Hussein, Mohamad A.

Abstract Introduction: In a multiple myeloma mouse model (MM), we determined that subcutaneous (SC) continuous lenalidomide (Len) delivery demonstrated superior tolerability and efficacy to the active control Len given by daily i.p. over a 28 day cycle. Healthy volunteer studies showed that at a daily dose of 9.6 mg a day (400 mcg/h) the Len AUC0-24 was ∼60% less than that observed with an oral 25 mg Len dose. We hypothesized that this modality could improve Len’s therapeutic index by lowering the hematologic toxicity while maintaining or improving the efficacy. Methods: A phase 1b study in 2nd line or greater relapsed/refractory MM was performed to confirm the animal findings and determine if continuous Len can improve its therapeutic index with no negative impact on the cellular immune system. In brief, an RVd regimen was utilized wherein SC Len 9.6 mg/day was administered with an FDA registered ambulatory pump in a continuous fashion using a 28/28 day cycle. Patients were either trained to operate their pump and change the pre-filled cassettes at home or were managed in the clinic on M-W-F. All patients were seen in the clinic to receive weekly bortezomib 1.3mg/m2 and dexamethasone dosed weekly at 40/20mg, according to age. Patients who received bortezomib in a prior cycle were required to demonstrate sensitivity defined as durability for 6 months after discontinuation of the bortezomib. Results: Between September 2023 and November 2024, 6 relapsed/refractory MM patients were enrolled from 2 US community-based investigational sites in the phase 1b study. Median age was 73, male to female ratio 1/1, Caucasian 100%, and median lines of previous therapy were 2 (range 1-7). Two patients were refractory and 4 were relapsed to their prior treatment. Four patients were previously exposed to Len, one of which was discontinued from a prior regimen because of severe fatigue, and 6 had received prior bortezomib. Patients had received 3-12 cycles of study therapy. No drug-related grade 3/4 hematologic or non-hematologic toxicity occurred within cycle 1. No patients experienced drug-related anemia, neutropenia, leukopenia, or thrombocytopenia greater than grade 2 in up to 12 cycles of therapy. All 6 patients achieved an objective response (CR=1 / PR=5). One patient who achieved a partial response experienced grade 2 skin reaction during cycle 3 and withdrew from the study. Five patients are continuing treatment per protocol with a median PFS of > 10 mo. Len pharmacokinetics produced median steady-state blood levels (Cmax) of 39 ng/mL (range 26-94) (N=6) and were above the minimum target of 25 ng/mL. The Len regimen produced a median AUC0-24 of 921-1h*ng/ml (range 630-1503). Immune profiling did not show significant increases in immune checkpoint expression associated with T-cell exhaustion while CD19+ B cells were significantly depleted. Conclusion: Continuous delivery of low dose Len provides meaningful efficacy and improved tolerability with no grade >3 drug-related hematologic toxicity. Further studies in MM and chronic lymphocytic leukemia are planned. Citation Format: Nash Gabrail, Keith Lerro, Mohamad A. Hussein, Asher A. Chanan-Khan, Jamie C. Oliver. Continuous subcutaneous lenalidomide delivery improves the therapeutic index and avoids drug-related grade 3/4 hematologic toxicity in patients with relapsed/refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB207.

Abstract Background: Race/ethnicity is associated with disparate incidence and outcomes in MM, as seen in population-based studies. Their effect on outcomes has not been reported in prospective studies. Obesity is the most consistently associated modifiable risk factor for MM and is influenced by race/ethnicity but its association with outcomes has not been explored. We analyzed patient-level data from published ECOG-ACRIN/SWOG clinical trials in newly diagnosed MM (NDMM) patients (pts) to explore the interplay of race/ethnicity, obesity and outcomes. Methods: Pooled data from 9 ECOG-ACRIN/SWOG clinical trials (E1A06, E4A03, E1A00, E2A02, E5A93, E9486, S0204, S0232, S9321) in NDMM (1988-2011) were analyzed. Pts were divided by race: White (W), African-American (AA), other (O); race/ethnicity: Hispanic (H), non-Hispanic White (NHW), non-Hispanic AA (NHAA), non-Hispanic other (NHO); and body mass index (BMI): <25, 25-29.9, ≥30. Associations between these and baseline pt/disease characteristics were assessed using chi-square (categorical) and Wilcoxon rank sum (continuous) tests. Survival distributions were estimated with Kaplan-Meier method and compared between groups using log-rank test. Cox proportional hazards regression was used to estimate hazard ratios in univariate and multivariate models. Time to event data was censored at 6 yrs. Results: Pt distribution by race, race/ethnicity and BMI is shown in Table 1. Race: AA were younger than W (median 59 vs 62 yr), had significantly more females (48% vs 40%; p=0.001) and had a smaller proportion of pts ≥70 yr (18% vs 26%; p<0.001). Median BMI was highest in AA (27.2) and lowest in O (24) (p=0.001) but not significantly different categorically between W and AA only (p=0.908). AA had significantly more pts with hemoglobin (Hb) ≤10 g/dL than W (55% vs 36%; p<0.001). Median creatinine (Cr) was 1.3 mg/dL in O and 1.1 mg/dL in W (p=0.03). There were no differences by race for ECOG performance status (PS), MM stage, lytic lesions, paraprotein subtype, serum calcium (Ca) or β2-microglobulin (β2M). Enrollment to clinical trials over years was significantly different by race (p=0.009). The only study design showing different enrollment by race was with/out stem cell transplant (SCT) (p=0.03; 37% of AA vs 31% of W got SCT trials). Race/Ethnicity: NHO were the youngest (median 58 yr) and NHW the oldest (median 62 yr) subgroup (p<0.001). NHAA had the highest proportion of pts with BMI ≥30 (16%) and NHO the lowest (7%) (p=0.018). H had the smallest proportion of females (33%) while NHO had the largest (54%) (p=0.002). H had the highest number of pts ≥70 yr (28%) and NHAA the smallest (18%) (p=0.003). Anemia rates were significantly different (p<0.001) with Hb ≤10 g/dL in 36% NHW vs 56% in NHAA. No significant differences were seen for PS, MM stage, lytic lesions, paraprotein subtype or other lab parameters. H and NHAA were enrolled in larger numbers in 1992-2011 rather than prior or later years (p<0.001). Among the subgroups, H had largest proportion of patients (75%) on trials without novel agent vs 61.5% for NHW (p=0.047). NHAA had the highest proportion of patients on trials with SCT (38%) while NHO had the smallest (27.3%) (p=0.034). BMI: By gender, 30% of males and 39% of females having BMI <25 (p<0.001). BMI <25 had the highest proportion of pts with ISS stage III (31%) vs 21.5% for ≥30 (p=0.001). A similar trend was seen for DS stage (p=0.005). 64% of ≥30 pts had Hb >10 while 51% of <25 did (p=0.003). There was significant difference in continuous Cr distribution by BMI (p=0.004). Efficacy analysis did not show any significant difference in response rate by race (p=0.132), race/ethnicity (p=0.286) or BMI (p=0.896). In univariate/multivariate analysis, significantly worse overall survival (OS) was seen in males, age ≥70 yr, ECOG PS >0, ISS and DS stage III, presence of lytic lesions, Cr ≥2 mg/dL, Ca >12 mg/dL, Hb ≤10 g/dL. No significant difference was seen in OS or progression free survival by race, race/ethnicity or BMI (Figure 1). Conclusions: Significant differences exist in demographic and clinical characteristics of NDMM pts by race/ethnicity. Median OS was significantly associated with these characteristics but not with race/ethnicity itself. Observed racial/ethnic disparity in outcomes for MM pts may be overcome by access to comparable therapeutic options as seen in clinical trials. Obesity, while associated with MM incidence, does not seem to influence outcomes. Figure 1 Figure 1. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Stewart:Janssen Pharmaceuticals: Consultancy; Takeda Oncology: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy. Hussein:Celgene: Employment. Zonder:Takeda: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership; Prothena: Consultancy, Honoraria. Barlogie:Mount Sinai Hospital: Employment.

Abstract Abstract 924 Background: Therapy-related myeloid neoplasia (t-MN), including myelodysplastic syndrome and acute myeloid leukemia, has been reported at a higher frequency with chlorambucil + fludarabine as compared to fludarabine alone, but has not been rigorously studied in the context of cyclophosphamide as an alkylator agent. The intergroup prospective randomized Phase 3 trial, E2997, compared FC with F alone as initial therapy for patients (pt) with chronic lymphocytic leukemia (CLL). FC therapy led to higher complete and overall response rates and longer progression-free survival at the initial analysis (Flinn et al JCO 2007). One rationale for combining F with C is that F can inhibit repair of DNA damage induced by C. FC did cause more myelosuppression that could lead to more long-term effects on myeloid hematopoietic function, including t-MN. Methods: E2997 enrolled 278 pts, 141 on FC and 137 on F. These cases were assessed for t-MN by required reporting of these events. Baseline genetic and molecular features of CLL were available through a companion lab correlative trial for 235 pts, 122 on FC and 113 on F. Results: With median follow-up of 6.4 yrs, there have been 13 (4.7%) reported cases of t-MN, 9 after FC and 4 after F. By cumulative incidence methodology, adjusting for the competing risk of death, the rates of t-MN at 7 yr are 8.2% after FC and 4.6% after F (p=0.18 by the Gray test). Median age at study entry of the t-MN pts was 60 (range 45–80) yrs vs 61 (range 33–86) yrs among those not reported to have t-MN. Median time from initial therapy to diagnosis of t-MN was 5 (range 0.7–8) yrs and did not differ between FC and F. Ten of 13 affected pts received 6 chemotherapy cycles. Additional therapy prior to occurrence of t-MN was given to only 2 of 9 FC pts, in contrast to 3 of 4 F pts. Thus, t-MN occurred in only 1 pt treated with F and no further therapy vs 7 who received FC and no further therapy. Ten of 12 pts with available cytogenetics at diagnosis of t-MN had an abnormality of chromosome 5 and/or 7, common to alkylating agent-induced t-MN, usually (n=8) with complex karyotype. Of the 9 pts with t-MN after FC, all 7 with available CLL data had lower risk IgVH mutated disease, in contrast to 1 of 4 with t-MN after F and 44% in the entire cohort. Conclusion: Our analysis suggests that a higher incidence of t-MN has occurred after FC than after F. t-MN after FC occurred most often without additional therapy and in IgVH mutated CLL which is associated with more favorable outcome. The increased incidence of t-MN after FC in this study, usually in the absence of additional treatment, suggests that FC is more leukemogenic than F. This finding emphasizes a need for longer follow-up of toxicity and survival before concluding that FC is preferable to F as the chemotherapy backbone for initial therapy of both low and high risk CLL. Disclosures: No relevant conflicts of interest to declare.

Abstract Purpose: Deep vein thrombosis (DVT) is increasingly recognized as a major complication of thalidomide (T; Thal) and lenalidomide (R; Rev) based therapy for multiple myeloma. Estimated incidence varies widely in the literature. There is no consensus on specific risk factors, indications for thromboprophylaxis or the agent of choice for DVT prophylaxis. The purpose of this study was to develop a consensus among members of the IMWG. Patients and Methods: A survey was electronically mailed to 67 IMWG members on July 21, 2006 and consisted of 24 multiple-choice questions. Results: Twenty-three IMWG members (34%) sent in their responses by the cut-off date. All (100%) felt that DVT was an important question, but most (95%) did not avoid Thal/Rev based therapy because of the DVT risk. Overall results are summarized in the Table below. A majority of physicians felt that concomitant therapy with high dose dexamethasone (90% of physicians), alkylators (55%), doxorubicin/liposomal doxorubicin (90%), and erythropoietin (75%) increase the risk of DVT associated with Thal or Rev based therapy. Aspirin (81 mg or 325 mg per day) was the preferred choice of prophylaxis when necessary. However, 65% of respondents preferred warfarin to a therapeutic INR or LMW heparin if either doxorubicin or liposomal doxorubicin was added to the regimens. Most (95–100%) felt that DVT prophylaxis was not indicated for: VAD, MP, bortezomib +/− dexamethasone regimens. Seventy-five percent felt it to be safe to resume therapy with Thal/Rev after therapeutic anticoagulation. Most (95%) believed randomized trials were needed. Conclusion: DVT is recognized as a major clinical problem associated with Thal/Rev containing regimens. Most respondents felt that the DVT risk did not warrant any prophylaxis when either Thal or Rev were used as single agents. Aspirin was the preferred form of DVT prophylaxis for most Thal/Rev containing regimens, except when doxorubicin/liposomal doxorubicin or melphalan were added. Additional responses will be analyzed both electronically and by conference call prior to the meeting. Therapy Estimated incidence of DVT (% respondents) Choice of thromboprophylaxis (% respondents) Single agent thal <5% (61%) None (65%) Single agent Rev <5% (80%) None (65%) Thal-Dex 10–20% (52%) Aspirin (60%) Rev-Dex 10–20% (48%) Aspirin (60%) MPT 10–20% (65%) Aspirin (40%) R-MP 5–10% (57%) Aspirin (70%)

Abstract Purpose: Updated results, including response rate data, from a randomized, double-blind, placebo-controlled study comparing thalidomide plus dexamethasone versus dexamethasone alone as primary therapy for newly diagnosed multiple myeloma (MM). Methods: Patients (pts) with previously untreated, symptomatic MM were eligible. Pts were randomized to Thal/Dex (Arm A) or placebo plus Dex (Arm B). Pts in Arm A received Thal 50 mg PO daily, escalated to 100 mg on day 15, and to 200 mg from day 1 of cycle 2; Dex 40 mg PO was given on days 1–4, 9–12, and 17–20. Pts in Arm B received placebo instead of Thal, and Dex as in Arm A. Each cycles was 28 days long. Treatment was continued until progression or undue toxicity. The primary endpoint was time to progression (TTP) defined using EBMT criteria. All analyses were conducted on an intent to treat basis. An independent data monitoring committee recommended release of results. Results: 470 pts were enrolled: 235 were randomized to Thal/Dex and 235 to placebo/Dex. Median follow up is 18 months. Median age was 65 yrs. The response rate (CR+PR) was significantly higher with Thal/Dex compared to placebo/Dex, 59% vs 42%, respectively, P<0.001. Eighty-two percent of patients have gone off-study. TTP was significantly superior with Thal/Dex vs placebo/Dex, median TTP not reached with Thal/Dex versus 8.1 months (95% CI: 6.5–12.8 months) with placebo/Dex, P<0.001. Major grade 3–4 events are summarized in the Table below. Deep vein thrombosis (DVT) was higher with Thal/Dex vs placebo/Dex, 15.4% vs 4.3%, respectively. Conclusions: Thal/Dex yields superior response rates and TTP compared to Dex alone when used as first-line therapy for multiple myeloma. Major Grade 3–4 adverse events Adverse Event Thal/Dex (n=234) Placebo/Dex (n=232) Venous thromboembolism (Grade >=3) 17.9% 4.3% Cerebral ischemia (Grade >=3) 3.0% 1.3% Myocardial ischemia (Grade >=3) 3.8% 2.2% Neuropathy (Grade >=3) 3.0% 0% Any toxicity (Grade >=4) 30.3% 22.8%

Abstract Abstract 5045 Observation remains the standard approach to patients with monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic multiple myeloma (AMM) who lack end-organ impairment characteristic of symptomatic MM. Institution of early MM therapy has not been shown to improve survival or alter the natural progression of the disease. Cyclooxygenase-2 (COX2) inhibitors inhibit proliferation and induce apoptosis in drug resistant MM cell lines. 23 asymptomatic adult patients with a serum monoclonal protein >1g/dL, from Cleveland Clinic, Mayo Clinic, or University of Arkansas Medical Center between August 2005 and April 2008 were randomized to either celecoxib or placebo in a double-blind, 1:1 fashion. The primary end point was change in the monoclonal protein concentration after 6 months. Correlative biomarkers, including IL6 and IL-6R, CD4/CD8+ T-cell ratios, and beta-2 microglobulin, were examined before and after treatment. Celecoxib had no significant effect on the median monoclonal protein concentration, which went from a median of 1. 44 to 1. 65 g/dL with placebo and 2. 42 to 2. 24 g/dL with Celecoxib (p=0. 36), or on any of the analyzed correlative markers (all p-values >0. 34). One patient's monoclonal protein concentration increased on placebo, but he did not require treatment for symptomatic MM. There were no adverse events of Grade 2 or higher. Celecoxib was well tolerated in contrast to previous reports when given in higher doses and in combination with thalidomide. Although accrual was limited we conclude that celecoxib has no clinical or immunologic effect on high risk asymptomatic plasma cell disorders. This study does not support using celecoxib for preventing progression to symptomatic MM. Future studies on progression of MGUS to symptomatic MM would require more patients and a longer follow-up period. Disclosures: Off Label Use: Celecoxib for chemoprophylaxis. Hussein:Celgene: Employment. Reu:Celgene: Research Funding.

Abstract Abstract 1710 Poster Board I-736 Introduction Treatment regimens for cancer are typically based on cytotoxic chemotherapy, which is poorly tolerated. There is an unmet medical need for new therapies that retain efficacy, but combine this with an improved safety and tolerability profile. Vorinostat is a histone deacetylase (HDAC) inhibitor, approved in the United States for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients who have progressive, persistent, or recurrent disease on or following 2 systemic therapies. Vorinostat is also being investigated as a treatment for various other solid and hematologic malignancies, in which HDACs are further implicated as key regulators of transcription. Herein we present an overview of the safety and tolerability profile of vorinostat, gathered from prior clinical experience. Methods Safety and tolerability data, including adverse events (AEs), QTc interval data and incidence of thromboembolic events (TEE), were collated from patients who received vorinostat, administered as monotherapy or in combination therapy for solid or hematologic malignancies. Results (adverse events) In Phase I and II clinical trials, 498 patients who received vorinostat were analyzed. A total of 341 patients received vorinostat monotherapy (107 with CTCL, 105 other hematologic malignancies, 129 solid tumors) and the most common drug-related AEs in this group were: fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%); Grade 3/4 AEs included fatigue (12.0%) and thrombocytopenia (10.6%), and 3 drug-related deaths (ischemic stroke, tumor hemorrhage, unspecified) occurred. Thirty-eight patients (11.1%) discontinued due to drug-related AEs, 71 patients (20.8%) required dose modifications, and 1 patient (0.3%) discontinued due to Grade 2 chest pain. The remaining 157 patients received vorinostat combination therapy (with pemetrexed/cisplatin for advanced cancer [n=46], bortezomib for multiple myeloma [n=34], bexarotene for CTCL [n=23], and erlotinib [n=30], gemcitabine/platin [n=21] or carboplatin/paclitaxel [n=3] for non-small-cell lung cancer). The most common drug-related AEs in this group were: nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), and vomiting (31.2%); the most common Grade 3/4 AE was fatigue (13.4%), and 1 drug-related death (hemoptysis) occurred. Thirty-one patients (19.7%) discontinued due to drug-related AEs and 27 patients (17.2%) required dose modifications. Results (QTcF interval) A trial of 24 patients with advanced cancer was undertaken for rigorous assessment of QTcF interval. In this trial, a single supratherapeutic 800 mg dose of vorinostat did not prolong QTcF interval (monitored over 24 hours). The upper limit of the 90% confidence interval for the placebo-adjusted mean change-from-baseline of vorinostat was <10 msec at every timepoint, no patient had a QTcF change-from-baseline value >30 msec, and 1 patient had a QTcF interval >450 msec (after both vorinostat and placebo administration). The most common drug-related AE in this trial was nausea. There were no serious clinical or laboratory AEs, no discontinuations due to an AE and no patients experienced a cardiac-related AE. Results (incidence of TEE) A review of vorinostat clinical trials, published literature and post-marketing surveillance reports was conducted by a committee of independent academic experts to determine the incidence of TEE in cancer patients who had received vorinostat. In >1845 patients reviewed through November 3, 2008, 107 patients (<5.8%) reported TEE as a serious AE (SAE), 47 (<2.6%) of which were recorded as being related to vorinostat, and 4/47 (<0.3%) TEE SAEs were fatal. Conclusions In this review, the majority of observed AEs were 'Grade 2, there was no observed prolongation of the QTcF interval, and the incidence of TEE with vorinostat was similar to reported rates of TEE in advanced cancer patients. Vorinostat is generally well tolerated when administered as monotherapy or in a combination regimen in cancer patients. Disclosures Siegel: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celegne: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rubin:Merck: Employment, Equity Ownership. Iwamoto:Merck: Employment, Equity Ownership. Hussein:Celgene: Employment. Belani:Merck: Consultancy. Hardwick:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment, Equity Ownership.

Abstract Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10−5 to 10−6 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. Clin Cancer Res; 23(15); 3980–93. ©2017 AACR.

Abstract Chemotherapy-related myeloid neoplasia (t-MN) is a significant late toxicity concern after cancer therapy. In the randomized intergroup phase 3 E2997 trial, initial therapy of chronic lymphocytic leukemia with fludarabine plus cyclophosphamide (FC) compared with fludarabine alone yielded higher complete and overall response rates and longer progression-free, but not overall, survival. Here, we report t-MN incidence in 278 patients enrolled in E2997 with a median 6.4-year follow-up. Thirteen cases (4.7%) of t-MN occurred at a median of 5 years from initial therapy for chronic lymphocytic leukemia, 9 after FC and 4 after fludarabine alone. By cumulative incidence methodology, rates of t-MN at 7 years were 8.2% after FC and 4.6% after fludarabine alone (P = .09). Seven of the 9 cases of t-MN after FC occurred without additional therapy. Abnormalities involving chromosomes 5 or 7 were found in 10 cases, which suggests alkylator involvement. These data suggest that FC may induce more t-MN than fludarabine alone.

Purpose The long-term impact of thalidomide plus dexamethasone (thal/dex) as primary therapy for newly diagnosed multiple myeloma (MM) is unknown. The goal of this study was to compare thalidomide plus dexamethasone versus placebo plus dexamethasone (placebo/dex)as primary therapy for newly diagnosed MM. Patients and Methods In this double-blind, placebo-controlled trial, patients with untreated symptomatic MM were randomized to thal/dex (arm A) or to placebo plus dexamethasone (dex) (arm B). Patients in arm A received oral thalidomide 50 mg daily, escalated to 100 mg on day 15, and to 200 mg from day 1 of cycle 2 (28-day cycles). Oral dex 40 mg was administered on days 1 through 4, 9 through 12, and 17 through 20 during cycles 1 through 4 and on days 1 through 4 only from cycle 5 onwards. Patients in arm B received placebo and dex, administered as in arm A. The primary end point of the study was time to progression. This study is registered at http://ClinicalTrials.gov ( NCT00057564 ). Results A total of 470 patients were enrolled (235 randomly assigned to thal/dex and 235 to placebo/dex). The overall response rate was significantly higher with thal/dex compared with placebo/dex (63% v 46%), P < .001. Time to progression (TTP) was significantly longer with thal/dex compared with placebo/dex (median, 22.6 v 6.5 months, P < .001). Grade 4 adverse events were more frequent with thal/dex than with placebo/dex (30.3% v 22.8%). Conclusion Thal/dex results in significantly higher response rates and significantly prolongs TTP compared with dexamethasone alone in patients with newly diagnosed MM.