Gertz, Morie A.

Abstract Background: In multiple myeloma (MM), a complete response (CR) is defined by the European Group for Blood and Bone Marrow Transplantation (EBMT) and the International Myeloma Working Group (IMWG) Uniform Response Criteria as absence of monoclonal protein in serum and urine by immunofixation (IFE), and a bone marrow (BM) aspirate/biopsy containing <5% plasma cells (PC). This definition of CR is widely adopted in clinical trials, but there is a high degree of non-compliance with the BM requirement. As a result, differences in CR rates across trials can occur not just as a result of treatment efficacy, but also on how rigorously the BM requirement for CR is implemented. Moreover, requiring BM examinations merely to confirm CR is cumbersome in clinical practice. The goal of this study was to determine the added value of BM examinations in patients who can otherwise be considered to be in CR by virtue of a negative IFE in the serum and urine. Methods: For the purpose of the study, we included only patients with MM who had measurable monoclonal (M) protein levels at baseline (defined as >1 gm/dL in the serum and/or >200 mg/24 hour in the urine) on protein electrophoresis; patients with non-secretory and oligo-secretory MM were excluded. We then identified patients who since 1995 had a negative IFE in the serum and urine and a BM aspirate/biopsy, all done at the same time (within 30 days of each other). Baseline demographics and clinical characteristics; date of diagnosis, last follow up, and follow up status; serum and urine M protein levels at diagnosis; and results of serum and urine IFE, serum free light chain (FLC) ratio and BM aspirate/biopsy within 30 days of complete response were all collected from the existing databases. Results: Ninety-five patients met the criteria for the study, all of whom had measurable disease at baseline and subsequently achieved negative IFE in serum and urine (‘IF- CR’). Of these, only 83 patients (87%) met criteria for CR by the EBMT/IMWG criteria with less than 5% PC in the BM; 13% of patients had 5% or more PC despite the apparent IF-CR on serum and urine IFE. In fact, the BM showed 10% or more PC in 5% of IF-CR patients. We then assessed whether a normal serum FLC ratio in addition to negative serum and urine IFE would eliminate the need for a BM biopsy. The additional requirement of the serum FLC ratio to negative IFE was not fully adequate in eliminating false positive CR’s. Among 34 patients who had IF- CR plus a normal serum FLC ratio, only 88% of patients met CR definition with <5% BM PC; 12% had 5% or more PC, and one patient (3%) had 10% or more PC. We studied the survival (from time of diagnosis) of patients who had true CR’s (negative IFE and <5% PC) versus patients who had IF- CR’s but BM had 5% or more PC. Overall survival from diagnosis between the two groups was 10.7 years versus 5.6 years, respectively, P=0.001 (see Figure 1). Conclusions: BM examination is essential to accurately estimate CR. Up to 13% of patients with negative IFE in serum and urine fail to meet the BM requirement. The addition of a normal serum FLC ratio to negative IFE did not significantly reduce the proportion of patients who fail to meet the BM requirement. Based on this study, we recommend that the CR definition in the EBMT and IMWG criteria should not be revised to eliminate the need for BM examination. Moreover, the consistent collection of BM samples is essential for future strategies to evaluate immunophenotypic CR and molecular CR in MM. Figure 1: Kaplan-Meier curve showing survival benefit (in years) of patients in complete response with less than 5% bone marrow plasma cells. Figure 1:. Kaplan-Meier curve showing survival benefit (in years) of patients in complete response with less than 5% bone marrow plasma cells.

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder with a poor survival, especially in patients (pts) with multiple organ involvement. For pts with limited organ involvement, high dose chemotherapy with autologous stem cell (SCT) support is an effective approach. However, the toxicity of SCT limits its widespread use. Melphalan and dexamethasone has been previously shown to be effective in pts ineligible for SCT. Methods: We reviewed our experience with melphalan and dexamethasone for treatment of AL. Eighty one pts were treated between 2001 and 2003; median age at start of therapy was 63 years (range, 38–80) and 56 pts (69%) were males. Among these, 46 pts (57%) had 2 or more major organs (cardiac, renal, hepatic) involved. Intravenous melphalan (IV) was used in 45 pts (56%), 32 (40%) received oral melphalan (PO) and the rest received cycles of both. The most common doses were 16 mg/m2 for IV administration (every 4–6 weeks) and 0.22 mg/kg for PO administration (every 4 weeks). Dexamethasone was usually given at a dose of 40 mg for the first 4 days of each cycle. Results: Patients received a median of 5 cycles (range; 1–17). At the time of analysis, 53 (65%) pts were alive with a median follow up of 10.8 months (range, 1.4–47.1).The estimated median overall survival (OS) was 25.6 months for the entire group, with the number or type of organs involved not impacting survival. Hematological response (HR) was defined by a 50% reduction in either serum M-spike, urine M-spike, or the absolute difference between the involved and uninvolved immunoglobulin free light chains. A HR was observed in 43 pts (67%) of the 64 pts measurable for HR by conventional criteria. Achievement of HR was associated with a superior OS with a median post-therapy OS that was not reached, while non-responders had a median OS of 11.1 months (p<0.0001) (Figure 1). Among these pts, an organ response as defined by conventional criteria, was seen in 14 pts (22%), which was significantly correlated with obtaining a hematological response (33% vs. 5%, p=0.01). A 25% reduction in the difference between the involved and uninvolved FLC strongly predicted prolonged OS, with a median post-therapy OS that was not reached for responders vs. 11.3 months for non-responders (p<0.0001) (Figure 2). A decrease in post-therapy brain natriuretic peptide (BNP) also predicted for a survival improvement, with the median OS not reached for responders vs. a median OS of 17 months for non-responders (p<0.016). Conclusion: Treatment with melphalan and dexamethasone is effective and a significant survival advantage is achieved in patients with a hematological response. FLC and BNP response can help identify patients that are likely to benefit from this therapy. Figure Figure Figure Figure

Abstract Background: High dose melphalan & autologous peripheral blood stem cell (PBSC) transplantation is increasingly utilized for primary systemic amyloidosis (AL). PBSC mobilization with filgrastim is safe in various patient & normal donor populations. While there is a case report of filgrastim-induced fatal pulmonary edema in an AL patient undergoing PBSC mobilization, we elucidate the incidence & magnitude of fluid-related complications in this patient population, describe the management & outcomes, & identify features predictive of risk. Methods: IRB approval & patient consent were obtained prior to review of medical records for all adult Mayo Clinic AL patients who underwent PBSC mobilization with filgrastim 10 mcg/kg once daily from 7/98 – 8/03. Three patient episodes were excluded: 1 refused consent & 2 had a 2nd PBSC mobilization & were included once. A fluid-related complication was defined as documented increased fluid retention (peripheral edema, pleural effusion or ascites) or use of additional therapy (diuretics, albumin or dopamine) to facilitate diuresis. Results: Sixty-three of 123 patients (51%) developed a fluid-related complication. Significant interventions were needed during mobilization & prior to PBSC transplant, including admission to ICU (n=3), hemodialysis to manage fluid status (n=3), paracentesis (n=2), & thoracentesis (n=3), including one requiring chest tube placement & pleurodesis. Patients with complications had more hospitalizations during PBSC mobilization compared to those that did not (24 vs 6; p=0.001); with 20 of 24 directly related to fluid status. While not statistically significant, the complications group was more likely to fail to collect adequate PBSC or have mobilization prematurely discontinued (6 vs 2; p=0.32). One patient in each group died suddenly during mobilization. Characteristics Predictive of Fluid-related Complications Patients with Fluid-Related Complications N (%) p-value AL Organ Involvement 1 vs 2 vs 3 23/58 (40%) 26/45 (58%) 14/20 (70%) 0.01 Kidney: yes vs no 48/85 (57%) 15/38 (40%) 0.08 Heart: yes vs no 41/61 (67%) 22/62 (35%) 0.0004 Baseline edema: yes vs no 47/77 (61%) 16/46 (35%) 0.005 Diuretic: 0 vs 1 vs >1 15/52 (29%) 37/59 (63%) 11/12 (92%) <0.0001 Albumin: ≤ 2 vs > 2 mg/dL 18/24 (75%) 45/99 (45%) 0.009 On univariate analysis patients with complications had increased septal wall thickness (median 13 vs 12 mm, p=0.05), increased total urinary protein (median 3.698 vs 2.9575 g/day, p=0.04), & lower serum albumin (median 2.8 vs 3.3 mg/dL, p=0.005). Via multivariate regression patients with albumin < 2 mg/dL had an OR=3.8 (CI 1.2 – 13.6), those with cardiac AL had an OR=5.5 (CI 2.2 – 15.4), & patients utilizing diuretics at baseline had an OR=12.1 (CI 2.8 – 61.2) for the likelihood of complications. Patients with fluid-related complications during mobilization had a lower survival rate at 100 days (78 vs 92%, p=0.003) & 1 year after PBSC transplantation (65 vs 91%, p=0.003). Conclusions: Over 50% of AL patients who undergo PBSC mobilization with filgrastim 10 mcg/kg once daily develop clinically significant fluid retention & subsequent complications. Cardiac AL, hypoalbuminemia, & diuretic use prior to filgrastim administration were more likely to develop complications. Fluid-related complications during PBSC mobilization are associated with poorer survival after transplantation for AL.

Abstract Background: Primary systemic amyloidosis is an uncommon plasma cell dyscrasia characterized by organ deposition of immunoglobulin light or heavy chain fragments. It is related to the other plasma cell dyscrasias such as multiple myeloma and monoclonal gammopathy of undetermined significance. cIg-FISH on bone marrow plasma cells has become well established in the initial evaluation of myeloma as the t(4;14), t(14;16),13q-, and the 17p- abnormality are of major prognostic value. The corresponding data does not exist in amyloidosis, as there are only three small studies published to date. Methods: Using a prospectively held dysproteinemia database, we reviewed all cases of amyloidosis seen at our institution who had cIg-FISH or cytogenetics performed as part of their routine clinical testing. Three hundred thirty nine patients were identified with amyloidosis and cytogenetic testing. Of these 69 had cIg-FISH testing results. cIg-FISH was performed with fluorescent-tagged antibodies to kappa/lambda immunoglobulin and FISH probes corresponding to the following anomalies: trisomies 3, 7, 9 and 15; del17p/-17; -13/del13q; 14q32 split; and t(11;14). CCND1/IGH. If an IGH rearrangement was detected that did not involve CCNDI, we also evaluated t(4;14) or IGH/FGFR3 and t(14;16) or IGH/c-MAF. These probes constitute the standard screening panel used in MM at our institution. Results: The study population had a median age of 61 years with a male to female ratio of 1.6:1. Median follow up time was 13.5 months. By conventional cytogenetics, 88% of patients had no detectable abnormality. In contrast, only 33% were normal by cIg-FISH. The abnormalities demonstrated were 28% 13-/del13q, 42% IgH translocation, 33% t(11;14), and 3% t(14;16). No patients had a -17/del 17p- or t(4;14). Nine patients had del13q/-13 with an IgH translocation, with 7 of these having t(11;14). Both t(14;16) patients had del 13q. A trend towards increased mortality was seen in patient with any abnormality (p=0.11), but this could not be demonstrated for any single abnormality, likely due to lack of statistical power. There was no correlation between renal involvement or cardiac involvement and cIg-FISH results. Conclusion: The majority of chromosomal abnormalities in amyloidosis are undetected by conventional cytogenetics. With further study, chromosomal abnormalities may carry the same prognostic value in amyloidosis that they currently enjoy in myeloma. This effect may be independent of currently recognized risk factors. Chromosomal abnormalities in Amyloidosis as detected by cIg-FISH Abnormality Amyloidosis % (n=69) Normal 33(23) −13/del13q 28(19) IgH Abnormality 42(29) t(4;14) 0(0) t(11;14) 33(23) t(14;16) 3(2) del 17 0(0) Other 3(2)

Abstract Background: In patients (pts) with newly diagnosed myeloma (MM) eligible for high dose therapy and autologous stem cell transplantation (ASCT), the standard approach is 4–6 months of induction therapy followed by ASCT. The combination of thalidomide and dexamethasone is one of the commonly used induction regimens, and has superior response rates compared to dexamethasone or VAD. Almost all patients undergoing an ASCT relapse at a median interval of 18–24 months. The choice of treatments at first relapse is variable, but re-application of the original induction regimen, if effective is often considered. It is not clear if the responses obtained at the time of induction therapy can be replicated at the time of relapse. We studied the response of thalidomide based regimens when used as first treatment after relapse from an ASCT in patients receiving thalidomide as induction treatment. Methods: Pts who received thalidomide and dexamethasone as induction therapy, and thalidomide ± dexamethasone at first relapse after ASCT were identified for the current study. A group of patients receiving dexamethasone as induction therapy and thalidomide ± dexamethasone at first relapse after ASCT was used as the control group. Results: There were 20 pts in the study group (group 1) and 14 patients in the control group (group 2) identified between 2002 and 2007. There were 15 (75%) males in group 1 and 10 (71%) in group 2. In group 1 there was 1(5%) complete response (CR), 5 (25%) very good partial response (VGPR) and 14 (70%) partial responses (PR) to induction therapy. In group 2 there was 1 (7%)VGPR, 12 (86%) PR and 1 (7%)stable disease following dexamethasone induction. Upon treatment with thalidomide based regimens at first relapse after ASCT, there was a high rate of treatment failures in group 1 as compared to group 2 (no response in 14 out of 20 patients (70%) versus 5 of 14 pts (35%), respectively, p = 0.04). Of the 10 patients with progressive disease in group 1 post transplant, 30% had previously achieved a VGPR and 70% had previously achieved a PR to thalidomide/dexamethasone pre-ASCT. Conclusions: Our study provides evidence toward the lack of efficacy of thalidomide based regimens on post ASCT relapse in patients who had thalidomide responsive disease prior to ASCT. It is possible that this applies to other induction regimens when used at post ASCT relapse and raises the possibility of selection of drug resistant clones with initial therapy. Response rates seen with drug regimens prior to ASCT may not be reproducible at the time of relapse after ASCT.

Abstract Background: The international staging system is a simple, but powerful staging system that is based on two simple and easily available laboratory measurements. The system was developed and validated on a large group pf patients from across the world and has become the standard for patients with newly diagnosed myeloma. While it’s prognostic value is clear in patients with newly diagnosed myeloma, its value at relapse has not been explored. Methods: We examined a uniform cohort of patients relapsing after an autologous stem cell transplant to assess the utility of ISS determined at the time of documented relapse. Relapse was defined using standard EBMTR response criteria. Beta-2 microglobulin and albumin values from within 30 days of the date of relapse were extracted from the medical records. ISS was determined based on the published cut offs. Results: Of the 389 patients evaluated, 132 had values available for B2M and 276 patients had the serum albumin available. Only 131 patients had both the data available and the ISS stage could be determined. Of these patients, 64 patients (49%) were ISS stage I, 50 (38%) were stage II and 17 (13%) were stage III. An albumin < 3.5 mg/dL was prognostic for overall survival post relapse with a median survival of 10.5 months for those with albumin < 3.5 mg/dL compared to 26.3 months for the rest of the group (P < 0.0001). Similarly the median OS from relapse was 15 months for those with B2M > 3.5 mg/dL compared to 23.3 months for those with lower B2M (P = 0.014). The ISS stage predicted overall survival for this group of patients with the OS from relapse estimated at 27.3 mos, 17.8 mos and 12.3 months for ISS stage I, II and III respectively. Conclusions: In a uniform group of patients relapsing after autologous stem cell transplantation, the B2M and albumin maintain their prognostic value and allows the use of the International Staging System for determining prognosis. This supports the use of ISS stage in relapsed trials and will allow comparisons across studies. Results should be validated in a larger dataset that will allow comparisons to other known prognostic factors. Figure Figure

Abstract Background: Recent advances in the therapy of multiple myeloma (MM) have greatly increased the treatment options for this uniformly fatal plasma cell malignancy. It is not clear if introduction of novel therapies and the increased use of high dose therapy (HDT) in the past decade have translated into better outcome for patients (pts) with MM. Methods: We examined the outcome of two cohorts of pts seen at our institution. The first cohort consisted of 387 pts who relapsed after HDT and was examined for potential improvement in survival following relapse after HDT. These pts were divided into two groups; those who relapsed before or after December 31, 2000. The second cohort consisted of 2981 patients with newly diagnosed MM seen between January 1971 and December 2006 and was used to examine the trends in overall survival (OS). Results: Among those relapsing after HDT, there were 245 males (63%); median (range) age at HDT was 57 years (32.8–75.4) and the median time to HDT was 8.1 months (1–90 months) from diagnosis. The median time to relapse was 13.2 months (1.1 months-10.3 years) from HDT. In this cohort, a clear improvement in OS from time of relapse was seen over the past decade, with those relapsing after 2000 having a median OS of 23.9 months (95% CI; 19.8, 27.6) compared to 11.8 months (95% CI; 8.7, 14.9) for the rest (P < 0.001) (Figure 1). In a multivariate analysis, the effect of the date of relapse on survival was independent of other prognostic factors such as relapse <12 months after HDT, abnormal cytogenetics, and B2M > 5.5 mg/dL. Pts who were treated with one or more of the newer drugs (thalidomide, lenalidomide, bortezomib) had longer survival from relapse (30.9 months (95% CI; 23.6, 38.2) compared to 14.8 months (95% CI; 11.3, 18.4); P < 0.001) for others. Among the newly diagnosed MM cohort, the median age at diagnosis was 66 years (20.2 – 97 years), and 1,770 (59.4%) were males. The median follow up for the entire group was 27.4 months (0–29.4 years); and at the time of analysis 558 patients (18.7%) were alive with a median follow up of 32.7 months (0–29.4 years). Pts diagnosed in the last decade had an improved OS (44.8 months) compared to those diagnosed before this period (29.9 months; P < 0.001) (Figure 2). The improvement in survival seen in the last decade among newly diagnosed patients was predominantly among those younger than 65 years (60.3 mos vs. 33.3 mos improvement in median survival); compared to those over 65 at diagnosis (26.5 mos vs. 32 mos). Conclusion: In this study, for the first time, we demonstrate definite proof for improved outcome in patients with myeloma, both in the relapsed setting as well as at diagnosis, a change that is likely to continue with increased use of these drugs. Figure Figure Figure Figure

Abstract Background: Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell proliferative disorder with a high risk of progression to symptomatic multiple myeloma. Identification of risk factors that predict progression of SMM to symptomatic MM could identify higher risk patients who might benefit from chemoprevention or more intensive surveillance. We hypothesized that increased monoclonal free kappa or lambda immunoglobulin light chains in smoldering myeloma (SMM), as detected by the serum free light chain (FLC) assay, indicates an increased the risk of progression to active myeloma. Methods: Of 276 pathologically confirmed SMM patients seen at the Mayo Clinic from 1970 to 1995, baseline serum samples obtained within 30 days of diagnosis were available in 273. Results: At a median follow-up of surviving patients of 12.4 years, transformation to active disease has occurred in 161 (59%) patients. An abnormal FLC ratio was present at baseline in 90% of patients. The best break-point for predicting risk of progression was a FLC ratio less than or equal to 0.125 or greater than or equal to 8 (hazard ratio, 2.3; 95% CI, 1.6–3.2) [Figure 1]. The extent of abnormality of FLC ratio was independent of SMM risk categories defined by number of plasma cells in the bone marrow and size of serum M-proteins (bone marrow plasma cells ≥ 10% and serum M protein ≥ 3 g/dL; bone marrow plasma cells ≥ 10% but serum M protein < 3 g/dL; and serum M protein ≥ 3 g/dL but bone marrow plasma cells < 10%). Incorporating the FLC ratio into the risk model, the division of patients into high-, intermediate-, and low-risk groups is 28, 42, and 30% with 5 year progression rates of 76, 51, and 25%, respectively [Figure 2]. Conclusions: The serum immunoglobulin FLC ratio is an important additional determinant of clinical outcome in patients with SMM. Figure Figure Figure Figure

Abstract Background: Cytotoxic T-cell infiltrates are a nearly universal finding in the bone marrow of patients with multiple myeloma. It has been postulated that presence of T-cells in the bone marrow of multiple myeloma (MM) patients represents an immune response against the tumor and therefore, might be associated with an improved prognosis. However, the impact of bone marrow T-cells on the prognosis of multiple myeloma patients has not been studied systematically. Methods: Bone marrow biopsies of patients with newly diagnosed multiple myeloma were stained by immnohistochemistry for the CD8 antigen and reviewed by a blinded hematopathologist. Three high power fields are reviewed for each biopsy and the total number of CD8 positive cells counted and reported. For patients with more than 300 cells per 3 fields, results were reported as >300. The number of bone marrow CD8 positive cells was then correlated with patients’ clinical data, including other prognostic factors and overall survival. Results: Bone marrow biopsy specimens from 100 patients, performed within the week of a diagnosis of multiple myeloma and collected between May 1998 and January 2001 were evaluated. The median number of CD8 positive cells was 270 (33 – >300). Patients’ characteristics are shown in Table 1. Median follow up was 30 months (0–80). The number of cytotoxic T-cells as a continuous variable was a risk factor for shortened overall survival, HR 1.86 (95% CI 1.11–3.35). Using minimal p value approach, the cutoff of 270 cells (the median) risk stratified patients into two groups: the median survival of patients with > 270 CD8 positive cells was 16 months vs. 48 months in patients with ≤270 cells, p=0.005 (Figure). In multivariate analysis including age, B2M, albumin, CRP, bone marrow plasma cell percentage and plasma cell labeling index, the number of cytotoxic T-cells was an independent predictor of overall survival was HR 3.1, p=0.0017. Conclusion: We show that the number of cytotoxic T-cells in the bone marrow is a strong and independent prognostic factor in patients with newly diagnosed multiple myeloma. Our observation does not contradict the hypothesis that cytotoxic T-cells participate in an immune response against the tumor since our findings may represent a higher level of immune response associated with baseline aggressive disease biology. However, our study suggests for the first time that increased marrow cytotoxic T-cells have an adverse effect on outcome in myeloma, and suggest that these cells may have a direct facilitating effect on tumor growth and on the marrow microenvironment. Further studies of the biology of behind this observation are warranted. Characteristic N Median (range) Gender male 61 CRP 81 0.4mg/L (0.01–11.2) Albumin 99 3.6 g/dL (2.6–5.4) B2microglobulin 94 4.0 (0.9–28) μg/mL Marrow PC% 90 45% (11–99) PC labeling index 90 high (>1%) 36 BM CD8 cells 100 270 (33 – >300) ISS 94 1 19 2 41 3 34 Figure Figure

Abstract Introduction Antisense oligonucleotides are used to inhibit messenger RNA function and inhibit protein translation. Bcl-2 expression proteins have been implicated in mediating resistance to apoptotic cell death in Waldenstrom Macroglobulinemia (WM). Oblimersen sodium is a specific inhibitor of Bcl-2 expression and has shown activity in multiple myeloma and in Waldenstrom cell lines. The in vitro data led to the development of a phase I study for WM patients with relapsed or refractory disease. Materials and Methods Eligible patients had symptomatic WM who had failed prior cytotoxic chemotherapy. All patients had to have one of the following: a hemoglobin <11 g/dL, a platelet count <100,000/uL, bulky lymphadenopathy, or hyperviscosity syndrome. As a phase I study, the primary end point was toxicity assessment, but all patients were assessed for response, using monoclonal protein levels. Patients were enrolled and evaluated in cohorts of three. Drug was administered as a 24-hour continuous infusion for 7 days every 21 days, with intrapatient dose escalation each subsequent cycle beginning at 3 mg/kg/day up to a maximum of 7 mg/kg/day days 1–7 for a maximum of 8 cycles. Results To date 9 patients have been accrued, six at dose level one and three patients at dose level two. Data is available for the first six entered. Five women and 1 man have been accrued with a median age of 74.5 years, ranging from 58 to 81. Four patients had relapsed from prior therapy, 2 were refractory. Three had a history of transfusions. The median number of prior regimens was 4 (range 2–7). One patient had a dose-limiting toxicity on the first cycle of therapy, which was grade 3 fatigue and anorexia, and the dose for this patient was reduced. Two patients had non-hematologic grade 3 toxicity, possibly related to therapy. Five out of six patients on dose level one had grade 3 or greater hematologic toxicity. These toxicities occurred after cycle 1 was completed, during the toxicity observation period and were not considered dose limiting toxicities influencing dose escalation. Three patients required dose reductions in subsequent cycles. To date one patient has had a partial response with her serum M spike falling from 3.6 to 1.1 g/dL. Her quantitative IgM fell from 6,000 mg/dL to 1,000 mg/dL(figure). Conclusion Oblimersen was well tolerated at the first dose level in patients with WM. Hematologic toxicity is frequent in this cohort with heavily involved bone marrows when the dose was escalated during successive cycles. Dose reductions with subsequent cycles were frequently required. Evaluation of the maximum tolerated dose continues. Data on response for this dose level is promising, where efficacy will be fully evaluated in the phase II portion of this trial. Figure Figure