Lenalidomide (Revlimid), Bortezomib (Velcade) and Dexamethasone (RVD) for Heavily Pretreated Relapsed or Refractory Multiple Myeloma

Abstract Abstract 5028 Lenalidomide (len) and bortezomib (btz) are active in multiple myeloma (MM). In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone (Mitsiades N, et al). The combination of lenalidomide (Revlimid), bortezomib (velcade), and dexamethasone (RVD) has shown excellent efficacy in relapsed/refractory (rel/ref) multiple myeloma (MM) patients (pts), with an overall response rate (ORR) of 84% and a partial response (PR) rate of 68%, including 21% complete/near complete responses (CR/nCR), median duration of response was 24 weeks in responding patients and median number of cycles was 6 (Anderson KC, et al. ASCO 2009: abstract 8536). The aim of this study is to assess the efficacy and toxicity profile when len is used in combination with btz and dexamethasone (dex) for pts with relapsed/refractory (rel/ref) disease outside the setting of clinical trials. Patients and Methods We retrospectively reviewed the records of all pts with rel/ref MM who were treated with RVD at Princess Margaret Hospital between March 2009 and March 2010. Eighteen pts were treated with at least 1 full cycle of RVD therapy given as len 10 mg/d on days 1–14, btz 1.0 or 1.3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles and dex (20 mg or 40 mg on days of and after btz). Pts routinely received concomitant antithrombotic and antiviral prophylaxis. Primary endpoints were response rate, time to progression (TTP) and toxicity. Responses were assessed according to modified EBMT and Uniform criteria. Toxicity was assessed using NCI-CTC, version 3.0. Results Clinical characteristics are seen in Table 1. Median age was 57 (37-71) years; 55% were female. The median number of prior therapies was 3 (2-6), and the majority of pts had already been treated with len (83%) and btz (78%) separately, and 77% had received both drugs previously but not in combination. In many instances, pts previously treated with len had len added to btz + dex at progression (n=5), or pts previously treated with btz had btz added to len + dex, at progression (n=4). After a median of 4.9 cycles (range 1–14), PR was observed in 7 (39%) and stable disease (SD) in 2 (11%) pts, for an ORR of 39%. Disease progression was seen in 14 pts at a median TTP of 4 months (1-13.6 months). Currently, 6 pts (33%) remain alive at a median F/U of 6.83 months (1.4-18.6 months). Median overall survival was 6.88 months (1-18.6 months) and six patients had a greater than 6 month response. Six pts have experienced grade 3/4 adverse events, including anemia, neutropenia, muscle weakness, hyperglycemia, and pneumonia. No deep vein thrombosis was observed. The side effect profile was manageable; importantly no patient experienced worsening of peripheral neuropathy. Conclusions The ORR for our heavily treated patient population was 39% which is lower than that reported by Anderson et al (ASCO, 2009). The median TTP was also short at 4 months. These differences can be partly explained by the fact the majority of our pts had previously received all the agents in RVD, while only 8% of the pts in the Anderson series had prior len exposure. These data suggest that the RVD combination can be effective in rel/ref MM, but responses/duration are affected by very advanced disease stage at relapse and the extent of prior treatment. Disclosures: Reece: Celgene: Honoraria, Research Funding. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

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Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.20.02259 ◽

2020 ◽

pp. JCO.20.02259

Author(s):

Paul G. Richardson ◽

Albert Oriol ◽

Alessandra Larocca ◽

Joan Bladé ◽

Michele Cavo ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Overall Response Rate ◽

Response Rate ◽

Progression Free Survival ◽

Free Survival ◽

Duration Of Response ◽

Heavily Pretreated ◽

Grade 3

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

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

Blood ◽

10.1182/blood.v116.21.3055.3055 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3055-3055

Author(s):

Donna E. Reece ◽

Esther Masih-Khan ◽

Arooj Khan ◽

Saima Dean ◽

Sharon Fung ◽

...

Keyword(s):

Multiple Myeloma ◽

Dose Level ◽

Research Funding ◽

Response Rate ◽

Objective Response ◽

Median Number ◽

Prior Therapy ◽

Best Response ◽

Level 3 ◽

Grade 3

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

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Phase 1 Study of Tabalumab, a Human Anti-BAFF Antibody and Bortezomib in Patients with Previously-Treated Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.447.447 ◽

2012 ◽

Vol 120 (21) ◽

pp. 447-447 ◽

Cited By ~ 6

Author(s):

Noopur Raje ◽

Edward Anthony Faber ◽

Paul G. Richardson ◽

Gary J. Schiller ◽

Raymond J. Hohl ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Median Number ◽

Phase 1 Study ◽

Advisory Committees ◽

Baseline Serum ◽

Lower Baseline ◽

Previously Treated

Abstract Abstract 447 Background: Tabalumab, a human mAb that neutralizes membrane-bound and soluble B cell activating factor (BAFF), has demonstrated both anti-myeloma activity and osteoclastogenesis inhibition in xenograft models of multiple myeloma (MM). We initially conducted a Phase 1 study with the combination of tabalumab and bortezomib in previously-treated MM patients who were not refractory to bortezomib. The results from the dose escalation (Part A) have been previously reported, where a tabalumab dose of 100 mg was selected based on several factors, most notably the stabilization of the peak to trough concentration ratio. The cohort expansion (Part B) has since completed enrollment, and we now report the preliminary results for the entire study. Methods: The primary objective was to identify a safe and potentially efficacious dose of tabalumab to be combined with bortezomib. Bortezomib was given in a standard biweekly fashion, 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21 day cycle, and tabalumab at 1, 10, 30, 100, or 300 mg (Part A) or 100 mg (Part B) IV (30 min) on day 1 in Cycles 1 – 3, 5, and 7. The study was later amended to include dexamethasone to assess safety, and 12 patients received dexamethasone in combination with bortezomib and tabalumab. Response was assessed per IMWG criteria and adverse events per CTCAE v3.0. Pharmacokinetic (PK) and pharmacodynamic (PD) samples were obtained throughout the study, including BAFF, IL-1beta, IL-6, IL-10, VEGF, and TNF-alpha. Results: Forty-eight patients were enrolled to the study; 20 to dose escalation (Part A) and 28 to cohort expansion (Part B). The median age was 65.7 years and 56% were women. The median number of prior therapies was 3 (range 1–10). All patients received either bortezomib or an IMiD; 75% received prior bortezomib and 88% received prior IMiD therapy. The median number of cycles was 5.5 (range 1–28). Grade 3/4 toxicities occurring in two or more patients included peripheral sensory neuropathy, pneumonia, thrombocytopenia, neutropenia, diarrhea, musculoskeletal pain, renal failure acute, fatigue, anemia, neuralgia, and gastrointestinal hemorrhage. Most patients discontinued treatment due to progressive disease or adverse events (neuropathy, neuralgia, fatigue, and thrombocytopenia). Two patients died during study participation - one during treatment from acute respiratory distress syndrome and another during follow-up from multiple myeloma. Confirmed responses included 2 complete responses, 4 very good partial responses, and 16 partial responses. Response associated with lower baseline serum BAFF or IL-6 levels, independent of the tabalumab dose. Also, response in patients treated with tabalumab 100 mg appeared to associate with lower baseline serum levels of IL-10 and undetectable TNF-alpha. With 14 patients censored, the TTP was 4.9 months (95% CI: 4 – 8). With 6 patients censored, the median response duration was 7.3 months (95% CI: 3.5 – 13.9). Conclusions: A 100 mg dose of tabalumab in combination with bortezomib was well tolerated; 22 patients achieved a PR or better despite prior bortezomib and/or IMiD therapy. Response correlated with lower baseline serum BAFF levels, supporting the hypothesis that a higher dose of tabalumab should be evaluated. A three-arm study randomizing patients to the combination(s) of bortezomib, dexamethasone, and tabalumab 100 mg vs. tabalumab 300mg vs. placebo is currently enrolling. Disclosures: Raje: Onyx: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Schiller:Eli Lilly & Company: Research Funding. Cohen:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: 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. Carpenter:Eli Lilly & Company: Employment. Cronier:Eli Lilly and Company: Employment. Kaiser:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

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A Phase II Open-Label, Multi-Center Study of Anti-CCR4 Monoclonal Antibody Mogamulizumab (KW-0761) in Patients with Previously Treated Peripheral T-Cell Lymphoma(PTCL)

Blood ◽

10.1182/blood.v124.21.1763.1763 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1763-1763 ◽

Cited By ~ 4

Author(s):

Pier Luigi Zinzani ◽

Bertrand Coiffier ◽

John Radford ◽

Dolores Caballero ◽

Paul Fields ◽

...

Keyword(s):

T Cell ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Trial ◽

Median Number ◽

Advisory Board ◽

Japanese Study ◽

Duration Of Response ◽

Previously Treated ◽

Grade 3

Abstract Background CC chemokine receptor 4 (CCR4) is the receptor for macrophage-derived chemokine (MDC/CCL22) and thymus activation-regulated chemokine (TARC/CCL17). CCR4 is expressed on tumour cells in approximately 30-65% of patients with PTCL (Ogura, 2014). PTCL-NOS patients who are CCR4 positive have been reported to have a poorer prognosis compared to CCR4 negative patients (Ishida T CCR 2004). Mogamulizumab (KW-0761) is a defucosylated, humanized, IgG1 Mab with enhanced antibody dependent cellular cytotoxicity, that binds to CCR4. Mogamulizumab was evaluated in both phase 1 and 2 trials in Japanese patients. A phase II trial in PTCL and cutaneous T-cell lymphoma (CTCL) patients (Ogura, 2014) reported an overall response rate (ORR) of 35% in patients who relapsed after last systemic therapy (ORR was 34% in PTCL), leading to its approval in Japan in patients with previously treated CTCL and PTCL, in addition to its first indication, previously treated adult T-cell leukemia-lymphoma. Here we report the preliminary results of a European phase II trial of mogamulizumab in patients with relapsed/refractory PTCL. Methods A multi-center phase II study of mogamulizumab monotherapy was conducted to determine efficacy, safety and immunogenicity in patients with CCR4+ PTCL. The primary endpoint was ORR and secondary endpoints included duration of response, progression-free survival (PFS) and overall survival (OS). At least 34 evaluable patients were needed to detect a significant improvement over 15% assuming 80% power and a 0.0240 alpha significance level (assumes 35% ORR for alternative). Patients received mogamulizumab once weekly for 4 weeks and subsequently once every 2 weeks until progressive disease (PD) or unacceptable toxicity at a dose of 1.0 mg/kg. Responses were assessed every 8 weeks according to IWG criteria (Cheson et al 2007). Results Based on a preliminary analysis of the data, a total of 38 patients received at least one administration of mogamulizumab and were evaluable for safety analysis; (Male/female 23/15 ;Median age 58.5 years (range 19-87)). Three patients are still ongoing in the study (1 complete response (CR) and 2 stable disease (SD)). ECOG performance status at baseline was 0 (32%); 1 (29%); 2 (39%) and 92% of patients had stage III (32%) or IV (61%) disease. The median number of prior treatments was 2 (range 1-8). Only 17 patients (49%) responded to the last treatment administered prior to study entry. The median number of mogamulizumab administrations was 6 (range 1-32). The majority of adverse events (AEs) were CTCAE grade 1-2. Skin rash related to drug was observed in 32% of patients (12/38) and related AEs > grade 3 occurred in 32% (12) of patients. Infusion related reactions occurred in 3 patients (2 were CTCAE grade 2 and 1 was grade 3). Thirty-five patients were evaluable for efficacy. The ORR rate was 11% and the stable disease rate was 34% with a SD or better rate of 46%. The response by histological subtype is specified in the table below. The median duration of response (including SD) is 2.9 months. The median PFS is 2.1 months. Two patients (ALCL-ALK-neg and PTCL-NOS) proceeded to allogeneic SCT. Although the ORR in this study was less than seen in the Japanese study, the PFS was comparable. There were differences in patient population/study conduct between the Japanese study and this study, respectively, which included: inclusion of only relapsed patients (100% vs 49%), ECOG PS 2 (0% vs 39%) and response assessments (after 4 and 8 weeks versus 8 weekly from week 8). Conclusions Based on preliminary data, mogamulizumab demonstrates a SD or better rate of 46% and an ORR of 11% with an acceptable safety profile in this phase II study of heavily pre-treated relapsed/refractory PTCL patients. TableBest Overall Response by Histological subtypeNo of subjectsCR/PR n (%)SDn (%)>SD n (%)PTCL-NOS152* (13%)6 (40%)8 (53%)AITL122 (17%)3 (25%)5 (42%)TMF301 (33%)1 (33%)ALCL-ALK neg402 (50%)2 (50%)ALCL-ALK pos1000Efficacy Evaluable Subjects354 (11%)12 (34%)16 (46%) *One patient had CR by CT scan but did not have bone marrow done for confirmation of CR Disclosures Zinzani: Sandoz: Consultancy; Celgene International Sàrl: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; MundiPharma International Ltd: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Pfizer Inc: Advisory Board Other, Honoraria, Speakers Bureau; Takeda Pharmaceutical Company Limited: Advisory Board Other, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Advisory Board Other, Honoraria; GlaxoSmithKline: Advisory Board, Advisory Board Other, Honoraria; Gilead: Advisory Board, Advisory Board Other; Bayer AG: Advisory Board Other, Consultancy. d'Amore:CTI Life Sciences: Speakers Bureau; Mundipharma: Speakers Bureau; Takeda/Seattle Genetics : Speakers Bureau; Sanofi-Aventis: Research Funding; Amgen: Research Funding; Roche: Research Funding; Kyowa-Kirin: Advisory Board Other. Haioun:Roche: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Morschhauser:Genentech: Honoraria; Bayer: Honoraria; Spectrum: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria.

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Phase II Study of Daratumumab in Combination with Azacitidine and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients Previously Treated with Daratumumab: Darazadex

Blood ◽

10.1182/blood-2020-138869 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 27-28

Author(s):

Swetha Kambhampati ◽

Sandy W. Wong ◽

Thomas Martin ◽

Jeffrey L. Wolf ◽

Priya Choudhry ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Duration Of Response ◽

Previously Treated ◽

Dose Modifications

Background: Daratumumab, a human anti-CD38 monoclonal antibody, is approved in many countries for use as monotherapy in relapsed/refractory multiple myeloma (RRMM), and in combination with standard-of-care regimens in RRMM. The phase 2 DARAZADEX study will evaluate the efficacy and safety of daratumumab plus azacitidine and dexamethasone in RRMM patients previously treated with daratumumab. Pre-clinical data from our laboratory has demonstrated that azacitidine induces a 1.2 - 2.4 increase in CD38 median fluorescent intensity (MFI) in a dose-dependent manner across four different MM cell lines. (Figure 1A) Using an immortalized transgenic natural killer (NK) cell line to mediate lysis, we observed a significant increase in antibody-dependent cell-mediated cytotoxicity (ADCC) in the azacitidine-treated MM cells as opposed to control. Importantly, this increase in ADCC correlated with CD38 MFI upregulation. (Figure 1B). Based on this data we hypothesize that azacitidine, by upregulating the expression of CD38, can potentially increase the ADCC and efficacy of daratumumab on multiple myeloma cells and help reverse daratumumab resistance. Methods: In this single-arm, 2-stage, phase II study, approximately 23 RRMM patients in the United States will be treated with combination of daratumumab, azacitidine, and dexamethasone. Eligible patients must have progressed on ≥2 lines of prior therapy, including an immunomodulatory drug (IMiD) and proteasome inhibitor, and have previously been treated with daratumumab with most recent daratumumab treatment being at least 6 months prior to enrollment to allow for CD38 normalization. Patients who were previously primary refractory to daratumumab will be excluded from the study. Patients will receive azacitidine at the standard 75 mg/m2 dose 5 days consecutively every 4 weeks starting day -7 to day -3 of Cycle 1 and then Day 22-26 of Cycle 1-3, and subsequently Day 1-5 of Cycle 5 and thereafter until disease progression or intolerance, with dose modifications for toxicities. Daratumumab will be administered intravenously at the standard dose of 16 mg/kg, with first dose administered on day 1. Daratumumab will be dosed in standard fashion: weekly for 8 doses (induction phase), every two weeks for 8 doses (consolidation phase), and then every 4 weeks thereafter (maintenance phase). Daratumumab will be switched to the subcutaneous formulation at a later timepoint. There will be no dose modifications for daratumumab. Dexamethasone at a dose of 40 mg PO (or IV if PO is not available) will be given weekly for Cycle 1 and 2, after which the pre-infusion medication dose can be reduced to 20 mg and non-pre-infusion dose can be reduced or stopped based on investigator's discretion. Bone marrow biopsies will be done within 14 days prior to Cycle 1 day -7 (first azacitidine dose) and on Cycle 1 day 1 prior to first daratumumab infusion (or after completion of first 5 days of azacitidine and prior to first daratumumab infusion), for correlative studies. (Figure 1C) Simon's minimax two-stage design will be used with a safety lead-in cohort of 6 patients. In the first stage, a total of 13 patients will be enrolled (including the safety cohort), and if there is ≥2 responses in 13 patients the study will enroll an additional 10 patients; if there is ≤ 1 responses in 13 patients the study will be stopped. Primary objective is to evaluate the efficacy, as determined by the overall response rate (ORR) of this combination. Secondary objectives include duration of response per international myeloma working group (IMWG) criteria, safety and toxicity, and the 1-year OS and PFS of this combination. An additional secondary objective is to evaluate the changes in CD38 expression on plasma cells induced by azacitidine in patients with RRMM and identify any correlation of this change with depth and duration of response. The exploratory objective will be to evaluate the tumor microenvironment changes induced by azacitidine via mass cytometry (CyTOF). NCT04407442. Figure 1 Disclosures Wong: Bristol Myers Squibb: Research Funding; GSK: Research Funding; Janssen: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Roche: Research Funding; Fortis: Research Funding. Martin:Janssen: Research Funding; GSK: Consultancy; Seattle Genetics: Research Funding; Sanofi: Research Funding; AMGEN: Research Funding. Wolf:Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. OffLabel Disclosure: Azactidine is being used off-label in multiple myeloma

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A Phase III Randomized Trial of Thalidomide (THAL) Plus Zoledronic Acid (ZLD) Versus Zoledronic Acid Alone In Patients with Early Stage Multiple Myeloma (MC0289)

Blood ◽

10.1182/blood.v116.21.3053.3053 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3053-3053 ◽

Cited By ~ 1

Author(s):

Thomas E. Witzig ◽

Sumithra Mandrekar ◽

Kristen Detweiler-Short ◽

Martha Q Lacy ◽

Kristina Laumann ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Zoledronic Acid ◽

Research Funding ◽

Response Rate ◽

Phase Iii ◽

P Value ◽

Monoclonal Protein ◽

Duration Of Response ◽

One Year

Abstract Abstract 3053 Background: Patients with smoldering multiple myeloma (SMM) have a higher chance of progression to active MM than patients with monoclonal gammopathy of undetermined significance (MGUS). Since active MM remains incurable and since patients with SMM can have a long time to requiring treatment, observation remains an option for these patients. Bisphosphonates can prevent the bone complications of myeloma. The immunomodulatory (IMiD) drugs are well-tolerated and have documented anti-tumor activity in active MM. We hypothesized that treatment with the IMiD THAL and a bisphosphonate (ZLD) would prolong the time to progression (TTP) over the control arm of ZLD alone. This is the first report of this phase III trial of THAL/ZLD vs ZLD alone for patients with untreated SMM. Goals: The primary goal of this trial was to compare the TTP between patients treated with THAL/ZLD versus ZLD alone in asymptomatic MM. Secondary goals were progression rate at one year, response rate, duration of response, time to next therapy, and toxicity. Methods: Patients were required to have measurable disease as defined by either a serum monoclonal protein >1.0 g by protein electrophoresis or nephelometry or >200 mg of monoclonal protein in the urine on 24 hour electrophoresis or a measurable soft tissue plasmacytoma; >10% plasma cells as measured on the bone marrow aspirate, bone marrow biopsy, or labeling index; absolute neutrophil count >1500/μL; platelet count >100,000/μL; creatinine <2.0 mg/dL, and a performance status of 0, 1, or 2. Patients could not have symptomatic MM that required chemotherapy. The statistical plan was to accrue 120 eligible patients (60 per arm) over 4 years and after a minimum follow-up of 12 months the study would provide >90% power at a type I error rate of 0.05 to detect an increase in the median TTP from 12 months (ZLD) to 24 months (THAL/ZLD), and >80% power to detect an increase in median TTP from 12 to 21 months). Results: The study was activated in July 2003 and closed March 2009 due to slow accrual. Sixty-eight patients (35 Thal/ZLD; 33 ZLD) with a median age 63 years (range, 47–84) were randomized. The median TTP for Thal/ZLD versus ZLD was 2.4 years versus 1.2 years, respectively, P=0.02 one-sided log-rank. After adjusting for pre-specified stratification factors, the hazard ratio for TTP was 2.2 (one-sided p value = 0.01, univariate stratified Cox PH model) for ZLD compared to Thal/ZLD. 89% of patients on the Thal/ZLD arm were progression-free survival (PFS) at one year compared to 55% on ZLD alone (one-sided p<0.001, chi-square). Similar results were obtained (Table and Figures) when the CRAB (calcium, renal, anemia, bone) criteria were applied. Confirmed response was evaluated using the first 12 months of treatment. In the Thal/ZLD arm the response rate was 31% with a median duration of response of 5.1 years (95% CI: 1.9 - NA). There were no confirmed responses in the ZLD alone arm. The median overall survival has not been reached for either arm. In regards to toxicity, no grade 5 adverse events (AEs) have been reported. Thirty patients have reported grade 3+ AEs (17 Thal/ZLD; 13 ZLD, Fisher's exact p-value 0.47). Eight patients have reported grade 4 adverse events (5 Thal/ZLD; 3 ZLD, Fisher's exact p-value 0.71). Overall, only one grade 4 event was felt to be at least possibly related to study treatment – grade 4 neutropenia in Thal/ZLD. Conclusions: While the trial did not meet its planned accrual goals, there was a significant improvement in improved in outcomes in the Thal/ZLD arm compared to control (ZLD). Thal/ZLD produces anti-tumor responses that are quite durable with the median response duration of over 5 years. ZLD alone did not produce any anti-tumor responses. This study indicates that a non-chemotherapy approach can be effective in SMM and may be a useful strategy to test in future studies. Disclosures: Off Label Use: Thalidomide for smoldering myeloma. Lacy:Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Gertz:Celgene: Honoraria; Millennium: Honoraria.

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Velcade an Active Agent for Multiple Myeloma Patients. Experience of a Single Center.

Blood ◽

10.1182/blood.v106.11.5151.5151 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5151-5151

Author(s):

Maria Teresa Petrucci ◽

Vincenza Martini ◽

Cristiano Gallucci ◽

Erica Finolezzi ◽

Anna Levi ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Disease Progression ◽

Day Treatment ◽

Active Agent ◽

Median Number ◽

New Drug ◽

Duration Of Response ◽

Heavily Pretreated ◽

Number Of Cycles

Abstract Velcade (PS-341, Bortezemib), a proteasome inhibitor, has recently been approved for the treatment of relapsed and refractory multiple myeloma (MM). We hereby report the results obtained using this new drug at our center. Between April 2003 and December 2004 we treated 23 patients with MM. The patient population consists of 13 males and 10 females, with a median age of 53 years (range 32–72); 16 were IgG MM, 6 IgA, 1 light chain. All patients were in stage III of their disease, with a median time of observation (from diagnosis to Velcade therapy) of 59 months (range 11–120), were pretreated with at least two lines of therapies and were refractory or in relapse after the last treatment. Velcade 1.3 mg/m2 was scheduled on days 1, 4, 8 and 11 of a 21-day treatment cycle for 8 cycles according to the tolerability and response. All cycles were delivered in day hospital. A median of 6 cycles (range 3–8) were administered to the overall population. Eleven patients concluded their program, while 12 discontinued the treatment: 1 because she received an allogeneic stem cell transplantation, 7 for adverse events and 4 due to disease progression. In this heavily pretreated population, our primary end point was to obtain a decline in the monoclonal component (MC) of at least 25%. All patients were considered evaluable for response because treated with at least 3 cycles of therapy. Thirteen patients responded to treatment: 1 (4%) obtained a disappearance of the MC, 4 (17%) achieved a reduction of the MC level >75% and 8 (34%) >50%. Six further patients (26%) obtained a decline in the MC <25%. The median number of cycles required to achieve a response was 3 (range 1–8) and the median duration of response was 6 months, with 8 patients presently still responsive. Among the responding patients, 5 relapsed and 4 of them have died due to disease progression. Among the 4 patients (17%) who did not respond to Velcade, 1 died. The majority of adverse events, which resolved with the discontinuation of treatment, were nausea, vomiting, diarrhea, fatigue, thrombocytopenia and peripheral neuropathy. Taking into consideration the very poor prognostic likelihood of our patients, this study adds further evidence con the efficacy of this new drug in MM. Velcade can be considered an effective anti-myeloma drug even though its toxicity must be taken into account in designing new clinical trials.

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Daratumumab Monotherapy for Patients with Relapsed or Refractory (R/R) Natural Killer/T-Cell Lymphoma (NKTCL), Nasal Type: An Open-Label, Single-Arm, Multicenter Phase 2 Study

Blood ◽

10.1182/blood-2018-99-111885 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1617-1617 ◽

Cited By ~ 3

Author(s):

Won-Seog Kim ◽

Hyeon-Seok Eom ◽

Su-Peng Yeh ◽

Seok-Goo Cho ◽

Dae Seog Heo ◽

...

Keyword(s):

Adverse Events ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

Median Number ◽

Phase 2 ◽

Nasal Type ◽

Cd38 Expression ◽

Phase 2 Study ◽

Duration Of Response

Abstract Introduction: NKTCLs are rare, Epstein-Barr virus-associated distinct subtypes of peripheral T-cell lymphoma that are predominantly extranodal and of the nasal type, and are more common in Asia and Central/South America (Tse and Kwong. Blood 2013. 121:4997-5005). There is no standard therapy for R/R NKTCL and patient (pt) outcomes are very poor. Thus, there exists a highly unmet medical need for R/R NKTCL pts. Clinical data from NKTCL pts suggest CD38 as a new prognostic biomarker and novel target for therapy (Wang et al. Ann Hematol 2015. 94:1381-8). Daratumumab (DARA) is a human CD38 monoclonal antibody approved across all stages of multiple myeloma (MM). DARA has a direct on-tumor and immunomodulatory mechanism of action, and has been associated with significant treatment-related reduction of NK cells that does not impact drug efficacy or safety in MM (Casneuf et al. Blood Adv 2017. 1:2105-2114). DARA monotherapy induced a sustained remission in a single extranodal NKTCL pt (Hari et al. New Engl J Med 2016. 375:1501-2). A phase 2 study (NCT02927925) with Simon's 2-stage design was conducted to evaluate DARA monotherapy in pts with R/R NKTCL. Interim data from the stage 1 of the study are presented. Methods: Pts had histologically confirmed extranodal NKTCL nasal type, per WHO classification, that was refractory to or relapsed after ≥1 line of chemotherapy and were not candidates for other treatment modalities. Pts without fresh or archived tumor samples for biomarker determination were excluded. DARA 16 mg/kg was administered by IV infusion once weekly for 8 weeks, every other week for 16 weeks, and every 4 weeks thereafter until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) based on blinded independent central review (BICR) per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification). Other endpoints included progression-free survival (PFS) and duration of response based on BICR, overall survival (OS), and safety. A protocol-specified futility analysis was planned after approximately 15 pts received ≥1 dose of DARA and had ≥1 post-baseline disease evaluation; futility criterion for ORR was defined as at most 1 of 15 pts with complete response (CR)/partial response (PR). Results: A total of 16 pts were treated in Korea (n = 13) and Taiwan (n = 3) at the time of clinical cut-off for the interim analysis (March 1, 2018). Median age was 58 years, and median time from initial NKTCL diagnosis was 35.9 months. Most pts had CD38 expression values ≥50% (n = 9). The median number of lines of prior therapy was 2 (range: 1-6), and 13 pts received prior radiotherapy. Median number of DARA cycles received was 2 (range: 1-11). At clinical cut-off, 81% of pts discontinued treatment (disease progression [56%], physician decision [13%], pt withdrawal [13%]). At a median follow-up of 3.1 months, 14 pts were response evaluable. ORR based on BICR was 35.7% (Table 1). Response rates were slightly higher for pts who received <3 vs ≥3 prior treatments (38% vs 29%). Among the 5 responders, median duration of response was not reached. Median PFS was 52 days (95% CI, 29-78 d), and 4-month PFS rate was 16% (Figure 1A). Median OS was not reached (95% CI, 65 d-not estimable), with 6-month OS rate of 58% (Figure 1B); all 5 responders remained alive at time of this analysis. The most common (>20%) all-grade treatment-emergent adverse events (TEAEs) are summarized in Table 2. Nine (56%) pts had grade 3/4 TEAEs; neutropenia, thrombocytopenia, and hypotension were most common (19% each). No pt discontinued treatment due to TEAEs. Infusion-related reactions (IRRs) occurred in 69% of pts, all during the first infusion, and all pts recovered and IRRs were resolved on the same day. Three (19%) pts died within 30 days of last treatment dose, 2 of which were due to adverse events (both pneumonia) unrelated to DARA and 1 due to progressive disease. There was no clear association between CD38 expression and DARA response. NK cell reductions in peripheral blood were observed in all pts after 1 cycle of DARA. Conclusions: DARA 16 mg/kg was well tolerated with no new or unexpected safety signals and no treatment discontinuations due to TEAEs. DARA demonstrated a promising response rate (ORR: 35.7%) in pts with R/R NKTCL. The interim results did not meet pre-specified futility criteria in this poor prognosis pt population, and stage 2 of the study is ongoing. Disclosures Kim: Takeda: Research Funding; Roche: Honoraria, Research Funding; Merck: Research Funding; Celgene: Research Funding; J&J: Research Funding; Novartis: Research Funding; Mundipharma: Research Funding; Kyowa-Kirin: Research Funding; Eisai: Honoraria, Research Funding; Celltrion: Honoraria, Research Funding. Yeh:GNT Biotech & Medicals Crop.: Research Funding. Gao:Janssen: Employment. Zhang:Janssen: Employment. Qi:Janssen Research & Development, LLC: Employment. Kwong:Bayer: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

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Randomized Phase 2 Trial of Two Different Doses of Ixazomib in Patients with Relapsed Multiple Myeloma Not Refractory to Bortezomib

Blood ◽

10.1182/blood.v126.23.3050.3050 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3050-3050 ◽

Cited By ~ 6

Author(s):

Shaji K Kumar ◽

Betsy R. Laplant ◽

Craig B. Reeder ◽

Vivek Roy ◽

Francis Buadi ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Proteasome Inhibitor ◽

Research Funding ◽

Response Rate ◽

Median Number ◽

Phase 2 ◽

Free Survival ◽

Grade 3 ◽

Randomized Phase 2

Abstract Background: Ixazomib is an experimental, orally bioavailable, proteasome inhibitor that has demonstrated anti-tumor activity in relapsed multiple myeloma (MM). In the dose escalation studies, ixazomib was tolerated up to a dose of 5.5 mg given every week as a single agent, while a dose of 4 mg was utilized in the combination studies with lenalidomide. We undertook this study to examine the efficacy and tolerability of the two doses of ixazomib in combination with dexamethasone in patients with relapsed MM. Patients and methods: This was a randomized phase 2 study of two doses of ixazomib (4mg; Arm A or 5.5 mg; Arm B) given weekly for three weeks with a week off along with weekly dexamethasone (40 mg) in patients with relapsed MM, who are proteasome inhibitor na•ve (including bortezomib) or have received less than 6 cycles of therapy with bortezomib and had a PR or better with no progression at the time of discontinuation. The primary objective was to determine the confirmed overall response rate (>=PR); secondary objectives included progression free and overall survival. A total of 71 patients were accrued from February 2013 to April 2015; one patient was ineligible. Results: Baseline characteristics were similar in the two arms; median age across the study was 70 years (46-84); 53% were male. Median number of prior therapies was 4 (range 2-6); 90% of the patients had prior IMiDs, 70% had prior transplant and 29% had prior bortezomib. At a median follow up of 10 months, 17 (49%) and 19 (54%) of patients had disease progression in arms A and B respectively with 12 (34%) patients in each arm still continuing on treatment. All patients in each arm were evaluable for response; the overall response rates were 31% in arm A (95%CI: 17-49) and 51% (95%CI: 34-69) in Arm B. The depth of response, event free survival and overall survival are outlined in Table 1. Among the patients with no prior bortezomib exposure the response rates were 38% for Arm A and 52% for Arm B. The treatment was well tolerated with 2 patients in each arm discontinuing treatment for adverse events; there were no on study deaths. A grade 3 or higher AE that was at least possibly related to treatment was seen in 21% and 54% in Arms A and B respectively; with 15% and 37% hematologic and 6% and 29% non-hematologic AEs. The most common attributable toxicities encountered included fatigue, thrombocytopenia, diarrhea and nausea with more grade 3 toxicities among Arm B. Peripheral neuropathy, possibly related to ixazomib, was seen in 55% (only grade 1 or 2) in arm A and 43% (2 patients with grade 3) in Arm B. Toxicities led to dose reduction of ixazomib in 17% and 43% of patients in Arm A and B respectively; the median number of cycles administered were 5 (1-24) and 5 (1-22) respectively. Conclusions: Ixazomib in combination with dexamethasone was well tolerated with significant anti-myeloma activity in this group of patients with relapsed MM. Deep responses including stringent CR were observed. The higher dose of ixazomib appears to be associated with a higher response rate but with higher rate of adverse events requiring dose reductions. Table 1. Treatment outcome in all patients Arm B (4 mg) (N=35) Arm C (5.5 mg) (N=35) Response Rate 31% (95%CI: 17-49) 51% (95%CI: 34-69) No. of Responders 11 18 sCR 0 1 CR 1 0 VGPR 7 8 PR 3 9 MR 5 1 Median Overall Survival1 NA NA 6 Months 100% 100% Median Event Free Survival1,2 8.4 mos (95%CI: 4.3-13.2) 8.2 mos (95%CI: 3.8-16.3) %Event Free at 6 Months 60% (95%CI: 45-81) 60% (95%CI: 45-81) Median Duration of Response1 16.7 mos (95%CI: 9.3-22.0) 16.3 mos (95%CI: 7.0-20.1) Median Time to Response 1.1 mos (range: 0.8-3.6) 1.0 mos (range: 0.8-7.5) CI: confidence interval; mo: month; NA: not attained 1Kaplan Meier 2Event-free survival time is defined as the time from registration to the first of disease progression, death due to any cause, or subsequent treatment for multiple myeloma. Disclosures Kumar: Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; Onyx: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy.

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Effect of Age on Efficacy and Safety Outcomes in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Receiving Lenalidomide and Low-Dose Dexamethasone (Rd): The First Trial

Blood ◽

10.1182/blood.v124.21.81.81 ◽

2014 ◽

Vol 124 (21) ◽

pp. 81-81 ◽

Cited By ~ 3

Author(s):

Cyrille Hulin ◽

Thierry Facon ◽

Chaim Shustik ◽

Andrew Belch ◽

Maria Teresa Petrucci ◽

...

Keyword(s):

Multiple Myeloma ◽

Primary Endpoint ◽

Research Funding ◽

Response Rate ◽

Age Groups ◽

P Value ◽

Newly Diagnosed ◽

Risk Of Death ◽

Duration Of Response ◽

Grade 3

Abstract Background: In the pivotal FIRST trial, a randomized, international, multicenter phase 3 study, continuous Rd compared with melphalan-prednisone-thalidomide (MPT) improved progression-free survival (PFS) which was the primary endpoint (HR = 0.72; P < 0.01). The interim overall survival (OS) analysis showed a 22% reduction in risk of death with continuous Rd vs. MPT (HR = 0.78; P = 0.02) (Facon, Blood 2013). This analysis evaluates outcomes based on age, which was a stratification parameter, and compared pts aged ≤ 75 yrs and > 75 yrs. Methods: Pts with NDMM were randomized to continuous Rd until progressive disease (PD) (N = 535); 18 cycles (72 weeks [wks]) of Rd (Rd18; N = 541); or 12 cycles (72 wks) of MPT (N = 547). Starting doses were reduced in pts aged > 75 yrs: dexamethasone (20 vs. 40 mg), melphalan (0.20 vs. 0.25 mg/kg), and thalidomide (100 vs 200 mg). The primary endpoint was PFS (continuous Rd vs. MPT) and the secondary endpoint were OS, overall response rate, time to response, duration of response, time to Tx failure, time to 2nd AMT, health-related quality of life, safety. Results: The proportion of pts aged > 75 yrs was > 34% across treatment (Tx) arms. In pts ≤ 75 yrs, 37% had ISS stage III vs. 51% in > 75 yrs. ECOG score ≥ 1 was observed in 74% and 69% of pts aged > 75 and ≤ 75 yrs, respectively. Severe renal impairment (CrCl < 30 mL/min) was observed in 14% of pts > 75 vs. 7% in ≤ 75 yrs. PFS and OS outcomes favored continuous Rd over MPT in both age groups. With a median follow-up of 37 months (mos), PFS was 27.4 mos in continuous Rd pts vs. 21.8 mos in MPT pts aged ≤ 75 yrs (HR = 0.68; P < 0.001); a trend for improved PFS was also seen for pts aged > 75 yrs (HR = 0.81; P = 0.11) (Table 1). PFS for continuous Rd vs. Rd18 pts was also increased in both age groups (HR = 0.68; P < 0.001 and HR = 0.75; P = 0.03, respectively). Response rates were consistently higher with continuous Rd vs. MPT in pts aged ≤ 75 yrs (77% vs. 66%; P < 0.001) and > 75 yrs (71% vs. 55%; P < 0.001). Duration of response with continuous Rd was longer vs. MPT in pts aged ≤ 75 yrs (40 vs. 22 mos) and pts > 75 yrs (31 vs. 24 mos). The interim analysis of OS showed an improved trend for continuous Rd vs. MPT in pts aged ≤ 75 yrs (HR = 0.77; P = 0.06) and > 75 yrs (HR = 0.80; P= 0.16). Grade 3–4 adverse events (AEs) in ≥ 10% of pts were similar across age subgroups (Table 2). Tx discontinuation due to AEs was comparable across the Tx groups and independent of age. Conclusions:Regardless of age (≤ 75 vs. > 75 yrs), continuous Rd was effective, increased PFS and interim OS, and was generally well tolerated vs. MPT in NDMM pts. Duration of response was improved with continuous Rd vs. MPT and Rd18, irrespective of age, and with a more profound benefit observed in younger pts. Continuous Rd represents a new clinical option and standard of care for these pts in the first-line setting. Abstract 81. Table 1 PFS, OS and Response Aged ≤ 75 yrs Aged > 75 yrs All pts ITT population Continuous Rd (n = 349) Rd18 (n = 348) MPT (n = 359) Continuous Rd (n = 186) Rd18 (n = 193) MPT (n = 188) Continuous Rd (n = 535) Rd18 (n = 541) MPT (n = 547) Median PFS, mos 27.4 21.3 21.8 21.2 19.4 19.2 25.5 20.7 21.2 PFS HR (95% CI); P-value Continuous Rd vs. Rd18 0.68 (0.55–0.83); P < 0.01 0.75 (0.58–0.98); P = 0.03 0.70 (0.60–0.82); P < 0.01 Continuous Rd vs. MPT 0.68 (0.56–0.83); P < 0.01 0.81 (0.62–1.05); P = 0.11 0.72 (0.61–0.85); P < 0.01 4-yr OS, % 66 61 58 47 47 39 59 56 51 OS HR (95% CI); P-value Continuous Rd vs. Rd18 0.88 (0.67–1.16); P = 0.36 0.94 (0.69–1.29); P = 0.70 0.90 (0.73–1.10); P = 0.31 Continuous Rd vs. MPT 0.77 (0.59–1.01); P = 0.06 0.80 (0.59–1.09); P = 0.16 0.78 (0.64–0.96); P = 0.02 Response rate (≥ PR), % 77 77 66 71 66 55 75 73 62 Duration of response (≥ PR), mos 40 23 22 31 20 24 35 22 22 CI, confidence interval; ITT, intent to treat; PR, partial response. Table 2 Grade 3–4 AEs Observed in ≥ 10% of Pts Aged ≤ 75 yrs Aged > 75 yrs Safety population, % Continuous Rd (n = 347) Rd18 (n = 348) MPT (n = 357) Continuous Rd (n = 185) Rd18 (n = 192) MPT (n = 184) Neutropenia 28 25 47 28 29 40 Thrombocytopenia 8 9 13 9 7 7 Anemia 18 12 20 19 23 17 Leukopenia 5 6 11 4 5 8 Infections 29 21 16 29 23 20 DVT and/or PE 10 6 8 7 8 4 Peripheral sensory neuropathy 1 1 10 1 0 8 Tx discontinuation due to AEs 28 18 28 32 25 30 DVT, deep-vein thrombosis; PE, pulmonary embolism. Disclosures Hulin: Celgene: Honoraria. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Belch:Janssen, Celgene, Onyx: Honoraria. Petrucci:Celgene, Janssen-Cilag, Sanofi, Bristol-Myers Squibb: Honoraria. Dührsen:Celgene: Honoraria, Research Funding. Song:Celgene: Consultancy, Honoraria, Research Funding. Houck:Celgene: Employment. Chen:Celgene: Employment. Ervin-Haynes:Celgene: Employment.

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