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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.

Abstract -Background: An increase in the Vitamin B12 (cobalamin) serum transport protein, transcobalamin II (TCII), has been noted in myeloma (MM) patients (Carmel, Blood. 1978.51(6):1057). Uptake of B12 bound to TCII is regulated by transcobalamin II receptors (TCII-R). Labeled thymidine studies have shown, in vitro, that TCII-R are up-regulated in proliferating malignant cells and correlate with increased incorporation of 3H-thymidine and DNA synthesis (Amagasaki, Blood, 76:1380; 1990). Via cobalt-57 labeled B12 studies, the up-regulation of TCII-R has been demonstrated in solid tumors, in vivo, by Flodh (Int J Cancer, 1968.4(5):694). Indium-111diethylenetriaminepentaacetate adenosylcobalamin (In-111DAC) is a novel radionuclide labeled B12 conjugate that has shown preferential uptake in malignant tissue compared to normal tissue via clinical gamma camera imaging of nude mice with sarcoma xenografts and human patients with various solid tumors (Collins, J Nuc Med, 1997.38(5):717 and Mayo Clin Proc, 2000.75(6):568). Nearly all the human tumors were visualized with In-111DAC and a correlation between increased In-111 uptake and higher invasiveness of the tumor at biopsy was observed. We questioned whether In-111DAC could be utilized to image MM, in vivo in murine models. Methods: In accordance with the Institutional Animal Care and Use Committee, we assessed In-111DAC as an imaging agent for MM in mice with subcutaneous (SQ) MM tumors and mice with systemic MM. 7 week old CB17/scid mice received total body irradiation 150cGy before 1x107 myeloma cells (KAS-6/1-gift of Dr. D.F. Jelinek) were injected SQ between the scapulae. Once tumors reached at least 5mm, both tumor bearing mice and saline control mice without tumor were injected intraperitoneally (IP) with 400 μCi In-111DAC. Mice with SQ tumors were injected with 400 μCi of free In-111 for comparison. Gamma camera images at 15h were followed by CT/SPECT (Single photon emission tomography) images at 18h after IP injection. To evaluate In-111DAC imaging in mice with systemic MM, 7 week old bg-nu-xid mice were injected via tail vein with 1x107 myeloma cells (5TGM1-gift of B.O. Oyajobi). Animals with late stage myeloma (day 23–28) and saline control animals were injected with In-111DAC 400 μCi, and were compared to control animals with late MM, injected with 400 μCi of free In-111. Animals underwent gamma camera and CT/SPECT imaging as in the time-frame above. All animals were sacrificed. Organs and tumors were harvested and weighed. Radioactivity was measured in a NaI scintillation well counter and recorded as cpm/mg. Results: Images and radioactivity measurements in the SQ MM model (KAS-6/1) demonstrated excellent uptake of In-111DAC within the tumor compared to normal tissue and controls. In the 5TGM1 systemic MM model, the spleen is a known sanctuary of MM and displayed especially strong uptake of In-111DAC compared to normal tissue. Conclusion: We report the first murine MM models to be imaged with In-111DAC. Our study affirms that In-111DAC is an excellent imaging agent for MM. In-111DAC imaging could be utilized clinically to complement standard staging studies to assess MM tumor burden in patients at time of diagnosis, relapse, or to assess treatment response; especially in patients with non-secretory disease. Moreover, our study strongly suggests the rationale to exploit TCII-R as a target for MM therapy.

Abstract Lenalidomide is an orally active immunomodulatory drug effective in the treatment of multiple myeloma. We evaluated the toxicity and efficacy of MPR combination in a phase I/II study. Patients with newly diagnosed symptomatic multiple myeloma who were not candidates or refused stem cell transplantation were eligible. Treatment consisted of M and P on days 1 – 4 and R on days 1 – 21 in a 28 day cycle. All patients received aspirin 325 mg a day. Routine antibacterial prophylaxis was not used. Patients were accrued in cohorts of 3 at dose level 0 (M 5mg/m 2/d P 60 mg/m2/d R 10 mg/d) and level 1 (M 8mg/m2/d P 60 mg/m2/d R 10 mg/d). Patients were followed for at least 2 cycles to assess Dose Limiting Toxicity (DLT). G/GM-CSF use was not allowed in the first 2 cycles unless DLT had occurred. DLT was defined as occurrence of at least grade (G) 4 hematologic toxicity, G3 febrile neutropenia, or G 3 non-hematologic toxicity in the first two cycles. Failure to start the next cycle within 7 days of day 1 due to toxicity also constituted DLT. Results: 7 patients have been accrued (4 at dose level 0 {one patient had to be replaced} and 3 at dose level 1). 4 were males. ECOG performance status was 0 or1 (2 and 4 patients). Median age was 74 yrs, range 72 – 85. Between 3 and 10 cycles (median 4) have been administered at the time of this reporting. The following G3 or higher toxicities were encountered and considered at least possibly related to treatment: 2 patients at level 0 had G3 neutropenia. Of the three patients at dose level 1, there was 1 G4 neutropenia, 1 G4 thrombocytopenia, 1 G3 hyperglycemia and 1 G4 vascular access device related thrombosis. Responses were defined by EBMT/IBMTR criteria. 1 had a complete remission (after 3 cycles), 4 had partial remission (at least 50% reduction in monoclonal protein) and 1 had minimal response (after 3 cycles). Due to 3 DLT’s in dose level 1, dose level 0 was chosen for phase II of the study. Conclusion: M 5 mg/m2, P 60 mg/m2 and R 10 mg combination is well tolerated and appears effective in patients with multiple myeloma. These results are similar to the experience reported by Palumbo et al (Blood2005, 106(11):abst 785) although a stricter definition of DLT was used in our study. Escalation of R dose in combination with M 5 mg/m2, P 60 mg/m2 may be possible and improve responses. Updated data will be presented.

Abstract Background: MM is an incurable disease with an anticipated overall survival ranging from months to decades. Novel therapies like bortezomib have activity in both the relapsed/refractory and up front settings. There are sparse data on whether novel therapies may overcome high risk features. Methods: Patients with newly diagnosed high-risk myeloma (beta-2 microglobulin [B2M] >= 5.5., plasma cell labeling index [PCLI] >= 1, or deletion 13q) were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients received bortezomib 1.3 mg/m2 every other week indefinitely. Patients relapsing on maintenance schedule resumed full induction schedule. Responses were defined by the EBMT criteria. The primary end-point was the response rate (90% power to detect a response rate of >=50% ). Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled. Among the 43 eligible patients, median age was 63; 51% were male. All had high risk disease: deletion 13q (6/41); PCLI >=1% (17/33); t(4:14) (4/27) and B2M >= 5.5 (34/43). Response data are available for 37 of the 43 eligible patients. The overall response rate was 49% (95% CI: 0.32, 0.66) (0 patients with CR, 1 VGPR, 15 PR, 2 MR, and 11 inevaluable). The response rate allowing for use of serum monoclonal protein levels when a measurable urine monoclonal protein was unavailable at follow-up was 59.5% (1 patient with CR, 1 VGPR, 18 PR, 2 MR, and 6 inevaluable). The median progression free survival is 9.4 months. Thirty-three percent of patients completed the 8 cycles of planned induction therapy and moved to maintenance. Reasons for discontinuing therapy have included progression or death (n=18), adverse events (n=6), and other (n=14). Only 12% of patients remain on active therapy: 0% of deletion 13q patients; 25% of t(4:14) and 12% each of high B2M and high PCLI patients. Of the 14 patients who entered the maintenance phase of treatment, 3 have progressed. Of these 3, 2 took re-induction, and neither responded. Median time to progression for those entering maintenance was12.4 months from the time of starting maintenance. The most common adverse events of grade 3 or higher included neutropenia (33%), diarrhea (31%), hyponatremia (21%), anemia (19%), thrombocytopenia (16%), fatigue (14%). Grade 1–2 sensory peripheral neuropathy occurred in 53% of patients, with only 2% having grade 3 sensory neuropathy. One patient had grade 3 peripheral neuropathy. One patient died after receiving 2 doses of protocol treatment due to heart block and asystole. Updated results on the full study population will be presented at the meeting. Conclusions: In high risk patients, upfront bortezomib appears to result in comparable response rates to those reported for unselected cohorts of newly diagnosed myeloma patients. Continued follow-up of these patients will provide information about whether this will translate into better overall outcomes. Figure Figure

Abstract Background: High dose therapy (HDT) and stem cell transplant has been shown to improve survival in patients with myeloma and remains the standard of care. However, the reported results of initial HDT in these patients reflect the combined effect of the initial therapy and the HDT. The contribution of HDT on its own is often difficult to analyze in this group of patients with varying degree of response to initial therapy. In this single institution retrospective study, we have analyzed the results of HDT in a group of patients with measurable disease at the time of HDT. Methods: We identified patients from our transplant database, who had measurable disease at the time of initiation of transplant as defined by a serum M protein of ≥ 1.0 g/dL, 24 hour urine M-protein ≥ 200 mg or a bone marrow plasma cell % of ≥ 30. Details regarding the clinical outcome were obtained from the database and from patient clinical records. Chi square test was used for comparison of nominal variables and t-test for continuous variables. Kaplan Meier analysis was used for comparing survival and Cox proportional hazards was employed to identify predictors of progression free and overall survival. Responses were defined by the EBMTR criteria, using the measurements at the time HDT and the lowest measurement obtained. VGPR required a 90% reduction in the serum M component with urine protein &lt; 100 mg/24 hours. Results: A total of 440 patients were studied; 271 (61.5%) of whom had a transplant within one year of their diagnosis. Among the 271 patients, 140 (52%) were in the initial plateau, 99 (36%) failed to achieve a PR to initial therapy and 32 (12%) were in their first relapse. Given the known differences in the outcome between these groups of patients, those receiving an early transplant were analyzed separately. The response rates included CR (24%), VGPR (7%), PR (52%), MR or less (17%) and among the late transplants CR (23%), VGPR (8%), PR (61%) and MR or less (8%). The median progression free survival was 23.6 mos and the overall survival from HDT was 62 mos. In a multivariate analysis, presence of cytogenetic abnormalities (RR: 2.5) and high plasma cell labeling index (≥ 1%) (RR: 2.4) at HDT and failure to achieve a CR or VGPR (RR: 1.7) were prognostic for decreased progression free survival post HDT. In a similar model, only high PCLI (RR: 2.8) and abnormal cytogenetics (RR: 2.5) at HDT predicted for poor overall survival after transplant. Conclusion: This study provides a sense of the contribution of HDT, independent of the initial therapy, by determining responses based on the immediate pre-transplant disease measurements and the best values observed post transplant. In this group of patients with residual measurable disease after the initial therapy, HDT therapy leads to complete responses in nearly a quarter of the patients and a VGPR in another 7%, an outcome associated with better progressin free survival. While measurements at transplant do not correlate strictly with response to initial therapy, the aim of this study was to understand the individual contribution of HDT in these patients. Thus some of the patients who would have been classified as having a partial response to induction and HDT may be classified as non-responders in this analysis. These numbers will provide a historical comparison for trials evaluating novel consolidation therapies for myeloma.

Abstract Background: Autologous stem cell transplantation (SCT) improves survival in patients (pts) with multiple myeloma (MM). We have previously demonstrated that the degree of response at transplant does not impact on the outcome of transplant. However, newer induction regimens such as thalidomide and dexamethasone (Thal-Dex) result in higher response rates compared to previously used regimens such as single agent dexamethasone or vincristine, doxorubicin, and dexamethasone (VAD). We examined the outcome of SCT following three different induction therapies for newly diagnosed MM, namely VAD, single agent Dex, and Thal-Dex. Patients and Methods: 340 patients with MM who received their SCT within 12 mos of diagnosis (median 5.8, range 3–12) were studied. Patients receiving more than one induction therapy as well as those in whom thalidomide was added to dexamethasone for lack of response were excluded from the analysis. There were 105 pts in the VAD group, 140 in the Dex group and 95 in the Thal-Dex group. Responses were defined using standard criteria. Results: The study cohort consisted of 209 males (59%), with a median age of 57 years (range 30–76) at transplant. Baseline characteristics were similar in the 3 groups, except for lower age in the VAD group (median 55.8) compared to Dex (59.6) and Thal Dex (57.4) and shorter time to transplant in the Dex group (5.4 m) compared to VAD (6.4) and Thal Dex (5.9). Markers of disease activity pre-transplant, including B2M and marrow plasma cell percentage were higher in the Dex group compared to either VAD or Thal Dex. The proportion of patients with any response to induction therapy was lower in the Dex group compared to the other two. All pts in the Dex and the Thal-Dex groups received melphalan only conditioning compared to 70% in the VAD group, the rest receiving Melphalan/TBI. An objective response was achieved after SCT in 96%, 97%, and 98% of pts in the VAD, Dex and Thal-Dex groups respectively (P=0.8). A complete response to SCT was seen in 49% of patients in VAD group, 45% among those in the Dex group and 38% among those in the Thal Dex group (P=0.38). There was no difference in the median progression free survival after transplant (P=0.21) or overall survival from diagnosis (P=.34) between the three groups. The proportion free from progression at 2 years post transplant was 54%, 55% and 46% for Dex, VAD and Thal-Dex respectively. The proportion surviving at 4 years from diagnosis was 64%, 65.4% and 72% respectively for the three groups. Conclusion: We did not observe any difference in the response rates including complete responses to SCT in the three groups with nearly all pts in each group achieving a response. The progression free survival and overall survival appear to be comparable between the three groups. The results from initial therapy cannot be compared between the three regimens since the study population is restricted to patients reaching stem cell transplant. Within the limits of the study, there does not appear to be any long term impact of the initial therapy for the patients going onto an early stem cell transplant. Figure Figure