Gertz, Morie A.

Abstract Background AL amyloidosis can be associated with coagulopathy due to acquired factor X (FX) deficiency. Published experience, limited to case reports, suggests that infusion of fresh frozen plasma (FFP), platelets, plasma exchange, and vitamin K are of limited hemostatic efficacy for periprocedural management of coagulopathy. Therefore, we reviewed our cumulative experience of managing patients (pt) with FX deficiency due to AL amyloidosis who underwent an invasive procedure. Methods Pt with AL amyloidosis and isolated FX deficiency (≤ 50%), who underwent an invasive procedure between January 1975 and May 2007, were retrospectively identified from institutional databases. We excluded bone marrow biopsies as well as procedures >3 months prior to the diagnosis of FX deficiency. Endpoints of the study were bleeding, thrombosis, and death. Results Sixty-one pt fit the study criteria. They were arbitrarily classified as having severe (<10%; n=6), moderate (10–25%; n=16), or mild (26–50%; n=39) FX deficiency. The pt underwent a total of 115 procedures, 13 (11.3%) of which were considered major procedures and 102 (88.7%) were minor procedures. Major Procedures 13 pt underwent a major procedure; 4 had severe FX deficiency, 2 moderate, and 7 mild. Procedures included splenectomy, colon resection, renal transplant, and others. All 4 of the pt with severe deficiency were treated with hemostatic agents (FFP, plasma exchange, tranexamic acid, danazol, aminocaproic acid, and rFVIIa) in the perioperative period. Two (50%) of these patients had complications: intraabdominal hematoma and death. The death occurred in a patient with splenic rupture and uncontrolled hemorrhage refractory to rFVIIa and FFP. None of the pt with moderate deficiency experienced complications, despite not receiving hemostatic agents. Similarly, 0/7 patients with mild deficiency developed complications (2 received hemostatic agents FFP, platelets, vitamin K, and DDAVP). Minor Procedures All 61 pt underwent a minor procedure; central venous catheter placement was the most common (n=26), followed by EGD with biopsy (n=16) and renal biopsy (n=10). Six pt with severe deficiency underwent 7 minor procedures, 2 (29%) of which were associated with excess bleeding, despite rFVIIa treatment in both cases. An additional 3 procedures were performed with hemostatic agents and were uncomplicated. 2/16 (13%) pt with moderate deficiency had excess bleeding, 1 of whom was treated with rFVIIa and the other was not treated. Two others received perioperative treatment and did not have a complication. There were 7 complications in the 39 patients with mild deficiency (18%), including 1 AV fistula thrombosis after rFVIIa. Five of the patients with a bleeding complication did not receive treatment. One patient with mild deficiency received procoagulants and did not have excess bleeding. Conclusions -This is the largest series examining the perioperative management of pt with FX deficiency due to AL amyloidosis -Complications occurred in 11.3% of procedures, including one death -In this series, there were no clear predictors of bleeding -FX deficiency did not contribute to mortality, with the exception of 1 case -Bleeding risk is relatively infrequent in pt with mild or moderate FX deficiency, particularly with non-vascular procedures -Although optimal management of pt with severe FX deficiency is unclear, options include rhFVIIa +/− FFP and aminocaproic acid in those requiring procoagulant therapy.

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder associated with varying degree of organ infiltration with light chain derived amyloid protein and consequent organ dysfunction. Various acquired coagulopathies, predominantly Factor X (FX) deficiency have been previously described in AL. The factor deficiencies are thought to be due to the direct binding of blood coagulation proteins to amyloid fibrils. Little is known regarding the prognostic significance of abnormal coagulation parameters in AL patients (pts). Methods: After Institutional Review Board approval, we performed a retrospective review of the medical records of 625 consecutive pts who had presented within 3 months of a diagnosis of AL to be evaluated at Mayo Clinic from June 2001 to June 2006. 540 pts had coagulation studies performed within 2 months of presentation. 51 of those pts were on oral anticoagulation and were excluded from the analysis. Results: Of the 489 pts included in the analysis, the median age was 62 years and 61% were male. The median overall survival (OS) of the entire cohort was 26.8 months. Table 1 lists the prevalence of abnormal coagulation tests in the remaining 489 patients. Prothrombin time (PT) was available in the majority of pts. 61 pts (12.6%) had elevated PT, and 63 pts (20.4%) had a decreased FX. 37 of the 61 pts with elevated PT had available FX levels, of which 31 (84%) of those had a decreased FX, suggesting that the cause of elevated PT was mostly due to a low FX. Indicators of hepatic involvement such as alkaline phosphatase and bilirubin levels were higher among the patients with prolonged PT and low FX. An elevated PT (more than 12.4 seconds) was strongly predictive of an adverse outcome, with a median OS of 8.7 months compared to a median OS of 29 months (p<0.0001) in pts with normal PT (Figure 1). Similarly, pts with decreased FX (less than 60% activity), was associated with significantly worse outcomes with a median OS of 14.9 months versus a median OS of 33 months (p<0.0001) in pts with normal FX (Figure 2). In a Cox proportional hazards model containing cardiac troponin (cTnT), NT-Pro BNP, serum alkaline phosphatase, and free light chain difference (involved minus uninvolved), prolonged PT or FX deficiency were independently prognostic for overall survival. Conclusion: Abnormalities of PT and FX are seen in a sizable proportion of pts with newly diagnosed AL. An elevated PT and or FX deficiency appear to adversely affect the outcome of these patients. It is likely that the elevated PT in these patients relate to FX deficiency in the majority which in turn may reflect the amyloid ‘burden’. The effect of other organ involvement like the hepatic involvement may also have an impact on FX and PT. Table 1. Prevalence of abnormal coagulation testing in patients with newly diagnosed primary systemic amyloidosis. Coagulation study N (Test results available) N of abnormal results (%) Elevated prothrombin time 486 61 12.6 Elevated activated partial thromboplastin time 312 48 15.4 Elevated thrombin time 315 84 26.7 Elevated fibrinogen 140 118 84.3 Decreased Factor II activity 62 26 41.9 Decreased Factor V activity 63 9 14.3 Decreased Factor VII activity 63 17 27 Decreased Factor X activity 309 63 20.4 Elevated D-dimer 130 72 55.4 Figure 1. Survival grouped by normal versus elevated Prothrombin time. Figure 1. Survival grouped by normal versus elevated Prothrombin time. Figure 2. Survival grouped by normal versus low Factor X levels. Figure 2. Survival grouped by normal versus low Factor X levels.

Abstract Melphalan (M), Prednisone (P) and Lenalidomide (R) are active in the treatment of multiple myeloma (MM). We evaluated the toxicity and efficacy of MPR in a phase I/II trial. Results of phase I part were previously reported (Blood2006, 108(11) abst 3558). M 5 mg/m2 on days (d) 1–4, 60 mg/m2 d 1–4 and R 10 mg d 1–21 of a 28 day cycle was determined as MTD for the phase II study. Methods: Patients with previously untreated MM who were not candidates for stem cell transplantation, age ≥18 yr, ECOG PS 0–3, evaluable or measurable disease, ANC >1500, platelets > 100,000 and creatinine ≤ 3.0 mg/dL were eligible. All patients received aspirin 325 mg/d as DVT prophylaxis. Routine antibacterial prophylaxis was not used. G/GM-CSF was used at the discretion of the treating physician for neutropenia. Response rate (RR), confirmed on two consecutive determinations was the primary end-point. The study had 90% power to detect a RR of at least 45%. Results: Twenty-six patients were accrued between July ’06 and Feb ’08. The median age was 74 y (64 – 87y), 17 (65%) were men. Six, 13, 6, 1 (23%, 50%, 23%, and 4%) patients had ECOG PS 0, 1, 2, and 3, respectively. Three (12%), 11 (42%) and 10 (38%) patients were ISS stage 1, 2 and 3. A total of 106 cycles were administered; median 4.5 (1–13). Seventy-seven % patients experienced at least 1 grade 3 or 4 toxicity. Neutropenia (42%/8%) and thrombocytopenia (20%/8%) were the most common grade 3/4 adverse events followed by anemia (16%/0%), fatigue (8%/4%), rash (11%/0%), and hyperglycemia (4%/0%). There were 20 treatment delays in 9 patients, and 18 dose reductions (9 in R, 11 in M and 1 P) occurred in 7 patients, most commonly because of neutropenia or thrombocytopenia. Eleven patients (42%) required G-CSF treatment. Eleven patients are currently receiving treatment; 15 have gone off study (4 completed per protocol, 3 refused, 3 adverse effects, 3 unrelated illnesses, 2 other). Median follow up of survivors is 8 m (0 – 22m). Eighteen (69 %; 95%CI 48–86) patients had a PR or better according to International Myeloma Working Group Uniform Response criteria; 3 (12 %) CR, 5 (19 %) VGPR and 10 (38%) PR. Median number of cycles before achieving a response was 2 (1 – 11). Median Progression Free and Overall Survival is 16.7m (95% CI 11.2–23.0), and 23 m (95% CI: 22 – 23), respectively. Conclusions: MPR combination is feasible with a manageable toxicity profile and has significant activity in the treatment of patients with MM who are not candidates for stem cell transplant, with an overall response rate of 69%, and a CR plus VGPR rate of 31%. Grade 3 or 4 neutropenia and thrombocytopenia was the most common toxicity, seen in up to 50% of patients in this cohort of predominantly elderly patients. Dose reduction in R and/or M was required in 27% patients. No patient developed neuropathy or thromboembolic complications.

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder. Lenalidomide, especially in conjunction with dexamethasone, has been shown to be highly active in patients with multiple myeloma. We previously reported a hematologic response rate of 41% and an organ response rate of 23% among 22 AL patients treated with lenalidomide and on-demand dexamethasone (Dispenzieri et al, Blood 2007). Long term outcomes of AL patients treated with lenalidomide have not yet been described. Methods: Thirty-seven patients were treated on an IRB approved treatment trial with single agent lenalidomide, starting doses of 25 mg in 22 and reduced dose of 15 mg in the last 15. If progression within or no evidence of hematologic response after 3 cycles, dexamethasone was added. Patients were classified according to cardiac biomarker stage (cut-offs for serum troponin T <0.035 ng/ml and NT-proBNP <332 pg/ml--Stage I neither above cutoff; Stage III, both above cut-off; and Stage II, any one above cut-off). Survival estimates were done according to the methods of Kaplan and Meier. Results: Median age was 64 years (range 44–88), with 70% male. Sixty-five percent of patients were previously treated, and the median time from diagnosis to study entry was 8.9 months (range 0.4–237). The biomarker staging breakdown was: I, 16%; II, 43%; and III, 41%. As of 7/11/08, 5 patients remain on active therapy. The overall hematologic response rate was 43% (1 CR and 15 PR), with only one patient responding to single agent lenalidomide, and the overall organ response rate was 20%. If one excludes the 13 patients who did not complete 3 months of therapy and have the opportunity of having dexamethasone added to their program, the respective hematologic and organ response rates were 62% and 32%. With a median follow-up of 33.6 months (range 14.4–42), twenty-two patients (59%) have died, but only 2 had deaths possibly related to treatment. Median duration of response, progression free survival and overall survival were 31 months, 14.8 months (95%CI: 5.7–28.1), and 18.8 months (95%CI: 11.7-not reached), respectively. Overall survival from diagnosis was 48 months (95%CI: 21.6–153.6). As shown in Table below, outcomes were dependent on underlying risk stratification and ability to stay on therapy. High risk patients were more likely to drop out early and less likely to respond. High risk patients had shorter OS All Patients Outcome Stage I Stage II Stage III p N 6 16 15 Survival from enrollment, mo NR 18.8 (11.7–33.6) 5.7 (3.2–18.3) 0.01 Survival from Diagnosis, mo NR 48.4 (20.4–62) 21.1 (11.2–31.7) 0.005 Progression Free Survival, mo 34.7 (33.7–NR) 18.3 (6.2–28.1) 4.4 (3–8.6) NS Drop out by cycle 4, % 17 31 60 NS Median # of cycles administered 31 6 3 0.04 Time to response, mo 6.2 (3.6–9.3) 6.4 (5.2–NR) 4.7 (3.8–NR) NS Hematologic response rate, % 83 38 27 0.05 Organ response rate, % 40 20 13 NS Duration of Response, mo NR 27.2 (13.6–NR) NR NS Subgroup analysis of patients receiving >3 cycles of therapy (i.e getting Len and Dex) N 5 12 7 Time on therapy, mo 35.2 8 10.5 Hematologic Response Rate, % 100 50 56 Organ response rate, % 50 27 25 Conclusions: Based on these data, single agent lenalidomide is not recommended for patients with AL; however, lenalidomide in combination with dexamethasone can be associated with good progression free and overall survival rates, even among patients with relapsed or refractory disease.

Abstract POEMS syndrome is defined by the presence of peripheral neuropathy (P), organomegaly (O), endocrinopathy (E), monoclonal protein expression (M), and skin changes (S). In addition, patients also have sclerotic bone lesions, papilledema, extravascular volume overload, thrombocytosis, and restrictive lung disease/pulmonary hypertension. A striking but inexplicable feature of the clonal plasma cells in patients with POEMS is that they are virtually always lambda restricted. More surprising is that of the 81 functional immunoglobulin light-chain variable-region genes (IgVL) available in the plasma cell/B cell repertoire, among the 13 cases in which variable gene light chain usage has been reported, all have been either IgVL1-40 or IgVL1-44. The molecular mechanisms triggering the initiation and the progression of POEMS syndrome or the clonal expansion of plasma cells marking this condition remain unclear. We have analyzed the immunoglobulin heavy and light chains sequences in the plasma cells of POEMS patients at the Mayo Clinic Rochester. We found that in 8 out of the 9 patients tested, we could document heavy chain clonality in any given patient; however, no restriction of gene usage among patients was observed in the variable regions of these chains. In the case of light chains, in 14 out of 17 patients we could document not only clonality but also restriction of light chain variable gene usage to IgVL1-40 or IgVL1-44. Our goal is to understand the relevance of this restricted expression of light chain variable region, and its effect on the communication between plasma cells and the neighboring stromal cells that might provide more insight into the disease pathology. To this end, we are generating viral vector constructs that will harbor the germline or mutant versions of IgVλ1-40 and IgVλ1-44 genes and introduced into pre-established malignant plasma cell lines (i.e. myeloma cell lines). We will assay the effects of this over expression in terms of alterations in the expression of cytokines such as VEGF and TNF, and on plasma cell-stromal cell interaction (in a co-culture system). Results from these assays will be discussed.

Abstract Introduction: Immunotherapy is most likely to work in a setting of low tumor burden, making vaccine strategies attractive as maintenance therapy post autologous peripheral blood stem cell transplantation (PBSCT) for multiple myeloma (MM). However, it is difficult to ascertain the effects of the vaccines from delayed responses to the transplant. A novel immunotherapeutic, APC8020 (Mylovenge), was studied as consolidation therapy after for MM post PBSCT (Mayo vaccine trial). Mylovenge is prepared from autologous antigen presenting cells, including dendritic cells, partially purified from an unmobilized leukapheresis product by gradient density isolation and then incubated for two days with autologous serum containing M protein obtained pretransplant. We report long term results of the Mayo vaccine trial compared retrospectively to a consecutive cohort of MM patients who underwent autologous stem cell transplant at Mayo Clinic during the same time period. Methods: The Mayo vaccine trial patients had transplants between July of 1998 and May of 2001. Using these cutoff dates we analyzed 151 total MM patients, 27 from the vaccine trial (9 newly diagnosed and 18 relapsed) and 124 from database (DB) (50 newly diagnosed patients and 74 relapsed). The median (range) of follow-up for alive patients in vaccine trial is 6.5 years (2.9 – 8), and in the DB is 7.1 years (6 – 8). Two-sided Fisher’s exact tests and stratified log rank tests (with newly diagnosed or relapsed as the stratum) were used to compare baseline patient characteristics and time to event distributions (overall survival – OS, progression free survival – PFS, and time to progression – TTP) between the two groups. Results: The median (range) of age in vaccine trial and DB was 56 (30–69) and 57 (36–71) years respectively. There were no significant differences in the known prognostic factors including PCLI, B2M, and CRP. The median (95% confidence interval - CI) TTP for the vaccine trial and DB patients was 1.5 years (1.3 – 2.4) and 1.6 years (1.3 – 1.8); stratified log rank p value = 0.46. The median (95% CI) PFS for the vaccine trial and DB patients was 1.5 years (1.3 – 2.4) and 1.5 years (1.1 – 1.8), stratified logrank p value = 0.30. The median (95% CI) OS for the vaccine trial and DB patients was 5.3 years (4.0 -N/A), and 3.4 years (2.7 – 4.6); stratified logrank p value = 0.02. Conclusions: Despite the fact that no difference was seen in TTP or PFS, post-transplant vaccine therapy was associated with prolonged survival. This is similar to what has been reported in other tumor systems including prostate cancer and glioblastoma multiforme. This approach warrants further investigation, including preclinical studies aimed at optimizing the immune response and randomized trials to define the role of vaccine therapy in myeloma. Figure Figure

Abstract Introduction: We retrospectively analyzed outcomes of 716 patients with multiple myeloma who were mobilized using cyclophosphamide and growth factor (n=370) or growth factor alone (n=346) before stem cell transplantation. Table. Patient Characteristics (N=716) Variable Cyclophosphamide (n=370) Growth Factor Only (n=346) P Value Abbreviation: IQR, interquartile range. *Or equivalent dosage. Men, No. of patients (%) 224 (61) 202 (58) .50 Age, median (IQR), y 58 (52–64) 60 (53–65) .11 b-2 Microglobulin, median (IQR), mcg/mL 2.7 (1.9–4.0) 2.3 (1.9–3.2) .01 Creatinine, median (IQR), mg/dL 1.1 (0.9–1.3) 1.0 (0.8–1.2) .002 Apheresis, median (IQR) collections, No. 2 (1–3) 4 (3–6) .001 Marrow plasma cells, % 17 (5–34) 5 (1–13) .001 CD34+cells, median (IQR), cells/kg Total collected 10.3x106(7.2x106–14.6x106) 9.9x106(7.6x106–11.9x106) .01 Infused 5.6x106(4.5x106–7.6x106) 4.2x106(3.8x106–5.0x106) <.001 Duration of hospitalization, median (IQR), d 4 (0–10) 4 (0–9) .92 Nonstaphylococcal bacteremia, No. of patients (%) 48 (13) 25 (7) .01 Melphalan dosage, No. of patients (%) .04 200 mg/m2* 337 (91) 298 (86) 140 mg/m2* 33 (9) 48 (14) Exposure before mobilization, No. of patients (%) Melphalan 45 (12) 44 (13) .50 Lenalidomide 14(4) 63(18) .01 Results: Patients receiving cyclophosphamide had higher stem cell yields than the growth factor only group (median number of apheresis sessions needed to achieve stem cell collection goals, 2 vs 4 sessions, respectively [P=.001]). However, patients treated with cyclophosphamide required more time for engraftment of platelets and neutrophils (P<.001 for both). For patients receiving cyclophosphamide, 75% achieved engraftment (defined as a platelet count of 50x109/L) by day 39, whereas 75% of patients not receiving cyclophosphamide achieved engraftment by day 18. Similar results were observed for neutrophil engraftment. These differences did not affect the duration of hospitalization, but patients treated with cyclophosphamide had a higher incidence of posttransplant nonstaphylococcal bacteremia. For cyclophosphamide-mobilized patients, considerably faster platelet engraftment (5 fewer days) resulted if stem cell reinfusion occurred more than 30 days after the first apheresis session. Conclusion: Our data suggested that cyclophosphamide damaged the microenvironment and slowed engraftment. By lengthening the period between the completion of apheresis and stem cell reinfusion, the microenvironment may recover and result in faster engraftment. We suggest that the cyclophosphamide used for mobilization may affect the marrow microenvironment. Cyclophosphamide improves yields but increases bacteremia rates after transplantation. Cyclophosphamide increases time required to collect stem cells and slows engraftment. Figure Figure

Abstract Background: Immunoglobulin free light chains (FLC) form the substrate for synthesis of amyloid fibrils in patients with AL amyloidosis. Development of FLC assay (Freelite) has allowed us to better assess the clonal cell burden in patients with AL amyloid. The relationship of the light chain types and their levels in serum to the clinical feature at presentation and the eventual outcome has not been systematically studied. Methods: We identified 730 patients with biopsy proven AL amyloidosis, who were seen at Mayo Clinic between January 1980 and July 2006, who were seen within 90 days of their diagnosis and in whom FLC levels were performed or had stored serum available for analysis. Cardiac biomarkers (cTnT, NT ProBNP) were also performed on stored serum for some of the patients as part of previous studies. Clinical data and follow up status are prospectively collected into the Dysproteinemia database, which was used for the study. Results: The median age of the study population was 63 years (range; 32–90) and 463 patients (63%) were male. The median estimated survival for the entire group was 37 months from diagnosis and the median follow up for the 263 patients (37%) alive at the time of the analysis was 27.8 months (range; 1–177 months). The plasma cell clone was lambda in 528 patients (72%) and kappa in 202 (28%) patients. The median absolute difference between the FLCs was 19.6 mg/dL for the entire group (range; 0.01–2478); for the kappa patients was 29.4 mg/dL (range; 0.01–1359) and for the lambda patients was 18.2 mg/dL (range; 0.03–2478). Kappa AL was associated with more involvement of the GI tract and liver as indicated by higher alkaline phosphatase (1.8 vs. 1.3 fold; P=0.03), higher total bilirubin (0.95 vs. 0.78 mg/dL, P = 0.04) and lower serum carotene (119 vs. 155 ug/dL; P = 0.0002). On the contrary, renal involvement was more in the lambda AL with the 24 hour urinary albumin higher in the lambda AL (2.4 gm vs. 1.4 gm; P = 0.0002) and lower serum albumin (2.77 vs. 2.97 mg/dL; P = 0.001). While there was no difference in the overall survival (OS) between the kappa and lambda AL, the median OS for those without a heavy chain was significantly shorter (12.6 months vs. 29.9 months; P= 0.01) compared to those with a heavy chain identified. There was also a correlation between high FLC difference and degree of organ involvement, especially cardiac. Among the 202 kappa AL patients, the median survival for those with a high FLC difference ( > 29.4 mg/dL) was 13 months vs. 48.8 months for those with low difference (P = 0.001). Similarly among the 528 patients with lambda AL, those with high difference (> 18.2 mg/dL) had a median OS of 9.3 months compared to 33 months for those with low difference (P < 0.0001) (Figure). The FLC difference was independent of the cTnT, NT Pro BNP, uric acid and fold-increase in alkaline phosphatase, all of which were significant in the multivariable analysis. Conclusions: The type of FLC impacts the spectrum of organ involvement, with gastrointestinal involvement observed more frequently with kappa, and renal involvement with lambda FLC. The FLC burden correlates with the degree of organ involvement, and is a significant predictor of overall survival in AL amyloidosis. Lambda FLC exerts similar effect as kappa FLCs, but at lower levels confirming the increased “amyloidogenicity” of lambda FLC. Finally, lack of a chaperone heavy chain is associated with a poorer outcome. Figure 1. Overall survival form diagnosis in patients with high vs. low FLC difference (using median values for cutoffs for kappa and lambda FLC) Figure 1. Overall survival form diagnosis in patients with high vs. low FLC difference (using median values for cutoffs for kappa and lambda FLC)

Abstract Background: The combination of lenalidomide and dexamethasone (Rev/Dex) has been shown to be a highly effective therapy for multiple myeloma (MM). Over half of the patients with newly diagnosed MM achieve a complete response with prolonged therapy. More recently, a phase III trial demonstrated improved survival with use of lenalidomide and low dose dexamethasone with one year survival in excess of 90%. We report the initial results from a phase II trial combining lenalidomide and low dose dexamethasone with cyclophosphamide (CRd) as initial therapy of newly diagnosed MM. Methods: The trial was initiated in July 2006 and completed the target accrual of 33 patients by July 2007. The treatment protocol consisted of lenalidomide given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle. Dexamethasone (dex) was given orally at a dose of 40 mg on days 1, 8, 15, and 22 of each cycle. Cyclophosphamide at a dose of 300 mg/m2 was given on days 1, 8, and 15 of each cycle. Patients also received an aspirin once daily as thromboprophylaxis. Response was defined as a decrease in serum monoclonal (M) protein by 50% or higher and a decrease in urine M protein by at least 90% or to a level less than 200 mg/24 hours, confirmed at least 4 weeks apart. Results: The median age was 63 years (range, 44–79). Eight patients (24%) had ISS stage III disease. At this time, 19 of the 33 patients are evaluable for confirmed responses (i.e., off-study or completed at least 4 cycles of therapy). Of these, 2 achieved VGPR and 13 had a partial response giving an overall response rate of 79%. The response rate was affected by 5 of 19 patients who went off study within three cycles due to toxicities [interstitial nephritis (1 pt), multiple grade 3 toxicities including infection (1 pt) atrial fibrillation and infection (1 pt)] or alternative treatment [no response and possible renal toxicity (1 pt) and progression at 4 cycles (1 pt)]. Overall, hematological toxicity was the most common with grade 4 toxicity seen in 6 patients (20%). Non-hematological grade 3 or higher toxicities included fatigue (4 pts), thrombosis (3 pts) and renal failure (2 pts). One patient with thrombosis came off study for other toxicities, and the other two continued on study with anticoagulation. Thirteen patients (43%) had dose reductions of both cyclophosphamide and lenalidomide, most commonly due to hematological toxicity. So far, 12 patients have gone off study, 6 went to stem cell transplant, 3 due to adverse events, 1 due to disease progression and 2 patients went to alternate treatment. Conclusions: CRd has excellent activity in newly diagnosed myeloma with an estimated overall response rate of 79%. Response evaluation of the entire 33 patients will be presented at the meeting. We believe that the initial use of a 300 mg/m2 dose of cyclophosphamide resulted in 5 of the first 19 pts experiencing early toxicity and withdrawal. As a result, an expansion of the current trial is evaluating lower doses of cyclophosphamide (300 mg fixed dose). Full analysis of this study will be needed to determine if CRd can improve outcome compared to Rd.

Abstract Waldenström’s Macroglobulinemia (WM) is a low-grade lymphoplasmacytic disorder associated with an IgM monoclonal protein that may present with anemia, lymphadenopathy, and hepatosplenomegaly. Since combination chemotherapy and Rituximab are both active in this disease, it is possible the response rate can be enhanced by using a combined modality of Rituximab and CHOP. This approach has been used in indolent lymphoma with remarkable results and limited toxicity. Objective: To determine the response rate in previously untreated patients with Waldenström’s Macroglobulinemia receiving rituximab and CHOP. Methods: This was a phase II study of standard R-CHOP in symptomatic WM patients. The study was activated on June 15, 2004 and closed on April 26, 2007 due to poor accrual. The median age of the sixteen patients enrolled was 60 (44–79 years), β2M 3 ug/ml (2.1–7.6), median hemoglobulin was 9 g/dl (7.7–10.9), Viscosity 3.4(1.6–10), and IgM 6389 (3229–13300 mg/dl). The most common symptoms were Fatigue (13/16), visual disturbance (7/16) and parasthesias or painful/numb feet (6/16). Only one patient had bulky adenopathy (6.3%). Results: Of 16 patients treated, 5 patients have no response data available (it will be presented at the meeting). Objective response was 91% (90% CI: 63.5% ∼ 99.5%) and 1 patient had a minor response with an overall response rate of 100%. Median time to response was 1.6 months from registration and median time to maximum response was 2.1 months. Median duration of response has not been reached. The median follow up time of the 16 patients was 18.3 months with a range of 3.6–24.8 months. Among the 16 treated patients, there were 8 (50%, 90% exact binomial CI: 27.9%∼72.1%) grade 4 neutropenia. 8 patients experienced grade 3 lymphopenia (50%, 90% exact binomial CI: 27.9%∼72.1%). Only 2 grade 3 febrile neutropenia were noted. As of August 4, 2007, none of the 16 patients has died. R-CHOP is a promising regimen in the treatment of patients with Waldenström’s Macroglobulinemia. To succeed in completing clinical trials in this rare disease better international collaboration and involvement in advocacy groups are required.