Greipp, Philip R.

Abstract Abstract 2970 Background: Over a quarter of patients (pts) with symptomatic multiple myeloma (MM) have some degree of renal insufficiency at the time of diagnosis. Multiple studies show that presence of renal failure is strong predictor of inferior overall survival in MM. With effective therapy, renal function improves in a considerable number of patients. It is not clear if the return of renal function to normal levels will improve their outcome to that expected for patients without renal dysfunction. Methods: We evaluated 1478 patients with newly diagnosed myeloma seen at Mayo Clinic within 90 days of diagnosis, between January 1999 and January 2009. We examined these patients for improvement in renal function and identified the lowest serum creatinine obtained during the disease course. The outcomes were analyzed with respect to the renal function improvements. Results: The median age at diagnosis was 64 years (range; 22–93) and 50% were male. The median estimated follow up for the entire cohort was 53 months, with 781 patients alive at the time of analysis with a median follow of 3 years. The serum creatinine was over 1.5 mg/dL at diagnosis in 333 (22.5%) pts and over 2.5 mg/dL in 148 (10%) pts. The median overall survival for the 333 patients was 37 mos (95% CI; 28, 40) compared to 56 mos (95% CI; 51, 63) for those < 1.5 mg/dL; P < 0.001. Among the 333 pts with baseline Cr > 1.5 mg/dl, any improvement in Cr was seen in 263 (79%) including an improvement of at least 0.5 mg/dL in 208 (62%) pts. Among the 263 pts with any improvement, the median time to lowest Cr was 4 months (range; 1–13). The median survival of the group of patients with Cr <= 1.5 mg/dl, over 1.5 mg/dL at diagnosis but improved to <= 1.5 mg/dL, or remained >1.5 mg/dL were 56., 40 and 27 mos respectively; P < 0.001, Figure). We then examined the impact of renal function improvement in the group of patients where the baseline Cr was >2.5 mg/dL. The median OS for the 42 (out of 148 pts with Cr > 2.5 at diagnosis) who had improved to <=1.5 mg/dL was 40 mos compared to 56 mos for those with a Cr <= 1.5 mg/dL at diagnosis and 27.4 mos for the 106 pts whose Cr did not decrease to <= 1.5 mg/dL; P < 0.001. Conclusion: The results of this study point toward improved outcome among patients with renal dysfunction in whom renal function improves. However, it shows that this improvement in renal function does not necessarily improve survival to that observed for the patients with a comparable level of serum creatinine at diagnosis. While early treatment of asymptomatic myeloma has been shown to have little impact on overall survival, a strategy of waiting for serious features of target organ damage to appear before initiation of treatment may have a negative impact on survival in some patients, especially patients with high light chain production who have a higher predilection for renal insufficiency. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Lacy:Celgene: Research Funding.

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.

Abstract Abstract 3017 Introduction: Multiple myeloma (MM) is a malignancy of clonal plasma cells with resulting in an increase production of ineffective immunoglobulins with suppression of non-involved immunoglobulins. Patients with MM are at increased risk of infectious complications, particularly to those organisms in which opsonization is one of the key defense mechanisms, e.g. strep and staph infections. Treatment of MM is virtually always associated with further immunosuppression, at least in the immediate term, until the malignant clone is eradicated and normal immunoglobulins are produced. Rationale: Due to further compromise of an already incompetent immune system by initial chemotherapy and the previous suggestion (Oken et al Am J Med 1996; 100:624-628) that prophylactic antibiotics may reduce infectious complications, this study was designed to evaluate the impact of prophylactic antibiotics on the incidence of serious bacterial infections during the first two months of treatment. Methods: Pts with untreated MM receiving chemotherapy were randomized on a 1:1:1 basis to receive either a daily ciprofloxacin (C; 500 mg), trimetheprim-sulfamethoxazole (T; DS bid) or observation (O) for the first 2 months of treatment. Pts were evaluated for serious bacterial infection (grade 3 or 4) during the first two months of myelotoxic/suppressive therapy. Secondary endpoints (EP) included: incidence of non-bacterial infections, resistant organisms due to prophylaxis, the incidence of infection the third month OFF of antibiotic prophylaxis and whether protection against infection is associated with an improved response rate. Results: From July 1998 to January 2008, 212 untreated, symptomatic MM pts being treated with myelotoxic/suppressive chemotherapy were randomized to C (n=69), T (n=76) or O (n=67) for the first 2 months of treatment. The incidence of serious infection (&gt; grade 3 ECOG toxicity criteria and/or hospitalization) was comparable among groups: C=10 (14.7%), T=5 (6.9%), O=9 (14.5%); p= 0.268 which was the primary EP. The incidence of any infection during the first 2 months was also comparable (20% vs 23% vs 22%, respectively, p=0.910). There were 25 grade 2 infections and 4 grade 3 infections involving respiratory (n =13), sepsis/bacteremia (n = 4), and urinary (n =3), joint/bone (n =2), unknown (n =2) or various GI tract (n = 5) and skin (n =1). Eight pts expired within the first 2 months: 2 from MM, 3 cardiac, 2 respiratory, 1 renal (unrelated to MM or Rx) occurring in the C (4), T (1), O (2). Secondary EPs failed to show a difference in the incidence of serious bacterial infection during the third month in the absence of prophylaxis (C=3%, T=4%, O=2%; p=0.874), development of resistant infections, initial response to therapy or overall survival. Conclusions: The use of prophylactic antibiotics did not decrease the incidence of serious infection (&gt; grade 3 and/or hospitalization) nor of any infection within the first 2 months of treatment. Infection prophylaxis did not affect the incidence of infection upon completion of 2 months of therapy (nor, ultimately, at any time during the subsequent 2 years), the response to therapy or to overall survival. Incidentally, there were no documented cases of PCP despite the assumption that MM pts, with compromised immune systems, are more susceptible. The incidence of serious infections in this study, in which few patients received novel agents, is comparable to that observed in more modern regimens even in the presence of mandated/recommended prophylactic antibiotics. Utilizing either lenalidomide plus dexamethasone or clarithromycin, lenalidomide and dexamethasone resulted in &gt; grade 3 infectious complications in 16.7% and 9.7%, respectively, as reported by the Mayo Clinic and Cornell groups, respectively (Gay et al Am J Hematol, in press). Furthermore, in the ECOG E4A03 randomized trial of lenalidomide plus either high dose dexamethasone (LD) or low dose dexamethasone (Ld) in which prophylactic antibiotics were recommended, the incidence of &gt; grade 3 infectious complications were 9.4% and 6.4%, respectively (Rajkumar et al Lancet Oncol 2010; 11: 29–37). We conclude that routine use of prophylactic antibiotics should not be mandated for patients receiving induction chemotherapy. Prophylactic antibiotics should be considered on a case-by-case basis after analyzing the potential infection risk in individuals. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 308 Introduction: The Eastern Cooperative Oncology Group (ECOG) has previously reported the superior 1 and 2 year survival of Ld versus LD as initial therapy in newly diagnosed symptomatic multiple myeloma (MM) (Rajkumar et al Lancet Oncol 2010; 11: 29–37). The 1 year and 2 year OS for Ld vs LD were 96% and 85% vs 88% and 78%, (p < 0.01), respectively. This despite higher ORR in LD vs Ld (79% vs 68%; p = 0.008). The difference in OS was predominantly due to early death in the LD group (5% vs 0.5%; p = 0.003). As a result of this analysis, Ld is now considered the standard of care. However, it should be noted that the majority of these deaths occurred in pts > 65. In this analysis, we evaluated the impact of age on dexamethasone dose intensity and OS. Methods: 445 pts were randomly assigned: 223 to LD and 222 to Ld. Pts were analyzed on an intent-to-treat basis for OS. The pts were analyzed by age in 2 groups: < 65 and > 65 (the age corresponding to transplant eligibility outside the US). The pts > 65 were then further subdivided into >70 and > 75 yrs. Results are expressed as OS probability at 1 and 2 years post randomization. In addition, to eliminate the early death ‘penalty’ in the LD group in the original analysis, a landmark analysis was performed at 4 months. Results: Overall Survival Probability: Intent-to Treat Analysis Overall Survival Probability: 4 month Landmark Analysis Conclusions: As previously reported, OS in the trial at 1 and 2 years was superior with Ld. OS was not superior with LD compared with Ld in any age group despite a higher response rate. This was true even when using a landmark analysis to eliminate the 5% early deaths seen in the first 4 months of treatment. We conclude the following: 1) LD is not definitively superior to Ld in any age group; 2) Given the higher toxicity in the absence of a clear survival benefit with LD, Ld remains the best choice for all ages. This analysis confirms the original opinion that low-dose dexamethasone is the standard of care for all newly diagnosed MM pts, regardless of age. Disclosures: Vesole: Millennium Pharmaceuticals: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centorcor-Ortho-Biotech: Speakers Bureau. Off Label Use: Lenalidomide for front-line therapy in multiple myeloma. Abonour:Celgene: Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau. Callander:Millennium Pharmaceuticals: Research Funding. Fonseca:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Consultancy; Onyx: Research Funding; Otsuka: Consultancy; Medtronic: Consultancy; Intellikine: Consultancy. Siegel:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 1892 Background: Primary or light chain amyloidosis (AL) is a clonal plasma cell disorder characterized by a relatively low plasma cell burden and multi-organ deposition of immunoglobulin light chain derived amyloid fibrils. The survival of patients with amyloidosis is quite variable with median survival of 12–18 months in different series, and largely dependent on the number and severity of organs involved. In addition to new drugs, the combination of melphalan and dexamethasone is an effective regimen for AL and risk adapted approaches to SCT has decreased treatment related mortality. It is not clear if the recent progress in risk stratification and treatment approaches have translated into improved survival for these patients. Methods: We studied two separate cohorts of patients; the first cohort consisting of 2118 patients with AL seen at Mayo Clinic over a 40-year period between November 1967 and August 2006 was used to examine the trends in overall survival from diagnosis during this time period. The second cohort of 443 patients seen between September 2006 and August 2009 were examined only for the changes in early mortality and for validation of a model for predicting early mortality developed using the first cohort of patients. Results: The estimated median follow up for the entire group was 7.8 years (95% CI; 7.1, 8.5). The patients were divided into 4 cohorts based on date of diagnosis; 1966–1976 (n=121), 1977–1986 (n=343), 1987–1996 (n=636) and 1997–2006 (n=1017). The median OS from diagnosis for the four cohorts were 0.9, 1.2, 1.2 and 1.5 years respectively, P < 0.001 (Figure 1). More importantly there was steady improvement in the long-term survival among these patients with 4-year survival estimates of 16%, 21%, 24% and 33% respectively. Next, we specifically looked at the survival trends within the last cohort (1996-2006), dividing the patients into three time periods; 1996–1999 (n=263), 2000–2003 (n=291) and 2003–2006 (n=463). While the OS from diagnosis was relatively unchanged between the first and second time periods (28 vs. 30% 4 year survival), there was significant improvement in the last three year period (42% survival at 4 years); P =0.02. Given the high early mortality in this disease, we specifically examined the one-year mortality among the entire patient cohort and found no clear improvement in terms of one-year mortality. Using logistic regression analysis, we identified cTnT > 0.01, NT-ProBNP > 4200 and Uric Acid > 8.0 mg/dL to be the best predictors of death within one year of diagnosis. The probability of death within one year for those with none, 1, 2, and 3 risk factors was 19, 38, 61, and 78% respectively, P < 0.01 (Figure 2). This model was further validated among patients seen during the most recent three years, September 2006 and August 2009. Conclusion: Survival in AL amyloidosis has improved over time, particularly in the recent years and likely reflects the recent improvements in therapy. However, early mortality remains a problem and baseline factors can be used to identify patients at risk for early mortality, who then can be targeted for risk adapted therapy approaches in clinical trials. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Abstract Abstract 1964 Background: Thalidomide (thal), lenalidomide (len) and pomalidomide (pom) have been shown to have considerable efficacy in patients with newly diagnosed as well as relapsed multiple myeloma (MM). They are often used as initial therapy in patients proceeding to stem cell transplant (SCT), and based on the initial response, are usually considered for salvage therapy during their disease course. However, the retreatment efficacy of these compounds is unknown. We conducted this study to ascertain the degree of response that can be obtained by retreatment with immunomodulatory compounds. Patients and Method: 410 patients with newly diagnosed MM who received either thalidomide-dexamethasone or lenalidomide-dexamethasone were studied. Of these, 183 patients received thalidomide, lenalidomide or pomalidomide (with or without dexamethasone) as one of the salvage regimens following relapse, and form the study group. We included all patients who received the repeat immunomodulatory therapy as salvage treatment at any time during the MM disease course. Results: The median (range) age of the MM patient group was 60 (29-80) years; 117 (64%) were male. Thalidomide and lenalidomide were used as initial therapy in 106 (58%) and 77 (42%) patients, respectively. Patients received a median of 2 treatments (range, 1–6) prior to salvage therapy; bortezomib was used as one of the salvage treatment (prior to the repeat immunomodulatory therapy) in 41 (22%) patients. An autologous stem cell transplant was performed in 118 (64%) patients after the initial immunomodulatory therapy. Almost one half (89; 49%) of the patients went off the first line therapy to undergo a SCT; whereas drug toxicity (26; 14%) and disease progression (21; 11%) were other causes requiring a treatment change. The compound used for salvage therapy was thalidomide, lenalidomide or pomalidomide in 40 (22%), 129 (70%) and 14 (8%) patients, respectively. The responses to salvage therapy based on the initial therapy and the salvage regimen are as shown in Table 1. Overall, 67 (37%) patients achieved a partial response or better and 73 (40%) patients achieved less than a partial response (stable and progressive disease) to repeat immunomodulatory therapy, while the remaining 43 (23%) had non evaluable disease response. Conclusions: Retreatment with an immunomodulatory therapy, especially a different compound, was associated with excellent response rates. Lowest response rates were seen in patients retreated with thalidomide after having received lenalidomide as their initial therapy after the diagnosis of MM. This information is valuable in deciding on the choice of repeat therapy with immunomodulatory compounds in patients with relapsed disease. Disclosures: 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.

Abstract Abstract 2803 Poster Board II-779 Background. The rate of asymptomatic amyloidosis (asym-amyloidosis) detected in patients with newly diagnosed multiple myeloma (MM) or smoldering multiple myeloma (SMM) is unknown. This topic is significant because unrecognized AL may be associated with increased mortality may change the patient's management. The objective of the present investigation was to evaluate the number and clinical significance of asym-amyloidosis in MM and SM patients at the time of the diagnostic bone marrow (BM) biopsy for MM. Materials and Methods. The study population was selected from the Mayo Clinic Dysproteinemia database and consisted of consecutive patients with an established diagnosis of MM or SMM without recognition of symptomatic AL. Bone marrow biopsies at diagnosis of MM or SMM were retrospectively stained with Congo Red and reviewed by a single pathologist. A patient was considered to have asym-amyloid if Congo Red staining with apple green birefringence was found. Results. Biopsies from 144 (M 84, F 59) patients were evaluated: 77 had a diagnosis of MM and 67 of SMM. The median age was 59 (range 26-84) years. No differences were found regarding hemoglobin, platelets, prothrombin time, serum and urine proteins, serum albumin, alkaline phosphate, creatinine and β2-microglobulin among MM and SMM patients. At a median follow-up 76 months (range 0-216), 32% patients were alive, 65% dead and 2.7% lost to follow-up. Immunoglobulin isotypes were as follows: 96/144 (67%) had IgG 23/144 (16%) IgA, 12/144 (8%) had light chain only, 1/77 (1%) had IgD, none had IgM and 12/144 (8%) had biclonal or indeterminate; 84/144 (58%) were κ restricted. The presence of amyloid was found in only 2 cases (1%, 95% CI – 0.6 to 3.2), 1 in MM and 1 in SMM group. Neither of these patients had or developed signs or symptoms suggestive of organ involvement by amyloid. Among the 142 other patients without amyloid deposition in their index bone marrow, 1 (0.7%, 95% CI -0.6 to 2.0) developed symptomatic AL after 119 months of follow-up. Characteristics of these three patients are shown in table 1. Conclusions. We found only 2 cases (1%) of amyloidosis in the 144 cases of MM or SMM. Our estimates are lower than the rates which have been reported by others, perhaps because of our high level of suspicion for amyloid at our Amyloidosis Center. These data do not support the need for searching for asym-amyloidosis in patients with newly diagnosed MM or SMM as long as they have no clinical features of AL. Disclosures: Off Label Use: Hydroxyurea use in myelofibrosis. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Witzig:Novartis: Research Funding. Kumar:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: A phase III trial comparing thalidomide plus dexamethasone (Thal/Dex) versus dexamethasone alone (Dex) as first line therapy in newly diagnosed multiple myeloma (MM). The results of an interim analysis on 109 of 207 enrolled patients (pts) were reported earlier (Rajkumar et al, Proc ASCO 2004). This report provides results from 198 of 202 eligible pts entered on this study. Methods: Pts with newly diagnosed, untreated, symptomatic MM were eligible. Pts in the Thal/Dex arm (Arm A) received Thal 200 mg/day PO with Dex 40 mg on days 1–4, 9–12, and 17–20 PO. Pts in the Dex arm (Arm B) received Dex alone, at the same dose as Arm A. Therapy was repeated monthly. The primary endpoint was best response at 4 months on intent to treat basis. At 4 months pts could go off study for stem cell transplant or elect to continue therapy. Response was defined as a decrease in serum and urine monoclonal (M) protein by 50% or higher. If serum M protein was unmeasurable, a 90% or higher decrease in urine M protein was required. Responses had to be verified on 2 consecutive determinations separated by at least 2 weeks. Results: 207 pts were enrolled as planned: 103 randomized to Thal/Dex and 104 to Dex alone. Median age was 65 yrs. 6 pts were ineligble for failing to meet eligibility criteria for study entry and are excluded from response analysis. Response to therapy could be assessed at this time on 198 of 202 eligible pts. Response rate with Thal/Dex was significantly higher than with Dex: 58% versus 42%, respectively, (p=0.0164; one-sided Fisher’s exact test). The corrected response rate allowing for use of serum M protein levels in pts in whom a measurable urine M protein was unavailable at follow-up was 69% with Thal/Dex versus 51% with Dex. Median time to response was rapid, and similar in both arms (1.1 months). 3% of pts in the Thal/Dex arm and 5% in the Dex arm met criteria for disease progression within the first 4 months. Toxicity data are available on 204 pts. Grade 3 or greater non-hematologic toxicities occurred within the first 4 months/cycles in 68% of pts on the Thal/Dex arm and 43% in the Dex arm. Grade 3 or higher cardiac ischemia occurred in 3 (2 prior to 4 months, 1 approx. 1 wk after 4 months) pts in Arm A and 2 pts (both prior to 4 months) in Arm B. As a planned analysis, incidence rates of grade 3 or higher deep vein thrombosis (DVT), rash, bradycardia, and neuropathy and any grade 4–5 toxicity in the first 4 months were compared (see Table). The p-value (one-sided Fisher’s exact test) for increased toxicity (of the specified types) is <0.0001. In this period, 18 pts died, 7 in arm A and 11 in Arm B. Conclusions: Thal/Dex demonstrates superior response rates in newly diagnosed MM compared to Dex, comparable to historical results with VAD. The use of Thal/Dex must be weighed in each pt given the higher toxicities compared to Dex alone. Both regimens have low progression rates as pre-transplant induction therapy, and negate the need for intravenous VAD. Major Grade 3–4 toxicities Toxicity Arm A (n=102) Arm B (n=102) DVT (Grade>=3) 18% 3% Rash (Grade>=3) 4% 0% Sinus Bradycardia (Grade>=3) 1% 0% Neuropathy (Grade>=3) 7% 4% Toxicity of Any Type (Grade>=4) 34% 17% Total 46% 20%

Abstract Abstract 2877 Poster Board II-853 Background and Objective: In newly diagnosed multiple myeloma (MM) patients, treatment with lenalidomide plus high-dose dexamethasone (RD) was superior to high-dose dexamethasone in terms of both response rates and 1-year progression-free survival (PFS) (Zonder JA et al, Blood 2007;110:77). Preliminary results suggest that the combination lenalidomide plus low-dose dexamethasone (Rd) compared to the RD regimen yields significantly better 2-year overall survival (OS) (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The combination of melphalan, prednisone, and lenalidomide (MPR) has been investigated in a phase I/II study showing promising results (Palumbo A et al, J Clin Oncol 2007; 25:4459-4465). The goal of this case –control study was to compare the efficacy and the toxicity of the lenalidomide/dexamethasone (len/dex) combination vs MPR as primary therapy for newly diagnosed elderly MM patients, to determine the additive value of melphalan compared to a regimen of lenalidomide plus corticosteroid. Patients and methods: Data from 51 newly diagnosed MM patients enrolled in Italy in a phase I/II dose-escalating trial, from January to October 2005, with MPR, were analyzed. For comparison of their outcome, 37 patients were identified among newly diagnosed patients seen at the Mayo Clinic from March 2005 to December 2008 who received len/dex as primary therapy and were enrolled in phase II or III trials. Patients treated with MPR received 9 monthly cycles of oral melphalan (doses ranging from 0.18 to 0.25 mg/kg on days 1-4), prednisone (2 mg/kg on days 1-4) and lenalidomide (doses ranging from 5 to 10 mg/day on days 1-21). After 9 cycles, patients started maintenance with lenalidomide alone (10 mg, days 1-21) until relapse or progression. Patients treated with len/dex received oral lenalidomide (25 mg/day, days 1-21) plus dexamethasone, either at low-dose (n=17) (40 mg orally days 1, 8, 15, 22) or at high-dose (n=21) (40 mg orally on days 1-4, 9-12, and 17-20). Treatment was continued until progression, relapse or unacceptable toxicity, or could be stopped at the physician's discretion. Patients (n=13) were allowed to receive transplant if they wished and were deemed eligible. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method and comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: On intention-to-treat analysis, 15.7% versus 23.7% patients, respectively in the MPR and in the len/dex group, (p=0.342) achieved a complete response, and 43.2% vs 47.4%, (p=0.691) achieved at least a very good partial response. Time-to-progression (TTP) (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.04; 95% CI 0.55-1.98; p=0.903), PFS (median: 24.7 vs 27.5 in MPR and len/dex groups, respectively; HR 1.03; 95% CI 0.55-1.92; p=0.926) and OS (2-year OS: 86.2% in MPR group vs 89.1% in len/dex, HR 0.86; 95% CI 0.38-1.98; p=0.730) were not significantly different between the 2 groups. No significant differences in TTP, PFS and OS were reported when MPR patients were compared with the subgroup of patients treated with low-dose dexamethasone plus lenalidomide. Similar results were found when the analysis was restricted to MPR patients and len/dex pair mates receiving lenalidomide plus low/dose dexamethasone, matched according to age and sex, and who did not received transplant. The toxicity profile was different in the two groups. Hematologic grade 3-4 toxicities were more common with MPR compared with len/dex, in particular neutropenia (66.7% vs 21.1%, p < 0.001) and thrombocytopenia (31.4% vs 2.6%, p < 0.001), respectively. Grade 3-4 gastrointestinal events (13.2% vs 2.0%, p= 0.080), thrombotic events (13.2 vs 5.9, p= 0.279) and fatigue (10.5% vs 3.9%, p= 0.395) were more common with len/dex compared with MPR. Conclusion: Results of this case-control study show that both MPR and Rd are efficacious regimens for elderly MM patients. Data need however to be carefully evaluated and randomized control trials are needed to confirm these results. Disclosures: Off Label Use: research drug in combination to standard of care. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; novartis: Research Funding; genzyme: Research Funding. Dispenzieri:celgene: Research Funding. Gertz:celgene: Honoraria; genzyme: Honoraria; millenium: Honoraria; amgen: Honoraria. Lacy:celgene: Research Funding. Musto:celgene: Honoraria. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Petrucci:celgene: Honoraria; Janssen Cilag: Honoraria. Greipp:celgene: Research Funding. Boccadoro:jansen Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; pharmion: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria.

Abstract Abstract 2868 Poster Board II-844 Background and Objective: In newly diagnosed multiple myeloma (MM), the combination of lenalidomide plus high-dose dexamethasone (RD) is superior to high-dose dexamethasone (Zonder JA et al, Blood 2007;110:77). Preliminary results show that lenalidomide plus low-dose dexamethasone (Rd) has better 2-year overall survival (OS) compared with RD (Rajkumar SV et al, J Clin Oncol 2008;26:8504). The addition of clarithromycin (Biaxin) to lenalidomide and low-dose dexamethasone (BiRd) has been investigated in a phase II study, demonstrating a high response rate and 2-year OS (Niesvizky R at al, Blood 2008;111:1101-1109). However, the additive value of clarithromycin is not known. No randomized trials have compared Rd versus BiRd, none are planned. The objective of this case–matched study was to compare the efficacy and the toxicity of BiRd vs Rd as initial therapy for newly diagnosed MM. Patients and methods: Data from 72 newly diagnosed MM patients treated at the New York Presbyterian Hospital–Cornell Medical Center, from December 2004 to December 2006, with BiRD, were analyzed. For comparison, an equal number of pair mates were selected among newly diagnosed patients seen at the Mayo Clinic who received Rd, from March 2005 to December 2008. Case matching was performed with respect to age, gender, and transplant status. Patients treated with BiRd received oral lenalidomide (25 mg/day, days 3-21 of cycle 1; days 1-21 of subsequent cycles); dexamethasone (40 mg days 1, 2, 3, 8, 15, 22 of cycle 1; days 1, 8, 15, and 22 of each subsequent cycle); clarithromycin (500 mg twice daily, from day 2 of cycle 1). Patients treated with Rd received oral lenalidomide (25 mg/day, days 1-21) plus low-dose dexamethasone (40 mg days 1, 8, 15, 22). In both groups patients were allowed to discontinue treatment to pursue transplant, but treatment until progression, relapse or unacceptable toxicity was permitted at the physician's discretion. Outcome was analyzed on an intention-to-treat basis. The Chi-square or the rank sum tests were used to compare variables. Time-to-event analysis was performed using the Kaplan-Meier method; comparisons were determined by the log-rank test and the Cox proportional hazards model. Results: Median duration of treatment was 11.8 months in the BiRd group vs 6 months in the Rd group. On intention-to-treat analysis, complete response was significantly higher with BiRd compared to Rd (45.8% vs 13.9%, respectively, p<0.001); similarly very good partial response (VGPR) or better was higher with BiRd (73.6% vs 33.3%, p<0.001). Rates of VGPR or better, after 6 months and 1 year of therapy, were significantly higher in BiRd patients. Both time-to-progression (TTP) (median 48.3 months vs 27.5 months; HR 0.51; 95% CI 0.25-1.06; p=0.071) and PFS (median 48.3 months vs 27.5 months, HR 0.50; 95% CI 0.25-0.98; p=0.044) were higher with BiRd. Median time to next treatment (TTNT) was not reached in BiRd group compared to 29.9 months in Rd patients (HR 0.37 95% CI 0.20-0.66, p<0.001). There was a trend toward better OS with BiRd, (3-year OS: 89.7% vs 73.0%), but the difference was not statistically significant (HR 0.48; 95% CI 0.17-1.37; p=0.170). Thirty-two patients in each group received transplant; median time to transplant was longer in BiRd group (13.5 vs 5.9 months). Results of survival, for patients who received transplant and patients who did not, were similar to those of the total population. On subset analysis, among patients presenting with International Staging System (ISS) stage I/II at diagnosis, TTP, PFS and TTNT were significantly longer in BiRd patients; no significant differences were found among patients with ISS stage III. Main grade 3-4 toxicities of BiRd were hematological, in particular thrombocytopenia (23.6% vs 8.3%, p=0.012); rate of neutropenia was similar between the 2 groups (19.4% vs 16.7%, p=0.665). Infections (16.7% vs 9.7%, p=0.218) and dermatological toxicity (12.5% vs 4.2%, p=0.129) were higher in patients who received Rd. Rate of venous thromboembolism was similar in the 2 groups (9.7% vs 12.5%, respectively in Rd and BiRd patients, p=0.596). Conclusion: Results of this case-control analysis suggest superiority of BiRd in terms of response rate and survival, compared with Rd, and suggest that there may be a significant additive value when clarithromycin is added to Rd. These data indicate the need for randomized prospective phase III studies to evaluate BiRd versus Rd in the treatment of MM. Disclosures: Off Label Use: research drug in combination to standard of care. Kumar:celgene: Research Funding; millenium: Research Funding; bayer: Research Funding; novartis: Research Funding; genzyme: Research Funding. Mark:celgene: Research Funding. Dispenzieri:celgene: Research Funding. Gertz:celgene: Honoraria; genzime: Honoraria; millenium: Honoraria; amgen: Honoraria. Leonard:celgene: Consultancy. Lacy:celgene: Research Funding. Witzig:celgene: Research Funding. Fonseca:medtronic: Consultancy; genzyme: Consultancy; celgene: Consultancy; amgen: Consultancy; BMS: Consultancy; otsuka: Consultancy. Greipp:celgene: Research Funding. Niesvizky:celgene: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Proteolix: Research Funding, data monitoring committee.