Impact Of FISH Abnormalities On Response To Lenalidomide In Patients With Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3210-3210 ◽  
Author(s):  
Shivlal Pandey ◽  
S. Vincent Rajkumar ◽  
Prashant Kapoor ◽  
Rhett P Ketterling ◽  
Martha Q Lacy ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Response Rate ◽  
Molecular Subtype ◽  
Wide Spectrum ◽  
Current Data ◽  
Genetic Abnormality ◽  
Best Response ◽  
Lower Response Rate

Abstract Background Multiple myeloma (MM) is a heterogeneous disease with variable responses to different therapeutic regimens and wide spectrum of survival. Much of the heterogeneity in the outcomes appear to be related to the underlying primary genetic abnormality, which in the majority of patients consist of either translocations involving the heavy chain region on chromosome 14 (IgH translocation) or trisomies of odd numbered chromosomes. We hypothesized that the response to lenalidomide (Len) therapy would vary significantly based on the underlying molecular subtype of myeloma. Methods We examined a cohort of 518 patients with available FISH results, who had been exposed to Len-based regimens. Medical records were reviewed and data regarding the best response and time to next therapy following treatment with Len-based regimen was obtained. Data from the first use of Len was collected. Len was given in combination with dexamethasone (Dex) with or without alkylators in combination. Patients who received a combination of IMiD and bortezomib as their first exposure to Len were excluded. Patients were grouped according to whether FISH showed a trisomy or an IgH translocation. Results The median age was 62 (28-91), and the median estimated follow up from diagnosis was 52 months (95% CI; 50, 54) with 359 (69%) alive at the time of analysis. An IgH translocation was seen in 129 (30%) of patients and a trisomy in 268 (62%) of patients. IgH translocations included t(11;14) in 92 (18%), t(4;14) in 45 (9%), t(14;16) in 21 (4%); 34 (8%) had both translocations and trisomies. For the current analysis, we included only patients with either a translocation or trisomy (n=397) excluding those with neither or both of the abnormalities. The median time to start of Len from diagnosis was 0 months (range, 0-64). A PR or better was seen in 80% of patients with trisomy compared with 63% of the patients with translocation (p<0.001); and the response rate was similar among the different translocation types. The median TTNT was 28 months among trisomy pts compared with 17 months for translocated patients (p<0.001, figure). The median TTNT was similar across the different types of translocations (Figure). Among this group, 134 patients proceeded to an autologous SCT after Len induction. Among these patients, no difference was seen in terms of TTNT (29 months for patients with translocation vs. 28 months for those with trisomy (p=0.8). Finally, the TTNT was no different if Len was used with Dex or as part of an alkylator combination. Conclusion The current data supports the hypothesis that the underlying primary genetic abnormality can affect the response to a particular therapy. In this study response to Len was significantly higher in myeloma with trisomy compared with IgH translocated myeloma. Although the routine use of combinations of a proteasome inhibitor plus Len in frontline therapy in all patients with myeloma may overcome the lower response rate in IgH translocated patients, in most countries such a regimen is not approved or economically feasible. Based on our study, newly diagnosed patients with evidence of trisomy on FISH could be considered for a Len-based regimen such as lenalidomide-low dose dexamethasone. Additional studies should examine if use of bortezomib in patients with IgH translocation will lead to better outcomes compared with Len based therapies. Disclosures: Lacy: Celgene Corporation: Research Funding. Gertz:Celgene: Honoraria. Dispenzieri:Celgene, Millenium, Jansenn, Pfizer: Research Funding. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Novartis: Research Funding; Genzyme: Research Funding.

scholarly journals A Single-Center Retrospective Cohort Analysis of Venetoclax in Relapsed/Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5576-5576 ◽  
Author(s):  
Swetha Kambhampati ◽  
Derek Galligan ◽  
Guy Ledergor ◽  
Thomas G. Martin ◽  
Jeffrey Wolf ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Off Label Use ◽  
Final Dose ◽  
Advisory Committees ◽  
Off Label ◽  
Best Response

Background Despite recent advances, treatment of relapsed refractory multiple myeloma (RRMM) remains a challenge. Venetoclax, a BH3 mimetic, is an oral, specific, and potent small molecule inhibitor of BCL-2 that has been approved for treatment of 17p-deleted CLL and in combination with azacitidine or decitabine in AML patients >/= 75 years of age.Pre-clinical and clinical studies suggest that bcl-2 inhibition can induce MM cell death and may synergize with bortezomib and dexamethasone. Based on this, several prospective clinical trials of venetoclax in RRMM have been performed. However, clinical use of this targeted therapeutic for salvage therapy in RRMM has not been well described. Methods We performed a single-center, retrospective chart review of all patients with RRMM diagnosed after January 1, 2009 who were treated with off-label use of venetoclax. The goal of this study was to describe the clinical characteristics of these patients, assess the response to salvage treatment with venetoclax as determined by the International Myeloma Working Group (IMWG) criteria, and assess the toxicities during salvage treatment with venetoclax in an academic practice setting. Results 43 patients were identified. Median number of lines of prior therapy was 7 (range 2-13). 12 patients had documented high risk cytogenetics, defined as the presence of a 17p deletion, t(14;16), t(14;20), t(4,14), gain (1q), or nonhyperdiploidy. Of the 36 patients with cytogenetics/FISH available, 8 had t(11;14). 34 patients were refractory to bortezomib. 40 patients had progressed after carfilzomib, 36 after pomalidomide, and 41 after anti-CD38 antibody therapy. 39 patients were treated with venetoclax in combination with a proteasome inhibitor (bortezomib (n=36); carfilzomib (n=3)). 23 patients were treated with venetoclax, proteasome inhibitor, and dexamethasone. Patients were started at 400 mg daily for 7 days then increased to the median dose of 800mg daily (11 received < 800mg/daily as a final dose and one received >800 mg/daily as final dose). Overall patients were on treatment for a median of 67 days (range 2-855). 2 patients received intermittent venetoclax therapy, defined as being off venetoclax for at least 3 months before restarting. Best response by IMWG criteria include; CR 5%( 2/43), VGPR 12% (5/43) and PR 16% (7/43) for an overall response rate of 33% (14/43). In addition, MR was seen in 5% (2/43) and stable disease in 9% (4/43). Fifty-one percent (22/43) had progressive disease (PD). Out of the 8 patients who had t(11;14), best responses were: 2 VGPR, 2 PR, 1 SD, and 3 PD for a response rate of 50% (4/8) in this subgroup. Median time to best response for all responding patients was 90 days (range 15-305) and median duration of response was 206 days (range 28-820). At time of data collection, median follow-up time from venetoclax treatment initiation was 192 days (range 8-1058). Four patients have not progressed and remain on therapy, 23 patients remain alive, and 4 patients have been lost to follow-up for over 6 months. The most common treatment related AEs were cytopenias including leukopenia in 26 /43 (60%) patients, neutropenia in 19/43 (44%) patients, and thrombocytopenia in 22/43 (51%) patients. Non-hematologic toxicities included diarrhea in 12/43 (30%) patients, nausea/vomiting in 15/43 (35%) patients, infections in 11/43 (26%) patients, and fatigue in 23/43 (53%) patients. 8/43 (19%) patients required dose reduction, 7/43 (16%) patients required temporary discontinuation of treatment, and 4/43 (9%) patients required permanent discontinuation due to treatment related AEs. 38/43 (88%) patients had any grade treatment related AEs, 27/43 (63%) patients had grade >/= 3 AEs and 2/43 (5%) patients had treatment related SAEs. One patient had a treatment related death from an infectious complication (CMV pneumonitis). Conclusions Venetoclax is an active and well-tolerated agent in relapsed multiple myeloma. Furthermore, it is easily administered in the outpatient setting. Additional areas of research with this therapy include understanding the importance of t(11:14) for response and selecting the best anti-MM partner for combination therapy. Disclosures Ledergor: Venetoclax: Other: off-label use; Immunai: Consultancy. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Wolf:Takeda: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Wong:Celgene Corporation: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Fortis: Research Funding; Juno: Research Funding. Shah:Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment; Indapta Therapeutics: Equity Ownership; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This study is looking at the safety and efficacy of venetoclax in relapsed refractory myeloma patients who are treated off-label since venetoclax is not currently approved for multiple myeloma

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1874-1874 ◽  
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Peter Anglin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Oral Cyclophosphamide ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 1874 Poster Board I-899 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen in relapsed/refractory multiple myeloma (MM) patients (pts), with an overall response rate of 60.6% and median time to progression (TTP) of 13.4 months (Dimopoulos MA, et al, Leukemia 2009 Jul 23 [Epub ahead of print]). Oral cyclophosphamide and prednisone is an older regimen with excellent patient tolerance, and we sought to enhance the efficacy of lenalidomide by adding oral cyclophosphamide and prednisone in this phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15; lenalidomide on days 1–21; and prednisone 100 mg every other day in a 28 day cycle. ASA 81 mg/day was given to all pts as DVT prophylaxis. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2009, 31 pts with relapsed/refractory MM who had not previously received lenalidomide were entered onto study. Median age was 61 (40–78) years and 61% were male. Immunoglobulin subtype was IgG in 19 pts (61%), IgA in 8 pts (26%) and light chain only in 4 pts (13%). Median number of prior regimens was 2 (1–5) and 28 pts had undergone previous ASCT, including double transplants in 6 pts. Prior therapy included thalidomide in 9 (29%) and bortezomib in 15 (48%). FISH cytogenetics were available in 13 pts; one had 13q deletion but none had t(4;14) or p53 deletion. At the time of protocol entry, median β 2-microglobulin level was 246 (92–767) nm/L, albumin 39 (34–48) g/L, creatinine 83 (50–126) μmol/L, platelet count 230 (75–337) × 109/L and ANC 2.5 (1.1–6.1) x 109/L. Protocol treatment is summarized in Table 1. Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities included thrombocytopenia in 5 pts (16%) and neutropenia in 9 pts (29%). These were managed with dose reduction and/or growth factor support. Four episodes of febrile neutropenia occurred. Other grade 3–4 non-hematologic toxicities included abdominal pain/bacteremia in 1 pt in cohort 1; hypokalemia in 1 pt in cohort 2; and DVT in 2 pts, dizziness in 2 pts and fatigue in 1 pt in cohort 3. Using the International uniform response criteria (Durie BG, et al, Leukemia 2006; 20:1467–1473), the best response was documented at a median of 6 (1–5) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (5 CR, 9 VGPR, 9 PR, 1 MR and 1 stable disease). At a median follow-up (F/U) of 12 (8–21) months, 20 pts remain on study, 2 have withdrawn and 9 pts have progressed at a median of 9 (4–13) months; only 1 one has died (due to MM). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with minimal toxicity; 2) the overall response rate (CR + VGPR + PR) in 31 pts to date is 93%; 3) at a median F/U of 1 year, only 9 pts (29%) have progressed; 4) longer follow-up is required to assess the TTP and survival of the CPR regimen. Disclosures: Reece: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Lenalidomide in combination with drugs other than dexamethasone. Anglin:Celgene: Honoraria. Chen:Celgene: Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Mikhael:Celgene: Honoraria. Trudel:Celgene: Honoraria.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3055-3055
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Sharon Fung ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Level ◽  
Research Funding ◽  
Response Rate ◽  
Objective Response ◽  
Median Number ◽  
Prior Therapy ◽  
Best Response ◽  
Level 3 ◽  
Grade 3

Abstract Abstract 3055 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen for relapsed/refractory (rel/ref) multiple myeloma (MM) patients (pts) with an overall response rate of 60% and median time to progression of 13.4 months (Dimopoulos ME, et al. Leukemia 2009; 23: 2147-52). We combined lenalidomide with the alkylating agent combination of cyclophosphamide and prednisone—an older regimen with minimal cumulative myelosuppression and good activity as second or third line therapy (Trieu Y, et al, Mayo Clin Proc 2005; 80: 1582). The CPR regimen consisted of cyclophosphamide (CY) on days 1, 8, and 15, lenalidomide on days 1–21 and prednisone 100 mg q 2 days in a 28-day cycle. ASA 81 mg/day was given as DVT prophylaxis. Three dose levels were evaluated using a 3 × 3 dose escalation design. Thirty-two pts were entered between 11/2007-06/2009; median age was 64 (42-80) yrs, 60% were male, and immunoglobulin isotype was IgG in 19 (62%), IgA in 8 (25%) and light chain in 4 (13%) pts. Median β2-microglobulin level was 257 (92-767) nm/L, albumin 39 (34-48) g/L, creatinine 83 (50-126) μmol/L, platelet count 355 (75-479) × 109/L and ANC 2.5 (1.1-6.1) × 109/L. The median number of prior regimens was 2 (1-5). Prior therapy included: ASCT (single in 91%; double in 19%), thalidomide (28%) and bortezomib (50%). FISH cytogenetics were available in 13 pts; 1 had del 13q but none had t(4;14) or del p53. Table 1 summarizes protocol treatment delivered. Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 12 (12–34+) 2 3 150 25 100 10 (9–23) 3 26 300 25 100 17 (5–28+) 1–3 (All) 32 150–300 15–25 100 19 (5–34+) Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities during the trial included: thrombocytopenia in 7 (22%) and neutropenia in 9 (29%), managed with dose reduction and/or growth factors; five episodes of febrile neutropenia occurred, all at dose level 3. In cohort 3, other grade 3–4 non-hematologic toxicities included 1 episode each of abdominal pain/bacteremia, hypokalemia, fatigue, sick sinus syndrome, cardiac amyloidosis, perforated diverticulum and 2 episodes of DVT. Two heavily pretreated pts developed 2° MDS, including 1 previously treated for lymphoma, 43 and 190 mos after the diagnosis of MM. The best response using modified EBMT criteria was documented at a median of 7 (1-26) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (4 CR, 14 VGPR, 11 PR, 1 MR and 1 stable disease). At a median F/U of 16 (5-34) months, 13 pts remain on study and 18 have progressed at a median of 10 (2-23) mos; 1 was lost to F/U and 9 have died of progressive MM. The 1-year actuarial OS and PFS rates are 93% (95% CI 76–98%) and 78% (95% CI 60–89%), respectively. We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with an acceptable safety profile; 2) the objective response rate (CR + PR + MR) in all 32 pts to date is 94%; 3) the 1-year OS of 93% and PFS of 78% compare favorably with other 3-drug combinations in rel/ref MM pts; 4) further evaluation of this regimen in newly diagnosed pts would be of interest. Disclosures: Reece: Celgene: Honoraria, Research Funding. Off Label Use: Combination of lenalidomide and cyclophosphamide and prednisone in relapsed and refractory myeloma patients. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

Therapy of Acquired Aplastic Anemia (AA) with Rabbit Antithymocyte Globulin (rATG): A Retrospective Analysis by the Working Group on Non-Malignant Disorders of Hematopoiesis of the German Society of Hematology and Oncology (DGHO),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3434-3434
Author(s):  
Britta Höchsmann ◽  
Christiane Neher ◽  
Ulrich Germing ◽  
Janne Vehreschild ◽  
Juliane Eggermann ◽  
...  
Keyword(s):  
Data Collection ◽  
Aplastic Anemia ◽  
Research Funding ◽  
Response Rate ◽  
Retrospective Data ◽  
First Line ◽  
Off Label ◽  
Best Response ◽  
Retrospective Data Collection

Abstract Abstract 3434 Introduction: Several clinical trials established treatment with horse ATG (hATG) and cyclosporine A (CsA) as standard treatment of AA in patients (pts) who are not candidates for stem cell transplantation (SCT). In 2007 the hATG brand Lymphoglobulin® was withdrawn from the market. As the hATG brand ATGAM®, is not approved in Europe, hATG was replaced by rabbit ATG (rATG). Recently a large prospective randomized one-center study from NIH, USA comparing hATG ATGAM®/CsA and rATG Thymoglobulin®/CsA in untreated AA showed significantly lower response rates and survival with rATG. To obtain further information on rATG treatment in an unselected AA population, especially with a higher median of age and use of different rATG dosages we performed a retrospective data collection of first line rATG therapy on several centers. This shall reflect outcome after rATG in a real-world situation. Methods: Retrospective data collection and analysis of first line rATG treatment of AA after approval by Ethical Committee. Results: Up to now retrospective data of 64 pts from 18 centres in Germany were analysed. Characteristics of the pts: 30 male, 34 female; median age at time of therapy 54 years (6–80 years); 87.5% of pts had idiopathic AA. 51.6% of pts had severe AA, 32.8% very severe AA and 15.6% non-severe AA. Median granulocyte count was 0.3 G/l. 86% of the pts required red blood cell and 92% platelet transfusions. 56 of the evaluable pts received Thymoglobulin® and 5 pts Fresenius ATG S®. 52 of the 56 Thymoglobulin®-treated pts got this therapy in the years 2007–2011, i.e. not as deliberate primary choice of rATG but because hATG was no longer available. Median daily dose of Thymoglobulin® was 3.5 mg/kg (range from 2.5 – 3.75 mg/kg) for 5 days. 62 of 64 pts received additional immunosuppressive therapy with CsA and 19 of 64 pts received G-CSF. The median follow-up for surviving pts was 558.5 days (range, 78–3800 days). Response rates at time of best response of pts were CR in 10/58 pts (17%), PR in 18/58 pts (31%) and NR in 30/58 pts (52%) (only surviving patients with a minimum follow-up of 120 days were analyzed). Median interval to best response was 217 days. Response rate (PR+CR) was 16/33 (48.5%) in pts who received a Thymoglobulin® dose of > 3.5 –3.75 mg/kg/day versus only 4/14 (28.6%) group of 14 pts with a dose of > 2.5 to < 3.5 mg/kg/day (p=0.17; Fisher`s exact test). Relapses occurred in 3/28 responders and clonal evolution was observed in 3 pts (2 PNH, 1 MDS). Eighteen of 63 evaluable pts received allogenic SCT after ATG-therapy and were censored at the date of SCT. 23% of 44 pts without SCT died. In 6 of these 10 pts death was caused by infections. Other causes of death were bleeding, cardiac event, acute respiratory distress syndrome, adynamia. Overall probability of survival at 3 years was 75.8% (95% confidence interval (CI): 61.8 – 89.9%) and survival censored for SCT was 79.9% (CI: 66.0–92.8%). Survival was significantly better in responders (PR and CR) (94.1% at 3 years; CI: 82.9–100%) than in non-responders (58.0% at 3 years; CI 34.0 – 81.3%) (p=0.04; log-rank test). Adverse events were reported in 79.4% of 63 evaluable pts consisting of anaphylaxis/allergy in 27.3%, serum sickness in 12.7%, fever/chills in 34.5%, and bacterial/viral/fungal infections in 54.5% of pts. Conclusion: Response rate and survival after rATG+CsA in this retrospective analysis is lower than in historical controls (e.g. hATG+CsA treatment in previous controlled studies of the German AA Study Group and the EBMT AA Working Party; Frickhofen et al., Blood 2003; Tichelli et al., Blood 2011) and rate of (early) infections seem to be high. Our results are in accordance with recent reports from other groups. Additionally the results of this retrospective data analysis suggest a benefit for the patient group treated with a Thymoglobulin® dosage of > 3.5 –3.75 mg/kg/day compared to lower doses (< 3.5 mg/kg/day). There is growing evidence that best results in terms of response and survival are obtained by hATG-based immunosuppression. hATG can not be replaced by rATG without negative impact on patient outcome. There is need for action to achieve availability of hATG worldwide. If hATG is not available, treatment with rATG should be considered instead of no treatment or treatment with CsA alone since still about half of the patients respond to rATG. Disclosures: Höchsmann: Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: The use of the horse ATG ATGAM in Aplastic Anemia is off-label in Europe. At the moment no horse ATG with approval is available in Europe. Schrezenmeier:Genzyme: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Research Funding.

scholarly journals A Multicenter, Open Label Phase I/II Study of Carfilzomib, Pomalidomide and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma (MM) Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1145-1145 ◽  
Author(s):  
Sara Bringhen ◽  
Valeria Magarotto ◽  
Anna Marina Liberati ◽  
Angelo Belotti ◽  
Alessandra Larocca ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Low Dose ◽  
Response Rate ◽  
Primary Objective ◽  
Advisory Board ◽  
Level 1

Abstract Background: Survival rates of multiple myeloma (MM) patients (pts) has improved over the past few years, but patients inevitably relapse and become more resistant to subsequent treatments. Carfilzomib and Pomalidomide were both approved for the treatment of relapsed/refractory MM (RRMM). Combinations including a proteasome inhibitor (PI) plus an immunomodulator (IMiD), such as Bortezomib-Lenalidomide-Dexamethasone (VRD) or Carfilzomib-Lenalidomide-Dexamethasone (CRD), showed a very high response rate with an acceptable toxicity. Moreover, in the CHAMPION1 study (Berenson et al Blood 2016), the weekly infusion of Carfilzomib showed to be as effective as the twice schedule. In this phase I/II study we assessed for the first time weekly Carfilzomib plus Pomalidomide and low dose Dexamethasone (wKPd) for the treatment of RRMM. Here we report preliminary results. Methods: the primary objective of the phase I part of the trial was to determine the maximum tolerated dose (MTD) of wKPd combination. The primary objective of the phase II was to determine the rate of partial response (PR). Patients with RRMM, who received 1-3 prior lines of treatments and were refractory to Lenalidomide were eligible. Treatment consisted of 28-day cycles of oral Pomalidomide at fixed dose of 4 mg on days 1-21 (1 week off), oral or intravenous (iv) Dexamethasone 40 mg on days 1,8,15,22 and iv Carfilzomib at escalating doses on days 1,8,15. Escalation started at the dose of 36 mg/m2 (0 level) and used a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Treatment was continued until relapse or intolerance. Results: A total of 57 patients were enrolled in 6 Italian centers. Fifty-two patients could be evaluated for this analysis (5 patients did not complete the first cycle yet). The median age was 62 years with a median time from diagnosis of 4 years. 17/39 (44%) of patients were considered high risk according to cytogenetic abnormalities [at least one among t (4;14) t (14;16) and deletion chromosome 17 (del17) detected by FISH]. In the phase I of the trial 15 patients were enrolled. The first 3 patients at the dose level 0 of Carfilzomib did not experience any DLT. In the next cohort with Carfilzomib 20/45 mg/m2 a G3 hypertension and a sudden death occurred. According to the protocol, 3 more patients were enrolled at dose level 0: 1 patient experienced G3 atrial fibrillation, 2 patients ≥ G3 hypertension. Considering the serious adverse events (SAEs) occurred, the trial was temporary stopped to evaluate the benefit of continuing the study. All the DLTs were cardiologic and occurred in patients with a prior history of cardiac disease. As per protocol, they were evaluated with ECG and echocardiogram before the enrolment and were considered eligible for the study. The safety committee established new procedures for the evaluation of cardiac function of potentially eligible patients, including 24 h continuing pressure monitoring before the enrolment and serial measurement of blood pressure during and after Carfilzomib infusions. Six more patients were enrolled at dose level -1 (Carfilzomib 20/27 mg/m2) and none experienced a DLT. The MTD was established at dose level -1 with Carfilzomib 20/27 mg/m2, Pomalidomide 4 mg and Dexamethasone 40 mg. In the phase II portion of the trial, 42 patients were enrolled. Considering both phase I and II portions of the study, the most frequent drug related, grade ≥ 3 AEs were hematologic (65% of neutropenia and 13% of thrombocytopenia) and cardiologic (17%, mainly hypertension). We recorded only 4% of infection and ≥ G3 peripheral neuropathy. The overall response rate (ORR) of phase I/II portions was 58% (30/52) including 25% (13/52) of ≥ very good partial remission (VGPR). The ORR of high risk patients was 44% (7/16) including 19% (3/16) of ≥ VGPR. With a median follow-up of 10 months, median progression free survival (PFS) was 9.5 months and the median overall survival was not reached. Conclusions: This is the first phase I/II trial that combined weekly Carfilzomib with Pomalidomide and Dexamethasone. This combination was highly effective in RRMM. After a median follow-up of 10 months, wKRd showed a double median PFS in comparison with Pomalidomide-low dose dexamethasone (Sanmiguel et al Lancet Oncology 2013): 9.5 vs 4 months respectively, confirming the efficacy of combining a PI with an IMiD. An updated analysis will be presented at the meeting. Disclosures Bringhen: BMS: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Other: ADVISORY BOARD; Mundipharma: Other: ADVISORY BOARD; Karyopharm: Other: ADVISORY BOARD. Larocca:Celgene: Honoraria; Janssen-Cilag: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Gaidano:Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Oliva:Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbivie: Honoraria; Mundipharma: Research Funding; SANOFI: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding.

scholarly journals Real World Outcomes with VTD and Cybord Induction Treatment for Transplant Eligible Multiple Myeloma Patients in a Latin American Country. Retrospective Cohort Study from Gamm (Grupo Argentino de Mieloma Multiple)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3301-3301
Author(s):  
Natalia Paola Schutz ◽  
Paola Ochoa ◽  
Patricio Duarte ◽  
Guillermina Remaggi ◽  
Sebastian Yantorno ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cohort Study ◽  
Adverse Events ◽  
Latin American ◽  
Research Funding ◽  
Response Rate ◽  
Response Rates ◽  
Induction Treatment ◽  
The Difference

Abstract Introduction: There are scarce data regarding treatment outcomes and toxicity in Latin American countries. Argentina is the second largest country in the region and the fourth most populated one. National Guidelines from the Argentinean Society of Hematology (SAH) recommends the use of bortezomib based triplets for induction treatment in transplant eligible newly diagnosed Multiple Myeloma patients. Objective: To compare response rates and adverse events after induction treatment with Cyclophosphamide Bortezomib and Dexamethasone (CyBorD) or Bortezomib Thalidomide and Dexamethasone (VTD) outside of clinical trials in a Latin American country. Methods: Retrospective multicentric cohort study. All centers participating in the Argentinean Multiple Myeloma Study Group (GAMM) were invited to participate in the study. Eligible patients were 75 years of age or younger, with a diagnosis of Multiple Myeloma according to the IMWG 2014 criteria, transplant eligible, treated with at least one cycle of CyBorD or VTD as induction therapy in the time period from December 2012 until December 2017. Main exclusion criteria were amyloidosis, plasma cell leukemia and previous neuropathy. Patients were identified from local registries at each center and included consecutively in the study database. Epidemiological and clinical data were obtained from medical records and collected in a standardized clinical report form. Patients were followed from diagnosis until death or lost to follow up. Response was evaluated according to IMWG Response Criteria 2016. Adverse events were graded by CTCAE 4.3. Comparisons of response rates were performed using a Chi2 test and differences in rates were expressed as proportions with 95% confidence intervals (CI). Crude odds ratios (OR) and OR adjusted by potential confounders were calculated using a logistic regression model. Kaplan Meier method was used to estimate progression free survival (PFS) and overall survival (OS). Stata 13 software was used. Results: A total of 322 patients from 15 centers in Argentina were included in the study. The median age at diagnosis was 57 years (range 26-74), 52% (167) of the patients were male, 18% (58) had renal failure, 28% (85) ISS 3 , 7% (22) extramedullary disease, and 14% (46) high risk cytogenetics. Median time of follow up was 34 months (IQR 21-58). CyBorD was the most common treatment, indicated as induction therapy in 74% (238) of the cases. The characteristics of the patients were similar in both groups except age and LDH levels. The median number of cycles was 5 (range 1-12). Bortezomib was administered once per week in 85% (272) of the patients and subcutaneously in 86% (276) with no differences between both treatment arms. The median cumulative cyclophosphamide dose per month was 1.5 g (IQR 1.5-2.4) and thalidomide dose per day was 100 mg. In the VTD arm, 72,62% (61) of the patients achieved at least very good partial response (VGPR) vs 53.36% (127) with CyBorD [OR of 2.31 (CI 1.35 - 3.99) p=0.002]. The difference in VGPR was 19.26% (CI 15 - 24). Complete response rate (CR) was 35.92% in patients treated with VTD vs 22.55% with CyBorD [OR of 1.87 (CI 1.04 - 3.35) p=0.03). The difference in CR was 13,37% (CI 9.6 -17.53). There was no difference in overall response rate (ORR) with 94.05% vs 91.18% (p=0.406). Adverse events were more common with VTD (69.05% vs 55.46% p=0.030), especially neuropathy grade 3 - 4 (7.14% vs 1.26% p=0.005) and thrombosis (13.10 % vs 3.36 % p=0.001). Deep venous thrombosis prophylaxis was inadequate in 20.24% of the patients. Hematologic adverse events were more common with CyBorD, especially thrombocytopenia (5.95% vs 16.39% p=0.017). Autologous stem cell transplantation (ASCT) was performed in 78% (249) of patients. There was 5% (17) stem cell mobilization failure, all in the CyBorD arm. Response rates after ASCT with VTD and CyBorD induction treatment were: 76.19 vs 73.11% VGPR (p=0.580) and 48.53% vs 40% CR (p=0.20). Maintenance treatment was indicated in 67.86% (57) and 65.13% (155) patients respectively (p=0.650). The PFS at 24 months was 83% (CI 71-90) with VTD vs 72% (CI 66-78) [(HR 0.92 (CI 0.59 - 1.42) p 0.715] and OS 96% (CI 87-99) vs 91% (86-94) respectively [(HR 1.2 (CI 0.62 - 2.32) p 0.587]. Conclusions: VTD has better CR and VGPR compared to CyBorD. Nevertheless, CyBorD continues to be the preferred induction regimen in Argentina based on safety profile. The optimal number of induction treatment cycles remains to be determined. Disclosures Schutz: Takeda: Honoraria, Research Funding; Sanofi Aventis: Research Funding; Roche: Research Funding; Glaxo: Research Funding; Janssen: Honoraria, Research Funding; Varifarma: Honoraria. Shanley:Brystol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Fantl:Janssen: Consultancy, Honoraria, Research Funding; Varifarma/Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Roche: Research Funding; Tecnofarma: Honoraria; BMS: Consultancy, Honoraria; Glaxo: Research Funding.

Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2310-2310 ◽  
Author(s):  
Christina S Lee ◽  
Allison Imahiyerobo ◽  
Micha Thompson ◽  
Marina Izak Karaev ◽  
Waleed Ghanima ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Response Rate ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Best Response

Abstract Background Adults with newly-diagnosed and persistent ITP usually respond to steroid based treatments such as prednisone but relapse with tapering. One 4-day cycle of Dexamethasone (dex) at 40 mg/day in newly diagnosed ITP resulted in a lasting effect in 50% of patients (pts) in 1 study. An Italian study showed that 3 cycles of dex are better than 1 cycle. Approximately 50% of pts with chronic ITP experience a complete or partial response (CR & PR) to rituximab, yet only 20% of pts have a lasting, unmaintained response after 3 years. Mechanistically, rituximab (which depletes B cells but not plasma cells) and dexamethasone (which may be the most potent anti-plasma cell agent) are a logical combination in treatment of antibody-mediated diseases such as ITP. In 2 studies of newly-diagnosed pts, dex 40mg/day x 4 followed by rituximab was more effective than dex alone (one study added more dex half way through). In our pilot study, pts at Weill Cornell Medical College (WCMC) with all stages of ITP were treated with a combination of rituximab (R) and usually 3 cycles of dex. The outcome of this combination was retrospectively analyzed. Methods Combination of standard-dose rituximab (weekly x 4) and usually 3 4-day cycles of 28mg/m2 (max. 40mg) dex at 2-week intervals (R+3Dex) was explored in 67 pediatric and adult pts with ITP at WCMC. Patients were monitored with CBCs obtained weekly and then at less frequent intervals if a response was achieved. Best response (after 8 weeks to avoid transient effects of dex) was determined. Patients were categorized as CR (platelet count≥100x109/L) or PR (50-100x109/L). Relapse was defined as either two consecutive platelet counts <50x109/L and/or need for additional therapy. The duration of response was calculated from date of first rituximab administration to relapse or latest follow-up as of July 31st 2013. Results Overall, 50 of 67 pts treated with R+3Dex achieved a best response of either a CR (n=43) or a PR (n=7) at 8 weeks or later from start of therapy for an overall response rate of 75%. Seventy-three percent of pts received R+3Dex; variations were primarily in the timing and amount of dex given. Fifteen responders, 9 CRs and 6 PRs, relapsed at a median of 9 months. Seventy percent of the responders (or 52% of all pts treated) maintain a continuous response with platelet counts ≥ 50 x 109/L as of their last visit at a median f/u of 20 months. Kaplan Meier Analysis estimates 44% of all pts treated (Figure) and 59% of responders (Figure) maintained a best response without relapse at 67 months after initiating treatment. If only those with ITP ≤ 24 months are included, the estimated long term response rate is 59% (p=0.0017) versus only 19% for those with a duration of ITP > 24 months (Figure). Of 36 responding children and adults who had ITP ≤ 24 months, 29 continued to respond as of last follow up. Adults initially responded better than children (p=0.0019) but the long-term responses were not different (Figure). Pts achieving a CR had longer response than those achieving a PR. Adverse events related to R+Dex were usually mild-moderate, although 3 pts had serum sickness and 2 had transient colitis. IgG levels fell to below the lower limit of normal for age in 14 of 67 pts, 10 of whom had their IgG levels return to normal. In 6 of 14, IgG levels were < 400 mg/dl, some of whom received IVIG. Fifteen patients had serial BK/JC levels without ever detecting virus. Conclusions R+3Dex provides clearly superior results to rituximab alone. Notably, there was a 75% response rate overall (50/67 pts) compared to 50% with R alone. The 5 year response rate was almost 50% of all patients and 3/5 of responders. In patients who had had ITP for ≤ 2 years, the response is comparable to what has been reported with splenectomy. Specifically the results in the ≤ 2 year group suggest that R+3Dex is an effective way to induce indefinitely normal platelet counts in pts with a “short” duration of ITP. R+3Dex was tolerable although patients had difficulty with 3 cycles of dex. The 21% rate of hypogammaglobulinemia, higher than that seen with R alone, is also evidence of the mechanism of R+3Dex affecting both B cells and plasma cells. The lasting, long-lived, unmaintained responses observed in this study suggest that this combination therapeutic strategy should be further tested in a controlled trial in patients with newly diagnosed, persistent, and early chronic ITP, whether or not they have been previously treated with other agents. Disclosures: Bussel: Sysmex: Research Funding; Cangene: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

scholarly journals Two Year Update of Phase II Trial of Pembrolizumab, Lenalidomide and Dexamethasone As Post -Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1911-1911 ◽  
Author(s):  
Meena Bansal ◽  
David S. Siegel ◽  
Jaeil Ahn ◽  
Rena Feinman ◽  
David H. Vesole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Best Response ◽  
Grade 3

Introduction: Patients with high-risk multiple myeloma (HRMM) who have undergone autologous stem cell transplant (ASCT) will inevitably relapse and have a progression free survival (PFS) ranging from 8-14 months (Gaballa et al, American Journal of Hematology, 2016) and 24-39 months while on lenalidomide (Len) maintenance therapy (Jackson et al, The Lancet Oncology, 2019). Unlike in solid tumors, PD-1 blockade has no single agent activity in relapsed and refractory multiple myeloma (MM) patients suggesting that immune stimulating agents, immunomodulatory agents (IMiDs), such as lenalidomide (Len) or pomalidomide (Pom) are necessary in combination with anti-PD-1 blockade to increase depth and duration of response post-ASCT. The Keynote-023 study revealed an overall response rate (ORR) of 76% with the combination of pembrolizumab (Pem), Len and dexamethasone (Dex). Similarly, the Keynote 135 study using the combination of Pem, Pom, and Dex revealed an ORR of 60%. Unfortunately, the phase III studies comparing an IMiD vs Pem with the IMiD upfront at the early relapsed setting were halted because of increased deaths on the Pem arm and a decreased median PFS. With our Phase II study currently on clinical hold by the FDA, we are presenting here the 2-year follow-up of the original patient cohort including some preliminary safety and efficacy data of Pem-Len-Dex in HRMM patients as post-ASCT consolidation (NCT02906332). Methods: Patients with HRMM who have undergone induction therapy followed by single or tandem melphalan-based ASCT were considered eligible 2-6 months post ASCT. HRMM criteria are defined by any of the following: ISS stage 3; del 13q by cytogenetics; FISH with 1q amplification, 1p deletion (del), p53 del, t(4;14), t(14;16), t(14;20), hypodiploidy; or a high-risk gene expression profile score. Patients were excluded if they had progression of disease at time of screening or if there was evidence of organ dysfunction. Patients received Pem 200 mg IV at day 1;Len 25 mg po daily at days 1-14; and Dex 40 mg daily at days 1,8,15 of a 21-day cycle for a total of 2 cycles and then an additional 2 cycles of Pem + Len without Dex at the same dose and frequency. Survival outcomes post-ASCT were measured using the log-rank test. Results: Of 15 patients screened, 12 received at least one dose of therapy and were deemed evaluable. One patient withdrew consent and did not follow up after cycle 2. Baseline characteristics are shown in Table 1. Thirty-three percent were ISS 3, 66.7% had a p53 deletion by FISH, 41.6% received induction Bortezomib-Len-Dex; 33% received induction Carfilzomib-Len-Dex, and the remaining 24.9% received other bortezomib-based induction. Best ORR during the 2 year follow up showed 8 patients (73%) achieving stringent complete remission, 2 patients (18%) showing complete remission and 1 (9%) achieving very good partial remission. Table 2 shows best response to treatment by cycle of therapy. Table 3 shows best response during follow-up visits, which were 3 months apart. Of the 11 patients who completed therapy, 8 had minimal residual disease (MRD) status assessed and among them, 7 were MRD negative by flow cytometry, tested 30 days after the fourth cycle. With a median follow-up of 32.2 months, median PFS was 27.6 months. The PFS rates at 1 year and 2 year are 91.3% and 65.2%, respectively. All patients had adverse events (AEs), AEs were attributed to Pem, Len, or Dex rather than from ASCT. Of the 90 AEs that were reported, 5.6% were grade 3 and 94% were grade 1 or 2 (Table 3). The most common hematologic AE was neutropenia (41.7%), with 3 pts (25%) grade 1 and 2, and 2 pts (16.6%) grade 3. The most common non-hematologic AEs were intermittent constipation (16.6%), diarrhea (16.6%), fatigue (8.3%), and increased ALT (8.3%) and were graded as 1 or 2. Non-hematologic grade 3 AEs occurred in 2 pts and included hypoxia and maculopapular rash. There was 1 serious AE, H. influenza pneumonia requiring inpatient admission, which was not considered to be related to Pem. Conclusions: The combination of Pem, Len, and Dex given to HRMM patients in the post-ASCT consolidation setting is well tolerated. In comparison to historical controls of HRMM patients post-ASCT with a median PFS of 8-14 months, the PFS rates of 91.3% and 65.2% at 1 and 2 year post-ASCT respectively suggest an efficacy signal for the use of Pem, Len, and Dex as post-ASCT consolidation. Larger prospective studies are needed to validate these results. Disclosures Siegel: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Biran:Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding.

scholarly journals Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 580-580 ◽  
Author(s):  
Mark Bustoros, MD ◽  
Omar Nadeem ◽  
Adam S Sperling ◽  
Giada Bianchi ◽  
Lily Ardente ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Advisory Board ◽  
Induction Phase ◽  
Advisory Committees ◽  
Smoldering Multiple Myeloma

Background.This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods.Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al. (Blood 2014). The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and dexamethasone at days 1, 8, 15, and 22. The induction phase was followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle was defined as 28 consecutive days for a total of 24 months period. Bone marrow samples of all patients were obtained before starting therapy for baseline assessment for minimal residual disease (MRD) testing, whole-exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle for isolating cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Results.In total, 53 of the planned 62 patients have been enrolled in this study from February 2017 to May 2019. The median age of the patients enrolled was 61 years (range, 41 to 84) with 22 male (41.5%). The analysis was conducted on patients who have completed at least 1 cycle of therapy (n=45). The median follow-up for the trial is 14.4 months (range: 2- 27.6). Interphase fluorescence in situ hybridization (iFISH) was successful in 37 patients (82.2%). High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 20 patients (54%). The median number of cycles completed was 14 cycles (range: 1-24). According to the study's inclusion criteria, baseline markers showed that 15, 14, and 13 patients had 3, 4, and 5 high-risk features, respectively. Moreover, 24 patients (53.3%) met the criteria of high-risk SMM, according to the Mayo 2018 model. The most common grade 3 adverse events were hypertension (6.3%), hypophosphatemia (4.2%), and rash (4.2%). Grade 4 thrombocytopenia and neutropenia were each reported in 4.4% of patients, and hyperglycemia was reported in 2.2%. Stem cells were collected in all eligible patients by the end of the induction phase. As of the abstract date, the overall response rate (partial response or better) in participants who completed at least 1 cycle of treatment was 91.1% (41/45), with 14 Complete Responses (CR, 31.1%), 9 very good partial responses (VGPR, 20%), 18 partial responses (40%), and 4 minimal Responses (MR, 10%). ORR in patients who completed the induction phase (≥9 cycles) was 97% (n= 32/33), with 14(42.4%) and 9 (27.2%) having CR and VGPR, respectively. All patients who had a CR have also achieved a stringent CR. Six patients have completed the treatment protocol and are currently on follow-up. As of July 2019, none of the patients have progressed to overt MM. MRD testing by next-generation sequencing is ongoing for patients who achieved CR or VGPR and will be presented at the meeting. Conclusion.The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma with 91% ORR and 54.7% CR and VGPR to date. The high response rate, convenient schedule and manageable toxicity build on prior studies which have shown efficacy of lenalidomide and dexamethasone in high risk smoldering myeloma. Longer follow-up for disease outcome is ongoing. Disclosures Bustoros, MD: Takeda: Honoraria. Nadeem:Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sanofi: Consultancy. Prescott:Janssen: Equity Ownership. Munshi:Takeda: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Adaptive: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; Adaptive: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Oncopep: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Anderson:OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder ; Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board. Richardson:Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Amgen: Consultancy; Celgene: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Takeda: Consultancy. OffLabel Disclosure: Ixazomib, Lenalidomide and Dexamethasone is an investigational combination in high-risk smoldering multiple myeloma and has not been approved by the US Food and Drug Administration or any other regulatory agency worldwide for the use under investigation.

Induction with New Drugs and Planned Autologous Followed by Non-Myeloablative Allogeneic Transplantation in Newly Diagnosed Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4330-4330
Author(s):  
Luisa Giaccone ◽  
Moreno Festuccia ◽  
Roberto Sorasio ◽  
Nicola Mordini ◽  
Fabrizio Carnevale Schianca ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
New Drugs ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Post Transplant ◽  
The Impact

Abstract Abstract 4330 Introduction Immunomodulatory drugs have recently changed the treatment options in multiple myeloma. Moreover, thalidomide, bortezomib and lenalidomide have also been used in the setting of allografting as post-transplant salvage therapy or as maintenance. We are currently evaluating the impact of new drugs as induction therapy in newly diagnosed multiple myeloma before a planned standard autograft followed by a non-myeloablative allograft (Tandem auto-allo). Patients and methods Twenty-five newly diagnosed patients (median age 55 years old, range 26-65) entered a recently designed prospective phase II program of tandem auto-allo which included the use of so-called new drugs during induction. Here, we report data on the first 11 evaluable patients with a follow up of at least 1 month after the allograft. Induction consisted of lenalidomide and dexamethasone (n=5), thalidomide and dexamethasone (n=4), or bortemomib-containing regimens (n=2), followed by G-CSF mobilized peripheral blood stem cell harvest. A standard autograft after melphalan 200 mg/m2 was planned 2-4 months before a low-dose (2 Gy) TBI-based allograft from an HLA-identical sibling. GVHD prophylaxis consisted of cyclosporin and mycophenolate mofetil. Disease status at allografting and post-transplant outcomes were compared to those of 22 patients pair-matched for beta2microglobulin and age, who underwent tandem auto-allo after induction with VAD-based regimens without new drugs (Blood, 2009). Results At the time of allografting after induction with new drugs and the autograft overall response rate was 81% (9/11), including a immunofixation-negative complete remission (CR). Following allografting, all patients promptly achieved donor engraftment. After a median follow-up of 11 months (2-26), all patients are alive and the overall response rate was 91% (10/11). Incidence of grade II-IV GVHD was 34% (4/11), including 1 patient with grade III GVHD. Chronic GVHD was observed in 40% (4/10) of patients with at least 3 months of follow-up. The induction with new drugs did not increase allotransplant-related toxicity or incidence of acute GVHD (Table 1). We observed a higher response disease before allografting in patients treated with new drugs. Conclusions Induction with lenalidomide, thalidomide or bortezomib does not impact feasibility and safety of tandem auto-allo. Longer follow up and a larger cohort of patients are necessary to evaluate the impact of new drugs in improving disease control post-tandem auto-allo. Disclosures: Patriarca: Janssen Cilag: Honoraria; Celgene: Honoraria. Boccadoro:Celgene: Consultancy, advisory committees, Research Funding; Pharmion: Consultancy, advisory committees, Research Funding; Janssen Cilag: Consultancy, advisory committees, Research Funding.

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