ALBERT

Description: Background Elotuzumab is an approved monoclonal antibody targeting SLAMF7 on plasma and NK cells that enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM). A recent study showed improved outcomes with the combination of pomalidomide, bortezomib, and dexamethasone vs. bortezomib and dexamethasone in relapsed or refractory MM (Richardson PG et al., Lancet Oncol 2019). We therefore studied elotuzumab with pomalidomide, bortezomib, and dexamethasone (elo-PVD) in relapsed and refractory MM. Methods The primary objective was to determine the overall response rate (ORR). Patients with relapsed and refractory disease and ≥1 prior lines of treatment (including lenalidomide and a proteasome inhibitor) were eligible to participate. Prior treatment with pomalidomide was permitted. Elotuzumab was weekly for the first 2 cycles and then every other week. Pomalidomide was given on days 1-21; bortezomib was on days 1, 8, 15; and dexamethasone was weekly. Each cycle was 28 days. Results The trial has completed accrual in September 2018 with 48 patients receiving treatment. The median age was 64 (range 40-80), and median number of prior regimens was 3 (range 1-9); 25% had high risk FISH. All patients had prior lenalidomide and proteasome inhibitor (bortezomib 96%, 29% carfilzomib) and were refractory to their last line of therapy. Other prior therapies included: autologous stem cell transplant (48%), pomalidomide (33%), daratumumab (25%), and isatuximab (4%). 46 patients were assessable for response (2 patients did not complete cycle 1 and were not evaluable for response: 1 due to rapid disease progression; 1 stroke. The median length of follow up was 18.8 months (range 0.5-23.4): 16 patients continue on study; 27 patients discontinued for progressive disease; 3 patients discontinued for adverse events (AEs) (sepsis, pneumonia, stroke); 1 patient underwent auto SCT; and 1 patient was lost to follow up. Best ORR was 61% (PR = 16, VGPR = 10, CR = 2). ORR for patients with prior anti-CD38 antibody, 46%; carfilzomib, 46%; pomalidomide, 43%. Median PFS was 9.8 months (95% CI 6.8-Inf). In patients with 1 prior line of therapy, ORR was 74% and median PFS was not reached (95% CI 12-Inf); 18 month PFS was 68%. Grade ≥ 3 hematologic AEs included anemia (10%), neutropenia (29%), and thrombocytopenia (15%). Additional common grade ≥ 3 AEs included lung infection (27%) and hypophosphatemia (15%). Common non-hematologic AEs all grades included fatigue (grade 1-2 only, 70%), upper respiratory infection (grade 1-2, 56%; grade 3, 2%), diarrhea (grade 1-2 only, 42%), constipation (grade 1-2 only, 35%), hyperglycemia (grade 1-2, 46%; grade 3, 4%), and sensory neuropathy (grade 1-2 only, 31%), with 2 possibly related deaths (sepsis, pneumonia). Conclusions Elo-PVD is one of the first trials of a quadruplet regimen in relapsed and refractory MM incorporating a monoclonal antibody. In patients with refractory disease, elo-PVD shows encouraging responses. With the limitations of cross trial comparisons and small patient numbers, for patients with 1 prior line of treatment and refractory disease, a PFS at 18 months of 68% with elo-PVD compares favorably with a median PFS of 17.8 months in a similar subgroup of PVD in the OPTIMISMM trial (Dimopoulos MA et al., ASH 2018). Patients who received prior pomalidomide, carfilzomib, and/or anti-CD38 monoclonal antibody also benefited. Treatment was well-tolerated with manageable toxicity and with attention to infectious AEs. Disclosures Yee: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; Adaptive: Consultancy; Amgen: Consultancy, Honoraria. Lipe:Celgene: Consultancy; amgen: Research Funding; amgen: Consultancy. Nadeem:Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy. O'Donnell:Celgene: Consultancy; Amgen: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Branagan:Pharmacyclics: Consultancy; Janssen: Consultancy; Surface Oncology: Consultancy. Lohr:Celgene: Research Funding; T2 Biosystems: Honoraria. Anderson:Sanofi-Aventis: Other: Advisory Board; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Richardson:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. OffLabel Disclosure: The combination of elotuzumab, pomalidomide, bortezomib, and dexamethasone is an off-label use in relapsed and refractory multiple myeloma.

Description: INTRODUCTION: In previous studies, we observed that CC-5013 enhanced rituximab mediated ADCC killing of lymphoplasmacytic cells (BJH2005; 128:192). As such, we conducted a phase II study of CC-5013 with rituximab in WM patients naïve to either agent. Intended therapy was as follows: Weeks 1-48 CC-5013 (25 mg po qD for 3 weeks, then 1 week off); Weeks 2–5, 13–16 Rituximab (375 mg/m2/week). METHODS: Twelve patients were enrolled, 10 of whom were previously untreated with a median age of 65 (range 53–76 yrs), along with baseline BM involvement of 50 (range 5–90%), serum IgM of 4175 (range 1180–7130 mg/dL), hematocrit of 31.9% (range 24–36.6%), and B2M of 3.5 (range 1.8–6.0 mg/L). RESULTS: Four patients were taken off study due to intolerance to therapy (3 to CC-5013, 1 to CC-5013 and Rituximab) and were non-evaluable. Unexpected acute decreases in hematocrit occurred in 10/12 (85%) patients within the first 2 weeks of therapy, resulting in hospitalization for 4 patients. The median decrease in hematocrit, which coincided with CC-5013 administration was 4.2% (range 1.7-7.5%), and was not associated with blood loss, hemolysis, or generalized myelosuppression. Other grade 3/4 toxicities attributed to CC-5013 therapy were expected and included neutropenia (n=4); tinnitus (n=2); thrombocytopenia (1); myositis (n=1); and rash (n=1). Five patients had a spike in serum IgM levels following rituximab, accompanied with epistaxis (n=1), headaches and blurry vision (n=2) requiring plasmapheresis. Toxicities led to the discontinuation and dose reduction of CC-5013 for 8 and 4 patients, respectively, and discontinuation of rituximab in 1 patient due to recurring allergic reactions. Discontinuation of CC-5013 within the first 28 days of therapy occurred in 6 out of 8 patients. Responses among the 8 evaluable patients: PR (n=3); MR (n=4); SD (n=1); ORR 88% among evaluable patients. In two patients with bulky adenopathy and splenomegaly, a significant reduction in the node/spleen size was noted by week 12. Both of these pts have subsequently achieved a PR. With a median follow-up of 7+ months, no patient who received at least 2 months of CC-5013 have progressed. CONCLUSION: The response data achieved with CC-5013 and rituximab in this study is encouraging, though the dose and schedule of CC-5013 administration, and mechanism for the unexpected acute drops in hematocrit observed in WM patients warrants further investigation. Such studies are in progress in our laboratory.

Description: We report the long-term outcome of a multicenter, prospective study examining fludarabine and rituximab in Waldenström macroglobulinemia (WM). WM patients with less than 2 prior therapies were eligible. Intended therapy consisted of 6 cycles (25 mg/m2 per day for 5 days) of fludarabine and 8 infusions (375 mg/m2 per week) of rituximab. A total of 43 patients were enrolled. Responses were: complete response (n = 2), very good partial response (n = 14), partial response (n = 21), and minor response (n = 4), for overall and major response rates of 95.3% and 86.0%, respectively. Median time to progression for all patients was 51.2 months and was longer for untreated patients (P = .017) and those achieving at least a very good partial response (P = .049). Grade 3 or higher toxicities included neutropenia (n = 27), thrombocytopenia (n = 7), and pneumonia (n = 6), including 2 patients who died of non–Pneumocystis carinii pneumonia. With a median follow-up of 40.3 months, we observed 3 cases of transformation to aggressive lymphoma and 3 cases of myelodysplastic syndrome/acute myeloid leukemia. The results of this study demonstrate that fludarabine and rituximab are highly active in WM, although short- and long-term toxicities need to be carefully weighed against other available treatment options. This study is registered at clinicaltrials.gov as NCT00020800.

Description: INTRODUCTION: Xbp-1 is a ubiquitously expressed basic leucine zipper protein which serves as key transcription factor for plasma cell differentiation and immunoglobulin production. XBP-1 mRNA undergoes splicing at an IRE-1a specific cleavage site to produce a spliced form (Xbp-1s) which due to a frame shift results in a more stable and potent transcription factor than the unspliced form (Xbp-1us). Previous observations demonstrated that Xbp-1 was highly expressed in multiple myeloma (MM), though its expression in other B-cell disorders including Waldenstrom’s macroglobulinemia (WM) remains to be clarified. METHODOLOGY: In this study, we investigated the different forms of Xbp-1 in CD19+ selected bone marrow (BM) cells from 61 patients with the consensus panel definition of WM using semi-quantitative PCR analysis. CD19+ selected BM cells from 6 healthy donors, and CD138+ selected BM cells from 4 MM patients were used as controls. All RT-PCR results were normalized to b-actin levels. Sequencing of Xbp-1 in CD19+ selected LPC was also performed for 20 WM patients. RESULTS: In 9/61 (15%) WM patients, Xbp-1 transcripts were undetectable. Among WM patients expressing Xbp-1, as well as all MM patients evaluated, higher levels of XBP-1us were observed in comparison to normal healthy donors (p=0.001). Decreased XBP-1s transcript levels were also observed among WM and MM patients versus healthy donors, but did not reach statistical significance. Sequence analysis of Xbp1 in CD19+ selected BM LPC demonstrated variants 10/20 WM patients in exon 1 that are currently under investigation. CONCLUSIONS: Abnormal expression of Xbp-1 is common in patients with WM, and includes loss of expression, and aberrations in splice patterns. The genetic basis for these findings is under investigation.

Description: Waldenström macroglobulinemia (WM) is a B-cell malignancy characterized by an IgM monoclonal gammopathy and bone marrow (BM) infiltration with lymphoplasmacytic cells (LPCs). Excess mast cells (MCs) are commonly present in WM, and provide growth and survival signals to LPCs through several TNF family ligands (CD40L, a proliferation-inducing ligand [APRIL], and B-lymphocyte stimulator factor [BLYS]). As part of these studies, we demonstrated that WM LPCs secrete soluble CD27 (sCD27), which is elevated in patients with WM (P 〈 .001 vs healthy donors), and serves as a faithful marker of disease. Importantly, sCD27 stimulated expression of CD40L on 10 of 10 BM MC samples and APRIL on 4 of 10 BM MC samples obtained from patients with WM as well as on LAD2 MCs. Moreover, the SGN-70 humanized monoclonal antibody, which binds to CD70 (the receptor-ligand partner of CD27), abrogated sCD27 mediated up-regulation of CD40L and APRIL on WM MCs. Last, treatment of severe combined immunodeficiency–human (SCID-hu) mice with established WM using the SGN-70 antibody blocked disease progression in 12 of 12 mice, whereas disease progressed in all 5 untreated mice. The results of these studies demonstrate a functional role for sCD27 in WM pathogenesis, along with its utility as a surrogate marker of disease and a target in the treatment of WM.

Description: Background: Patients with plasma cell disorders (PCDs) are among the most susceptible to common infections including influenza and these infections are a major source of morbidity. Although seasonal influenza vaccination is routinely employed in patients with PCDs, the data about its efficacy are limited, as few studies have focused on this population. Based on historical data, PCD patients have a 10 fold increased risk of influenza and an expected yearly flu infection rate of at least 20%. The major surrogates for influenza vaccine response are hemaglutination antibody inhibition (HAI) titers; however rates of achieving protective HAI titers after standard influenza vaccination in PCD patients range from 5-19%. One approach to enhancing the efficacy of influenza vaccination is the use of standard dose boosters, and a recent study in multiple myeloma patients suggested improved seroprotection. Another approach may be increasing the amount of antigen in vaccines. Fluzone® high-dose vaccine was FDA approved in 2009 for adults aged 65 and older based on data regarding higher seroprotection rates but has not been studied specifically in PCD patients. Methods: In order to directly address the significant unmet need of improving vaccination strategies in patients with PCDs, we evaluated a novel vaccine strategy in patients with PCDs over the 2014-15 flu season that involved two doses of Fluzone® High-Dose influenza vaccination 30 days apart, regardless of age. Eligibility criteria allowed any patient with a PCD and no contraindication to trivalent inactivated influenza vaccine. The primary endpoint was laboratory confirmed flu infection rate. Patients were asked to report all flu-like illnesses for viral testing (PCR) and patients were asked about infectious symptoms at all study visits and at the end of the flu season in May 2015. A secondary endpoint is comparing rates of seroprotection with HAI titers and virus neutralization assays. Another secondary endpoint is to explore cell-mediated immunity through characterization of T cell subpopulations, cytokine profiles, and flu-specific T-cell responsiveness. Results: 51 total PCD patients were enrolled (41 with disease requiring therapy and 10 with asymptomatic gammopathy) and all patients received two doses of Fluzone High-Dose vaccine. Median age was 75 years (range 36-90). This novel vaccination strategy was safely tolerated in all patients with no ≥ grade 2 adverse events attributed to vaccine. With close clinical follow-up, only 4% (2/51) of patients developed laboratory confirmed influenza. Preliminary data on a cohort of 30 multiple myeloma patients demonstrates that only 7% (2/30) had baseline protective HAI titers to all three seasonal influenza vaccine strains and after one Fluzone® High-Dose vaccine the seroprotection rate increased to 33% (10/30). Final seroprotection analysis and measurements of cell-mediated immunity are underway. Conclusions: This pilot study demonstrates that the two dose strategy of Fluzone® High-Dose influenza vaccine was safely tolerated in patients with PCD. The observed rate of seroprotective HAI after one dose of high dose vaccine was 33%, approximately double the historically observed rate of 5-19% after standard dose vaccine. The rate of seroconversion after the second dose is currently being analyzed and will be presented. Interestingly the rate of documented flu infections was only 4% compared to an expected 20% and may be due in part to the higher rate of seroconversion. These results suggest that this novel vaccination strategy is safe and may have a clinical benefit in improving HAI seroprotection and reducing documented flu infections in PCD patients. Given these encouraging clinical results, we are planning a randomized trial for the upcoming 2015-2016 influenza season comparing this novel vaccination strategy to standard of care vaccination in patients with plasma cell disorders. Disclosures Off Label Use: In order to directly address the significant unmet need of improving vaccination strategies in patients with plasma cell disorders, we present a pilot study which evaluated a novel vaccine strategy over the 2014-15 flu season. Fluzone® High-Dose influenza vaccine was administered in a booster strategy (two doses 30 days apart)..

Description: Next generation sequencing of purified plasma cells from myeloma patients has revealed the genomic complexity of tumors and is being utilized for developing personalized approaches to therapy. Evaluation of functional properties of these genetic changes and the growth potential of human tumors / their subclones has been limited by difficulties in reliable engraftment of primary human tumor cells in mice. The growth of human cells in mice is limited in part due to the presence of species non-cross-reactive cytokines/growth factors and innate immune rejection mechanisms. In order to overcome these barriers, we designed MISKI TRG6 mice, wherein human IL6 was additionally knocked in on the backbone of MISKI TRG mice. Both MISTRG and MISKI TRG support enhanced engraftment of human hematoipoietic cells (Rongvaux et al. Nat Biotechnol. 2014) and the addition of IL6 provides an essential MM growth factor. Injection of primary tumor cells from MM patients led to reliable engraftment of primary tumor cells in these mice. In this study, we utilized whole exome sequencing (WES) to compare the genomic changes in paired tumors isolated from (n=3) patients versus those growing in xenografts. In some patients, tumor cells from more than one xenografted mouse were analyzed separately to allow for evaluation of tumors growing in each individual mouse. Tumor cells were sorted by flow cytometry and subjected to DNA isolation followed by whole exome capture and sequencing. Germline and tumor DNA were captured on a Roche NimbleGen Sequence Capture V2.0 human exome array following the manufacturer's protocol, with protocol modifications at the Yale Center for Genome Analysis. Captured libraries were sequenced on the HiSeq 2500 sequencing system. Analysis of sequencing data was performed with the Yale exome-sequencing pipeline, as described (Choi et al. Nat. Genet. 2015). Mean depth of coverage for primary and xenografted samples was comparable. Comparison of loss of heterozygosity (LOH) patterns revealed that the majority of LOH changes in baseline tumors were also observed in xenografts, but the latter also contained additional changes. Profile of somatic copy number alterations (CNA) also revealed that while the xenografts captured the majority of CNA detected in freshly isolated tumor cells, they also exhibited additional genomic changes not detected in the initial tumor. Importantly, this included genomic changes in chromosome 1 typically associated with high-risk MM. Interestingly, the pattern of LOH and CNA were identical in individual mice transplanted with the same tumor cells, indicating that the new patterns of genomic changes observed in xenografts were likely already present at baseline, but clinically occult as in a minor subclone. Analysis of somatic non-synonymous variants (SNVs) revealed that the great majority of SNVs detected in the parent tumor were also identified in the xenografts, which also contained additional SNVs not detected at baseline. This included some targetable SNVs with known oncogenic potential. Together, these data demonstrate the capacity of MISKI TRG6 mice to recapitulate the genomic complexity of primary MM tumor cells and reveal their growth potential. These data provide a novel approach to investigate the genetics of human plasma cell neoplasia in vivo and reveal subclinical genetic lesions that may contribute to future relapse. Humanized models may be essential to fully understand genomic complexity of human tumors at a functional level and to optimize personalized approaches to therapy of human MM. Disclosures No relevant conflicts of interest to declare.

Description: Multiple myeloma (MM) is characterized by progressive growth of transformed plasma cells (PC) in the bone marrow. In nearly all cases, MM is preceded by clinically asymptomatic precursor states termed as monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic MM (AMM). Almost all prior attempts to study the growth of transformed PCs in vivo have been restricted to patients with clinical MM, and there is an unmet need for in vivo models to understand the biology of precursor states. Major obstacles to xenotransplantation of human cells in immune-deficient mice include murine innate immune rejection, as well as presence of species-restricted non-cross reactive growth factors/cytokines. In order to help overcome these obstacles, we utilized humanized mice in which human versions of 5 genes important for innate immune cell development and hematopoiesis were knocked into their respective murine loci. These mice termed MIS(KI)TRG for human M-CSF, IL-3, GM-CSF, Thrombopoietin and SIRPα knock-in on a Rag2-/-IL-2Rγ-/- background, exhibited superior multi-lineage engraftment of human hematopoietic stem cells including innate immune cells. Interleukin-6 (IL-6) is well established as a critical growth factor for human MM cells and lacks species cross-reactivity. Therefore, we knocked-in human IL-6 to MIS(KI)TRG mice to generate MIS(KI)TRG6 mice that were utilized for these studies. MIS(KI)TRG6 mice were transplanted intra-femoral with bone marrow mononuclear cells isolated from patients with plasma cell disorders (n=27). Growth of tumor cells was monitored by flow cytometry and by ELISA detection of tumor-derived clonal human Ig. We observed successful engraftment of tumor cells following transplantation of purified CD138+ cells as well as CD3-depleted CD138- mononuclear cells or simply CD3-depleted bulk bone marrow mononuclear cells in 〉80% of experiments. Importantly, the engrafted myeloma cells were primarily restricted to the transplanted bone confirming the niche requirement of these cells. Growth of tumor cells in the contralateral bone was typically observed when samples from patients with more aggressive disease were transplanted. Growth of tumor cells in the spleen was only observed in the setting of patients with circulating phase tumors, such as those with plasma cell leukemia. In contrast to tumor cells, non-malignant cells such as human T, NK or myeloid cells readily migrated to the periphery and were detected in the spleen by flow cytometry. Together these data indicate that the capacity to grow independent of the marrow niche is a late event in the pathogenesis of MM. Importantly, in addition to clinical MM, this model also allowed for the first time, efficient growth of asymptomatic precursor states (MGUS/AMM) in 5 of 5 patients engrafted. Interestingly, tumor cells from MGUS/AMM mediate progressive growth in vivo, indicating that the clonal stability observed in these patients is likely mediated by features extrinsic to the plasma cell clone. Detailed analysis of phenotypic features of engrafted plasma cells by single cell mass cytometry revealed phenotypic similarities between freshly isolated tumor cells and those growing in mice. In summary, our studies demonstrate that humanized MIS(KI)TRG6 mice are an excellent host for in vivo growth of the entire spectrum of human plasma cell tumors, including for the first time, pre-neoplastic states. Our studies provide evidence that clonal stability in MGUS/AMM is likely in part due to growth controls extrinsic to the tumor cells. The capacity to metastasize from bone to bone and eventually to extra-medullary sites is acquired later during evolution of tumors. The ability to faithfully reproduce homing and growth patterns of primary tumor cells will allow detailed evaluation of plasma cell tumors in their natural microenvironment. Disclosures No relevant conflicts of interest to declare.

Description: CD25, CD27, CD30 and CD40 are receptors for IL-2, CD70, CD153 and CD154, respectively, which provide important signaling for both B- and T-cell immune responses. We therefore examined the sera of patients with Waldenstrom’s macroglobulinemia (WM), a B-cell disorder characterized by excess IgM secreting bone marrow lymphoplasmacytic cells (LPC) for the presence of soluble CD25, CD27, CD30, CD40, IL-2, CD153, and CD154. Sera were from patients with active disease and off-therapy. Sera from healthy age matched donors (HD) was used for controls. The results of these studies were as follows: WM ELISA Results HD ELISA Results p-value n= median range n= median range sCD25 pg/ml 2.647x10−6 41 3418.99 3–19756.2 20 573.6 184.96–891.03 IL-2 pg/ml 0.72385 41 22.96 3–76.83 20 11.07 5.64–64.7 sCD27 U/ml 2.4727x10−7 26 7.45 0–19.42 10 0 0–2.78 sCD70 ND ND ND ND ND ND ND sCD30 U/ml 0.00088 25 89.25 0–550.81 15 39.12 0–135.25 sCD153 ng/ml 0.68388 25 8.18 0–43.8 15 5.65 0–24.82 sCD40 pg/ml 0.02484 25 101.39 11.76–584.99 11 50.73 0–150.5 sCD154 pg/ml 0.81317 55 949.58 92–4973.16 17 1078.03 351.88–2323.38 Considering our recent studies demonstrating a role for mast cells (MC) in supporting WM cell growth (JCO 2004 22:571S), we examined bone marrow LPC along with MC from WM patients for expression of CD25, CD27 and CD40 and/or their ligands by flow cytometry and RT-PCR analysis. The results of these studies are as follows: Flow Cytometry RT-PCR WM MC WM MC CD25 4/10 (40%) 2/7 (29%) 7/9 (78%) 7/15 (47%) IL-2 ND ND ND ND CD27 5/12 (42%) 2/8 (25%) 7/7 (100%) 4/7 (57%) CD70 6/6 (100%) 10/11 (91%) 7/7 (100%) 2/7 (29%) CD30 1/21 (4.7%) ND ND ND CD153 3/7 (43%) 12/13 (92%) 2/2 (100%) 9/11 (82%) CD40 25/30 (83%) ND ND ND CD154 2/3 (67%) 9/13 (69%) 7/9 (78%) ND The above studies demonstrate high levels of circulating immunoregulatory receptors, and expression of these receptors and/or their ligands on WM tumor and mast cells. Studies addressing their role in immune dysregulation in WM are underway.

Description: INTRODUCTION: Rituximab is active in Waldenstrom’s macroglobulinemia (WM), producing major (CR + PR) response rates of 40–50% using an extended dose schedule. Lower response rates though are observed among patients with the FcgRIIIA-158 F/F polymorphism (JCO 23:474) and higher serum IgM levels (〉6,000 mg/dL) (Ann Oncol 16:132). Thalidomide enhances rituximab mediated ADCC killing of lymphoplasmacytic cells and produces response rates of 25% in WM. As such, we conducted this phase II study using combination thalidomide and rituximab in patients naïve to either agent. METHODS: Intended therapy was as follows: Weeks 1–52 Thalidomide (200 mg po qHS for 2 weeks, then 400 mg po qHS);Weeks 2–5, 13–16 Rituximab (375 mg/m2/week). Twenty-five patients were enrolled, 20 of who were previously untreated, with a baseline median age of 62 (range 44–86 yrs), BM involvement of 40 (range 5–90%), serum IgM of 3670 (range 924–8610 mg/dL), B2M of 2.6 (range 1.4–7.8 mg/L), Hct of 33.0 (range 24.5–37.7%). RESULTS: Grade 3/4 toxicities to thalidomide included paresthesia (n=10); somnolence (n=8); rash (n=7); neuropathic pain (n=6); confusion (n=4); tremors (n=2); and bradycardia (n=2). Dose reduction occurred in all patients and led to premature discontinuation in 11 patients. All evaluable patients received the intended rituximab therapy. Paradoxical IgM spikes following rituximab occurred during both courses of therapy and were observed in 12 patients. Two patients succumbed, unrelated to therapy, and were unevaluable. Responses were as follows: CR (n=1); PR (n=15); MR (n=2); SD (n=1) for an overall and a major response rate of 78% and 70%, respectively, among evaluable patients. Four patients had no response to therapy. With a median follow-up of 19 months, 6 patients have progressed. The median duration of response was 19.6+ months (range 7 to 26+ months) Overall response was associated with median cumulative dosed thalidomide: CR/PR/MR (29,275 mg) vs. SD/NR (7,400 mg); p=0.004. Importantly, overall responses were unaffected by FcgRIIIA-158 polymorphism status (75% vs. 71% for VV/FV vs. FF); serum IgM (83% vs. 80% for 6,000 mg/dL); and B2M levels (86% vs. 78% for