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.

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.

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 ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3856-3856 ◽  
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.

Cryotherapy Reduces Mucositis in Multiple Myeloma Patients Receiving High-Dose Melphalan Conditioning Prior to Autologous Stem Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4265-4265 ◽  
Author(s):  
Mabel Rodriguez ◽  
Nelly G. Adel ◽  
Sean Devlin ◽  
Sergio A Giralt ◽  
Heather Landau
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Research Funding ◽  
High Dose ◽  
Cell Transplant ◽  
Grade 3 ◽  
High Dose Melphalan ◽  
Hospital Days ◽  
Severe Mucositis

Abstract Abstract 4265 Background: High-dose melphalan (MEL) followed by autologous stem cell support has been an integral component of multiple myeloma (MM) therapy since the 1980's. In general, high-dose melphalan is well-tolerated however grade 3 and 4 mucositis has been reported in up to 75% of patients (Lilleby et al. Bone Marrow Transpl, 2006). The efficacy of cryotherapy in preventing mucositis was initially documented in patients receiving infusional 5- fluorouracil (Rubenstein et al. Cancer, 2004). It is presumed that vasoconstriction reduces exposure of the oral mucosa to chemotherapy. Due to similar pharmacokinetic properties of melphalan including its short half life, cryotherapy has been used in MM patients undergoing MEL and stem cell transplant (SCT) with small series and one randomized trial supporting its use (Lilleby et al. Bone Marrow Transpl, 2006). At Memorial Sloan-Kettering Cancer Center, ice chips administered for 30 minutes before, during and after melphalan administration was adopted in March 2011 for all MM patients receiving MEL (≥ 140 mg/m2). In this study we sought to determine if the incidence of mucositis has been reduced since instituting cryotherapy into our standard practice. Methods: We retrospectively identified MM patients who received MEL 140 or 200 mg/m2 prior to SCT between January 1, 2009 and June 12, 2012 using our pharmacy database and electronic medical record. We analyzed two groups of patients by date of SCT and confirmed that patients transplanted prior to 3/2011 did not receive cryotherapy while all others did. Mucositis grade was recorded as documented by medical staff or determined by the investigators using the CTCAE version 4 criteria. Disease and treatment characteristics were collected in addition to narcotic use, total parenteral nutrition (TPN) requirement, and days of hospitalization. Fisher's exact test was used to compare the proportion of patients with mucositis, severe mucositis (defined as grade 3 or higher) and those requiring patient controlled analgesia (PCA), by cryotherapy use. Logistic regression was used to adjust for prior radiation and the number of prior lines of therapy. The number of hospital days was compared using a t-test. Results: During the study period, 214 patients underwent one or more autologous SCTs for MM; for patients who had more than one, only the initial SCT was included in this analysis. Of 214 patients, 85 (40%) received cryotherapy of whom 34% developed mucositis compared to 47% who did not receive cryotherapy (P = 0.08). Grade 3 mucositis was seen in 2% and 16% of patients who did and did not receive cryotherapy respectively (P = 0.004). No patient in either group developed grade 4 mucositis. After adjusting for radiation and lines of prior therapy the association between grade 3 mucositis and cryotherapy remained significant (OR: 0.13 (0.02, 0.47); P = 0.01). PCA use was lower in patients who received cryotherapy (19%) compared to those who did not (37%) (P = 0.01), with the median duration of use being 5 days in both groups. TPN was not required for any patient. Hospital days were similar in both groups (P = 0.88). Conclusion: Cryotherapy administration at the time of high-dose melphalan reduces the incidence of severe mucositis and PCA use. Cryotherapy is readily available and should be offered to all MM patients receiving ≥ 140 mg/m2 of melphalan. Disclosures: Landau: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding.

scholarly journals Phase II Study of the Combination of Daratumumab, Ixazomib, Pomalidomide, and Dexamethasone As Salvage Therapy in Relapsed/Refractory Multiple Myeloma: Results of a Safety Run-in Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3117-3117 ◽  
Author(s):  
Caitlin L. Costello ◽  
Michelle Padilla ◽  
Edward D. Ball ◽  
Carolyn Mulroney
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Residual Disease ◽  
Refractory Multiple Myeloma ◽  
Overall Response ◽  
Grade 3 ◽  
Observation Period

Background: Triplet combination strategies have widely been accepted as the standard of care for the management of multiple myeloma due to improved outcomes as compared to doublets. The combination of daratumumab, pomalidomide and dexamethasone (DPd) has previously demonstrated deep and durable responses, including high rates of MRD negativity, in a heavily pretreated patient population. Quadruplet regimens offer an opportunity to further improve upon these results. We report preliminary findings from an ongoing phase 2 multicenter trial of the addition of ixazomib to the combination of DPd in patients with relapsed/refractory multiple myeloma. The primary objective is to determine overall response rate and the safety and tolerability of this novel regimen. Key secondary endpoints include PFS, OS and MRD negativity rates. Methods: Eligible patients may have received ≥1 and ≤3 prior lines of therapy, have had no prior exposure to daratumumab or ixazomib, and may have not progressed on prior pomalidomide. Patients receive daratumumab 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, pomalidomide 4mg PO days 1-21/28, ixazomib 4mg PO days 1,8,15 every 28 days, and dexamethasone 40mg PO weekly. Patients continue on therapy until disease progression, intolerability or preference. Dose-limiting toxicities (DLT) were defined as grade 3-4 hematologic adverse events (AE) or any AE that required a dose modification of pomalidomide or ixazomib at the lowest dose levels on a dose de-escalation plan. An interim safety review was performed after the first 6 patients were enrolled and completed the DLT observation period, which is the first cycle (28 days) since the start of a new dose level of pomalidomide and/or ixazomib. Results: At the time of this analysis, six patients have been enrolled and treated, and completed the DLT observation period. Patients had a median age of 62 (range 52-65) and median number of 2 prior lines of therapy (range 1-2). All patients were refractory to lenalidomide and pomalidomide-naïve. Common adverse events (AEs) included neutropenia, thrombocytopenia, GI upset, and upper respiratory infection. Grade 3-4 AEs were predominantly hematologic including neutropenia and thrombocytopenia, but also included grade 3 hypertension in 1 patient, and grade 3 hypophosphatemia, grade 4 hypokalemia, and grade 3 small bowel infection in 1 patient. No IRR > grade 2 occurred with daratumumab administration. No DLTs occurred in the first six patients in the safety run-in. The overall response rate of the cohort is 100% with 3 patients achieving a stringent complete response (CR), and 3 patients achieving a very good partial response (VGPR) after a median of 7 cycles of treatment. One patient discontinued therapy due to influenza A, the other five remain on therapy. Minimal residual disease assessments are being performed by EuroFlow for patients in VGPR or better due to concern for daratumumab interference. Pharmacodynamic changes in patients' tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Conclusion: The quadruplet regimen DIPd in patients with relapsed/refractory myeloma is a well-tolerated combination and has shown early safety in an initial safety run-in analysis. Enrollment continues in an expansion cohort to assess efficacy at multiple sites with the University of California Hematologic Malignancies Consortium. Figure Disclosures Costello: Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Phase II Study of Carfilzomib (CFZ) Combined with Other Anti-Myeloma Agents in Relapsed-Refractory Multiple Myeloma (RRMM) - Updates on the UARK Compassionate Use Protocol

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2947-2947 ◽  
Author(s):  
Saad Usmani ◽  
Jackie Szymonifka ◽  
Rachael Sexton ◽  
Susan Panozzo ◽  
Bijay Nair ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Research Funding ◽  
Cox Regression ◽  
Phase Ii Study ◽  
Univariate Analysis ◽  
Cell Transplant ◽  
Compassionate Use ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 2947 Background: CFZ is an epoxomicin derivative with ability to irreversibly inhibit proteosomes. It has been shown in preclinical and early clinical studies to have activity in newly diagnosed as well as RRMM. We have previously reported on the UARK compassionate use phase II study of CFZ which allowed for the addition of other anti-MM drugs in RRMM. We are now presenting data with 7 additional patients and longer follow-up, with data cut-off on August 9 2011. Methods: All patients with relapsed or resistant refractory multiple myeloma were eligible for the trial. First cycle CFZ was given at 20mg/m2 IV day 1, 2, then 27mg/m2 IV days 8, 9, 15, 16 every 28 days; 4mg of dexamethasone (DEX) was given with each CFZ dose. In the absence of at least PR, CFZ dose was escalated to 36 mg/m2 IV and DEX increased to 20mg. Additional anti-myeloma drugs were added Cycle 2 onwards in absence of PR. 16-day continuous infusion cisplatin (3–5 mg/m2/d) and doxorubicin (1.5–3 mg/m2/d) were commonly added from Cycle 2 onwards, along with other novel agents. Cox regression modeling was employed for overall survival (OS) and progression free survival (PFS). Results: 81 patients with RRMM were enrolled. Baseline characteristics included age >=65yr in 32%, ISS stage >=II was seen in 72% of patients, cytogenetic abnormalities (CA) in 68%, and GEP-defined high risk in 53% of patients. 77 patients had prior autologous stem cell transplant. 63 patients (78%) had at least 2 transplants. All 81 patients had received regimens containing bortezomib, thalidomide, lenalidomide, melphalan or steroids. At least 1 cycle of treatment was administered to all 81 patients enrolled, 69% of patients received >1 cycle of treatment and only 19% received >5 cycles. 71 patients (88%) discontinued therapy primarily due to progression, death or toxicity. 5% patients achieved nCR/CR/sCR, additional 19% patients had stable disease. OS benefit was observed in patients receiving >= cycle 3 (HR= 0.40, p=0.006) on univariate analysis and multivariate analysis (HR=0.09, p<0.001) with adjustment for GEP-defined risk status. Most common toxicities, counting all toxicities (>=grade 3) were thrombocytopenia (84%), anemia (77%), leukopenia (73%), hypophosphatemia (58%), hypokalemia (27%) and fatigue (25%). Grade 1–2 peripheral neuropathy (PN) was present at baseline in 53%, >grade 3 PN was observed in 7% (6/81) after cycle 1, whereas >grade 3 PN was observed in 8% (1/12) >5 cycles.OS and PFS at 12 months were 41% and 5%, respectively (Figure 1). Conclusions: The data presented herein, confirm and extend the previously reported results on CFZ demonstrating anti-myeloma activity and clinical benefit, alone and in combination with other agents, in our heavily pre-treated RRMM population. Surprisingly, worsening or new PN was not observed in majority of patients. Utilizing the novel proteasome inhibitor CFZ in combination with other anti-MM agents on a compassionate basis afforded us the opportunity to make observations regarding potential clinical synergy of particular combinations. In particular, combination of CFZ-DEX with lenalidomide and vorinostat has shown promise in a subset of RRMM patients. Disclosures: Barlogie: Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.

Safety and Efficacy of Pomalidomide Plus Low-Dose Dexamethasone (POM + LoDEX) in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM) in Italy: A Subanalysis of the Stratus Trial (MM-010)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5376-5376
Author(s):  
Michele Cavo ◽  
Paolo Corradini ◽  
Francesco Di Raimondo ◽  
Mario Petrini ◽  
Anna Maria Cafro ◽  
...  
Keyword(s):  
Research Funding ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
The United States ◽  
High Dose ◽  
Open Label ◽  
Safety And Efficacy ◽  
Overall Response ◽  
Heavily Pretreated ◽  
Grade 3

Abstract Introduction: For pts with RRMM who have failed or progressed on treatment (Tx) with newer agents, such as lenalidomide (LEN) and bortezomib (BORT), there are few Tx options, and overall survival (OS) is short (Kumar et al, Leukemia, 2012). POM is a distinct immunomodulatory agent with tumoricidal and immunoregulatory effects, and POM + LoDEX is approved in the United States and European Union for the Tx of pts with RRMM who have had ≥ 2 prior Tx, including LEN and BORT. Tx with POM + LoDEX has shown statistically greater survival benefits than high-dose DEX (MM-003; San Miguel et al, Lancet Oncol, 2013) or POM alone (MM-002; Richardson et al, Blood, 2014). POM + LoDEX has also demonstrated high overall response rates in pts with RRMM in the STRATUS trial (MM-010), a single-arm, open-label phase 3b study being conducted in 19 countries across Europe with a primary endpoint of safety (Dimopoulos et al, EHA 2015). Italian pts constituted the largest national subset in MM-010; hence, this subanalysis examines the safety and efficacy of POM + LoDEX in pts from Italy. Patients and Methods: Pts with RRMM (progressive disease [PD] on or within 60 days of last prior Tx) who had experienced Tx failure with BORT and LEN and had received adequate prior alkylator therapy were eligible. Pts received POM 4 mg on days 1-21 of a 28-day cycle in combination with DEX 40 mg (20 mg for pts aged > 75 yrs) on days 1, 8, 15, and 22. Thromboprophylaxis was required for all pts, and Tx was continued until PD or unacceptable toxicity. Results: A total of 219 pts were enrolled in MM-010 in Italy. The median age of this patient population was 67.0 yrs (range, 42-84 yrs), and 54.8% of pts were male. The median time since diagnosis was 5.5 yrs, and 37.0% of pts were International Staging System stage III. Patients were heavily pretreated, with a median of 4 prior anti-myeloma regimens (range, 2-11), and most pts were refractory to LEN (95%), BORT (82.2%), or both LEN and BORT (78.1%). As of May 4, 2015, 2 pts (0.9%) were not treated, 54 pts (24.7%) were still on treatment, and 163 pts (74.4%) had discontinued. After a median follow-up of 11.3 mos, in the intention-to-treat population, the overall response rate was 37.9% (range, 31.4%-44.7%), the median duration of response was 6.8 mos (95% CI, 4.9-10.8 mos), progression-free survival (PFS) was 5.2 mos (95% CI, 4.4-6.4 mos), and OS was 12.0 mos (95% CI, 10.6-15.2 mos). The most frequent grade 3/4 treatment-emergent AEs were neutropenia (56.7%), anemia (25.8%), thrombocytopenia (23.5%), and pneumonia (12.4%). Incidence of grade 3/4 venous thromboembolism (deep vein thrombosis and pulmonary embolism) and peripheral neuropathy were infrequent (2.3% and 0%, respectively). The most common reasons for discontinuation were disease progression (49.8%), death (10.0%), and adverse events (AEs; 5.0%). AEs led to dose reductions or interruptions of POM in 23.0% and 71.0% of pts, respectively, and the median relative dose intensity for POM was 0.90. Conclusions: In line with previous studies, POM + LoDEX was active in Italian pts, a representative subset of the heavily pretreated MM-010 population. PFS and OS were consistent with those seen in previous trials. POM + LoDEX treatment was well tolerated, and discontinuations due to AEs were infrequent, consistent with the well-known toxicity profile and the appropriate drug management. This study confirms that POM + LoDEX is effective in patients with advanced RRMM, including those who have experienced failure of prior Tx with BORT and/or LEN. Disclosures Cavo: Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Petrini:Novartis: Research Funding; Celgene Corporation: Research Funding; Italfarmaco: Research Funding; Roche: Research Funding. Caravita di Toritto:Celgene Corporation: Honoraria, Research Funding. Offidani:Celgene, Janssen: Honoraria. Petrucci:Celgene Corporation: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Mundipharma: Honoraria; BMS: Honoraria. Rodeghiero:Celgene Corporation: Honoraria, Research Funding. Simcock:Celgene Corporation: Employment. Slaughter:Celgene Corporation: Employment, Equity Ownership. Herring:Celgene Corporation: Employment. Peluso:Celgene Corporation: Employment. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria.

Bendamustine Combined with Bortezomib Has Efficacy in Patients with Relapsed or Refractory Multiple Myeloma: A Phase 1/2 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1857-1857 ◽  
Author(s):  
James R. Berenson ◽  
Ori Yellin ◽  
Alberto Bessudo ◽  
Ralph V. Boccia ◽  
Stephen J. Noga ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Progressive Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
The United States ◽  
Overall Response ◽  
Previous Level ◽  
Grade 3

Abstract Abstract 1857 Background: Multiple myeloma (MM), the second most common hematologic cancer in the United States, has a 5-year survival rate of 38%. Bendamustine is a unique alkylating agent with multiple actions leading to cancer cell death in several tumor types. In patients with MM, bendamustine, alone and in combination with prednisone, has been shown to be efficacious, with durable responses. Bortezomib is a proteasome inhibitor approved as monotherapy for MM. It has been found to sensitize highly chemoresistant MM cell lines to alkylating agents such as melphalan. Subsequent clinical trials have reported anti-MM activity and acceptable safety for bortezomib plus melphalan for relapsed or refractory MM and for bortezomib, ascorbic acid, and melphalan (BAM) for patients with newly diagnosed MM. The present phase 1/2 study assessed the safety, tolerability, and efficacy of bortezomib plus bendamustine for patients with relapsed or refractory MM. Methods: All patients were ≥18 years old and had biopsy-confirmed MM, measurable by a serum monoclonal immunoglobulin spike ≥1 gm/dL and/or a urine monoclonal spike ≥200 mg/24 hours. Also, all patients received ≥1 prior MM treatment, not including bendamustine, and showed signs or symptoms of progressive disease, either relapsed (progression following stabilization or response) or refractory (progression during or within 6 months after an antimyeloma regimen). Patients were enrolled in successive groups of 3 to 5. The groups received open-label bendamustine administered as a 1-hour intravenous (IV) infusion of 50, 70, or 90 mg/m2 on days 1 and 4 of each 28-day treatment cycle. Each infusion was preceded by bortezomib administered as a 3- to 5-second IV push of 1.0 mg/m2. Bortezomib was also given on days 8 and 11. Enrollment at each dose level was permitted only if the first 3 patients at the previous level received 1 cycle without unacceptable dose-limiting toxicity (DLT). If not, an additional 3 patients would be treated at the previous level (for a maximum 6 at each level). The maximum tolerated dose was defined as the highest dose at which <33% of recipients had unacceptable DLT. Additional patients were then enrolled and were treated to maximum response plus 2 cycles, for a total of up to 8 cycles without progressive disease. Overall response rate (complete, very good partial, partial, and minimal response rates), duration of response, time to progression, and adverse events (AEs) were assessed by International Myeloma Working Group criteria. Results: Because no DLT was observed in phase 1, the bendamustine dosage selected for phase 2 was 90 mg/m2 (plus bortezomib at 1.0 mg/m2). A total of 40 patients (median age, 67.0 years; range, 43–89) were enrolled and had received a median of 6 (range, 2–20) prior therapies, including bortezomib (75%) and alkylators (70%). Following enrollment, 5 patients received a mean (SD) of 3.0 (1.7) cycles of 50 mg/m2 of bendamustine, 4 received 4.0 (2.9) cycles of 70 mg/m2, and 31 received 4.7 (2.8) cycles of 90 mg/m2. Among the 39 patients with efficacy data, the overall response rate was 48.7% (n=19); 53.3% in the subgroup of patients receiving 90 mg/m2 (n=16). Of the 19 responses, 1 was complete (in the 90 mg/m2 group), 2 were very good partial (both in the 90 mg/m2 group), 8 were partial, and 8 were minimal. Another 16 patients (41.0% of 39) had stable disease, and the remaining 4 (10.3%) individuals showed progressive disease. Among all 40 patients, 28 (70.0%) had grade 3 or 4 AEs: 3 of 5 patients (60.0%) receiving 50 mg/m2, 3 of 4 (75.0%) receiving 70 mg/m2, and 22 of 31 (71.0%) receiving 90 mg/m2. There were 3 deaths (unknown/old age, disease progression, and septic shock). Grade 3 or 4 AEs in ≥10% of patients were neutropenia (37.5%), thrombocytopenia (25.0%), anemia (12.5%), and leukopenia (10.0%). Conclusions: In pretreated patients with relapsed or refractory MM, 28-day cycles of bendamustine 90 mg/m2 on days 1 and 4 plus bortezomib 1.0 mg/m2 on days 1, 4, 8, and 11 were well tolerated and showed promising efficacy. This research was sponsored by and conducted by Cephalon, Inc., Frazer, PA. Disclosures: Berenson: Millennium: Consultancy, Honoraria, Research Funding; Cephalon, Inc.: Research Funding. Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Boccia:Millennium: Speakers Bureau. Noga:Cephalon, Inc.: Honoraria; Janssen Pharmaceuticals: Honoraria; Celgene Corporation: Honoraria; Millennium: Honoraria; Takeda: Honoraria. Gravenor:Cephalon, Inc.: Research Funding. Siegel:CVS/Caremark: Consultancy; Cephalon, Inc.: Research Funding. Kewalramani:Cephalon, Inc.: Research Funding. Swift:Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mayo:Cephalon, Inc.: Employment.

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.

scholarly journals Phase 2 Trial of LDE225 and Lenalidomide Maintenance Post Autologous Stem Cell Transplant for Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1905-1905
Author(s):  
Francis K. Buadi ◽  
Martha Q. Lacy ◽  
Angela Dispenzieri ◽  
Gabriela Perez ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Grade 3

Background: Lenalidomide maintenance therapy post-autologous stem cell transplantation (ASCT) is associated with improved progression-free survival (PFS) and possibly overall survival in multiple myeloma (MM). However, almost all patients do relapse as a result of residual multiple myeloma cells that remain after the high-dose chemotherapy. In the myeloma setting it has been found that the hedgehog (Hh) pathway is essential for maintaining a subset of tumor causing stem cells. LDE 225 (Sonidegib) is a potent selective oral bioavailable antagonist of Smoothened (SMO), a component of the Hh signaling pathway. In in vitro experiments, LDE225 treatment of myeloma cell lines resulted in a modest inhibition of cell proliferation at increasing doses. When LDE225 was combined with lenalidomide, a more than additive effect was observed in terms of cell proliferation, an effect that was more pronounced in the context of myeloma cell lines growing in co-culture with marrow derived stromal cells. These findings form the basis of evaluation of LDE 225 as a strategy to enhance the activity of lenalidomide in the post-transplant maintenance setting. The minimal residual state post SCT provides the most optimal situation for evaluation of a drug that is likely to work by inhibiting the tumor cells that escaped high dose therapy. Methods: Multiple myeloma patients without evidence of progression, who were 60 - 120 days after a single autologous stem cell transplant (SCT), performed within 1 year of diagnosis were eligible for the study. Maintenance therapy was started approximately 3 months after SCT. Treatment consisted of lenalidomide 10 mg days 1-21 and LDE225 400 mg days 1-28 in 28-day cycles for a total of 18 cycles. The goal of the study was to assess toxicity of this combination, complete response rate (CR) progression free survival (PFS) at 1 and 2 year and overall survival (OS). CR and PFS were estimated using an exact binomial distribution and Kaplan Meier curves respectively. Results: A total of 28 patients were accrued from Jan 2014 to Aug 2016, 1 patient canceled prior to treatment and 1 patient was deemed ineligible resulting in 26 evaluable pts for CR and PFS. The median age of all pts (n=26) was 60 years (range 43-69) and 50% were males. Seventy-three percent of patients reported one treatment regimen prior to SCT, while 27% reported 2 or more prior regimens. The other characteristics of the patient are summarized in Table 1. Twenty seven pts received at least one cycle of treatment and are evaluable for toxicities (AE). Patients were treated for a median of 12.5 (range 1-18) cycles. While 10 pts (38.5%) completed protocol treatment (18 cycles), the remaining 16 pts went off treatment due to AEs (6, 23%), disease progression (3, 11.5%), refusal of further treatment (3, 11.5%) and other reasons (4, 15.4%). A grade 3 or higher AE at least possibly attributed to either drug was seen in 63%. Grade 3+ hematologic toxicities were noted in 30%, with 7% neutropenia and 4% thrombocytopenia. Notable grade 2+ non-hematologic toxicities with more than 5% incidence were dysgeusia 22%, alopecia 11%, and anorexia 7%. Grade 3+ non-hematologic toxicities were fatigue, myalgia and arthralgia each at 7%. The CR rate in evaluable patients was 46% (5 CRs and 7 sCRs) with a 95% CI of 27% - 66%. CR rate improved from 31% to 46%. VGPR or better improved from 42% to 85%. The 24-month PFS (time from SCT to progression or death due to any cause) was 73% (95% CI: 57.9 - 92.3%) with a median time to censoring of 38 months. Conclusion: Lenalidomide in combination with LDE225 as posttransplant maintenance therapy was associated with some toxicity but manageable. The combination improved the depth of response after autologous stem cell transplant. Long-term follow-up is needed to determine overall survival. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Spectrum: Honoraria, Research Funding; Janssen: Honoraria. Kapoor:Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Celgene: Honoraria; Sanofi: Consultancy, Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Russell:Imanis: Equity Ownership. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. OffLabel Disclosure: Sonidegib (LDE 225) is a selective oral bioavailable antagonist of Smoothened (SMO), a component of the hedgehog signaling pathway.

scholarly journals Utilization of Autologous Stem Cell Transplantation in Older Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5701-5701
Author(s):  
Justin King ◽  
Mark A. Fiala ◽  
Scott R. Goldsmith ◽  
Keith E. Stockerl-Goldstein ◽  
Mark A. Schroeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Older Patients ◽  
Research Funding ◽  
Small Sample ◽  
Poor Performance Status ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Equity Ownership

Historically, high-dose therapy in combination with autologous stem cell transplants (ASCT) for multiple myeloma (MM) was reserved for younger patients. In more recent years, the use of ASCT has expanded in the older population. However, there is still limited data on the utilization and efficacy of ASCT in older patients, particularly those over the age of 75. To further evaluate this issue, we retrospectively analyzed all patients with newly diagnosed MM between the ages of 75-78, the institutional cutoff for ASCT eligibility, that were referred to the stem cell transplant unit at our institution for consultation from the years 2012-2018. Baseline characteristics, anti-myeloma treatments, and patient outcomes were abstracted through chart review. Seventy-five patients were referred to our institution. 71% were male, 29% female. 39% patients were considered ineligible for ASCT by the consulting transplant physician. Most patients were considered transplant ineligible due to comorbidities or poor performance status. Of the 46 patients eligible for ASCT, 52% underwent the procedure during their first-line therapy. The majority of those patients received reduced intensity melphalan (140 mg/m2) while 2 patients received conventional dosing (200 mg/m2). The other 22 patients eligible for ASCT declined or elected to defer the procedure and to be treated with conventional therapy. The characteristics of these three groups were similar and are detailed in Table 1. After a median follow-up of 30 months, 25% of the patients had expired. Estimated median overall survival (OS) was 71.3 months (unable to quantitate 95% CI) for all patients. Compared to transplant eligible patients, regardless of transplant receipt, those who were transplant ineligible had a 186% increase risk for death (HR 2.86; 95% CI 1.12-7.35; p = 0.029). There was also a notable trend for longer OS in those who underwent ASCT compared to those who were eligible but declined the procedure, but it was not statistically significant (HR 0.36; 95% CI 0.10-1.28; p = 0.114). At a transplant center, two-thirds of patients referred for newly diagnosed MM between the ages 75-78 were considered eligible for ASCT and one-third underwent the procedure. Outcomes were better for patients eligible for ASCT, regardless of whether they underwent the procedure. There was also a trend for better OS in patients who underwent the procedure compared to those who declined. While small sample sizes and the retrospective nature of the study limit our ability to draw conclusions, it appears that ASCT has an OS benefit among patients age 75-78. Disclosures Fiala: Incyte: Research Funding. Stockerl-Goldstein:AbbVie: Equity Ownership; Abbott: Equity Ownership. Vij:Genentech: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wildes:Janssen: Research Funding; Carevive: Consultancy.

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