We conducted a retrospective evaluation of response and survival for 293 patients with multiple myeloma treated since June 2000 with primary thalidomide- or bortezomib-based combinations, of whom 207 patients received intensive therapy supported by autologous blood stem cells within the first year. Survival times were calculated after a landmark of 1 year from start of therapy, so that subsequent median survival was 8.9 years for patients with CR, 4.9 years for those with PR and 0.6 year for patients with NR ( P < 0.001). Multivariate analyses confirmed CR or PR as the major favorable factors with less impact on prognosis for age or disease stage. Both novel agents and high-dose therapy (HDT) resulted in high frequencies of PR or CR, with early HDT useful for many patients with NR or PR in improving response status and subsequent survival.

e18512 Background: Solitary plasmacytoma is a rare plasma-cell neoplasm. We wanted to assess the outcome and prognostic factors in patients with solitary plasmacytoma. Methods: The data from 79 patients with bone (n=55), and/or extramedullary (n=25) solitary plasmacytoma with no evidence of multiple myeloma treated with definitive radiation at a single institution from 1988-2007 were collected. The median follow-up time was 56 months. A serum myeloma protein was present in 36 patients (46%), and Bence Jones proteinuria was present in 24 patients (31%). The median radiation dose was 45 Gy. Overall-survival, local control, and freedom from multiple-myeloma progression were calculated actuarially. Results: The five-year overall survival rate was 78%. The median overall survival was 11 years. Local control was achieved in 72 patients (91%). Radiation dose above or below 45 Gy was not a predictor of local control (p=0.452). The five-year probability of progression to multiple myeloma in all patients was 47%. The five-year probability of progression to multiple myeloma was higher in patients with bone plasmacytoma than extramedullary plasmacytoma (57% versus 27%, p = 0.008). In patients with solitary plasmacytoma of the bone, the 5-year probability of progression to multiple myeloma was 47% in patients with resolution of serum or urine myeloma protein, versus 75% in patients without resolution of myeloma protein (p =0.056). Conclusions: Local control is excellent in this disease. Progression to multiple myeloma remains the main problem. Patients with extramedullary plasmacytoma had the best outcomes. There was a trend towards a lower rate of progression to multiple myeloma in patients with bone plasmacytoma that had resolution of myeloma protein. No significant financial relationships to disclose.

To assess the impact of CR on survival in multiple myeloma. Retrospective evaluation of response and survival among 758 consecutive patients with multiple myeloma treated at a single center, of whom 395 patients received intensive therapy supported by autologous stem cells within the first year. Survival times were calculated after 1 and 2 years from the start of chemotherapy. On the basis of the response status after a 2-year landmark, the subsequent median survival was 9.7 years for patients with CR, 4.4 years for those with PR and 2.7 years for patients with NR (P<0.001). Longer survival was attributed in part to intensive therapy that converted the myeloma of 67% of patients with NR to PR or CR, and induced CR in 26% of patients with PR. Intensive therapy did not prolong survival for patients with CR after primary therapy. For patients with multiple myeloma, Cox regression analyses showed that CR was the dominant prognostic factor for long survival, followed by stage I disease, PR and intensive treatment as independent factors. A cure fraction of 2% was identified for nine patients who have remained in CR >10 years.

8596 Background: The introduction of novel therapeutic options with bortezomib and immunomodulatory agents in the up-front management of multiple myeloma (MM) has significantly improved induction response rates. However, the role of high dose chemotherapy and autologous stem cell transplant (ASCT) after induction with these highly active agents is not known, especially in patients with only a partial response to induction therapy. Methods: We conducted a retrospective review of 95 newly diagnosed MM patients treated with induction bortezomib-lenolidomide-dexamethasone (BLD) or bortezomib-thalidomide-dexamethasone (BTD) prior to ASCT. Responses were graded according to IMWG criteria. Results: 19 patients received BLD and 76 patients received BTD. All patients were conditioned with a melphalan-based regimen. Of the 19 patients who underwent induction with BLD, complete response (CR), very good partial response (VGPR) and partial response (PR) were achieved in 2 (11%), 8 (42%) and 9 (47%) respectively for an overall response rate (ORR) of 19/19 (100%). After ASCT, CR, VGPR and PR were achieved in 9 (47%), 5 (26%) and 5 (26%) respectively for a continued ORR of 21/21 (100%). Notably, 4/8 (50%) of patients with a VGPR after induction therapy with BLD improved to a CR after ASCT. 3/9 (33%) of patients with an initial PR to BLD improved to a CR and 1/9 (11%) with a PR improved to VGPR after ASCT. Of the 76 patients who underwent induction with BTD, CR, VGPR and PR were achieved in 6 (8%), 37 (49%) and 31(41%) respectively for an ORR of 74/76 (97%). 1 patient had stable disease and 1 patient had progressive disease. After ASCT, 27/76 (36%) achieved a CR, 30/76 (39%) a VGPR and 18/76 (24%) a PR for an ORR of 75/76 (99%). Of the patients who initially had a VGPR to BTD 16/37 (43%) improved to a CR while 5/32(16%)of PR patients improved to a CR and 9/32 (28%) of PR patients improved to a VGPR. Conclusions: Of the 40 patients who only achieved a PR after induction therapy with BLD or BTD, 16 (40%) had further improvement to a CR or VGPR after ASCT. Thus there is a significant benefit of ASCT in these patients who initially demonstrate relative resistance to induction therapy with highly active regimens. [Table: see text]

8523 Background: While longer survival has been the ultimate index of better treatment in multiple myeloma, earlier endpoints have included the frequencies and durations of partial (PR) and complete remission (CR). This report describes a retrospective review with multivariate analysis of outcomes among newly diagnosed patients who received the sequence of primary chemotherapy followed by intensive therapy within the first year. Methods: Clinical outcomes were assessed in 759 consecutive patients with multiple myeloma, treated between 1987–2007, of whom 406 patients also received intensive therapy supported by autologous stem cells within the first year. Response to treatment was rated according to EBMT criteria. CR required disappearance of serum myeloma protein by immunofixation on two consecutive studies. Multiple prognostic variables were assessed in order to identify features associated with long survival. All survival times were compared by landmark analyses for those alive after 1 year, in order to avoid potential bias from the guaranteed survival of patients with responsive disease. Results: The response rate among all patients was 66% (including CR in 8%) after primary chemotherapy and then 75% after including results after high-dose therapy (including CR in 20%). The median survival for all patients was 56 months. Survival comparisons dating from 12 months after start of treatment were significantly longer for 144 patients whose disease was in CR (median 9.6 years), than for those with PR or NR (median 4.0 and 2.2 years, respectively). For those patients evaluated at 12 months, Cox regression analysis indicated that the occurrence of CR, the presence of ISS Stage I disease, and provision of intensive therapy were associated independently with long survival, in that order. Median survival times from onset of CR were similar (10–15 years) for groups of patients who achieved CR after only chemotherapy or after intensive therapy for NR, PR or as consolidation of CR. Conclusions: Survival times were similar at approximately 10–12 years for different groups of patients with CR by whatever pathway that may have been achieved. Prospective clinical trials are needed for definitive evaluation of CR as a surrogate marker for long term survival. No significant financial relationships to disclose.

New uniform response criteria are required to adequately assess clinical outcomes in myeloma. The European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry criteria have been expanded, clarified and updated to provide a new comprehensive evaluation system. Categories for stringent complete response and very good partial response are added. The serum free light-chain assay is included to allow evaluation of patients with oligo-secretory disease. Inconsistencies in prior criteria are clarified making confirmation of response and disease progression easier to perform. Emphasis is placed upon time to event and duration of response as critical end points. The requirements necessary to use overall survival duration as the ultimate end point are discussed. It is anticipated that the International Response Criteria for multiple myeloma will be widely used in future clinical trials of myeloma.

In a previous trial among 137 previously untreated patients with multiple myeloma, the combination of thalidomide-dexamethasone induced remission in 66% of patients, including complete remission in 13%. In an attempt to induce more frequent remissions, we added bortezomib to this program. Between 7/03 and 3/06, 38 newly diagnosed patients with multiple myeloma received at least one, but no more than 3, courses of bortezomib in a dose of 1.3 mg/m(2) IV x 4; dexamethasone 20 mg/m(2) PO for 4 days beginning on days 1, 9, 17; thalidomide 100 mg PO daily increasing to a maximum of 200 mg. There was rapid onset of remission in 33 patients (87%) including 6 patients with complete remission (16%). Most side effects were preventable, but otherwise were usually mild and reversible. After a median of 4 months, 25 eligible patients received intensive therapy with high- dose melphalan supported by autologous blood stem cells, so that the myeloma was in complete remission in 14 patients (37% of all patients). The combination of bortezomib-thalidomide-dexamethasone was a highly effective primary treatment for newly diagnosed patients with multiple myeloma.

7610 Background: Painful vertebral compression fractures are a major source of morbidity in MM. Vertebroplasty involves percutaneous injection of polymethylmethacrylate (PMMA) into a vertebral body, while kyphoplasty involves inflation of a balloon for painful kyphotic deformity prior to stabilization with PMMA. Methods: We assessed safety and efficacy of 100 vertebroplasties and/or kyphoplasties in 81 consecutive myeloma patients between 12/2000 and 2/2005. Results: Median age was 63 (range 32–84), with 29% having prior radiotherapy to the vertebra treated. Contraindications included epidural compression of neural elements and failure to localize a symptomatic level. Kyphoplasty was preferred if kyphosis of > 20 degrees contributed to pain, or if the posterior vertebral cortex was disrupted so that controlled delivery of bone cement was difficult. Vertebroplasty was performed when vertebral collapse was either slight or so severe that insertion of balloon device was not possible, or if patient could not tolerate the general anesthesia required for kyphoplasty. The median preoperative visual analog pain score (0–10) was 8(range 2–10); the median postoperative pain score was 3 (range 0–10) (p < 0.01). There were no significant complications . Conclusions: Percutaneous vertebroplasty and kyphoplasty provided rapid and marked pain relief. These procedures are safe and feasible and represent the treatment of choice in selected MM patients with severe refractory pain due to pathologic compression fractures. No significant financial relationships to disclose.

Background:166Holmium-DOTMP is a beta emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high dose radiation both to the bone and bone marrow. Phase I/II trials have shown feasibility and tolerability when combined with a standard conditioning regimen of melphalan with or without total-body irradiation (TBI) in pts with multiple myeloma (MM) undergoing autologous stem cell transplantation (SCT).

Less than 5% of patients with a plasma cell dyscrasia present with a single bone (SBP) or extramedullary plasmacytoma (EMP) without evidence of systemic disease (normocalcemia, absence of anemia, preservation of uninvolved immunoglobulins, or renal disease attributable to myeloma). Diagnosis requires biopsy confirmation of a monoclonal plasma cell infiltrate from a single site. The treatment of choice for both entities is radiotherapy given with curative intent (> 4000 cGy) resulting in long term disease-free survival in approximately 30% of patients with SBP and 65% of patients with EMP.

Atiprimod (N-N-diethl-8, 8-dipropyl-2-azaspiro [4,5] decane-2-propanamine) is an orally bioavailable cationic amphilic compound that inhibited STAT 3 activation in MM cells. It effectively blocked the signaling pathway of interleukin-6, resulting in activation of caspase 3 and apoptosis (Amit-Vazina et al, Br J Cancer, 2005). Atiprimod has also induced cytotoxicity in dexamethasone, doxorubicin, and melphalan resistant MM cell lines (Hamasaki et al, Blood, 2005). Based on these encouraging in vitro data, we initiated a multi-center, phase I trial of atiprimod for patients (pts) with refractory or relapsed MM who had 2 prior lines of therapy and serum creatinine less than 2 mg/dl. Primary objectives were to evaluate the safety of atiprimod in MM pts and to identify the maximum tolerated dose (MTD). Each cycle of treatment consisted of 14 consecutive days of oral atiprimod followed by 14 consecutive days without treatment. A standard phase I dose escalation was used to determine MTD with atiprimod dose levels at 30 mg, 60 mg, 90 mg, 120 mg, and 180 mg. To date, 14 pts from 4 centers have been enrolled with evaluable data in 12 patients. Median age was 60 (range 44–64); median prior lines of therapy were 4 (range 3–7); median duration from initial treatment to registration to this trial was 36 months (range 19–76). Cohorts of 3 patients have been treated at 30, 60, 90,120 mg/day and 2 patients have been enrolled at the 180 mg/day level; no cohorts have been expanded because of dose-limiting toxicity. Median number of cycles received by MM pts was 2 (range 1–5). Common Grade 1 toxicity events included diarrhea, liver enzyme elevation and dyspepsia. There were two Grade 2 toxicity events with 1 neutropenia at the 90 mg/day level and 1 diarrhea at the 120 mg/day level. One pt had Grade 3 transaminase elevation (peak AST 402, ALT 469 units/L, bilirubin 0.5 mg/dl) during the second cycle that resolved on its own during the 14 day period off treatment. Two patients with rapidly rising serum M proteins prior to enrollment had a transient but clear reduction of their M proteins (30% and 80%) after the first 14 days of atiprimod. Two pts at higher dose levels noted subjective improvement in their bone pain. Atiprimod was generally well tolerated in this heavily treated group of MM pts. The MTD has not been reached. Although there has been no response to date, clinical activity is not expected until higher dose levels are evaluated (240 mg/day, 300 mg/day, and 360 mg/day). After the MTD has been established, the study of atiprimod combinations should be considered based on the in vitro assessment of synergy with other active agents.

BACKGROUND. Bortezomib, a first-in-class proteasome inhibitor, is active with manageable toxicities in relapsed and/or refractory myeloma,METHODS. Bortezomib 1.0 or 1.3 mg/m(2) was administered Days 1, 4, 8, and 11 every 21 days for tip to 8 cycles to patients with relapsed and/or refractory myeloma participating in two Phase II trials. Dexamethasone IIcould be added because of progressive disease after 2 cycles or stable disease after 4 cycles. Continuation of or retreatment with bortezomib was offered to patients who, in the investigator's opinion, would benefit from extended treatment.RESULTS. Sixty-three patients with relapsed/refractory myeloma treated in this extension trial received a median of 7 additional cycles of therapy, for a total of 14 cycles (range, 7-32) over a median duration of therapy of 45.1 weeks in the parent and extension studies. Seventy-eight percent of patients completed this study at the same or higher bortezomib dose than they started on during this study, and the treatment schedule of twice-weekly administration remained unchanged in 89%. Overall, 75% of patients received dexamethasone in combination with bortezomib for a median of 5 cycles starting either in the parent or extension study. The safety profile was similar between the extension mid parent trials, with no evidence of new cumulative toxicity. The most commonly reported Grade 3/4 toxicities were thrombocytopenia (29%), with a consistent pattern of recovery during the rest period of each cycle, diarrhea (11%), anemia (11%), and neutropenia (10%). Neuropathy was reported less frequently.CONCLUSIONS. Retreatment with or continuation of bortezomib +/- dexamethasone beyond 6 months was safe, and toxicities were manageable, in patients with relapsed and/or refractory myeloma. (c) 2005 American Cancer Society.

BACKGROUND:Bortezomib is a potent, reversible proteasome inhibitor that has been approved for the treatment of recurrent and/or refractory multiple myeloma, but its activity in patients with renal impairment has not been studied to date. METHODS:Response rates, safety, and 20S proteasome activity were assessed in relation to baseline creatinine clearance (CrCl) among patients with recurrent and/or refractory myeloma (n = 256 patients) who were treated with bortezomib in 2 Phase II trials. Bortezomib was administered by intravenous bolus on Days 1, 4, 8, and 11 of a 21-day cycle at 2 doses, 1.0 mg/m2 (n = 28 patients) and 1.3 mg/m2 (n = 228 patients). RESULTS:Of 10 patients with CrCl < or = 30 mL/minute, 7 patients completed the protocol-specified 8 cycles of treatment; 4 patients received the 1.3 mg/m2 bortezomib dose, and 3 patients received the 1.0 mg/m2 bortezomib dose. Using the European Group for Blood and Marrow Transplantation criteria, responses were assigned by an independent committee to 3 of the 10 patients (2 partial responses and 1 minimal response), a response rate similar to that of the overall treated population. Patients with CrCl > 80 mL/minute (n = 105 patients), 51-80 mL/minute (n = 99 patients), and < or = 50 mL/minute (n = 52 patients) had similar rates of discontinuation and similar adverse event profiles. Renal function did not appear to affect the 1-hour postdose proteasome inhibition or its recovery. CONCLUSIONS:Clinical experience in a limited number of patients with impaired renal function suggests that bortezomib provides clinical benefit with manageable toxicities in this high-risk population.