RVD Induction Followed by Consolidation with ASCT in Patients with Newly Diagnosed Multiple Myeloma,

Abstract Abstract 4134 Introduction: Lenalidomide, bortezomib, and dexamethasone (RVD) is an active and well tolerated induction regimen in newly diagnosed multiple myeloma (MM). Clinical trials show this regimen to have an overall response rate (ORR) of 95–100%. Appropriately selected patients who receive RVD induction may proceed to consolidation with high-dose therapy and autologous stem cell transplantation (ASCT). In this retrospective study we characterize the experience of patients at our center who received RVD induction followed by ASCT. Methods: Demographic and outcome data were collected retrospectively among patients with MM who underwent ASCT between January 1, 2005 and December 31, 2010 (n=482) and received at least 2 cycles of RVD induction (n=82). Data collected include demographics, disease sub-type and International Staging System (ISS) stage, cytogenetics, treatment summary, treatment-related peripheral neuropathy and venous thromboembolism (VTE), CD34+ stem cell yield, time to hematopoietic recovery post-ASCT, disease response to induction and ASCT, and time to progression after ASCT. Response was based on M-protein or serum free light chain (FLC) response and bone marrow findings. Results: The cohort was 63% male with median age at induction of 57.5 years (range 24 to 71). By ISS stage, 51, 32, 12, and 5% had stage I, II, III, and unknown disease, respectively. Based on cytogenetic findings, 56, 33, and 12% had standard, high, and unknown-risk disease, respectively. IgG was the most common subtype (48% IgG, 24% IgA, and 26% light chain disease). Patients received a median of 5 cycles (range 2 to 16) of RVD induction. 50% of patients reported any-grade peripheral neuropathy. Two patients developed VTE. In 8 (10%) patients, bortezomib or lenalidomide was discontinued due to drug toxicity. In 5 (6%) patients, omission of lenalidomide in the final cycle prior to stem cell collection was planned. Partial response (PR) or better M-protein (or FLC) response was observed in 96% (95% CI: [88%, 99%]) with 44% complete response (CR), 26% very good partial response (VGPR), 26% PR, 4% stable disease (SD) pre-ASCT. 50% of patients who achieved a CR by M-protein response had no evidence of clonal plasma cells in their bone marrow. Sixty-three (77%) patients proceeded directly to ASCT after RVD induction with median time to ASCT 187 days (range 119 to 510). Nineteen (23%) patients received further therapy prior to ASCT: 8 patients to either deepen treatment response prior to ASCT (n=6) or for progressive disease (PD) after a transient response to RVD (n=2), while 11 were either observed (n=7) or received maintenance therapy (n=4) after induction with further therapy for PD or for cytoreduction prior to ASCT. Among patients who received additional therapy, 16% improved their response with median time to ASCT 394 days (range 155 to 975). Median CD34+ stem cell collection was 10.0 × 10^6 (range 2.0 × 10^6 to 75.4 × 10^6). More than 4 × 10^6 stem cells were collected in 95% of patients. Median time to neutrophil and platelet engraftment was 11 (range 6 to 19) and 19 (range 10 to 92) days, respectively. At 100 days post-ASCT, 33% showed improvement in disease response, 59% showed the same response, no one had PD, and 7% had unknown response due to no assessment ≤ 150 days post-ASCT. Lenalidomide maintenance was given to 71% of patients after day 100 post-ASCT. At median follow-up of 12.1 months, 12 subjects progressed and one patient died of angioimmunoblastic lymphoma on day 289 post-ASCT without myeloma progression (3 subjects had no follow-up data). No other second new primary malignancies were reported. The Kaplan-Meier estimate of progression-free survival (PFS) at 12 months post-ASCT is 85% (95% CI:[72;92]). Similar results were observed among the 63 patients who proceeded directly to ASCT. Conclusion: RVD is a well tolerated, highly active induction regimen for patients with newly diagnosed MM. The ORR of 96% and CR rate of 44% to RVD induction prior to ASCT in our study are consistent with previous results. Stem cell collection following RVD induction was successful in all patients and post-ASCT engraftment was rapid. ASCT improved disease response and these responses appear durable at median 12 month follow-up. Data from on-going phase III trials will provide insight in a prospective manner on outcomes after RVD induction followed by ASCT (either early or late) for MM patients. Disclosures: Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Koreth:Millennium Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobrial:Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Munshi:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: 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; Onyx: Membership on an entity's Board of Directors or advisory committees. Anderson:Onyx: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Merck: Consultancy; Acetylon: Founder.

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Upfront Autologous Stem Cell Transplantation for Newly Diagnosed Elderly Multiple Myeloma (MM) Patients: A Prospective Multicenter Study

Blood ◽

10.1182/blood.v126.23.1989.1989 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1989-1989

Author(s):

Laurent Garderet ◽

Cyrille Touzeau ◽

Anne-Marie Stoppa ◽

Denis Caillot ◽

Lionel Karlin ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Median Time ◽

Autologous Stem Cell Transplantation ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Introduction: Previous trials have shown that autologous stem cell transplantation (ASCT) is superior to conventional chemotherapy in terms of remission rate and PFS in younger MM patients. Concerns about toxicity and potential efficacy of ASCT in older MM patients lead most centers to limit ASCT indications to patients aged <65 years. However, at the era of novel induction regimens, and because of better patient selection and supportive care, ASCT may prove to be a valid treatment option even in older MM patients. Therefore, some investigators are questioning the widely used 65 years age limit. Patients and Methods: We prospectively analyzed the outcomes of 56 consecutive MM patients who had received ASCT between September 2012 and September 2014 in 6 institutions in France (protocol ClinicalTrials.gov Identifier: NCT01671826). Patients were newly diagnosed MM. For induction therapy, all patients received a bortezomib-based induction regimen (VD, VTD, VCD, or VRD, 4 to 6 cycles) according to center's local guidelines. Mobilization was performed with G-CSF or G-CSF+cyclophosphamide and plerixafor whenever needed. High-dose chemotherapy consisted of either 140 mg/m2 or 200 mg/m2 Melphalan. A short two months consolidation phase post ASCT was allowed (lenalidomide-dexamethasone, VD, VTD, VCD or VRD). No maintenance treatment was given. Response, disease progression and relapse were defined according to the IMWG uniform response criteria. All patients signed an informed consent form according to the EBMT guidelines. Results: At time of diagnosis, median age was 67 (range, 64-74) years with 23% of patients being >70 years. There were 30 males and 26 females. The immunoglobulin subtype was IgG (n=29), IgA (n=15), light chain (n=10), other (n=2). The Salmon and Durie stage was III in 89% of cases (n=47), and the ISS score was I (n=18; 35%), II (n=19; 37%), III (n=14; 27%). Patients had high risk cytogenetics features (t(4;14) and/or del17p) in 9 cases (16%). 10% of patients had a serum creatinine level >176 micromol/L. None of the patients underwent hemodialysis. The Sorror comorbidity score was 0 (34), 1 (6), 2 (2), 3 (6), 6 (1), unknown (7). The median age at time of ASCT was 68 years, and the median time from diagnosis to ASCT was 5 months. In an intention to treat analysis, out of 56 patients, 6 patients could not proceed to ASCT because of an early infectious death (n=1), serious comorbidity (n=2), disease refractoriness to induction (n=1), and failure to collect an adequate PBSC graft (n=2). A median of 5.31x106/Kg CD34+ cells could be collected. Disease status at time of ASCT was: CR (n=12; 24%), VGPR (n=19; 38%), PR (n=17; 34%), and SD/non-responding (n=2; 4%). The conditioning regimen consisted of 140mg/m² melphalan in 18 cases (36%) and 200mg/m2 in 32 patients (64%). Moreover, 4 patients (8%) received a tandem ASCT. The median time for neutrophils and platelets engraftment was 12 days. The day-100 post ASCT non-relapse mortality was 0% and the 2-year NRM was 4.2% (95% CI:[0.3-18.3]). The overall response rate at day 100 was 96% (CR: 34%, VGPR: 47%, PR: 15%, SD/non-responsive: 4%). At 3 months post ASCT, 82% patients were able to receive the planned post ASCT consolidation treatment. After a median follow-up of 12 months, the estimated progression-free (PFS) and overall survival (OS) rates at 2 years were 76% (95%CI: [61.6-94.1]) and 88% (95%CI: [76.7-100]), respectively. The incidences of infectious complications post ASCT, and response rates were comparable between the two melphalan dose levels (p=0.28). However, in the univariate analysis, the 200 mg/m2 melphalan conditioning group showed a better OS rate compared to the 140 mg/m2 group (1-year OS: 100% vs. 67%; p=0.012). Conclusion: These prospective multicenter results indicate that ASCT is a safe and effective treatment modality for elderly, but fit MM patients at the era of novel induction agents. Of note, patients above age 70 did not experience a worse prognosis. Thus, age per se should not be used as an exclusion criterion for ASCT. Longer follow-up data will be presented, but these results already set the frame for a randomized comparison to the non-transplant approaches in this patients' subgroup. Disclosures Garderet: Bristol-Myers Squibb: Consultancy. Touzeau:AbbVie: Research Funding. Stoppa:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. Karlin:Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees.

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Routine Use of Gemtuzumab Ozogamicin in 7+3-Based Inductions for All "Non-Adverse" Risk AML

Blood ◽

10.1182/blood-2020-142691 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Gavin Hui ◽

Abdullah Ladha ◽

Edna Cheung ◽

Caroline Berube ◽

Steven Coutre ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Gemtuzumab Ozogamicin ◽

Intermediate Risk ◽

Newly Diagnosed ◽

Myeloablative Conditioning ◽

Advisory Committees ◽

Monosomy 7

Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

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A Phase III Study Of ASCT Vs Cyclophosphamide-Lenalidomide-Dexamethasone and Lenalidomide-Prednisone Maintenance Vs Lenalidomide Alone In Newly Diagnosed Myeloma Patients

Blood ◽

10.1182/blood.v122.21.763.763 ◽

2013 ◽

Vol 122 (21) ◽

pp. 763-763 ◽

Cited By ~ 16

Author(s):

Antonio Palumbo ◽

Francesca Gay ◽

Andrew Spencer ◽

Francesco Di Raimondo ◽

Adam Zdenek ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Study Endpoint ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

To Receive

Abstract Background High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). The introduction of novel agents challenged the role of ASCT at diagnosis. We conducted a multicenter 2X2 randomized trial comparing conventional chemotherapy plus lenalidomide with ASCT followed by maintenance with lenalidomide-prednisone (RP) or lenalidomide (R) alone in newly diagnosed young MM (NDMM) patients. Methods Eligible patients with NDMM ≤ 65 years were enrolled. All patients received Rd induction (four 28-day cycles of lenalidomide 25 mg day 1–21 and low-dose dexamethasone 40 mg day 1,8,15,22) followed by stem cell mobilization. Patients were randomized to receive consolidation with CRD [six 28-day cycles of cyclophosphamide (300 mg/m2 day 1,8,15), dexamethasone (40 mg days 1,8,15,22) and lenalidomide (25 mg days 1–21)] or MEL200-ASCT (melphalan 200 mg/m2 with stem-cell support). Patients were randomly assigned to receive subsequent maintenance with RP (28-day cycles of lenalidomide 25 mg days 1–21 plus prednisone 50 mg every other day) or R alone (28-day cycles of lenalidomide 25 mg days 1–21). Primary study endpoint was progression-free survival (PFS); secondary endpoints included safety, responses and overall survival (OS). Data cut off was May 30th, 2013. Results Three-hundred and eighty-nine patients were enrolled in the trial. Patient characteristics were well balanced between CRD (n=194) and MEL200-ASCT (n=195), and between R (n=195) and RP (n=194) arms. Median follow-up was 31 months. In the intent to treat (ITT) analysis, the median PFS was not reached with MEL200-ASCT and 28 months with CRD (the respective 3-year PFS was 60% vs. 38%, HR=0.62, 95%CI: 0.49-0.85, P=0.003). Median time from enrolment to maintenance was 14 months. In the population of patients eligible for maintenance, 2-year PFS from the start of maintenance was 73% for RP and 56% for R patients (HR= 0.57, 95%CI: 0.34-0.93; P=0.03). In the subgroup of patients who received MEL200-ASCT, 2-year PFS from the start of maintenance was 83% for patients who received RP and 64% for those who received R alone (HR=0.36 95%CI: 0.15-0.87, P=0.02). In the subgroup of patients who received CRD, 2-year PFS from the start of maintenance was 64% for patients who received RP and 47% for those who received R alone (HR=0.75, 95%CI: 0.40-1.39, P=0.36). At present, no differences in OS were noticed between patients randomised to received CRD or MEL200-ASCT, and between patients who received RP or R maintenance. As expected, the rates of grade 3-4 hematologic (85% vs. 26%, P<0.001) and non-hematologic (35% vs. 19%, P=0.003) adverse events (AEs) were higher in the MEL200-ASCT arm compared with the CRD arm. The main non-hematologic AEs were infections (18% vs. 5%, P=0.001) and gastrointestinal AEs (18% vs. 3%, P<0.001). Rates of grade 3-4 hematologic (8% vs. 7%, P=0.85) and non-hematologic (12% vs. 13%, P=0.88). AEs were similar in the RP and R arms. The main non-hematologic AEs in both RP and R groups were infections (3% vs. 3%). At present, 6 second primary malignancies and 3 cases of cutaneous basalioma have been reported. Conclusions MEL200-ASCT significantly prolonged PFS in comparison with CRD. At present no difference in OS was reported, this may be due to the low number of events and to the length of follow-up. The increase in toxicity with MEL200-ASCT did not adversely impact on efficacy. The addition of prednisone to lenalidomide maintenance significantly reduced the risk of progression in comparison with lenalidomide alone, without increasing the toxicity. Updated data with longer follow-up will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Gay:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Spencer:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Larocca:Celgene: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Petrucci:Celgene: Honoraria. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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

Blood ◽

10.1182/blood.v122.21.3216.3216 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3216-3216 ◽

Cited By ~ 2

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.

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Phase 2 Study Of Bendamustine, Bortezomib (Velcade) and Prednisone (BVP) For Newly Diagnosed Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v122.21.2155.2155 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2155-2155 ◽

Cited By ~ 2

Author(s):

Maria-Victoria Mateos ◽

Albert Oriol ◽

Laura Rosiñol ◽

Felipe de Arriba ◽

Jesús Martín ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Response Rates ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cd34 Cells ◽

Stem Cell Collection ◽

Poor Mobilizers

Abstract Background Bortezomib-based combinations, including alkylating agents (VMP or CyBorD) or immunomodulatory drugs (VTD or RVD) have been established as regimens widely used in newly diagnosed MM patients. Bendamustine is a bifunctional alkylating agent effective in relapsed and/or refractory MM patients, and approved in Europe in combination with prednisone for elderly newly diagnosed MM. Since bendamustine may be more efficient than other alkylators, an attractive possibility would be to explore it in combination with bortezomib and prednisone (BVP) in newly diagnosed MM patients both transplant and non transplant candidates. Patients and Methods 60 newly diagnosed MM patients were included in the trial. The first cycle consisted on bendamustine at 90 mg/m2 given IV on days 1 and 4, in combination with bortezomib at 1,3 mg/m2 given IV on days 1, 4, 8, 11, 22, 25, 29 and 32 and prednisone at 60 mg/m2 given PO on days 1 to 4. In the following cycles, bendamustine was given on days 1 and 8, and bortezomib on days 1, 8, 15 and 22 (weekly schedule), and prednisone as it was previously described. Patients younger than 65 years proceeded to peripheral blood stem cell collection (PBSC) using growth factors alone after 4 cycles; HDT-ASCT was performed after 6 cycles. Patients older than 65 years received up to nine 28-day cycles. Results Between May 2011 and July 2012 enrollment was completed (60 pts). Median age was 61 years (range 38-82; 18 pts ≥65), 67% had ISS stage II/III, and 67% had unfavorable cytogenetics: t(4;14), t(14;16), del 17p or 1q gains by FISH. After a median of 6 cycles (2-9), 75% of patients achieved at least PR, including 16% of sCR, 9% CR and 28% of VGPR. Although the differences were not statistically significant, there was a trend to higher CR rate in the group of patients <65 years (31%) compared with elderly patients (11%). No differences were observed in overall response rates and CR rates in patients with standard and high risk cytogenetic abnormalities. Forty patients proceeded to stem cell collection after a median of 4 cycles of BVP. Upon using G-CSF alone, 14 pts (35%) failed to collect a minimun of 2 x 106 CD34+ cells/Kg. An ammendment was done and plerixafor was recomended for poor mobilizers (peripheral CD34 cell count inferior to 10/μL on day 4); all patients but 2 achieved, with G-CSF plus plerixafor, the minimum of CD34+ cells required to proceed to ASCT. These 2 patients successfully collected CD34+ cells using chemotherapy plus G-CSF and plerixafor. Of the 31 patients who received HDT-ASCT, sCR and CR rate before transplant was 18% and 13%, respectively, upgrading up to 39% of sCR and 13% CR after transplant. 7 pts (22%) achieved immunophenotypic CR. After a median f/u of 12 months (5-25), 8 pts have progressed, resulting in a 15-m TTP of 85%. Concerning OS, 89% of patients remained alive at 15 months. None of patients achieving sCR and CR have progressed and all of them are alive at 15 months. Regarding cytogenetic abnormalities, although there were not significant differences, one patient progressed in standard risk group and five in the high risk subgroup resulting in a 15 m-TTP of 93% vs 85%. No significant differences have been observed in terms of 15 m-OS between standard and high risk cytogenetic subgroup (100% vs 92%, respectively). As far as toxicity is concerned, hematologic toxicities included: G3/4 anemia (11%), neutropenia (23%), and thrombocytopenia (14%). The most common G3/4 non-hematologic toxicities were: asthenia (10%), infections (9%), and peripheral neuropathy (4%). Conclusions In patients candidates to HDT-ASCT, response rates obtained before and after transplant are comparable to other three drug bortezomib-based combinations, such as VTD or CyBorD. However, growth factors alone for stem cell collection after four BVP cycles as induction resulted in a 35% of poor mobilizers who were rescued with plerixafor. In the elderly population, although the number of patients included was small, BVP seems not superior to VMP in response rates. Disclosures: Mateos: Janssen, Mundipharma: Honoraria. Off Label Use: bendamustine plus bortezomib and prednisone is not an approved combination for first line of therapy. Oriol:Celgene: Consultancy. Ocio:Onyx: Consultancy, Research Funding; Novartis: Consultancy; Array Biopharma: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding. Alegre:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Bladé:Janssen, Mundipharma: Honoraria. San Miguel:Janssen, Mundipharma: Membership on an entity’s Board of Directors or advisory committees.

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Splenic Irradiation and a Reduced-Intensity Conditioning Regimen Prior to Allogeneic Stem-Cell Transplantation for Myelofibrosis

Blood ◽

10.1182/blood.v124.21.3170.3170 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3170-3170 ◽

Cited By ~ 2

Author(s):

Ojas H. Vyas ◽

Esha Kaul ◽

Aaron S. Rosenberg ◽

Gunjan L Shah ◽

Urvi Ajay Shah ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Conditioning Regimen ◽

Advisory Committees ◽

Disease Response ◽

Hematologic Response ◽

Complete Hematologic Response

Abstract Background: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with myelofibrosis (MF). Reduced-intensity conditioning (RIC) regimens have been used to extend this therapy to older and sicker patients. Splenectomy prior to HSCT for MF has been shown to enhance neutrophil engraftment and decrease transfusion requirements, but has a reported operative mortality of 9% or higher. Splenic irradiation (sXRT) has been historically used as a palliative treatment in MF. We present our experience with a RIC regimen incorporating extracorporeal photopheresis (ECP) in combination with either pre-HSCT splenectomy or sXRT. Methods: The Tufts BMT database, the Center for International Bone Marrow Transplantation Registry (CIBMTR) database, and chart review were used to gather data. All patients underwent conditioning consisting of ECP administered on days -6 and -5, pentostatin 4mg/m2by continuous infusion over 48 hours on days -4 and -3, and a total dose of 600 cGy total body irradiation (TBI) administered in 3 fractions on days -2 and -1 (PPT). sXRT, when employed, was given in the week prior to start of PPT (days -6 to -11) with total doses ranging from 300 to 500cGy. Cyclosporine and methotrexate were used for GVHD prophylaxis. Patients surviving a minimum of six months were considered evaluable for response assessment. Complete hematologic response was defined as resolution of clinical signs of MF as well as normalization of peripheral blood counts (Hgb>10gm/dL, ANC>1000/µL, Platelets >100K and all counts below upper limit of normal) and the absence circulating blasts. Histological response could not be assessed due to lack of follow-up bone marrow data. Clinical improvement, stable disease, progressive disease, spleen response were defined using revised IWG-MRT guidelines. Overall survival (OS) was estimated using the Kaplan Meier method from time of stem cell transplant to death. Non-relapse mortality (NRM) was estimated from time of transplant to death, treating death due to MF and relapse as competing risks. Results: Ten patients (7 females, 3 males) with MF underwent allogeneic HSCT with PPT conditioning between February 2001 and December 2012. Median age was 54 years (40-60 years). Median time from diagnosis to transplant was 48 months (6-137 months). MF was primary in 8 and secondary to essential thrombocytosis in 2 patients. According to DIPSS scoring, 1, 2, 5 and 2 patients were low, intermediate-1, intermediate-2 and high risk respectively. Donors were equally distributed between matched related and matched unrelated. Bone marrow was used as the source in all but one patient. Nine patients (90%) had palpable splenomegaly. Six underwent splenectomy of which 1 died of a related complication (sepsis from abscess in the splenic bed). Three received sXRT prior to HSCT with no associated complications. All but one patient (who had a prior splenectomy) engrafted successfully. Median time to engraftment was 18 days (sXRT 18 days, splenectomy 19 days) for neutrophils and 26 days for platelets regardless of splenic therapy. Only 2 patients developed acute grade III-IV GVHD and 1 patient developed extensive chronic GVHD. 4/7 patients with a prior splenectomy were evaluable for disease response. Of these 2 had complete hematologic response, 1 had clinical improvement with eventual relapse, and 1 had progressive disease. Among the 3 patients receiving sXRT, 2 patients had complete hematologic response as well as a spleen response and 1 had stable disease.Three patients were alive at last follow-up. Causes of death included disease relapse (n=2), GVHD (=3) and sepsis (n=2). Cumulative incidence of NRM was 40% at 1 year. Five year OS was estimated at 30%. Discussion: Our data demonstrates that splenic XRT is well tolerated and equivalent to splenectomy in terms of engraftment outcomes and disease response. Survival and GVHD outcomes with PPT conditioning were similar to those reported with other RIC regimens. PPT is a reasonable conditioning regimen for these patients. Further study to optimize timing of HSCT and patient selection to reduce NRM is needed. Disclosures Comenzo: Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Effect of Autologous Transplantation on PFS2 in Myeloma Patients Receiving Front-Line Bird (clarithromycin, lenalidomide, dexamethasone)

Blood ◽

10.1182/blood.v124.21.5778.5778 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5778-5778

Author(s):

Ekta Aneja ◽

Adriana C Rossi ◽

Tomer M Mark ◽

David Jayabalan ◽

Roger Pearse ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Second Line ◽

Newly Diagnosed ◽

Advisory Committees ◽

Line Therapy ◽

Progression Of Disease

Abstract Background: BiRd (clarithromycin, lenalidomide, dexamethasone) combination therapy yields >90% overall response rates in newly diagnosed patients with symptomatic multiple myeloma (MM). Long term follow up of the phase II BiRd study revealed 49% of patients went on to receive autologous hematopoietic stem cell transplants (ASCT), either as consolidation or salvage. Here we evaluate progression free survival 2 (PFS2) and overall survival (OS) in our cohort of patients, and assess the impact of ASCT. Methods: Seventy-two patients with newly diagnosed MM were enrolled on the BiRd trial between Dec 2004 and Nov 2006. BiRd is lenalidomide 25mg PO daily (d1-21), clarithromycin 500mg PO BID, dexamethasone 40mg PO weekly, for 28 day cycle. Patients remained on BiRd until progression of disease, consolidation with autologous stem cell transplant (ASCT), or unacceptable toxicity, and all continued to be monitored through subsequent lines of therapy. We performed a retrospective chart review of all patients enrolled in the BiRd trial. PFS2 was defined as the time elapsed from start of BiRd until progression of disease on 2nd line therapy. Results: With over 8 years of follow up, 6 patients remain on continuous BiRd, 28 received ASCT consolidation, and another 6 received ASCT as salvage. Nine patients died on induction therapy and the remaining patients received second line chemotherapy. Patients were stratified by no ASCT, consolidation ASCT and salvage ASCT. Median PFS2 was 98 months, 94 months, and 53 months, respectively (p<0.22). Twenty-three patients died during second line therapy. Median OS was not reached, 102 months, and 55 months respectively (p<0.92). Discussion: Advances in the treatment of patients with multiple myeloma over the past decade have introduced increasing numbers of therapeutic options, improving survival considerably. While multiple myeloma is still considered an incurable disease, patients today will likely receive several lines of therapy. The contribution and timing of each option must be considered. In our cohort of patients, receiving ASCT in the salvage setting trended toward shorter PFS, however failed to reach statistical significance. Consolidation with ASCT in our patient cohort did not translate into survival advantage. The optimal timing and utility of ASCT in the era of novel agents and increasing treatment options warrants further review, and is an area of active investigation. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Rossi: celgene: Speakers Bureau; millenium: Speakers Bureau. Mark:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Pekle:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Coleman:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Speakers Bureau. Niesvizky:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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

Blood ◽

10.1182/blood-2019-131476 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 864-864 ◽

Cited By ~ 5

Author(s):

Prashant Kapoor ◽

Morie A. Gertz ◽

Betsy Laplant ◽

Gabriella C Malave ◽

Eric Wolfe ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Partial Response ◽

Board Of Directors ◽

Research Funding ◽

Phase 2 ◽

Newly Diagnosed ◽

Advisory Committees ◽

Increased Risk

Background: The current commonly used regimens in newly diagnosed multiple myeloma (NDMM) utilize steroids (dexamethasone or prednisone) in various combinations: bortezomib, lenalidomide and dexamethasone (VRd), bortezomib, thalidomide and dexamethasone (VTd), daratumumab, lenalidomide and dexamethasone (DRd) and daratumumab, bortezomib, melphalan and prednisone (DVMP). However, steroid therapy may be associated with various adverse effects, including, but not limited to mood changes, insomnia, hypertension, hyperglycemia, osteoporosis, adrenal suppression, muscle weakness, and increased risk of opportunistic infections. A recent trial demonstrated improved tolerability of a regimen (Rd-R) involving an abbreviated course of dexamethasone, without compromising the efficacy in patients with intermediate-fit NDMM (Lorocca A., et al., ASH 2018). We designed a phase 2 clinical trial to examine the safety and efficacy of daratumumab, an anti-CD38 monoclonal antibody in combination with an all-oral regimen of ixazomib, a proteasome inhibitor, lenalidomide, an immunomodulatory drug, and modified dose dexamethasone (IRd). Patients and Methods: NDMM patients 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 (CR) to daratumumab-IRd. Treatment consisted of daratumumab, 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and then every 4 weeks, ixazomib, 4 mg days 1, 8, 15, lenalidomide, 25 mg days 1-21, and dexamethasone upto 40 mg intravenously weekly for no more than two cycles, followed by use only as a prophylactic premedication for daratumumab-associated infusion reactions. Myeloma risk stratification was assessed by cytoplasmic immunoglobulin fluorescence in-situ hybridization (cIg FISH) analysis. Results: Overall, 40 patients were accrued, with data available on all patients for analysis at the cutoff date of July 19, 2019. The median age at enrollment was 64.5 (33-81) years; 37.5% were female. Eight (20%) patients were high risk by FISH. The median number of cycles was 6 (2-11) and the median follow up was 6.1 (2-11.7) months. Among 40 patients who had received at least 2 cycles of therapy, responses were attained rapidly; at the end of cycle 2, 88% patients achieved at least a partial response and 33% at least a very good partial response (VGPR) that improved to 52% at the end of 4 cycles among 29 patients who had completed at least 4 cycles. The overall best confirmed response rate among all 40 patients (Figure 1) was 95%, including 10% stringent CR, 5% CR and 23% near CR (13% VGPR excluding nCR). Stem cell collection was completed in 17 patients so far, all of whom required filgrastim and plerixafor. The median CD34+ cell count was 7.7 (range 2.9-11.6) million/kg . All patients were alive and 39 (97.5%) patients were progression-free at last follow up. Four (10%) patients proceeded to autologous stem cell transplantation off study, per patient and/or investigator discretion (1 in CR, 2 in PR, 1 with progressive disease). Overall, 224 cycles have been administered across the study, with dose reduction/ hold required in a subset of patients; ixazomib (10%), lenalidomide (20%), daratumumab (0%) and dexamethasone (13%); the most frequent reasons for dose adjustment were skin rash and hematologic toxicities. A grade 3 or higher adverse event, at least possibly attributed to the study drugs, was observed in 40% of patients; hematologic in 30% (lymphopenia 25%, neutropenia 15%, thrombocytopenia 5% and anemia 2.5%) and non-hematologic in 18% of patients (hyperglycemia 8%, diarrhea 5%, infections 5%, ileus 2.5%, maculopapular rash 2.5%, and fatigue 2.5%). Updated results with additional 6 months of follow up and minimal residual disease assessment related data will be presented at the meeting. Conclusion: Our early results suggest that the combination of daratumumab, ixazomib, lenalidomide and modified dose dexamethasone is well-tolerated, with excellent activity, and does not adversely impact stem-cell mobilization in patients with NDMM. Disclosures Kapoor: Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Janssen: Research Funding; Glaxo Smith Kline: Research Funding; Cellectar: Consultancy. Gertz:Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Dispenzieri:Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. OffLabel Disclosure: Daratumumab in combination with Ixazomib, lenalidomide and dexamethasone for the management of newly diagnosed multiple myeloma

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A Phase II Study of Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma

Blood ◽

10.1182/blood-2021-146284 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 5043-5043

Author(s):

Elizabeth K. O'Donnell ◽

Clifton C. Mo ◽

Andrew J. Yee ◽

Omar Nadeem ◽

Andrew R. Branagan ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibody ◽

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Residual Disease ◽

Newly Diagnosed ◽

Advisory Committees ◽

Stem Cell Collection ◽

Minimal Residual

Abstract Background: Clinical data support the combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid for the treatment of newly diagnosed multiple myeloma (NDMM). Recently, the GRIFFIN study evaluated the addition of the CD38 antibody, daratumumab to lenalidomide, bortezomib, and dexamethasone in transplant-eligible NDMM and demonstrated improved efficacy with an acceptable safety profile. Isatuximab is a newer CD38 monoclonal antibody that binds to a specific epitope of the CD38 receptor. In addition to antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity, isatuximab eliminates MM cells via direct apoptosis without the need for crosslinking. Isatuximab enhances immune function by boosting the activation and cytotoxic activity of natural killer cells and by depleting CD38+ immune suppressor cells such as regulatory T cells and inducing clonal expansion of T cells. Isatuximab is approved in combination with carfilzomib and dexamethasone for relapsed, refractory MM based on the results of the IKEMA study. The MANHATTAN study evaluated the 4-drug combination of daratumumab, lenalidomide, carfilzomib, and dexamethasone. The primary end point, minimal residual disease negativity was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%). Building upon these data, our study evaluates the addition of isatuximab to weekly carfilzomib, lenalidomide, and dexamethasone. Study Design and Methods: A phase II, open-label clinical trial is being conducted to evaluate the efficacy of once weekly carfilzomib, lenalidomide, dexamethasone, and isatuximab (Isa-KRd) in 50 patients with newly diagnosed, transplant-eligible MM (NCT04430894). Eligible patients will have NDMM, age ≥18 years, ECOG PS of 0-2, and are deemed eligible for stem cell transplantation (SCT). All patients will receive 4 cycles of induction therapy with Isa-KRd followed by stem cell collection with the option to either proceed to upfront SCT versus deferred SCT. Patients undergoing upfront SCT will receive 4 cycles of therapy followed by stem cell collection, high-dose chemotherapy, and autologous SCT followed by 2 additional cycles of therapy then maintenance. Patients deferring SCT following collection will receive 4 cycles of therapy followed by stem cell collection followed by 4 additional cycles of therapy then maintenance. Each 28-day cycle will consist of isatuximab 10 mg/kg IV Q1 week for 8 weeks, then Q2 weeks for 16 weeks, thereafter Q4 weeks; carfilzomib (20 mg/m 2 Day 1 only) 56 mg/m 2 IV on Days 1, 8, 15; lenalidomide 25 mg po on Days 1-21; and dexamethasone 20 mg po day of and day after all doses of carfilzomib (Days 1, 2, 8, 9, 15, and 16) and isatuximab (Cycles 1 and 2 Days 22 and 23). For maintenance, patients will be stratified based on cytogenetics (high-risk cytogenetics include deletion (del) 17p, translocation t(4:14), t(14;16), t(14;20)). Patients with standard-risk cytogenetics will receive lenalidomide 10 mg po Days 1-21. Patients with high-risk cytogenetics will receive carfilzomib 56 mg/m 2 Days 1, 15; lenalidomide 10 mg po Days 1-21; and isatuximab 10 mg/kg IV Day 1. Dexamethasone, 20 mg orally or IV will be administered to patients as a pre-infusion medication prior to isatuximab dosing. Main Outcomes and Measures: The primary end point is complete response (CR + stringent CR) rate after 4 cycles of Isa-KRd as assessed by the International Myeloma Working Group (IMWG) Uniform Response Criteria. Secondary endpoints include determining safety and tolerability of Isa-KRd, minimal residual disease (MRD) after 4 cycles, at completion of consolidation (post-transplant) or induction (transplant-deferred), and sustained MRD at 24 months, progression-free survival, overall survival rates, and quality of life. Efficacy analysis will be performed both in the intent-to-treat (ITT) population and efficacy evaluable (EE) population. The ITT population will include all treated patients, and the EE population will include all patients who receive at least 1 cycle of study drug. The primary analysis will be based on the EE population, and will use the investigator-assessed response data evaluated according to consensus recommendations based on the IMWG criteria. CR (CR+sCR) rate after 4 cycles of Isa-KRd will be reported with 90% confidence interval. Support: Amgen and Sanofi Figure 1 Figure 1. Disclosures O'Donnell: Oncopeptide: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Bristol Myer Squibb: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy. Mo: Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee: Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy; Oncopeptides: Consultancy; Adaptive: Consultancy; Janssen: Consultancy; GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Nadeem: GSK: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy; Bristol Myer Squibb: Consultancy. Branagan: Sanofi-Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive: Consultancy; CSL Behring: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rosenblatt: Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imaging Endpoints: Consultancy; Attivare: Consultancy; Wolters Kluwer Health Inc: Consultancy, Patents & Royalties. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Richardson: AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Oncopeptides: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AstraZeneca: Consultancy; Regeneron: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding.

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Maintenance Therapy With Lenalidomide Significantly Improved Survival Of Yong Newly Diagnosed Multiple Myeloma Patients

Blood ◽

10.1182/blood.v122.21.2089.2089 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2089-2089 ◽

Cited By ~ 10

Author(s):

Francesca Gay ◽

Federica Cavallo ◽

Tommaso Caravita ◽

Maide Cavalli ◽

Arnon Nagler ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Maintenance Therapy ◽

Board Of Directors ◽

Solid Tumors ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3

Abstract Background High-dose chemotherapy (HDT) with autologous stem cell transplant improves outcome of multiple myeloma (MM) patients in comparison to conventional chemotherapy. The incorporation of new drugs into induction, consolidation and maintenance therapy is changing the treatment paradigm and is questioning the role of HDT in newly diagnosed MM (NDMM) patients <65 years. Previous finding have been presented (Boccadoro, ASCO 2013) and this analysis provides a longer follow-up. Aims To compare in a prospective randomized trial melphalan-prednisone-lenalidomide (MPR) with tandem melphalan (200 mg/m2) (MEL200) both followed by maintenance with lenalidomide or no maintenance in NDMM patients. Methods A 2x2 factorial randomized trial was designed. The induction treatment consisted of four 28-day cycles of lenalidomide (25 mg d 1-21) and low-dose dexamethasone (40 mg d 1,8,15,22) (Rd). As consolidation, patients were randomized to MPR (N=202) [six 28-day cycles of melphalan (0.18 mg/k g d 1-4), prednisone (2 mg/kg d 1-4) and lenalidomide (10 mg d 1-21)] or MEL200 (N=200)[tandem melphalan 200 mg/m2 with stem-cell support]. Patients were further randomized, within each group, to receive lenalidomide maintenance (10 mg, days 1-21, N=198) or no maintenance (N=204). Primary study endpoint was progression free survival (PFS). The secondary study endpoints included response rates, safety and overall survival (OS). Data were analyzed in the intent-to-treat (ITT) population. Results From November 2007 to July 2009, 402 patients with NDMM <65 years of age were enrolled. All patients were stratified according to International Staging System (ISS) and age. Patient characteristics were well balanced in all groups. In the MPR group, the Very Good Partial Response (VGPR) rate was 50% with 13% of Complete Response (CR) while the VGPR rate was 52% including 19% of CR in the MEL200 group. In the MPR group the CR rate improved from 13% after consolidation to 17% after maintenance. In the MEL200 group the CR rate improved from 19% after consolidation to 25% after maintenance. After a median follow-up of 48 months, the median PFS was 24.2 months in MPR group and 38.6 months in MEL200 group ( P< 0.0001). A multivariate analysis confirms the PFS benefit associated with MEL200 across all subgroups of patients defined by stratification factors and baseline characteristics. The 5-year OS rate was similar between MPR (62%) and MEL200 (71%; P= 0.27). In a landmark analysis, lenalidomide maintenance significantly extended PFS from the start of maintenance (median 42,7 months) compared with no maintenance (median 17.5 months; P<.0001). The 4-year OS rate from the start of maintenance was higher in patients who received lenalidomide maintenance (80%) compared with patients who did not (62%; P= 0,01). No significant interaction was detected between MPR/MEL200 (P=0.704) and maintenance/observation (P=0.984) effects. During consolidation, the incidence of grade 3-4 adverse events (AEs) between MPR and MEL200 were as follow: neutropenia (50% vs. 90%), thrombocytopenia (8% vs. 89%), infections (1% vs. 15%) and gastrointestinal (0% vs. 18%), with complications being higher with MEL200. During the maintenance phase, grade 3-4 hematologic AEs were reported in 17% of patients receiving lenalidomide (16% neutropenia). For individual group comparisons during maintenance, grade 3-4 hematologic AEs were observed in 20% of patients receiving MPR plus lenalidomide maintenance compared with 15% receiving MEL200 plus lenalidomide maintenance. Second primary malignancies were observed in 11 patients (3%), and were mainly solid tumors. Four solid tumors were observed in the MEL200 group and one in the MPR group in the maintenance arm, while three solid tumors were observed in the MEL200 group and three in the MPR group in no maintenance arm. Conclusion The administration of MPR was significantly inferior to MEL200 in terms of PFS. Toxicities were significantly higher in MEL200 group, but manageable. OS is similar between MPR and MEL200. Lenalidomide maintenance significantly reduced the risk of progression and of death independently from the previous treatment. Disclosures: Gay: Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Cavallo:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Caravita:Celgene: Honoraria, Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

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