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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5642-5642 ◽  
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.

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

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1994-1994
Author(s):  
Arti Alagappan ◽  
Rupin A Shah ◽  
Sheeba K. Thomas ◽  
Donna M. Weber ◽  
Michael Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Single Agent ◽  
Cancer Center ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Overall Response

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.

Stem Cell Transplant without Growth Factor In Multiple Myeloma: Engraftment Kinetics, Bacteremia, and Hospitalization.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3469-3469
Author(s):  
Morie Abraham Gertz ◽  
Dennis Gastineau ◽  
Martha Lacy ◽  
Angela Dispenzieri ◽  
Suzanne R. Hayman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Growth Factors ◽  
Growth Factor ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
The United States ◽  
Median Number ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant

Abstract Abstract 3469 Introduction: Stem cell transplantation is important in the management of multiple myeloma. In the United States, the standard of care is administration of growth factors to accelerate neutrophil recovery after stem cell transplant. The need for growth factors after transplant has not been investigated recently. Patients: We analyzed a cohort of 166 patients at our institution who underwent autologous transplant for multiple myeloma without receiving growth factors after transplant and compared them with 498 patients who received standard filgrastim beginning on posttransplant day 5. TABLE Results: A neutrophil count of 500/μL was achieved in a median of 12.5 days in patients receiving growth factor, compared with 13.5 days in those not receiving growth factor (P<.001) Fig 1. Platelet engraftment was identical (median, 14.5 days; P=.12) in both groups, despite a lower median number of CD34+ cells infused in patients who did not receive growth factors. Incidence of nonstaphylococcal bacteremia was identical in both groups. The median hospital stay was 3.5 days shorter in the group not receiving growth factor. Bacteremia impacted platelet but not neutrophil engraftment. Figure 2 Conclusion: It is feasible and reasonable to perform autologous stem cell transplant for multiple myeloma without administering growth factors. Estimated savings would be $4,600 for each transplanted patient. Growth factor administration is not required for a safe outcome and decreases the number and severity of some of the fluid-related complications after transplant such as acute respiratory distress syndrome, allergic reactions, alveolar hemorrhage, and rarely splenic rupture. Disclosures: Gertz: Celgene: Honoraria; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lacy:Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

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

Blood ◽  
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.

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

Blood ◽  
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.

Salvage Therapy with Vorinostat, Lenalidomide, and Dexamethasone (ZRD) in Lenalidomide/Dexamethasone Relapsed/Refractory Multiple Myeloma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3986-3986 ◽  
Author(s):  
Joshua R. Richter ◽  
Elizabeth Bilotti ◽  
Laura McBride ◽  
Linda Schmidt ◽  
Zhijie Gao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
The United States ◽  
High Dose ◽  
Cell Transplant ◽  
Significant Activity ◽  
Phase I Clinical Trials ◽  
Refractory Multiple Myeloma ◽  
Overall Response ◽  
Grade 3

Abstract Abstract 3986 Background: Multiple Myeloma (MM) is an incurable plasma cell neoplasm. Although current lenalidomide (R) and bortezomib containing up-front regimens can now achieve overall response rates approaching 100%, patients eventually relapse with progressively refractory disease. Histone deacetylase inhibitors (HDACi), in Phase I clinical trials in patients with multiple myeloma, have shown promising activity when combined with other agents such as bortezomib. Vorinostat, (suberoylanilide hydroxamic acid; SAHA) is an oral HDACi, currently FDA approved in the United States for the treatment of cutaneous T-cell lymphoma. Here we report the findings of the combination of vorinostat (Zolinza®), lenalidomide and dexamethasone (ZRD) in multiple myeloma patients who were refractory to RD. Methods: Patients received oral vorinostat 300 mg or 400 mg once daily (days 1–7 and days 15–21), lenalidomide 10–25 mg (days 1–21) and dexamethasone 20–40 mg weekly (days 1, 8, 15, 22) in a 28-day cycle Subjects: Twenty-nine patients were treated and all were refractory to RD; 76% were refractory to at least one bortezomib containing regimen and 48% were refractory to the combination of VRD. Twenty-six patients (90%) had undergone prior high dose therapy with autologous stem cell transplant. The median number of prior therapies was 4 (range 2–13). Results: The overall response rate (ORR) was 24 % with 1 VGPR and 6 PR. The clinical benefit rate (ORR + MR) was 51% including 8 MR. Nine patients (31%) had stable disease. The median duration of response (DOR) was 4 months (range, 0–36). The median overall survival (OS) was 11 months (range, 4–36). Common toxicities including diarrhea and fatigue (all grades) were 41% and 34% respectively. The incidence of grade 3/4 neutropenia was 45 % and grade 3/4 thrombocytopenia was 34%. Conclusion: The combination of ZRD showed significant activity in patients with RD relapsed/refractory multiple myeloma. ZRD was well tolerated and is a viable option for patients who do not respond to lenalidomide-based therapy. Further, since all 3 agents are available in oral formulations, ZRD provides an additional option for those patients wishing to avoid intravenous therapy. Formal phase II studies of this combination are in preparation. Disclosures: Off Label Use: Vorinostat is an oral HDAC inhibitor and is being evaluated in the treatment of Multiple Myeloma. Bilotti:Celgene: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau. McNeill:Celgene: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau. Graef:Merck: Employment. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Siegel:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Consultancy.

Weekly Cyclophosphamide and Alternate Day Prednisone: An Effective, Convenient and Well Tolerated Treatment for Relapsed Multiple Myeloma Following Autologous Stem Cell Transplant.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4917-4917
Author(s):  
A. Keith Stewart ◽  
Young Trieu ◽  
Suzanne Trudel ◽  
Greg Pond ◽  
Joseph Mikhael ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Median Time ◽  
Stem Cell Transplant ◽  
Alkylating Agents ◽  
Progression Free Survival ◽  
Median Number ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Protein Reduction

Abstract Alkylating agents remain among the most potent therapies available for treatment of Multiple Myeloma (MM). Their use prior to, or following, autologous stem cell transplant (ASCT) is, however, compromised by concerns about stem cell quality and by myelosuppression limiting effective dose delivered. To address this concern we have studied a combination of cyclophosphamide 500 mg p.o. once weekly and prednisone 100 mg p.o. on alternate days in 66 patients requiring salvage therapy post-ASCT. Dose reductions were allowed for toxicity beginning at cycle 2. On an intent to treat basis, 66 patients received this regimen, however, 7 of these patients were not fully evaluable for response due to non-secretory disease. Of the 59 patients evaluable for response, the median time from transplant to treatment was 26.4 months (range, 6.0 to 66.6). The median time from post-transplant relapse to start of cyclophosphamide and prednisone (C/P) therapy was 1.4 months. The median number of therapies from time of diagnosis to C/P initiation was 2 (range, 1.0 to 5.0). At the date of analysis, treatment with C/P is ongoing in 12 (20.3%) patients, with a median duration of 3.6 months (range, 1.9 to 11.6). The 47 patients who have completed C/P therapy were treated for a median time of 5.5 months (range, 0.5 to 21.7). The reason for discontinuation among these 47 patients included disease progression (42.6% of patients discontinued), plateau disease (21.3%), receiving a second transplant (17.0%), toxicity (10.6%), or switched to another regimen (8.5%). A partial response (&gt;50% protein reduction) was obtained in 37.3% of patients, 18.6% attained minimal response (25–50% protein reduction), 33.8% patients stable disease, while 10.2% patients had progressed on treatment. The estimated median (95% CI) months of progression-free survival after start of C/P treatment is 14.9 (8.7, 21.7). Twenty-three (38.9%) of patients have relapsed after C/P treatment, a median (range) of 8.7 (0.5–65.7) months after start of C/P treatment. At 6 months 74.3% (95% C.I. 61.9% – 89.1%) of patients were progression-free with 28% (95% CI: 16.1–49.2%) progression free at two years. At time of analysis, 44 (74.6%) patients are still alive, with a median follow up of 10.6 months (range, 1.2 to 65.7) since the start of C/P therapy. Fifteen patients have died at a median 13.0 months (range, 1.4 to 61.7) since the time of C/P initiation. The median overall survival (95% C.I.) is estimated to be 35.9 months (24.2, NA). These results demonstrate that the combination of oral cyclophosphamide and prednisone is an effective (56% MR or PR), very well tolerated (10% discontinued due to toxicity) and convenient treatment as salvage MM therapy post-ASCT. The relative lack of myelosuppression allows for re-collection of stem cells and salvage transplant while retaining other active second line agents for later relapse. This regimen thus compares favorably with recent salvage therapeutics introduced in MM and is now being studied in combination with these newer active agents and in induction therapy.

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

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4082-4082 ◽  
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.

scholarly journals A Multi-Center Phase 1b, Open-Label, Dose-Finding Pilot Study to Evaluate the Combination of Carfilzomib and Cyclophosphamide with Dexamethasone (CCyD) Prior to Autologous Stem Cell Transplant (ASCT) in Patients with Transplant Eligible Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4739-4739 ◽  
Author(s):  
William I. Bensinger ◽  
Robert Vescio ◽  
Cristina Gasparetto ◽  
Elber S. Camacho ◽  
Rajneesh Nath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Autologous Stem Cell Transplant ◽  
Dose Finding ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Open Label ◽  
Advisory Committees

Abstract Background: Carfilzomib is an epoxy ketone, second generation proteasome inhibitor approved for the treatment of relapsed and refractory multiple myeloma. It has shown very high activity when combined with lenalidomide and dexamethasone for the treatment of newly diagnosed patients with multiple myeloma. This is the first reported trial of carfilzomib, cyclophosphamide, and dexamethasone (CCyD) in newly-diagnosed, transplant eligible patients. Methods: This study was a multi-center Phase Ib, open-label, dose-finding study in newly diagnosed transplant eligible multiple myeloma patients (pts) studying the combination of CCyD as induction therapy prior to autologous stem cell transplant (ASCT). Pts could receive a minimum of 4 cycles and up to 6 cycles prior to ASCT. Pts were enrolled into a dose-escalation treatment cohort. A standard 3+3 dose escalation schedule was used with cohorts of carfilzomib 36 (initial), 45 and 56 mg/m2 (administered over 30 minutes on days 1, 2, 8, 9, 15 and 16) combined with 300 mg/m2 of oral cyclophosphamide weekly on days 1, 8, 15 and 40 mg of oral dexamethasone once weekly. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the IMWG criteria. Prior therapy was limited to up to 160 mg of dexamethasone or limited field radiation. Results: 28 patients were enrolled from 5 centers. Of 28 patients enrolled, 3 did not complete 4 cycles of therapy (1 proceeded to ASCT after Cycle 3) and are not evaluable for response (pts came off secondary to AE of pulmonary HTN unrelated, secondary to SAE of CHF possibly related, due to PI discretion related to maximum benefit achieved), 8 patients did not undergo ASCT (1 had PD after Cycle 5), 8 patients proceeded to ASCT (1 the aforementioned patient after Cycle 3), 6 patients have completed induction and are still pre-transplant and 4 patients are still on treatment. The median age was 64 years (range 44–74), 57% were male. Cytogenetic abnormalities included 13 patients with del(13), 4 with del(17p), 2 with t(14;16) and 1 with hypodiploidy for a total of 16 patients with high-risk cytogenetics. In the dose-escalation portion of the study, the maximum administered dose tested was 56 mg/m2 carfilzomib. There was one DLT in cycle 1, of Grade 3 dyspnea, at the 56 mg/m2 level. Drug-related AEs occurring in >20% of patients included fatigue (23%) and thrombocytopenia (31%). Thirty-one percent experienced at least one Grade ≥3 AE with dyspnea and nausea as the most common. There were no deaths on study with a median follow-up of 4.9m (range: 1.1 to 13.1m). One pt came off study after Cycle 5 for PD as evidenced by new plasmacytomas. Six patients received 36-45 mg/m2 carfilzomib on the dose escalation portion of this study and 22 patients received the maximum administered dose of carfilzomib at 56 mg/m2. One patient yet to be enrolled to obtain 20 efficacy evaluable pts at the maximum dose. Twenty-three patients were response evaluable. Median of 5.7 cycles of therapy with 2 CR, 9 VGPR, 10 PR, 1 MR and 1 PD for ≥ PR rate of 91%. Of the 12 response-evaluable patients with high risk cytogenetics, 92% were ≥ PR; of the 11 standard risk patients, 91% were ≥ PR. Of 9 patients who underwent stem cell mobilization, all collected adequate stem cells and median number of stem cells collected was 12.58 (5.07-25.31) x106 CD34+ cells/kg. Conclusions: The combination of CCyD given to untreated, symptomatic patients with myeloma was well tolerated and highly active with an 87% RR and a 48% ≥ VGPR after 4 to 6 cycles. This study compares favorably with other regimens used for induction prior to transplant for the management of newly diagnosed multiple myeloma. Disclosures Bensinger: Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Carfilzomib for use in front-line tx of multiple myeloma . Vescio:Onyx Pharmaceuticals: Honoraria, Speakers Bureau. Gasparetto:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nath:Celgene: Consultancy. Shah:Novartis: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Array: Consultancy, Research Funding. Durie:Onyx Pharmaceuticals: IRC Other; Millennium Pharmaceuticals: IRC, IRC Other.

scholarly journals VD Versus VTD Induction: Similar Efficacy in Controlling Disease in Transplant Eligible Multiple Myeloma Patients Outside Clinical Trials

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5711-5711
Author(s):  
Federica Cocito ◽  
Silvia Mangiacavalli ◽  
Virginia Valeria Ferretti ◽  
Claudio Salvatore Cartia ◽  
Maya Ganzetti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Control ◽  
Real Life ◽  
Standard Of Care ◽  
Similar Efficacy ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Overall Response ◽  
Free Rate

Abstract Autologous stem cell transplant (ASCT) remains the standard of care for Multiple Myeloma (MM) patients younger than 70 years old. The role of induction therapy is crucial within a program of high-dose therapy since deeper is the response before, higher is the outcome of transplant. In this study, we analyzed a real life setting of patients treated with three different induction approaches: VAD (Vincristine-Adriamycin-Dexamethasone), VD (Bortezomib - Dexamethasone), and VTD (Bortezomib-Thalidomide-Dexamethasone) in terms of depth of response, 2 years therapy-free rate and toxicity. One hundred and sixty-three MM patients (pts) were included in the analysis: 62 pts treated with VAD (38%), 44 with VD (27%) and 57 with VTD (35%). In VTD group 49 pts (86%) received Bortezomib subcutaneously. As shown in Table 1, patients of the three groups were similar for D&S stage (p 0.59), a higher rate of ISS stage 3 was observed in VAD group (p=0.019), patients in VTD group were significantly older (p=0.024), median follow-up was significantly lower in VTD pts (p<0.001). The overall response rates after induction were similar in all three groups (p=0.156), with higher rate of responses of good quality (CR+VGPR) for patients treated with Bortezomib-based combinations: VAD 24.2%, VD 52.3%, VTD 63.2% (p<0.001). No difference was observed between VTD and VD (p=0.258). A different pattern of responses was observed after transplant, VTD, in fact, was superior to VAD (p<0.001) and VD (p=0.012), while no difference was highlighted between VAD and VD (p=0.352). As a matter of fact, 2 years therapy-free rate were: 48% for patients treated with VAD vs 73% with VD vs 74% with VTD (p=0.189). Of note, however, bortezomib base therapy maintained its superiority with respect to VAD (p=0.03). No differences were observed between VD and VTD regimens in terms of toxicity of any grade and type (52.3% VD vs 52.6% VTD, p> 0.9), and of discontinuation rate (14% in VTD and 18% in VD, p=0.395). The incidence of all grades peripheral neuropathy (PN) was similar between VD and VTD (28.2% and 31.4% p=0.835), but grade 3-4 PN was significantly higher in VD group (no patients in VTD vs 18% in VD pts, p=0.078), probably due to different way of Bortezomib administration in VTD group (86% of pts received subcutaneous Bortezomib). In this study, we confirm that Bortezomib-based regimens are better than VAD in terms of overall response rate, good quality responses and long-term disease control. VTD is superior to VD in terms of good quality responses after transplant but disease control at 2 years is similar. Disclosures Corso: Janssen-Cilag: Honoraria.

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