s):

Multiple Myeloma ◽

Proteasome Inhibitor ◽

Research Funding ◽

Median Number ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Duration Of Treatment ◽

Effective Treatment Option ◽

Refractory Multiple Myeloma ◽

Overall Response

Abstract Background: Daratumumab triplet regimens containing dexamethasone and lenalidomide or bortezomib are an effective treatment option for patients with relapsed/refractory multiple myeloma (RRMM). Daratumumab was recently FDA-approved in combination with the second-generation immunomodulatory drug, pomalidomide, and dexamethasone based (DPd) on results of the EQUULEUS study where overall response rates (ORR) of 60% were seen. The goal of this retrospective study was to analyze clinical outcomes of the DPd triplet regimen in either a daratumumab and pomalidomide naïve or refractory population of heavily pretreated RRMM patients at our institution. Methods: Thirty-two patients with RRMM treated with DPd at the University of Kansas Health System between November 2015 and July 2018 were included in our analysis. DPd consisted of 28-day cycles of daratumumab 16 mg/kg intravenously (weekly for cycles 1 and 2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression); pomalidomide 4 mg orally (PO)on Days 1-21 and adjusted for cytopenia or toxicities; and dexamethasone 40 mg PO weekly adjusted based on tolerance. based on age. Responses were evaluated using IMWG criteria. Patient characteristics, disease course, and outcomes were summarized with descriptive statistics. Kaplan-Meier analyses were used to estimate progression-free (PFS) and overall survival (OS). Results:The median age was 64 years (range 44-83). Twenty-three patients (72%) had IgG isotype, 11 patients (34 %) had ISS stage III disease at diagnosis, 13 patients (41%) had high risk cytogenetics, and 13 patients (41%) had extramedullary disease. Median number of previous lines of therapy was 4 (1-9). Twenty-two patients (69%) received ≥3 prior therapies. Twenty-three patients (72%) were proteasome inhibitor refractory, 28 patients (88%) were immunomodulator refractory, 9 patients (28%) were daratumumab refractory, and 3 patients (15%) were double refractory to daratumumab and pomalidomide. Twenty-eight patients (88%) had received autologous stem cell transplant (ASCT) prior to DPd; 12 patients (38%) had ≥2 prior transplants. Median number of DPd cycles received was 6 (2-30) and the median duration of treatment was 5 months (2-30). At a median follow-up of 8.4 months (range: 2-29), the overall response rate (ORR) for all patients was 72% which compares favorably to the ORR of 60% in the EQUULEUS study. However, about half of the responses were partial responses (PR) (47%). The ORR rate for those who were refractory to either pomalidomide or daratumumab was 65%. The PFS was 8.3 months, while the median OS was not reached. Conclusion: DPd was recently approved for the treatment of RRMM. Our ORR compares favorably to the EQUULEUS study, however about half of responses were partial responses or better. Surprisingly, our analysis shows an impressive ORR in patients with previous exposure to proteasome inhibitor and immunomodulatory therapies in RRMM population, suggesting a benefit of DPd even in patients who received prior pomalidomide or daratumumab. Disclosures McGuirk: Astellas Pharma: Research Funding; Gamida Cell: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Pluristem Ltd: Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Fresenius Biotech: Research Funding; Bellicum Pharmaceuticals: Research Funding. Ganguly:Daiichi Sankyo: Research Funding; Janssen: Consultancy; Amgen: Consultancy; Seattle Genetics: Speakers Bureau.

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Phase 1 Study of the Novel Kinesin Spindle Protein Inhibitor ARRY-520 + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.4082.4082 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4082-4082 ◽

Cited By ~ 2

Author(s):

Jatin J. Shah ◽

Donna M. Weber ◽

Sheeba K. Thomas ◽

Raymond Alexanian ◽

Michael Wang ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Single Agent ◽

Autologous Stem Cell Transplant ◽

Hematologic Toxicity ◽

Cell Transplant ◽

Advisory Committees ◽

Kinesin Spindle Protein

Abstract Abstract 4082 Background: ARRY-520, a novel kinesin spindle protein (KSP) inhibitor, has been studied as a single agent and in combination with dexamethasone, and demonstrated promising clinical activity in patients with bortezomib- and lenalidomide-refractory multiple myeloma (MM). Carfilzomib, a novel irreversible proteasome inhibitor (PI), has also demonstrated single agent activity in relapsed and refractory MM, and recently received regulatory approval for this indication. Preclinical data support the presence of synergy with the combination of a PI and a KSP inhibitor via the latter's ability to down-regulate Mcl-1, supporting our hypothesis that the combination of carfilzomib and ARRY-520 (Car-ARRY) would be highly active in relapsed and/or refractory myeloma. We therefore aimed to combine these two agents for the first time, and here report the initial findings from the phase I dose-escalation in patients with relapsed and/or refractory MM. Methods: The primary objective was to determine the maximum tolerated dose (MTD) and the safety/tolerability of the Car-ARRY combination. Secondary objectives were to determine efficacy as measured by the overall response rate, time to progression, progression free survival and time to next therapy. Patients had to have myeloma that was relapsed and/or refractory, be ineligible for autologous stem cell transplant, bortezomib refractory/intolerant, and prior lenalidomide exposure. ARRY-520 was administered intravenously over 1 hour on days 1, 2, 15 and 16, while carfilzomib was administered intravenously over 30 minutes on days 1, 2, 8, 9, 15 and 16 on a 28 day cycle. All patients received growth factor support with filgrastim. Dose-escalation used a standard 3+3 schema proceeded based on dose-limiting toxicities (DLTs) during cycle 1, with planned escalation of the dose of ARRY-520. Dose level 1 was ARRY-520 0.75 mg/m2, and carfilzomib was dosed at 20 mg/m2 for cycle 1 on days 1 and 2 and all subsequent dose were at 27 mg/m2. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results: To date, 8 patients have been enrolled in the ongoing dose escalation phase. The median age was 66 (range 47–80), 6/8 were males, and the median number of prior therapies was 4 (range 2–10). 7/8 patients had undergone prior autologous stem cell transplant, and all patients were bortezomib refractory or intolerant. In the first cohort, 3 patients were enrolled and no dole limiting toxicity (DLT) was observed. During the second cohort, ARRY-520 was escalated to 1 mg/m2 with carfilzomib at 20/27 mg/m2, and among the first 3 patients, one patient suffered a DLT in the form of an admission for influenza pneumonia with non-neutropenic fever. Expansion of cohort 2 is currently underway. Among the 6 patients who completed the first cycle of therapy, 5 remain on study. In the first cohort, one patient remains on study with 6 cycles and achieved a near complete remission, 1 patient achieved stable disease, and 1 patient suffered disease progression after first cycle. In the second cohort, all three patients who completed the first cycle have stable disease and remain on trial. In the first 6 toxicity-evaluable patients who have completed one cycle, grade (G) 3 events included one each of pneumonia, diarrhea, and hyperglycemia. There was limited hematologic toxicity with 4/6 patients with G1/2 thrombocytopenia, 3/6 patients with G1/2 anemia, and 1/6 patient with G1/2 neutropenia. Additional G1/2 non-hematologic toxicity included 3/6 patients with diarrhea, 3/6 patients with dyspnea, 3/6 patients with transient elevations in creatinine and 3/6 patients with aspartate aminotransferase elevations. An MTD has not been established and enrollment is ongoing in cohort 2 with carfilzomib at 20/27mg/m2 and ARRY-520 at 1.0 mg/m2. Conclusions: The combination of ARRY-520 and carfilzomib is well tolerated with limited hematologic toxicity and a manageable side effect profile. Notably, in this patient population, with patients who have bortezomib refractory/intolerant myeloma, the combination has demonstrated early signals of activity. Updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: This presentation will include information about Arry-520 which is not yet approved for use in patients with multiple myeloma. Wang:Pharmacyclic: Research Funding; onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hilder:Array BioPharma: Employment. Orlowski:onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; array biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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An Open-Label Phase I Study of the Safety and Efficacy of RAD001 in Combination with Lenalidomide in the Treatment of Patients with Relapsed and Relapsed/Refractory Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.3856.3856 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3856-3856 ◽

Cited By ~ 5

Author(s):

Noopur Raje ◽

Paul Richardson ◽

Parameswaran N Hari ◽

Anuj Mahindra ◽

Sarah Kaster ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Oral Steroid ◽

High Dose ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Grade 3

Abstract Abstract 3856 Poster Board III-792 Background Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (MM) patients following ≥1 prior therapy. mTOR inhibitor RAD001 has been studied as a single agent in MM, and although well tolerated, did not have single agent activity. Given the increased toxicity noted with pulsed high dose steroids, we sought to study a non-steroid containing oral regimen for the treatment of relapsed MM predicated upon our previous studies which demonstrated synergistic anti-MM activity of mTOR inhibitors when combined with len. Here, we extended our in vitro observations to a phase I clinical trial combining RAD001 with len in patients with relapsed or refractory MM. The primary objective was to assess toxicity of this combination and to determine the maximum tolerated dose (MTD). The secondary objective was to determine the activity of this combination. Methods Patients with relapsed and refractory MM were assigned to len and RAD001 to be taken for 21 days of a 28 day cycle. Dose escalation followed a modified Fibonacci design. Patients were allowed to continue therapy until disease progression or unacceptable toxicity. Patients received concomitant anti-thrombotic (aspirin 81 or 325 mg/day) therapy. Response was assessed according to modified EBMT and Uniform Criteria, and toxicities were assessed using NCI CTCAE v3.0. Results Eighteen MM patients have been enrolled to date. One patient in cohort 1 (Len: 10mg and RAD001: 5 mg x 21 days) developed grade 3 neutropenia requiring expansion of the cohort. Cohort 2 (Len: 15mg and RAD001: 5 mg x 21 days) also required expansion because of grade 4 thrombocytopenia noted in 1 patient. Dose limiting toxicities included grade 4 neutropenia and thrombocytopenia in 2/3 patients in cohort 3 (Len: 20mg and RAD001: 5 mg x 21 days). The MTD for patients with MM was therefore declared at 15 mg of len and 5mg of RAD001 for 21 days with a 7 day rest period. Apart from the hematological toxicities expected with the combination, patients otherwise tolerated the regimen well. Most common (≥10%) grade 1 / 2 events included nausea, fatigue, dyspnea, diarrhea, constipation, neuropathy and muscle cramps, all of which were manageable with supportive care. No thromboembolic events were noted. Grade 3 / 4 adverse events ≥ 5% included thrombocytopenia (11%) and neutropenia (22%). Fifteen patients have finished at least 2 cycles of therapy: 8 of 15 patients have either stable disease (SD: 1), minimal response (MR: 5) or a partial response (PR: 2), including 7 of 9 patients treated at the recommended MTD for an overall response rate (MR or better) of 50% (90% CI: [30.76%]). One patient with SD continued therapy for a total of 10 cycles, without significant toxicities. Conclusions The combination of Len plus RAD001 is a well tolerated regimen with predictable hematological toxicities. Promising responses were noted in this heavily pretreated patient population. This combination provides an oral steroid free combination alternative strategy which warrants future evaluation in phase II studies. Disclosures: Raje: Astrazeneca : Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: RAD001 not labelled for use in myeloma. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hari:Celgene: Research Funding, Speakers Bureau. Laubach:Novartis:. Ghobrial:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Adams:Novartis: Employment. Makrides:Celgene: Employment.

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Alternative Dosing of Cyclophosphamide, Bortezomib and Corticosteroids (CyBorD) for Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.5142.5142 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5142-5142

Author(s):

Viet Q. Ho ◽

Elizabeth Finley-Oliver ◽

Kenneth H. Shain ◽

Melissa Alsina ◽

Leonel Ochoa ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Standard Dose ◽

Optimal Schedule ◽

Cancer Center ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Dose Reductions

Abstract Abstract 5142 Background: The combination of an alkylating agent and bortezomib has been shown to be synergistic both preclinically and in the clinical arena. Although the combination of cyclophosphamide, bortezomib and corticosteroids (CyBorD) has been evaluated by several investigators, many have used different doses and schedule of cyclophosphamide and an optimal schedule has not been established. Herein, we report the safety and efficacy of this combination in patients with relapsed and refractory multiple myeloma. Methods: All patients with myeloma that received this schedule of CyBorD at the Moffitt Cancer Center were included. CyBorD was comprised of cyclophosphamide 1000 mg/2 IV on Day 1, Bortezomib 1.3 mg/m2 IV on Days 1, 4, 8, and 11 and either low dose dexamethasone (equivalent of 120– 160mg/cycle) or prednisone (100 mg PO day 1–5). Demographic, laboratory and clinical data was collected and evaluated via descriptive statistics. Response and progression are defined as per the IMWG uniform response criteria. Results: A total of 20 patients were identified and included for analysis. Demographic data is shown in table 1. At baseline, 35% of patients were platelet transfusion dependent, and the median ß2m was 6.2mg/L. 8 patients (40%) received prophylactic GCSF and 9 patients (45%) received secondary GCSF after significant neutropenia was noted. Overall response rate (PR and better) was 50% (70% minimal response and better), including 1 complete response (CR) and 5 very good partial response (VGPR). Median progression free survival was 3.4 months (95% CI 0–7.5 months) and median overall survival was 11.9 months (95% CI 3.3–20.0). The incidence of grade 3/4 neutropenia and thrombocytopenia was 80% and 75%, respectively. Grade 2 and 3 peripheral neuropahty developed in 1 and 1 patient respectively. Nine patients required dose reductions of cyclophosphamide (only 2 of the 8 who received prophylactic GCSF therapy) and 3 patients required dose reductions of the bortezomib. Conclusion: In this cohort of patients with high burden of disease, intermediate dose cyclophosphamide administered once every 3 weeks in combination with standard dose and schedule of bortezomib results in a meaningful response rate (albeit short PFS) with mainly hematologic toxicities that are manageable with growth factor support. Disclosures: Off Label Use: Cyclophosphamide in combination with bortezomib for relapsed/refractory multiple myeloma. Finley-Oliver:Millenium: Speakers Bureau. Alsina:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding. Djulbegovic:Millenium: Research Funding. Baz:Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding.

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Phase 1/1b Study of the Efficacy and Safety of the Combination of Panobinostat + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.4081.4081 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4081-4081 ◽

Cited By ~ 6

Author(s):

Jatin J. Shah ◽

Sheeba K. Thomas ◽

Donna M. Weber ◽

Michael Wang ◽

Raymond Alexanian ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Single Agent ◽

Advisory Committees ◽

Overall Response ◽

Elevated Creatinine

Abstract Abstract 4081 Background: Carfilzomib, a novel irreversible proteasome inhibitor (PI), has demonstrated single agent activity in, and was recently FDA approved for relapsed and refractory myeloma. Panobinostat, a potent histone deacetylase inhibitor (HDACi), has been studied as a single agent and in combination with bortezomib, demonstrating promising response rates and a favorable safety profile in bortezomib-refractory patients. Our hypothesis proposed that the combination of carfilzomib and panobinostat (Car-Pan) would also be highly active, and we therefore aimed to combine these two agents for the first time. We report the initial findings from the phase I dose-escalation and expansion portions of our phase I/II trial of this novel combination regimen. Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of Car-Pan in patients with relapsed or refractory multiple myeloma. Secondary objectives included determination of the overall response rate, time to progression, progression free survival, and time to next therapy. Panobinostat was administered orally on days 1, 3, 5, 8, 10, 12 of every 28-day cycle, while carfilzomib was given intravenously over 30 minutes on days 1, 2, 8, 9, 15, and 16. Dose level 1 started carfilzomib at 20 mg/m2 with 15 mg of panobinostat, and escalated from there using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. An amendment was later introduced to allow carfilzomib to be given at 20 mg/m2for days 1 and 2 of cycle 1, followed by an increase to the full dose level for that cohort. Adverse events (AEs) were graded using the NCI-CTCAE v4, and responses were assessed with the modified International Uniform Response Criteria. Results: To date, 20 patients have been enrolled, 3 of whom are still in their first cycle, leaving 17 evaluable patients who are described herein, who have received a median of 4 cycles (range 1–8). The median age was 62 years (range 46–73), 11/17 (70%) were male, and the median number of prior regimens was 5 (range 2–15). Patients were very heavily pretreated, with 16/17 (94%) having undergone stem cell transplantation, 16/17 (94%) having prior bortezomib, including 8/17 (47%) who were bortezomib-refractory, and 17/17 (100%) having prior lenalidomide, including 12/17 (70%) who were lenalidomide-refractory. Cytogenetic abnormalities were common, including: 4 with del(17p), 4 with t(4;14), 2 with t(11;14), 9 with del(13), of whom 7 had additional mutations. Grade 1–4 AEs regardless of causality occurring in >20% of patients included anemia (14/17), thrombocytopenia (17/17), neutropenia (8/17), diarrhea (9/17), nausea/emesis (7/17), fatigue (10/17), elevated creatinine (8/17), and pneumonia (5/17). Grade ≥3 AEs regardless of causality included anemia (7/17), thrombocytopenia (10/17), neutropenia (6/17), diarrhea (2/17), nausea/emesis (1/17), fatigue (4/17), elevated creatinine (2/17), and pneumonia (4/17). An MTD has not been established, and dosing is ongoing in cohort 4, with Carfilzomib at 45mg/m2and 20 mg of Panobinostat. Of the 17 evaluable patients, the overall response rate was 35% (6/17) who achieved at least a partial response (PR); including 2 with very good PR (VGPR). In addition, one patient had a minor response, and 65% overall achieved stable disease or better. Conclusions: The combination of Carfilzomib + Panobinostat is well tolerated with a manageable side effect profile. Importantly, the combination achieves a promising response rate in a very heavily pre-treated, lenalidomide/bortezomib/high dose melphalan-refractory population, with an overall response (≥PR) rate of 35%. Updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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. Thomas:Celgene: Research Funding; Millenium: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Johnson & Johnson: Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees. Wang:Onyx Pharmaceuticals: Honoraria, Research Funding. Orlowski:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Belantamab in Combination with Dexamethasone in Patients with Triple-Class Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2021-149791 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1642-1642

Author(s):

Tahani Atieh ◽

Shebli Atrash ◽

Meera Mohan ◽

Leyla Shune ◽

Zahra Mahmoudjafari ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Dose Reduction ◽

Research Funding ◽

Progression Free Survival ◽

Median Number ◽

Cell Transplant ◽

Antibody Drug Conjugate ◽

Advisory Committees ◽

Refractory Multiple Myeloma

Abstract Background Relapsed and refractory multiple myeloma (RRMM) remains a major challenge. With each relapse, patients (pts) experience decreased response duration leading to shortened survival. Pts with triple-class refractory disease (refractory to one class of the following: immunomodulatory agents (IMiDs), proteasome inhibitors (PI) and anti-CD38 monoclonal antibody) have a poor prognosis. Belantamab mafodotin is a first-in class B-cell maturation antigen (BCMA) antibody-drug conjugate. The aim of this study was to analyze the clinical outcomes of belantamab/dexamethasone (Bd) in triple-class RRMM. Patients & Methods Twenty-eight pts with triple-class RRMM receiving Bd were identified at University of Kansas Health System between October 2019 and June 2021 and reviewed retrospectively. These pts received belantamab 2.5 mg/kg IV every 3 weeks and dexamethasone (20-40) mg PO weekly. Descriptive analyses were performed on available data for patient characteristics. Survival curves were generated using the Kaplan-Maier method. Responses were evaluated using the International Myeloma Working Group (IMWG) criteria. Results The median age was 67 yrs (42-85). Eleven pts (39%) had IgG isotype, 14 pts (50%) had R-ISS stage III disease, 20 pts (71%) had high-risk cytogenetics, and 13 pts (46%) had extramedullary disease (EMD). Patients characteristics are summarized in Table 1. Median number of Bd cycles received was 3 (2-18). The median number of previous lines of therapy was 5 (3-15). All pts were triple-class refractory, whereas 15 pts (54%) were penta-refractory. Twenty-one pts (75%) received autologous stem cell transplant, and 8 pts (29%) had previously received BCMA-targeted therapy. The response rate for all pts was 46% with 18% achieving very good partial response and better. Median follow-up was 7.4 months. Median progression-free survival (PFS) was 4.9 months, while median overall survival (OS) was 7.4 months. The response rates are summarized in Table 2. Keratopathy was one of the most common adverse events (AEs), occurring in 23 (82%) pts, 13 (56%) pts had grade 3 or 4 keratopathy. Nineteen patients (68%) required dose reduction or delay due to keratopathy. Other common AEs included: anemia (83%), thrombocytopenia (70%), neutropenia (30%), and elevated liver function tests (53%). Eighteen patients (64%) discontinued due to progression of disease or death. No treatment-related mortality was noted in this review. Conclusion Our analysis demonstrates a reasonable efficacy of Bd in those who are heavily treated triple-class RRMM patients in the real world. Keratopathy remains a challenging AE and the main cause of dose reduction and delay. Figure 1 Figure 1. Disclosures Atrash: AMGEN: Research Funding; Jansen: Research Funding, Speakers Bureau; GSK: Research Funding. Mahmoudjafari: GSK: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. McGuirk: Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Novartis: Research Funding; EcoR1 Capital: Consultancy; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding; Bellicum Pharmaceuticals: Research Funding; Pluristem Therapeutics: Research Funding.

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D.C.E.P. in Patients with Quad- or Penta-Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-117713 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2021-2021

Author(s):

Scott Goldsmith ◽

Mark A. Fiala ◽

Brandon B. Wang ◽

Mark A. Schroeder ◽

Tanya M. Wildes ◽

...

Keyword(s):

Multiple Myeloma ◽

Retrospective Study ◽

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Cell Transplant ◽

Advisory Committees ◽

Salvage Regimen ◽

Overall Response

Abstract Introduction: Despite the recent introduction of novel agents for multiple myeloma (MM), the disease remains incurable and invariably progresses through these new therapies. Patients with quad-refractory MM (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) and penta-refractory MM (refractory to an anti-CD38 monoclonal antibody as well) are left with few treatment options and poor prognoses. The chemotherapy regimen of dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) has demonstrated efficacy in the treatment of relapsed/refractory MM. We and others employ DCEP as a salvage regimen, however, few outcomes data exist in this heavily pretreated population. Methods: We conducted a retrospective study to identify all patients who received DCEP for quad- or penta-refractory MM at our institution between 2013 and 2018. Disease response and refractoriness were defined by IMWG criteria. The primary endpoint was overall response rate (ORR) defined as PR or better. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and duration of response (DOR). Results: We identified 31 patients who received DCEP, 8 (26%) for quad-refractory and 23 (74%) for penta-refractory MM (Table 1). Twenty-eight (90%) had at least one autologous stem cell transplant, and one had a prior allogeneic transplant. Sixteen (52%) were female, 27 (87%) were white, and median age at DCEP was 60. Median number of prior treatment regimens was 8. All patients received dexamethasone (40mg/day), cyclophosphamide (400mg/m2/day), etoposide (40mg/m2/day), and cisplatin (10mg/m2/day) on days 1-4 (Lazzarino et al. 2001). Cycles were generally 28 days in length, but doses were delayed in cases of cytopenias or other toxicities. Dose reductions occurred in cases of renal impairment or prolonged cytopenias. Twenty patients (65%) received more than one cycle (range: 1-5). The overall response rate was 35%. One patient achieved CR allowing him to proceed to a second autologous transplant. One patient achieved a VGPR, 9 (29%) a PR. Four of the 8 (50%) quad-refractory patients responded compared to 7 of the 23 (30%) of the penta-refractory patients. Eleven (35%) were primary refractory to DCEP, and two patients died after one cycle prior to response assessment. The overall median PFS was 2.7 months (95% CI 1.5-3.8) and median OS was 6.2 months (95% CI 4.4-7.8). For responders, median DOR was 4.2 months (95% CI 3.0-5.4) and median OS was 9.0 months (95% CI 7.2-10.9). Conclusion: Quad- and penta-refractory MM carry a grim prognosis. In our retrospective study, DCEP led to a notable ORR of 35% (95% CI 19%-55%) in this very heavily-treated population, and suggests that it remains a reasonable salvage therapy. Furthermore, it supports prospective study of this regimen, possibly in combination or in comparison with other agents effective in quad- or penta-refractory MM. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Bendamustine in Patients with Quad- and Penta-Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-112258 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5627-5627

Author(s):

Scott Goldsmith ◽

Mark A. Fiala ◽

Brandon B. Wang ◽

Mark A. Schroeder ◽

Tanya M. Wildes ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Advisory Committees ◽

Salvage Regimen ◽

Overall Response

Abstract Introduction: Despite significant advances in multiple myeloma (MM) therapy, disease progression through multiple novel treatments is often inevitable. Quad-refractory MM (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide), or penta-refractory MM (refractory to an anti-CD38 monoclonal antibody as well) portends a poor prognosis, with few subsequent lines of treatment currently available. We and others have used bendamustine combined with corticosteroids as a salvage regimen, but there is a paucity of outcomes data in this heavily pretreated population. Methods: We conducted a retrospective study to identify all patients who received bendamustine with corticosteroids for quad- or penta-refractory MM at our institution between 2013 and 2018. Disease response and refractoriness were defined by IMWG criteria. The primary endpoint was overall response rate (ORR) defined as PR or better. Secondary endpoints included overall survival (OS) and duration of response (DOR). Results: Twenty-seven patients were identified; 5 patients were quad-refractory, and 22 penta-refractory (Table 1). Twenty-two (81%) patients had at least one prior autologous stem cell transplant and 1 had a prior allogeneic. The median age at time of bendamustine was 61, 52% were female, and 85% were white. All patients received bendamustine at a dose of 90mg/m2 on days 1 and 2 of a 28 day cycle. Twelve patients (44%) received more than one cycle (range: 1-8). The overall response rate was 26%. While no patient achieved CR, 4 achieved VGPR and 3 a PR. Two of the 5 (40%) quad-refractory patients responded compared to 5 of the 22 (23%) penta-refractory. Sixteen (59%) were primary refractory to bendamustine and one patient went onto hospice prior to response evaluation. Overall the median PFS was 1.4 months (95% CI 1.1-1.6) and median OS was 8.7 months (95% CI 2.3-15.0). For responders (≥PR), median DOR was 6.6 months (95% CI 0.0-13.7) and median OS was 14.0 months (95% CI 0.6-27.4). Conclusion: The prognosis of quad- and penta-refractory MM remains poor. In this heavily pre-treated population, bendamustine demonstrates a 26% ORR (95% CI 11%-46%). The DOR and OS of the patients was poor but highly heterogeneous. Those who did respond to bendamustine had notably improved OS. Given the limited available options for quad- and penta-refractory MM, bendamustine remains a reasonable salvage therapy. Prospective trials are warranted perhaps including additional agents that are effective in penta-refractory patients. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Updated Results of a Phase I Study of RAD001 In Combination with Lenalidomide In Patients with Relapsed or Refractory Multiple Myeloma with Pharmacodynamic and Pharmacokinetic Analysis

Blood ◽

10.1182/blood.v116.21.3051.3051 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3051-3051 ◽

Cited By ~ 2

Author(s):

Anuj Mahindra ◽

Paul G Richardson ◽

Parameswaran Hari ◽

Aliyah R. Sohani ◽

Jacob P. Laubach ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

T Cell Subsets ◽

Oral Steroid ◽

Pharmacokinetic Analysis ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Grade 3

Abstract Abstract 3051 Background: Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (MM) patients following ≥1 prior therapy. RAD001, an mTOR inhibitor has been studied as a single agent in MM, and although well tolerated, did not have single agent activity. Informed by our previous studies demonstrating synergistic anti-MM activity of mTOR inhibitors when combined with Len, we studied this combination to evaluate its safety and activity as a non-steroid containing oral regimen in advanced MM. Methods: Patients with relapsed and refractory MM were assigned to Len and RAD001 to be taken for 21 days of a 28 day cycle (NCT00729638) in a standard 3+3 design. Patients were allowed to continue therapy until disease progression or unacceptable toxicity and were required to receive concomitant anti-thrombotic (aspirin 81 or 325 mg/day) therapy. Peripheral blood and bone marrow samples were collected before and after treatment for pharmacokinetic and pharmacodynamic studies. Results: Twenty-eight patients were registered on the trial between December 2008-December 2009. Two patients were inevaluable because of either rapidly progressive disease or failure to meet eligibility criteria on day 1. Data on 26 patients are therefore available. Pts had received a median of 4 prior lines of treatment.14 pts had received Len previously of which 11 pts had relapsed disease and 3 pts had relapsed/refractory disease. Both cohort 1 (Len: 10mg/day and RAD001: 5mg/every other day ×21 days of 28 day cycle) and 2 (Len: 15mg/day and RAD001: 5mg daily ×21 days of 28 day cycle) required expansion because of grade 3 neutropenia and grade 4 thrombocytopenia. Dose limiting toxicities included grade 4 neutropenia and thrombocytopenia in 2/3 patients in cohort 3 (Len: 20mg and RAD001: 5 mg × 21 days). The maximum tolerated dose (MTD) was therefore declared at 15 mg of len and 5mg of RAD001 for 21 days with a 7 day rest period. Most common (≥10%) Grade 1/2 events included nausea, fatigue, dyspnea, diarrhea, constipation, neuropathy and muscle cramps, all of which proved manageable with supportive care. One patient developed RAD related non-infectious pneumonitis requiring therapy discontinuation. Grade 3/4 adverse events (≥ 5%) included thrombocytopenia (11%) and neutropenia (22%). Nineteen patients completed 2 cycles and were evaluable for response. Median follow up is currently 8.7 months and median PFS is 4.3 months, with 12 patients receiving treatment at MTD. Overall response rate was 68% (13/19) (90% CI: [30-76%]) including CR(1) PR(2), MR(8) and SD(2). Four patients continue on the combination at 13, 14, 15 and 17 months respectively. Pharmacokinetic and pharmacodynamic data including immunohistochemistry for phosphorylated AKT, cytokine profiles, T cell subsets and transcription profile on MM cell pre and post treatment as well as correlation of response with pharmacodynamic studies will be presented. Conclusions: The combination of Len plus RAD001 is a well tolerated regimen with predictable hematological toxicities. Promising responses were noted in this heavily pretreated patient population with advanced MM. This combination thus provides an oral steroid free combination treatment strategy which warrants future evaluation in phase II studies. Disclosures: Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Adams:Novartis: Employment. Makrides:Celgene: Employment. Munshi:Millennium Pharmaceuticals: Honoraria, Speakers Bureau. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Raje:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Astra Zeneca: Research Funding; Acetylon: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide and RAD 001 for treatment of relapsed and refractory multiple myeloma.

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