Short, Kristen Detweiler

Abstract Abstract 429 Background: Patients with MM who have progressed after multiple novel agents have limited treatment options. Pomalidomide (CC4047) is the newest immunomodulatory (IMiD) agent that has demonstrated response rates of 63% in a Phase 2 trial of Pom/dex in patients with relapsed MM (in press, JCO). To better define the response rate in this group, we treated an additional cohort of patients who were truly resistant/refractory to lenalidomide. Methods: To be eligible, patients must:be refractory to lenalidomide therapy defined as relapsing on or within 60 days of stopping lenalidomide. Pomalidomide was given orally 2 mg daily on days 1–28 of a 28-day cycle. Dexamethasone was given orally at a dose of 40 mg daily on days 1, 8, 15 and 22 of each cycle. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily as prophylaxis against DVT. Pom/dex regimen would be declared promising if we observed at least 4 confirmed responses out of 34 patients based on a single stage Fleming design. Results: 34 patients (23 male and 11 female) resistant/refractory to lenalidomide were enrolled. The median age was 62 years (range, 39-77). The median time from diagnosis to enrollment was 62 months (range 8-179). 12 patients had high risk molecular markers including loss of 17p (6 pts), t(4;14) (1 pt) and del 13 by cytogenetics (5 pts). 70% had ≥3 prior regimens including 38% with ≥5 prior regimens; 56% had prior thalidomide, 59% had prior bortezomib, and 68% had prior SCT. Toxicity (at least possibly related to treatment) was mild and consisted primarily of myelosuppression: grade 3/4 neutropenia (21%); grade 3 thrombocytopenia (9%); and grade 3 anemia (12%). Grade 3/4 non-hematologic toxicities occurred in 24%: pneumonia (3%), non-infectious pneumonitis (3%), hyperglycemia (3%), edema(3%), fatigue(9%) skin rash(3%). Neuropathy occurred in 18% (12% grade 1; 6% grade 2). No thromboembolic events have occurred so far. Nine (26%) patients were confirmed responders (all PR), surpassing the threshold for a positive trial, and 18 (53%) had SD. With a median follow-up of 4 months (range:0-8), 65% remain progression free; 88% remain alive; and 12% have died, all due to progressive MM. Conclusions: Pom/dex is active and well tolerated in this heavily pre-treated population of lenalidomide-refractory MM patients. The majority of patients have not progressed and objective responses are seen in 26%. This study confirms that pomalidomide has non-cross resistance with lenalidomide and offers benefit for patients who have relapsed after other novel therapies. Disclosures: Lacy: Celgene: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kumar:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bergsagel:Genentech, Inc.: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria.

Abstract Abstract 3981 Background: Patients with multiple myeloma (MM) can present with life threatening complications including lethal infections during the disease course. The mortality is high during the early period following diagnosis, mostly as a result of complications of the disease or treatment. It is not clear if we can identify patients at the highest risk of early death based on the presenting clinical and laboratory features. Methods: From among 1545 patients seen at our institution between Jan 1999 and Dec 2008, we identified 265 patients who died within 12 months of diagnosis. For each of these patients we identified two “controls” who had at least 12 months of follow up, were alive at the time of last follow up and were closest to the ‘case' patient in terms of time of diagnosis. We performed logistic regression using the clinical and laboratory features, to identify parameters that predict for 12-month mortality and to determine the best cutoffs. Results: This study included 265 patients as cases and 530 controls. The gender distribution was similar in the two groups. We examined the impact of age, performance status (PS), hemoglobin, platelets, serum creatinine, calcium, LDH, albumin, B2M, free light chain difference, plasma cell labeling index, ISS stage, risk category and exposure to novel agents upfront. Based on the results of univariate and then multivariate analysis – age> 72, ECOG PS>2, Calcium >11.3 and ISS stage 3 were found to be significant. We developed the risk score using 1 point for each adverse factor, Age> 72, PS > 2, ISS 3, and Calcium > 11.3. The odds ratio of patients dying in the first year was 2.7, 9.2 and 37 in the presence of one, two and three or more risk factors compared to none of the risk factors. We then looked at the impact of the initial therapy on outcome. 279 patients (35%) received one of the novel agents (thalidomide, lenalidomide or bortezomib) as initial therapy. The odds ratio for dying in the first year was 0.35 for patients receiving a novel agent compared to the rest. The impact of the novel agent was independent of the risk score, with the risk score predicting outcome in both groups. Conclusions: In newly diagnosed MM advanced age, poor performance status, ISS stage and high calcium were associated with early mortality. If eligible all patients should get the benefit of use of novel agent upfront. Identifying these patients at the time of diagnosis is important and should help develop better risk-adapted strategies. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 863 Background: Patients with MM who have progressed after multiple novel agents have limited treatment options. Pomalidomide (CC4047) is the newest immunomodulatory (IMiD) agent. Pom/dex using a dose of 2 mg/day has demonstrated response rates (≥PR) of 63% in relapsed MM (Lacy, JCO 2009, 27:5008-5014) and 32% in a lenalidomide-refractory cohort (Lacy, Leukemia, in press). The maximum tolerated dose has been determined to be 4 mg/day for 21 of 28 days (Richardson, ASH, 2009), We opened two sequential phase II trials using the Pom/dex regimen at differing doses to study the efficacy of this regimen in patients who have failed both lenalidomide and bortezomib. Methods: Patients refractory to both lenalidomide and bortezomib therapy; defined as relapsing on or within 60 days of stopping each regimen, were enrolled. Pomalidomide was given orally 2 mg daily (Cohort A) or 4mg daily (Cohort B) on days 1–28 of a 28-day cycle with oral dexamethasone given 40 mg daily on days 1, 8, 15 and 22. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily for DVT prophylaxis. Results: 35 patients with relapsed and resistant/refractory to both lenalidomide and bortezomib were enrolled in each cohort. The median age was 62 years (range, 39–77) in Cohort A and 61 (range, 45–77) years in Cohort B. The median time from diagnosis to enrollment was 57 months for Cohort A (range 12–249) and 72 months(range, 13–183) for Cohort B. 15 patients had high risk molecular markers in Cohort A and 16 in Cohort B. The median number of prior regimens was 6 in both groups. The median (range) duration on treatment was 5(1-13) and 2(0-6) cycles in cohorts A and B respectively. Toxicity at least possibly attributed to drug consisted primarily of myelosuppression: grade 3/4 neutropenia (37% Cohort A vs. 55% Cohort B); grade 3/4 thrombocytopenia (11% Cohort A vs. 13% Cohort B); and grade 3/4 anemia (9% Cohort A vs. 16% Cohort B). Grade 3/4 non-hematologic toxicities occurred in 23% Cohort A vs. 13% Cohort B. Grade 1 or 2 fatigue was the most common non-hematologic toxicity seen in 43% Cohort A vs. 52% Cohort B. Grade 1 or 2 neuropathy occurred in 17% Cohort A vs. 16% Cohort B. Other non-hematologic toxicities occurring in <5% included pneumonitis, hyperglycemia, renal failure, thrombosis. One patient in cohort B had grade 4 hepatitis. Confirmed responses in Cohort A consisted of VGPR 14%, PR 11%, and MR 24% (ORR 49%, 95% CI: 31–66), and responses in Cohort B consisted of VGPR 9%, PR 20%, and MR 12% (ORR 40%, 95% CI: 23–58). The median follow-up on alive patients was 7.5 months, and 3 months in Cohorts A and B, respectively. The median PFS in cohorts A and B are respectively 6.4 months (95% CI: 4.7-NR) and 3.3 months (95% CI: 2.3-NR). Conclusions: Pom/dex is remarkably active and well tolerated in this heavily pre-treated population of dual bortezomib/lenalidomide-refractory MM patients. The majority of patients have not progressed and objective responses (MR or better) are seen in 40–49%. This study confirms therapeutic benefit for Pom/dex in patients relapsing after other novel therapies. These studies do not show an advantage for the 4 mg/day on days 1–28 of each 28 day cycle did not show an advantage over the 2 mg/day on days 1–28 of each 28 day cycle. Disclosures: Lacy: Celgene: Research Funding. Gertz:Celgene: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. 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. Fonseca:Genzyme: Consultancy; Medtronic: Consultancy; BMS: Consultancy; AMGEN: Consultancy; Otsuka: Consultancy; Celegene: Consultancy, Research Funding; Intellikine: Consultancy; Cylene: Research Funding; Onyx: Research Funding; FISH probes prognostication in myeloma: Patents & Royalties. Bergsagel:Celgene: Consultancy; Centocor: Consultancy; Genentech: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Stewart:Celgene: Honoraria.

Abstract Abstract 1965 Background: Pomalidomide is an immunomodulatory compound to be used for heavily pre-treated patients with relapse and refractory multiple myeloma and has shown considerable efficacy in recent clinical trials. It is not clear how patients may respond to other therapies, once the disease becomes refractory to pomalidomide. We examined this question among a cohort of patients receiving pomalidomide therapy in phase 2 clinical trials. Methods: Patients enrolled in an ongoing phase 2 clinical trial of pomalidomide (2-4 mg daily) along with dexamethasone (40 mg weekly), in relapsed myeloma, form the study population. Several cohorts of patients (>= 3 prior therapies not specified, lenalidomide refractory, and lenalidomide and bortezomib refractory patients were enrolled sequentially in this trial (Lacy, M.Q., et al., J Clin Oncol, 2009. 27(30): p.5008–14). Only those patients who have gone off study for disease progression were included in the current analysis. Details of subsequent therapies and survival data were obtained from the medical records. Results: Forty-seven patients from among 142 patients enrolled on the clinical trial between November, 2007 and April, 2010 were included in the study. The median (range) duration of pomalidomide therapy was 4 (0.6-16) months. 15 (32%) patients were lenalidomide refractory and 11 (23%) were refractory to both lenalidomide and bortezomib at the time of study entry. The best confirmed response to pomalidomide was MR (Minimal Response) or better in 23 patients (52%). Various regimens were employed following relapse on pomalidomide. The response to the first regimen following relapse in the 34 patients where salvage therapy was initiated is as shown in Table 1. Overall, 81 regimens were employed across 34 patients; median (range) number of regimens per patients was 1 (0-8). The response rates to the different regimens were as shown in the Table 1. The median overall survival (OS) from the time of progression on pomalidomide was 14.7 months (95% CI; 4, NR). The OS was similar between those patients who had a response to pomalidomide (MR or better) and those who did not. However the OS was shorter for patients who were refractory to lenalidomide and bortezomib (2.1 months) compared to those who were lenalidomide refractory only (6.5 months), and the non-refractory group (NR), P=0.06. Conclusions: This study confirms poor outcome of the patients relapsing after all available therapies. It also gives interesting insights into the activity of different regimens among patients who have relapsed after pomalidomide. The findings once again highlight the incurable nature of the disease and warrant further investigation to develop newer effective treatment regimens for this group of patients who presently do not have effective therapeutic options especially in the relapsed setting. Regimens: ASCT: Autologous Stem Cell Transplantation, Bz: Bortezomib, Mel=Melphalan, Dex: Dexamethasone, CRD: Cyclophosphamide, Revlimid (Lenalidomide), Dexamethasone, CTX; Cyclophosphamide, Len; Lenalidomide, Sor: Sorafenib, VDT-PACE: Velcade (Bortezomib), Dexamethasone, Thalidomide, Cisplatin, Adriamycin, Cyclophosphamide, Etoposide. Response: SD; Stable Disease; Prog; Progression MR: Minimal Response; PR: Partial Response. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Mikhael:Celgene: Research Funding; Onyx: Research Funding; Novartis: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Abstract Abstract 3047 Background: There is concern about the increased incidence of extramedullary plasmacytomas among patients with multiple myeloma (MM) in recent years (Varettoni et al Annals of Oncology 21: 325–330, 2010). There is controversy about whether novel agents increase the risk of extramedullary disease (EMD). EMD may be associated with decreased overall survival in MM. The purpose of this study was to determine the incidence of true, treatment-emergent EMD in MM among a cohort of patients who have been previously exposed to novel agent (thalidomide, lenalidomide, or bortezomib) therapy, and to evaluate the activity of pomalidomide in patients with EMD. Methods: We examined 174 consecutive patients with relapsed refractory multiple myeloma that were enrolled on a phase II clinical trial of pomalidomide plus low-dose dexamethasone. The study cohort was chosen since all patients had previously been exposed to novel agents, and were followed systematically. We adopted a strict definition of EMD which required that in order to be considered extramedullary, plasmacytomas must not have risen from any bone. Thus, masses arising from the bone with a soft tissue component were not considered extramedullary. Results: Of 174 patients studied, 16 patients (9.2%) had EMD prior to enrollment. In 3 of the 16 patients, EMD was present at time of diagnosis and was therefore not considered as treatment-emergent disease for this analysis. In 13 of 174 patients (7.5%) EMD developed during the course of MM, after starting therapy. All 13 patients by inclusion criteria were exposed to novel agents prior to the onset of EMD, including 100% to immunomodulatory agents (thalidomide or lenalidomide); and 78% (10 patients) were exposed to bortezomib prior to developing EMD. The median number of lines of prior therapy in these patients was 6, range 1–12). EMD occurred a median of 48 months following diagnosis (range, 16–183 months); the rate of EMD in the first 3 years following diagnosis of MM was 3%. Since all patients had prior exposure to immunomodulatory agents in this cohort, we were able to calculate the median length of time from initiation of immunomodulatory agents to onset of EMD as 24 months (range 7–119 months). The EMD sites involved included the temporal area soft tissue (3), muscle (3 [1 pt with 10 different areas of involvement, 1 pt with 5 muscles involved]), chest wall not attached to bone (3), abdominal/pelvic masses (3), kidney (2), scrotum (2), sinus (1), paraspinal (1), hilar/pleural based (1), paraesophageal (1), subcutaneous tissue (1), pancreas (1), spleen (1), mediastinum (1), pleural fluid (1), liver (1). Per protocol, all patients received pomalidomide (2-4 mg per day) and low dose dexamethasone (40 mg once a week). Of the 13 patients, there were 2 CR (with complete disappearance of EMD), 2 PR, 2 stable disease, 3 with progressive disease, and 4 patients who did not have their EMD re-evaluated. Thirty percent (n=4) of patients had a 50% or greater reduction in size of the EMD including one patient who received concomitant radiation. Overall survival from measured from trial entry was significantly shorter for patients who presented with EMD compared to those who did not have EMD, median 16 months versus not reached, p=0.002 (log-rank). Conclusion: We found that 7.5% of patients with relapsed refractory myeloma in the era of novel agents develop EMD during the course of their myeloma, including 3% within 3 years of diagnosis. The underlying reasons for the possible increased incidence of EMD may include better radiographic detection (the role of PET/CT scans and MRI), improved overall survival of patients in recent years, and the possibility that novel agents may increase the risk for strictly defined, true EMD among patients who did not have EMD at time of initial MM diagnosis. These need further study. Disclosures: Dispenzieri: Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Gertz:Celgene: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Abstract Pomalidomide at doses of 2 or 4 mg/d has demonstrated excellent activity in patients with multiple myeloma (MM). We opened 2 sequential phase 2 trials using the pomalidomide with weekly dexamethasone (Pom/dex) regimen at differing doses to study the efficacy of this regimen in patients who have failed both lenalidomide and bortezomib. Pomalidomide was given orally 2 or 4 mg daily with dexamethasone 40 mg weekly. Thirty-five patients were enrolled in each cohort. Confirmed responses in the 2-mg cohort consisted of very good partial response (VGPR) in 5 (14%), partial response (PR) in 4 (11%), minor response (MR) in 8 (23%) for an overall response rate of 49%. In the 4-mg cohort, confirmed responses consisted of complete response (CR) in 1 (3%), VGPR in 3 (9%), PR in 6 (17%), MR in 5 (14%) for an overall response rate of 43%. Overall survival at 6 months is 78% and 67% in the 2- and 4-mg cohort, respectively. Myelosuppression was the most common toxicity. This nonrandomized data suggests no advantage for 4 mg over the 2 mg daily. Pomalidomide overcomes resistance in myeloma refractory to both lenalidomide and bortezomib. This trial is registered at http://ClinicalTrials.gov, number NCT00558896.