scholarly journals EARLY Results of TOTAL Therapy 7 (TT7): High Response Rates of NEWLY Diagnosed High Risk Myeloma to Daratumumab

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4569-4569 ◽  
Author(s):  
Frits van Rhee ◽  
Sharmilan Thanendrarajan ◽  
Carolina D. Schinke ◽  
Jeffery R. Sawyer ◽  
Adam Rosenthal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rates ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Early Results ◽  
Research Grant

Background. The TT approach has significantly improved the outcome of multiple myeloma (MM) by combining new drugs with a regimen that comprises induction, tandem autologous stem cell transplantation (ASCT), consolidation and maintenance. However, a group of 15% of patients with high risk multiple myeloma (HRMM) have derived little benefit despite similar response rates to induction chemotherapy and ASCT when compared to low risk MM. The poor outcome of HRMM is explained by early relapse post ASCT resulting in a short progression free survival (PFS) with only 15-20% of patients surviving long-term. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody that has shown favorable results in early single-arm studies and more recently in phase III studies for relapsed/refractory and newly diagnosed MM. In TT7, we introduced Dara during all phases of therapy, including immune consolidation early post ASCT, to improve responses rate and PFS in HRMM. Methods. Patients had newly diagnosed HRMM as defined by high risk cytogenetic abnormalities, presence of extramedullary disease, >3 focal lesions on CT-PET, elevated LDH due to MM, or ISS II/III with cytogenetic abnormality. Dara (16mg/kgx1) was added to induction with KTD-PACE (carfilzomib, thalidomide, dexamethasone; and four-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning for tandem autologous stem cell transplantation (ASCT) was with fractionated melphalan (50mg/m2x4) (fMEL) based on prior observations that patients with adverse cytogenetics fare better with fMEL rather than single high dose MEL200mg/m2.In the inter tandem ASCT period immunological consolidation with Dara (16mg/kg) alone for 2 doses was followed by Dara (16mg/kg) on day 1 combined with K (36mg/m2) and D (20mg) weekly for 2 cycles. DaraKD was administered to avoid treatment free periods allowing for myeloma regrowth. The 2nd ASCT was followed by further immunological consolidation with Dara (16mg/k) for 2 doses, and maintenance therapy for 3 yrs with 3-months block of alternating Dara-KD (dara 16mg/kg day 1; K 36mg/m2 and dex 20mg weekly) and Dara-lenalidomide (R)D (dara 16mg/kg day 1; R 15mg day 1-21 q28 and D 20mg weekly). Results. TT7 enrolled 43 patients thus far. The median follow-up was 11 months (range: 1-22). The median age was 61 yrs (range 44-73). Sixteen patients were ≥65 yrs (37.2%). A mean of 29.4x106 CD34+ cells/kg (range: 4.6-86.4) were collected. 36 patients completed ASCT #1 (83.7%) and 18 (41.9%) ASCT #2, whilst 14 patients have proceeded to the maintenance phase. R-ISS II/III or metaphase cytogenetic abnormalities were present in 85.1 and 58.1% of patients, respectively. Elevated LDH or >3FL on CT-PET were noted in 30 and 41.8%. The 1-yr cumulative incidence estimates for reaching VGPR and PR were 87 and 83%, respectively. A CR or sCR was achieved in 68 and 46%. The 1-yr estimates of PFS and OS were 91.6 and 87.2%. 40 subjects are alive, whilst 5 progressed on study therapy and 3 subsequently died. 38 patients are progression free at the time of reporting. Dara was well-tolerated and no subjects discontinued therapy due to dara-related side effects. The CR and sCR rates compared favorably to the predecessor HRMM TT5 protocol where CR and sCR rates were 59 and 27%. Conclusion. The early results of TT7 point to increased response rates of HRMM to a dara-based TT regimen with especially higher rates of CR and sCR. Longer follow-up is required to determine if these early results translate into superior PFS and OS. Figure Disclosures van Rhee: Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.

Clinical Outcomes of Patients with Newly Diagnosed Multiple Myeloma Receiving Triplet Therapy in the Connect MM® Disease Registry

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4229-4229
Author(s):  
Jatin J. Shah ◽  
Rafat Abonour ◽  
Mohit Narang ◽  
Jayesh Mehta ◽  
Howard R. Terebelo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Equity Ownership ◽  
Triplet Regimen

Abstract Introduction: Triplet therapies are used for treatment (Tx) of both transplant-eligible and -ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). Actual patterns and outcomes of Tx are not fully understood. Connect MM® is the first and largest multicenter, US-based, prospective observational cohort study designed to characterize Tx patterns and outcomes for pts with NDMM. This analysis describes demographic and disease characteristics of pts who received triplet Tx as an induction regimen and for whom transplant was or was not intended. The analysis explores the relationship of these factors with overall survival (OS) and other efficacy endpoints. Patients and Methods: Pts aged ≥ 18 y with NDMM within 60 days of diagnosis were eligible for enrollment regardless of disease severity, medical history, or comorbidities. Data including transplant intent (yes/no) was collected at baseline; follow-up data was collected quarterly thereafter. Based on the initial intent, 2 groups were identified: patients with intent to transplant who received transplant (TT) and pts with no intent to transplant who did not receive a transplant (NT). Triplet Tx was defined as the combination of ≥ 3 concurrent therapeutic agents in the first course of Tx (within 56 days of study entry). KM analysis adjusted for age was conducted for OS. Because decisions on use of transplant and triplet therapy are influenced by multiple factors, a multivariable Cox regression analysis was performed to evaluate the contribution of the triplet therapy (yes/no) to OS and was adjusted for other variables, including age, comorbidities, and ISS staging. Results: Between September 2009 and December 2011, 1493 pts were enrolled. This analysis was on 1436 pts: 650 pts with transplant intent and 786 pts without transplant intent. The data cutoff date was November 30, 2014, and the median follow-up for overall survival (OS) was 33.8 mos. Of pts with transplant intent, 451 (69%) received transplant (TT) and 199 (31%) did not. Of pts without transplant intent, 62 (8%) received transplant and 724 (92%) did not (NT). The abstract focuses on TT and NT groups only. NT pts tended to be older and have more advanced ISS staging and higher β2-microglobulin levels than TT pts (Table). The most common triplet regimen given during the first course treatment (within 56 days) was lenalidomide, bortezomib, and dexamethasone (RVd). RVd was administered to 34% of the NT pts (76/225) and 59% of the TT pts (152/257). The most common non-triplet regimen was bortezomib and dexamethasone (Vd), which was given to 31% of NT pts (156/499) and 38% of TT pts (73/194). Within the NT group, pts given triplet Tx had a lower risk of death than those who did not receive triplet Tx (P = .0013). The multivariable analysis found triplet Tx to be associated with a 36% reduced risk of death (hazard ratio [HR] = 0.64 [95% CI, 0.50-0.82]; P = .001). ISS disease stage (HR = 1.43 [95% CI, 1.21-1.69]; P < .001) and history of diabetes (HR = 1.38 [95% CI, 1.08-1.78]; P = .012) were negative prognostic factors for OS. Within the TT group, pts who received triplet Tx did not attain an OS benefit (P = .8993), and no baseline characteristics were significantly associated with OS. These results may be limited by other factors not considered that may have influenced physicians' choice of treatment, including the use of maintenance therapy and a short follow-up period of 33.8 months. Conclusions: Triplet Tx as a first regimen is associated with longer OS in pts without transplant intent who did not receive a transplant. RVd and Vd were the most common first Tx regimens, respectively. Continued follow-up of these pts and enrollment of an additional cohort will provide additional data with mature follow-up. Table 1. Table 1. Disclosures Shah: Bristol-Myers Squibb: Research Funding; Array: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Research Funding, Speakers Bureau. Narang:Celgene: Speakers Bureau. Mehta:Celgene Corporation: Speakers Bureau. Terebelo:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacylics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gasparetto:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau. Toomey:Celgene: Consultancy. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Phase 2 Trial of Ixazomib, Lenalidomide, Dexamethasone and Daratumumab in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 304-304 ◽  
Author(s):  
Shaji K. Kumar ◽  
Prashant Kapoor ◽  
Betsy Laplant ◽  
Eli Muchtar ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Board Of Directors ◽  
Mayo Clinic ◽  
Research Funding ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Early Results ◽  
Dose Modifications

Abstract Background: The combination of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and dexamethasone is the current standard induction therapy for myeloma. Daratumumab, a monoclonal antibody directed against CD38, is highly effective in treating myeloma and improves response rates and progression free survival (PFS) when added to PI or IMiD. Ixazomib, lenalidomide and dexamethasone (IRd) is an effective, all oral, induction regimen that has been studied in phase 2 and 3 trials. We designed this trial to examine the feasibility and efficacy of adding daratumumab to the IRd regimen. Patients and Methods: Patients with previously untreated MM, with measurable disease and adequate organ function were enrolled irrespective of their transplant eligibility. The primary objective was to determine the rate of complete response to the IRD-Dara combination in patients with NDMM. Treatment consisted of Ixazomib 4mg days 1, 8, 15; lenalidomide 25 mg days 1-21, dexamethasone 40 mg, weekly and daratumumab 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and then every 4 weeks after that. Overall, 40 patients were accrued; data on 38 patients were available for analysis as of July 02, 2018 (Table 1). Results: The median age was 62 (41-81); 52.6% female. All patients were alive and progression free at last assessment with a median follow up of 5.2 (2.0-12.9) months (median 5 cycles, range 2-13). One patient had gone off for alternate therapy. Responses were rapid with 90% partial response or better (32% VGPR) after 2 cycles, and 100% PR or better (50% VGPR) for 32 patients who have completed 4 cycles. The overall best confirmed response rate among the 38 patients was 95% including 11% CR and 47% VGPR. Overall, 231 cycles have been administered across the study, with dose modifications/ hold required for ixazomib, lenalidomide, daratumumab and dexamethasone in 3 (8%), 11 (29%), 2 (5%), and 8 (21%) patients respectively, the most common reasons being hematologic and skin rash. A grade 3 or higher adverse event at least possibly attributed to the study drugs was seen in 42% of patients, hematologic in 37% and non-hematologic in 11% (Figure). 11 patients have so far proceeded to stem cell collection, all have collected adequate numbers of stem cells for one or two intended transplants(median CD34+ collected 8.4 million/kg; range 3.8-12.3). Updated results with additional 6 months of follow up and MRD testing will be presented at the meeting. Conclusion: This represents the first reported results of this combination for treatment of newly diagnosed myeloma. The early results from the use of IRd-Dara in newly diagnosed myeloma suggests excellent efficacy with rapid responses that deepen quickly over the initial cycles of therapy. The regimen was well tolerated with limited dose modifications and no discontinuation for toxicity and no influence on the ability to collect stem cells. Figure. Figure. Disclosures Kumar: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding. Lacy:Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Prothena: Honoraria; Amgen: Consultancy; Abbvie: Consultancy; Teva: Consultancy; annexon: Consultancy; janssen: Consultancy; celgene: Consultancy; Alnylam: Honoraria; Medscape: Consultancy; Apellis: Consultancy; spectrum: Consultancy, Honoraria; Physicians Education Resource: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy.

Car-Bird [Carfilzomib, Clarithromycin(Biaxin(R)), Lenalidomide/(Revlimid(R)), Dexamethasone) For Newly-Diagnosed Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3216-3216 ◽  
Author(s):  
Tomer M Mark ◽  
John N. Allan ◽  
Geoffrey Marano ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Disease Response ◽  
M Spike ◽  
Grade Iii

Abstract Background Carfilzomib (Cfz) synergizes with lenalidomide and dexamethasone (Len-dex) to provide impressive response rates as upfront treatment of multiple myeloma (MM) (Jakubowiak et al 2012). The addition of clarithromycin to Len-dex has shown superior time to progression compared to Len-dex alone (Gay et al 2010). We hypothesized that sequential treatment with Cfz-dex and BiRD would lead to enhanced efficacy, response duration, and tolerability. We thus tested a sequential approach of upfront carfilzomib / dexamethasone, consolidation with BiRd, and lenalidomide maintenance to evaluate overall response and safety as first line therapy for MM. Methods Twenty-four patients (pts) with symptomatic untreated MM were enrolled in a single institution study to evaluate the efficacy and tolerability of Car-BiRd. Car-BiRd therapy is: Cfz IV over 30 minutes on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of the 1st cycle only and 45mg/m2 for each successive dose thereafter and dex 40mg on D1, 8, 15, 22. Cfz-dex was continued until plateau in disease response defined as unchanged M-protein for 2 cycles. Elective autologous stem cell collection was then performed per physician and patient discretion and consolidation with BiRd initiated. Transplant ineligible pts proceeded directly to BiRd. BiRd is: Clarithromycin 500mg BID, lenalidomide 25mg daily on D1-21, and dex 40mg daily D1, 8, 15, 22 of 28-day cycle. Therapy was continued until a 2nd plateau in disease response after which lenalidomide maintenance at a dose of 10mg daily D1-21 of 28 day cycle was continued until disease progression or intolerability. Results 24 pts have currently been enrolled; 23 have completed at least 1 cycle of therapy and were evaluable for response. Sixteen pts (67%) harbored high-risk cytogenetics, as defined by the presence of one or more of the following on iFISH: del 17p, gain 1q, del 1p, t(4;14), t(14;16), or complex karyotypic abnormalities. Median study follow-up was 30.8 weeks (range 4.5-62.2). Response to the Car-BiRD regimen was: overall response rate (ORR) 87%, stringent complete response (sCR) 13%, very good partial response (VGPR) 48%, partial response (PR) 26%, stable disease (SD) 13%. Maximum response to the Cfz-dex induction was: ORR 87%, sCR 9%, VGPR 39%, PR 35%, SD 13%. Median time to PR and maximum response with Cfz-dex was 2 cycles (range 1-2) and 4 cycles (range 1-5) respectively. Median M-spike percentage decrease with Cfz-dex was 92% (range 13-100%). Twelve pts thereafter received BiRD consolidation with 5 pts (41%) further decreasing the M-spike by a median of 8% (range 1-45%). A median of 3 cycles (range 2-7) of BiRD was given until a 2nd response plateau was achieved. Seven pts subsequently received lenalidomide and all have maintained their response after a median of 5 cycles (range 1-8) of follow-up. Seven pts (30%) have come off study, 2 (8%) secondary to disease progression (1 during Car-Dex and 1 during BiRD) and 5 pts (22%) due to toxicity (2 pts due to Grade III renal failure, both attributable to Cfz, and 2 pts due to Grade III CHF during Cfz-Dex, 1 attributable to Cfz; 1 pt with Grade III Thromboembolic event during BiRD, attributable to Len-dex). Discussion This is the first prospective study evaluating the response to induction Cfz/Dex in treatment-naïve MM. Cfz/Dex therapy appears safe and effective in newly diagnosed myeloma patients. Responses deepen with subsequent IMiD(R)-based consolidation and maintenance. Toxicities due to each component of the regimen were manageable. The ORR of 87% and rate of VGPR or better of 61% in group with a high percentage of unfavorable cytogenetics compares favorably to similar studies using 1st generation proteasome inhibitor combinations, and may continue to improve with longer study follow-up. Disclosures: Mark: Onyx: Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib is not approved for front line use in myeloma. Rossi:Celgene: Speakers Bureau. Zafar:Onyx: Speakers Bureau; Millennium: Speakers Bureau; Celgene: Speakers Bureau. Pekle:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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 Impact of Bortezomib- or Lenalidomide-Based Induction Treatment on High Risk Cytogenetic Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Enrolled in the Gimema-MM-03-05 and EMN01 Trials

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 744-744 ◽  
Author(s):  
Alessandra Larocca ◽  
Massimo Offidani ◽  
Pellegrino Musto ◽  
Francesca Patriarca ◽  
Lorenzo De Paoli ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Significant Difference ◽  
Reduced Risk

Abstract Introduction : Cytogenetic abnormalities by fluorescence in situ hybridization (FISH) are clinically relevant prognostic factors in MM. Data in transplant ineligible patients treated with bortezomib or lenalidomide in first-line therapy for high-risk (HiR) patients is limited. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. This sub-analysis evaluates the impact of cytogenetics on outcomes in transplant-ineligible patients with newly diagnosed MM (NDMM) treated with bortezomib-based induction (BORT) or lenalidomide-based (LEN) treatment. Methods : In the GIMEMA-MM-03-05-trial, patients were randomized to bortezomib-melphalan-prednisone-thalidomide for 9 cycles followed by maintenance with bortezomib-thalidomide (VMPT-VT) vs VMP for 9 cycles, without maintenance. In the EMN01-trial, patients were randomized to melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd) for 9 cycles, followed by maintenance with lenalidomide alone or plus prednisone continuously. Results of these studies have previously been reported (Palumbo A et al JCO 2010 and 2014; Magarotto V et al Blood 2016 127(9)). Cytogenetics were assessed using FISH. Patients were categorized into cytogenetic risk groups according to International Myeloma Working Group criteria. HiR cytogenetics included del(17p), t(4;14), and t(14;16); all other patients were categorized as standard risk (StR). Subgroup analyses were performed to determine the consistency of treatment effects of BOR vs LEN in the different subgroups using interaction terms between treatment and FISH, ISS, age, sex, Karnofsky PS and LDH. The different effect of BORT vs LEN in cytogenetic subgroups was confirmed by one sensitivity analysis where the follow-up of the BORT study was reduced to make the follow-up times similar; and by another sensitivity analysis with multiple imputation method for missing cytogenetic value. Results : 902 of 1165 patients from the intent-to-treat population had available cytogenetic profiles, with 243 (27%) patients in the HiR group and 659 (73%) in the StR group. In the BORT vs LEN groups, median age was 71 vs 73 years (p&lt;0.001), ISS3 20% vs 27% (P=0.65), HiR patients were 29% vs 26%, StR patients were 71% vs 74% (p=0.32) and the median follow-up was 72.3 and 63.6 months, respectively. In the subgroup analysis, a significant difference was found in the cytogenetic subgroup with a superior advantage of BORT versus LEN in HiR group, whereas no significant difference was found between BORT and LEN in the other subgroups analyzed (ISS, age, sex, Karnofsky PS and LDH) (interaction-p=0.01) (Fig. 1 B). BORT treatment resulted in a reduced risk of death or progression compared with LEN in patients with HiR. In HiR patients, median PFS was 30.8 with BORT compared with 14.8 months with LEN (HR: 0.54; 95% CI: 0.41-0.72); in StR, median PFS was 29.1 with BORT compared with 22.1 months with LEN (HR: 0.87; 95%; CI: 0.72-1.05) (Fig. 1 A). Considering the standard of care VMP and Rd, in the HiR group (n=95) VMP resulted in a 48% reduced risk of death or progression compared with Rd (HR: 0.53; 95% CI: 0.34-0.83), whereas no significant difference in PFS was found in the StR group (n=273) (HR: 1.00; 95% CI: 0.75-1.33), interaction-p=0.02. BORT treatment resulted in a reduced risk of death in patients with HiR cytogenetics: median OS was 62.4 months with BORT compared with 43.2 months with LEN (HR: 0.68; 95% CI: 0.47-0.96); in StR, median OS was 78.1 months with BORT and was not reached with LEN (HR: 1.06; 95% CI: 0.82-1.36), interaction-p=0.04 (Fig. 1 A). In patients with del(17p) (n=131) median PFS was 18.0 vs 12.9 months for BORT vs LEN (HR: 0.71; 95% CI: 0.49-1.04), interaction-p=0.73. In patients with t(4;14) (n=118) median PFS was 31.5 vs 15.2 months for BORT vs LEN (HR: 0.41; 95% CI: 0.27-0.62) interaction-p=0.002. In patients with t(14;16) (n=31) median PFS was 36.2 vs 9.8 months for BORT vs LEN treated patients (HR: 0.34; 95% CI: 0.16-0.76), interaction-p=0.045. Conclusions : BORT treatment resulted in a PFS and OS benefit vs LEN in patients with HiR cytogenetics. Treatment with VMP led to a significant reduction of the risk of death or progression vs Rd in HiR patients. These results support VMP induction as a standard treatment option for patients with NDMM who are ineligible for transplant with HiR cytogenetics. Disclosures Larocca: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Janssen: Honoraria; Celgene: Honoraria. Patriarca: MSD Italia: Honoraria; Janssen: Honoraria. Corradini: Gilead: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Bosi: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Petrucci: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Boccadoro: Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria.

scholarly journals Heavy and Light Chain Monitoring in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Residual Disease IMWG Response Assessment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1852-1852
Author(s):  
Noemi Puig ◽  
Teresa Contreras ◽  
Bruno Paiva ◽  
María Teresa Cedena ◽  
José J Pérez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Response Assessment ◽  
Advisory Committees ◽  
Minimal Residual

Introduction: The GEM-CESAR trial is a potentially curative strategy for high-risk smoldering multiple myeloma (HRsMM) patients (pts) in which the primary endpoint is the achievement of bone marrow minimal residual disease (MRD) negativity. However, other methods of disease evaluation in serum such as heavy+light chain (HLC) assessment, with a potential complementary value to the IMWG response criteria, have also been tested. Aim: To evaluate the performance of HLC assay in HRsMM pts at diagnosis and after consolidation, comparing the results with standard serological methods and Next Generation Flow (NGF) for the assessment of bone marrow MRD. Patients and Methods: Ninety HRsMM pts included in the GEM-CESAR trial received six 4-weeks cycles of carfilzomib, lenalidomide and dexamethasone followed by high dose melphalan and 2 further cycles of consolidation with the same regimen. All pts received maintenance treatment with lenalidomide for up to 2 years. SPEP and IFE were performed using standard procedures. Serum IgGk, IgGl, IgAk and IgAl HLC concentrations were measured using Hevylite (The Binding Site Group Ltd, Birmingham, UK) on a SPA PLUS turbidimeter. HLC concentrations and ratios were considered abnormal if they were outside the 95% reference ranges provided by the manufacturer. MRD was analyzed by flow cytometry following EuroFlow recommendations (sensitivity, 2x10-6). Standard response assignment was carried out as per the IMWG guidelines. Hevylite responses were assigned and HLC-pair suppression was defined as in Michalet et al (Leukemia 2018). Results: Out of 90 HRsMM pts, 75 had monoclonal intact immunoglobulin and samples available at diagnosis (50 IgG and 25 IgA). HLC ratio was abnormal in 98% of IgG pts and in 100% of IgA pts. Response assessment by Hevylite and standard IMWG criteria were available in 62 pts post-consolidation (Table 1). A good agreement was found between the two methods (kappa quadratic weighting = 0,6327 (0,4016 - 0,8638)). Among 46 pts with assigned CR as per the IMWG response criteria, there were 3 and 8 pts in PR and VGPR according to the Hevylite method, respectively. In 62 cases, paired Hevylite and MRD assessment data were available. Concordant results were found in 72.5% of cases (45/62; HLC+/NGF+ in 15 and HLC-/NGF- in 30 cases) while in the remaining 27.4% of cases results were discordant (17/62; HLC-/NGF+ in 6 and HLC+/NGF- in 11 cases). Post-consolidation, 24, 25.8 and 42.3% of the 62 samples were positive by SPEP, NGF and Hevylite, respectively. HLC-pair suppression was identified in 13/62 pts; 10 had severe HLC-pair suppression at the end of consolidation. After a median follow-up of 32 months (8-128), 93% of pts remain alive and progression-free. Three patients that have already progressed had their responses assessed post-consolidation. The first pt was assigned VGPR by the standard IMWG criteria and PR by Hevylite and was MRD positive by NGF; the second pt was assigned CR by IMWG criteria and Hevylite but had severe HLC-pair immunosuppression and was MRD positive by NGF; the third pt was in CR by IMWG and HLC criteria and was MRD positive by MFC. Conclusions: Moderate agreement was found between response assessment by Hevylite and the standard IMWG methods as well as between Hevylite and MRD assessment by NGF. Most discordances were a result of Hevylite detecting disease in samples negative by the standard methods, but longer follow-up is needed to ascertain its clinical value. HLC assessment could have anticipated the progression noted in 2 (out of 3) patients. Disclosures Puig: Takeda, Amgen: Consultancy, Honoraria; The Binding Site: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Sanofi and Takeda: Consultancy. Rodriguez Otero:Kite Pharma: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy. Oriol:Celgene, Amgen, Takeda, Jansse: Consultancy, Speakers Bureau. Rios:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. de la Rubia:Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; AbbVie: Consultancy. De Arriba:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria. Ocio:Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; BMS: Honoraria; Novartis: Consultancy, Honoraria; Array Pharmaceuticals: Research Funding; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Mundipharma: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; AbbVie: Consultancy; Janssen: Consultancy, Honoraria. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2749-2749
Author(s):  
Omar Nadeem ◽  
Robert A. Redd ◽  
Julia Prescott ◽  
Kelsey Tague ◽  
Veronica Romines ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Induction Phase ◽  
Advisory Committees ◽  
Study Therapy

Abstract Background: Early therapeutic intervention in high-risk SMM (HR-SMM) has demonstrated benefit based on previous studies that included treatment with lenalidomide or lenalidomide and dexamethasone (Mateos et al. N Engl J Med 2013; Lonial et al. J Clin Oncol 2020). Combination therapy with triplets has shown higher rates of deep response and improved outcomes in patients with multiple myeloma, including the combination of ixazomib, lenalidomide, and dexamethasone (Moreau et al. N Eng J Med 2016). We present our results of phase II study of ixazomib, lenalidomide and dexamethasone in HR-SMM. Methods: Patients enrolled on the study met eligibility for high-risk SMM based on the 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: Sixty-one patients have been enrolled in this study from February 2017 to 2020. The median age of the patients at enrollment was 64 years (range, 40 to 84), with 33 males (54.1%). The analysis was conducted on patients who have completed at least 2 cycles of therapy (n=55). Thus far, 42 (69%) patients have completed the planned 24 cycles of therapy. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 14 patients out of the 33 evaluable (42.4%) Interphase fluorescence in situ hybridization (iFISH) results. The median number of cycles completed was 24 cycles (range: 2-24). According to the new IMWG risk stratification model (20-2-20), baseline markers showed that 32 patients (58%) were high risk, 18 (33%) were intermediate risk, and 5 (9%) were low risk. The most common grades 3 or greater toxicities were neutropenia (20%), hypophosphatemia (13%), leukopenia (11%), rash (9%), lymphocytopenia (5%), and thrombocytopenia (5%). Stem cells were collected from all eligible patients by the end of the induction phase. No patients discontinued treatment due to toxicity. At the time of data cut off, the overall response rate (partial response or better) in participants who completed at least 2 cycles of treatment was 90.9% (50 of 55), with 12 complete responses (CR, 21.8%), 10 very good partial responses (VGPR, 18.2%), 28 partial responses (50.9%), and 4 minimal responses (MR, 7.3%). ORR in patients who completed the induction phase (≥9 cycles) was 92.3% (n= 48 of 52), with 22 (40%) deep remissions including 12 (23.1%) and 10 (19.2%) having achieved a CR and VGPR, respectively. All patients who had a CR have also achieved a stringent CR. No patients developed progression to overt or active MM while on study therapy. After completion of study therapy, 4 patients progressed to active MM during follow up, 3 additional patients developed biochemical progression and started a new course of therapy but did not meet CRAB criteria and 7 patients confirmed biochemical PD and remain off therapy. Conclusions: The combination of ixazomib, lenalidomide, and dexamethasone is an effective all oral well-tolerated intervention in high-risk smoldering myeloma that demonstrated an ORR of &gt;90% and deep remission in &gt;40% of patients. While no patients progressed to overt MM while on therapy, some developed progression after completion of planned study therapy, indicating the possible need for higher intensification of therapy or maintenance therapy beyond 2 years in this high-risk group of patients. Longer follow-up for disease outcome is ongoing. Disclosures Nadeem: BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Mo: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Eli Lilly: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; AbbVIE: Consultancy. Sperling: Adaptive: Consultancy. Richardson: AstraZeneca: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene/BMS: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

Advanced Imaging and Targeted Myeloma Lesion Biopsies to Enhance Global Response Assessment and Evaluate Spatial Heterogeneity in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-22
Author(s):  
Sabrina L. Browning ◽  
Terri L. Parker ◽  
Noffar Bar ◽  
Tara Anderson ◽  
Madhav V. Dhodapkar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Assessment ◽  
Advisory Board ◽  
Newly Diagnosed ◽  
Advanced Imaging ◽  
Advisory Committees

Background: Multiple myeloma (MM) is a heterogeneous plasma cell neoplasm with significant genetic and biologic complexity. Limitations remain in our standard assessment of response to therapy, as random bone marrow biopsy may misrepresent the varied histologic and molecular features of this multifocal disease. Advanced imaging is crucial in evaluating bone and extramedullary (EM) lesions. We aim to refine global response assessment in MM, with incorporation of advanced imaging-guided lesion biopsies, to improve knowledge of residual tumor burden critical to patient outcomes. Methods: Patients ≥18 years of age with standard or high risk newly diagnosed clinical MM were eligible to participate in this study. Advanced imaging with positron emission tomography/computed tomography (PET/CT) or whole body magnetic resonance imaging (WB-MRI) based on access, standard bone marrow biopsy and aspiration, and targeted lesion biopsy occurred at enrollment and after 4 cycles of carfilzomib, lenalidomide, and dexamethasone (CRd). Carfilzomib was administered intravenously at a dose of 36 mg/m2 twice weekly, lenalidomide orally 25 mg daily days 1-21, and dexamethasone orally 40 mg weekly, with dose modifications as needed. Conventional clinical response, using IMWG Response Criteria (Kumar S et al, 2016), was assessed after each cycle of treatment. Results: An interim analysis was completed on 17 patients enrolled between June 2018 and March 2020, with 14 evaluable for global treatment response. Median age was 61 years (range, 43-76 years) and 82.4% of patients were male. 76.5% had Revised International Staging System (R-ISS) stage II or III disease and 58.8% had EM disease arising from bone (EM-B, 41.2%) or independently in soft tissue (EM-S, 17.6%). 70.6% of patients had at least one high risk feature at the time of diagnosis (Table 1). Of the 16 patients with conventional skeletal survey (CSS) at study entry, 68.8% had at least 1 myeloma-defining lesion on advanced imaging that was missed on CSS. Four patients had adequate sample from initial lesion biopsy for cytogenetics and fluorescence in situ hybridization (FISH), 3 of whom demonstrated discordant FISH results when compared to standard bone marrow samples. Clinical response rates after 4 cycles of CRd were notable with 85.7% of patients achieving ≥ very good partial response (VGPR) and 3 patients with stringent complete response (sCR) and minimal residual disease (MRD) negativity by flow cytometry with a sensitivity of 10-5. However, of the 12 patients with ≥ VGPR by conventional response assessment, 9 had residual disease on advanced imaging with PET/CT (2 patients), WB-MRI (6 patients), or total spine MRI (1 patient) (Figure 1). Repeat myeloma lesion biopsy was limited to 6 patients with targetable lesions after induction therapy, with diagnostic yield impacted by the presence of sclerotic tissue and insufficient marrow elements in some of the lesions sampled (Table 2). 85.7% of patients continued CRd or proceeded to high dose therapy and autologous stem cell rescue, with no patients transitioning directly to maintenance treatment after 4 cycles of CRd. At a median follow-up of 8 months, 14.3% (2/14) of patients have had progression of disease. Both individuals had residual lesions on imaging at end of treatment, despite one with flow MRD-negative sCR and normal FISH by standard assessment. There were no grade 4 serious adverse events or deaths. Conclusions: In our cohort of high risk newly diagnosed MM, CRd induction was potent and well-tolerated. While deep clinical responses were observed by conventional clinical assessment, two thirds of patients had persistent abnormalities on advanced imaging with concern that these sites could give rise to progressive MM. Our patients demonstrated spatial heterogeneity, highlighting the limitations of standard bone marrow evaluation. Use of advanced imaging and targeted lesion biopsies in response assessment enhances our understanding of tumor growth pattern in MM and consideration could be given to integrating these into clinical care when available. Current limitations of this study include a small number of patients with lesions amendable to repeat biopsy and their incomplete diagnostic yield. Ongoing investigation includes whole exome sequencing of paired bone marrow and focal lesion biopsies and application of a WB-MRI lesion scoring system to further augment this novel response assessment method. Disclosures Anderson: Celgene: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Dhodapkar:Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Lava Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Kite: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board. Prebet:Jazz Pharmaceuticals: Consultancy, Research Funding. Xu:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Haims:Pfizer: Consultancy. Neparidze:Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Diagnostic committee member ; GlaxoSmithKline: Research Funding; Janssen: Research Funding. OffLabel Disclosure: Carfilzomib has been shown to have significant anti-myeloma activity in relapsed myeloma. Phase I/II studies as well as one phase III study also showed favorable outcomes with carfilzomib-based regimens in newly diagnosed multiple myeloma, including in patients with high risk disease. We utilized an induction regimen with carfilzomib, lenalidomide, and dexamethasone given that patients enrolled in this study were required to have bone or soft tissue disease on advanced imaging, indicating a likely high risk feature with potentially aggressive disease biology. It has been shown that the combination of carfilzomib, lenalidomide, and dexamethasone is a safe regimen for patients with multiple myeloma. This combination is approved in the relapsed/refractory setting and included in NCCN guidelines for newly diagnosed multiple myeloma.

scholarly journals Hypomethylating Agent and Venetoclax Combination Therapy Yields Superior Outcomes When Compared to Hypomethylating Agent Monotherapy in Patients ≥70 Years with Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1368-1368 ◽  
Author(s):  
Yumeng Zhang ◽  
Hannah H Asghari ◽  
Onyee Chan ◽  
Dasom Lee ◽  
Martine Extermann ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Response Rates ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Entire Cohort ◽  
Response Data

Background: Older patients with acute myeloid leukemia (AML) have inferior outcomes when compared to younger patients. Hypomethylating agents (HMA) were established as the standard of care for patients who are unfit for intensive induction chemotherapy until HMA and venetoclax (HMA+ven) combination approval by the FDA in December 2018. Approval of HMA+ven was based on an early phase study which produced high response rates; however, the combination was not compared head-to-head with HMA alone. A randomized phase 3 study is currently underway. There is no data available comparing HMA+ven to HMA monotherapy in older patients (age ≥70 years), thus we aimed to characterize responses in older patients when treated with these two regimens. Methods: We retrospectively reviewed clinical and molecular data on 225 patients at Moffitt Cancer Center and Memorial Health System with newly diagnosed AML who were ≥ 70 years old and were treated with HMA monotherapy or HMA+ven combination. Clinical data was abstracted in accordance with institutional review board approved protocol. Patients were then divided in two subgroups: Cohort A) HMA monotherapy and B) HMA+ven combination. We calculated overall response rates (ORR) defined as patients achieving complete remission (CR), CR with incomplete hematologic recovery (CRi) or morphologic leukemia free state (MLFS). Fisher's Exact method was utilized to determine significance for categorical variables. All reported p-values are two sided. Next generation sequencing (NGS) results were analyzed using the TruSight Myeloid-54 gene panel with a sensitivity of 5%, and were characterized in patients treated in cohort B. Results: Among the 225 patients, 87% (n=196) were in cohort A and 13% (n=29) in cohort B. In cohort A, 36.7% were females compared to 27.6% in cohort B. Median age in both cohorts was 76 years (range: 70-90 years in cohort A) (range: 72-86 years in cohort B). Overall, 26% of the patients had adverse risk disease as defined by European Leukemia Net (ELN) classification in cohort A and 51.7% in cohort B. Baseline characteristics are described in Table 1. Overall response rate (ORR) of the entire cohort was 43.6% (n=92) (Table 2). ORR in cohort A was 25.5% (n=47) compared to 66.7% (n=18) in cohort B (p&lt;0.001). The median time to response in cohort A was 3.8 mos and was 1.9 mos in cohort B. Looking only at the 66 patients with ELN-defined adverse risk, response data were available in 62 patients, and the ORR in both cohorts was 25.8% (n=16), and was significantly lower in cohort A compared to B (14.9% vs. 60%, respectively, p=0.001) (Figure 1). Among the 136 patients with favorable or intermediate risk disease, response data were available in 127 patients, and the ORR was 35.4% (n=45). In cohort A the ORR in favorable/intermediate patients was 28.9% (n=37), and in cohort B it was significantly higher at 100% (n=8) (p&lt;0.001). Ten responding patients in cohort B had NGS data available at diagnosis and at the time of best response. Mutations cleared from the bone marrow in 60% (n=6) of these patients. With a median follow up of 11.7 months, the median overall survival (mOS) of the entire cohort was 15.03 months. The median follow-up time in cohort A is 46 months and in cohort B is 5.4 months, making assessment of relapse free survival or overall survival in cohort B premature. Early mortality rate was not different between the two cohorts (1.5% vs 3.4%, p=0.42). Conclusion: Our data provides convincing support that HMA+ven combination yields significantly higher response rates when compared to HMA monotherapy in newly diagnosed AML patients ≥70 years of age; an observation that is further strengthened by the short duration of follow-up in the HMA+Ven cohort. Responses are particularly striking in favorable and intermediate risk patients when treated with HMA+Ven. Overall our data supports the use of HMA+ven in the upfront setting for older patients with newly diagnosed AML. Additional follow-up in HMA+ven arm is needed to evaluate survival outcomes. Disclosures Kuykendall: Incyte: Honoraria, Speakers Bureau; Abbvie: Honoraria; Janssen: Consultancy; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Talati:Celgene: Honoraria; Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria. Sweet:Pfizer: Consultancy; Incyte: Research Funding; Jazz: Speakers Bureau; Stemline: Consultancy; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Prognostic Implications of Multiple Cytogenetic High-Risk Abnormalities in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5615-5615
Author(s):  
Moritz Binder ◽  
S. Vincent Rajkumar ◽  
Rhett P. Ketterling ◽  
Angela Dispenzieri ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Cumulative Effect ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Kaplan Meier ◽  
Prognostic Implications

Abstract Background: Cytogenetic evaluation using fluorescence in situ hybridization (FISH) at the time of diagnosis is essential for initial risk stratification in multiple myeloma. The presence of specific cytogenetic abnormalities is known to confer a poor prognosis, less is known about the cumulative effect of multiple cytogenetic high-risk abnormalities. We aimed to evaluate the prognostic implications of the presence of multiple cytogenetic high-risk abnormalities at the time of diagnosis. Methods: We studied 226 patients who were diagnosed with multiple myeloma between July 2004 and July 2014 at Mayo Clinic Rochester, underwent FISH evaluation within six months of diagnosis, and presented with cytogenetic high-risk abnormalities. High-risk cytogenetics were defined as t(4;14), t(14;16), t(14;20), del(17p), or gain(1q). Bone marrow aspirates were evaluated for deletions, monosomies, trisomies, and tetrasomies using chromosome- or centromere-specific FISH probes. IGH rearrangements were evaluated using an IGH break-apart probe and evaluating up to five potential partners (FGFR3, CCND1, CCND3, MAF, and MAFB). Kaplan-Meier overall survival estimates were calculated and the log-rank test was used to compare overall survival in patients with single and multiple cytogenetic high-risk abnormalities. A multivariable-adjusted Cox regression model was used to assess the effect of multiple cytogenetic high-risk abnormalities on overall survival adjusting for age, sex, and Revised International Staging System (R-ISS) stage. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis was 65 years (32 - 90), 129 (57%) of the patients were male. The median overall survival was 3.5 years (3.1 - 4.9) for the entire cohort (n = 226), 4.0 years (3.3 - 5.1) for those with one cytogenetic high-risk abnormality (n = 182, 80%), and 2.6 years (1.7 - 3.1) for those with two cytogenetic high-risk abnormalities (n = 44, 20%). There were no patients with more than two cytogenetic high-risk abnormalities. Ninety-eight patients (45%) had a high-risk translocation, 77 (35%) had del(17p), 39 (18%) had a high-risk translocation plus del(17p), and 5 (2%) had gain(1q) plus either a high-risk translocation or del(17p). Figure 1 shows the Kaplan-Meier overall survival estimates stratified by the number of cytogenetic high-risk abnormalities (n = 226). The presence of two cytogenetic high-risk abnormalities (compared to one) was of prognostic significance after adjusting for age, sex, and R-ISS stage (HR 2.01, 95% CI 1.27 - 3.19, p = 0.003, n = 205). Conclusions: Approximately one in five patients with newly diagnosed high-risk multiple myeloma presented with two high-risk abnormalities at the time of diagnosis. These patients experienced inferior overall survival suggesting a cumulative effect of multiple cytogenetic high-risk abnormalities. The relatively low number of observed gain(1q) was likely related to the fact that not all patients were evaluated for that abnormality. Therefore the presented hazard ratio represents a conservative effect estimate and may underestimate the true effect. Figure 1 Figure 1. Disclosures Dispenzieri: GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Kumar:Janssen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Kesios: Consultancy; Glycomimetics: Consultancy.

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