ALBERT

Description: CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular and/or bulbar motor weakness, in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurological symptoms. Main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia) (n=45, 100%), motor weakness (n=18, 40%), ophthalmoplegia (n=20, 45%) and bulbar symptoms (n=6, 13%). Forty five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiological studies showed a demyelinating or axonal pattern in respectively 60 and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40). Overt hematologic malignancies were diagnosed in 16 patients (36%), most frequently Waldenström macroglobulinemia (n=9, 20%). Forty-one patients (91%) required treatment for CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with respectively 53 and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line and rituximab-based regimens for second-line treatment. These compiling data argue for CANOMAD to be included in neurological monoclonal gammopathy of clinical significance.

Description: Key Points Pom-Dex is active and well tolerated in adverse cytogenetic patients with early RRMM, particularly in those with del(17p). Pom-Dex prolonged OS in adverse cytogenetic patients with early RRMM.

Description: Scleromyxedema is a rare skin and systemic mucinosis that is usually associated with monoclonal gammopathy (MG). In this French, multicenter, retrospective study of 33 patients, we investigated the clinical and therapeutic features of MG-associated scleromyxedema. Skin molecular signatures were analyzed using a transcriptomic approach. Skin symptoms included papular eruptions (100%), sclerodermoid features (91%), and leonine facies (39%). MG involved an IgG isotype in all patients, with a predominant λ light chain (73%). Associated hematologic malignancies were diagnosed in 4/33 patients (12%) (smoldering myeloma, n=2; chronic lymphoid leukemia, n=1; and refractory cytopenia with multilineage dysplasia n=1). Carpal tunnel syndrome (33%), arthralgia (25%) and dermato-neuro syndrome (DNS) (18%) were the most common systemic complications. One patient with mucinous cardiopathy died of acute heart failure. Intravenous immunoglobulin (HDIVig) treatment alone or in combination with steroids appeared to be quite effective in nonsevere cases (clinical complete response achieved in 13/31 patients). Plasma cell-directed therapies using lenalidomide and/or bortezomib with dexamethasone and HDIVig led to a significant improvement in severe cases (HDIVig-refractory or cases with central nervous system or cardiac involvement). The emergency treatment of DNS with combined plasmapheresis, HDIVig, and high-dose corticosteroids induced the complete remission of neurological symptoms in 4/5 patients. Quantitative reverse transcriptase-PCR (RT-PCR) analysis of 6 scleromyxedema skin samples showed significantly higher profibrotic pathway levels (transforming growth factor β (TGFβ) and collagen-1) than in healthy skin. Prospective studies targeting plasma cell clones and/or fibrotic pathways are warranted for long-term scleromyxedema management.

Description: Xanthomas are a common manifestation of lipid metabolism disorders. They include hyperlipemic xanthoma, normolipemic xanthoma, and a related condition, necrobiotic xanthogranuloma (NXG). All 3 forms can be associated with monoclonal immunoglobulin (MIg). In an attempt to improve diagnosis, understanding, and treatment of this association, we retrospectively analyzed a personal series of 24 patients (2 hyperlipemic xanthoma, 11 normolipemic xanthoma, and 11 NXG) and 230 well-documented reports from the literature. With the exception of the nodules and plaques featured in NXG, the clinical presentation of xanthomatous lesions usually resembled that seen in common hyperlipidemic forms and could not be used to suspect MIg-associated xanthomas. Extracutaneous sites were not rare. The MIg was an IgG in 80% of cases. Myeloma was diagnosed in 35%. Hypocomplementemia with low C4 fraction was present in 80% of studied patients. Low C1 inhibitor serum levels were found in 53%. Cryoglobulinemia was detected in 27%. These abnormalities suggest immune complex formation because of interactions between the MIg and lipoproteins and argue in favor of a causal link between MIg and xanthomas. Monoclonal gammopathy therapy could thus be an option. Indeed, among the patients who received chemotherapy, hematologic remission was accompanied by improvement in xanthoma lesions in several cases.

Description: Abstract 2934 Introduction: Len combined with Dexamethasone (Dex) is becoming a standard treatment in multiple myeloma (MM). As Len is mainly excreted by the kidneys, its dose should be adjusted according to renal function. Current dosing recommendations are based on a study conducted in non-malignant patients (pts) and on modelling/simulations. To assess whether these recommendations are actually valid in MM pts, we conducted a prospective study evaluating pharmacokinetics (PK), safety and efficacy of Len+Dex in pts with various degrees of renal impairment (RI). We also compared the glomerular filtration rate (GFR) estimated either by the Modification of Diet in Renal Disease (MDRD) dosage (GFR/MDRD) or by the Cockroft and Gault (CG) equation (GFR/CG) for determining Len dosage. Methods: 37 Caucasian pts (median age 65 yrs) with symptomatic MM who had received ≥ 1 previous line of treatment, were enrolled. All had stable renal function over 4 weeks prior to inclusion. They were divided in 5 groups according to GFR/CG at baseline: group 1, 〉 80mL/min (N = 10); group 2, ≥ 50 & ≤ 80 mL/min (N = 10); group 3, ≥ 30 & 〈 50 mL/min (N = 7); group 4, 〈 30 mL/min (N = 5); group 5, chronic hemodialysis (N = 5). Cast nephropathy and light chain deposition disease were documented by kidney biopsy as the respective cause of RI in 6 and 1 of the 17 pts from groups 3, 4 and 5. Pt characteristics were similar, except for pts in group 4 who were significantly older (p = 0.01). All pts received ≥ 3 cycles of oral Len+Dex (40 mg weekly) regimen from Days 1–21 of each 28-day cycle. Len starting dose was defined according to the current dosing guideline, i.e.: group 1 and 2: 25 mg/d; group 3: 10 mg/d; group 4: 15 mg/qod; group 5: 5 mg/d. Blood samples were collected on a dosing day in the first cycle for PK analyses, as follows: at pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 24 h (and 36 and 48 h in groups 3–5) after the Len dose on day 5, and at predose and 2 h (near tmax) after the Len dose on days 9 and 15. Results: Len clearance was highly correlated to GFR/CG (R2 = 0.86, p 〈 0.001). Mean Len clearance declined from 239 mL/min in group 1, to 160, 93, 54, and 41 mL/min, and mean terminal half life was prolonged from 3 h to 5, 7, 10, and 24h in groups 2, 3, 4 and 5, respectively. These findings were consistent with those reported for pts with RI due to non-malignant conditions. The average daily AUC values for groups 2–5 were 103–149% of that for group 1 (1794 h*ng/mL). No difference was found in mean plasma Len concentrations at 2 h post-dose between day 9 (Len alone) and day 15 (Len+Dex) across groups. GFR/MDRD and GFR/CG were highly correlated (R2 = 0.85, slope = 0.89) and similarly predicted Len clearance (slope = 2.38 and 2.15, respectively). When the same cutoff values were used for GFR/MDRD and GFR/CG, the % reduction in Len clearance in groups 3–5 compared with the combined groups 1 and 2 was very similar for GFR/MDRD- and GFR/CG-based renal function classifications. However, a dosage discordance between GFR/MDRD and GFR/CG would occur in 5/32 non-dialysis pts. All the 5 pts would be assigned to a lower starting dose according to GFR/MDRD. The estimated resulting AUC levels would have been reduced to 68–94% of the mean AUC in group 1 from the observed 91–238%. These estimated AUC levels would be considered to be in the therapeutic range. After 3 cycles of Len+Dex, hematological response rate (≥ PR) was 73% (VGPR 27%). Response rates were 70% in pts with 〈 50ml/min. Renal function remained stable in all pts. A total of 22 serious (≥ grade 3) adverse events (SAEs), including 16 hematological SAEs, occurred in 12 pts, leading to dose reduction in 7 cases. Of these, 2 pts would have been assigned to a lower starting dose according to GFR/MDRD. The frequency of SAEs was not significantly increased in group 5 compared to the other groups (60% vs 45%, p = 0.3). After a median follow-up of 10 months, pts had received a mean number of 7.6 ± 4.3 cycles, and 5 had died, because of MM progression in 4 cases. Conclusion: The study demonstrated that the effect of RI on the Len PK in MM patients receiving concomitant Dex was similar to that in non-malignant pts receiving Len alone. The recommended dose adjustments achieved the appropriate plasma exposure with similar efficacy and safety across different renal function groups in MM pts. GFR/MDRD and GFR/CG may be interchangeable for determining the Len dosage. Disclosures: Chen: Celgene Corporation: Employment. Alakl:Celgene Corporation: Employment. Neel:Celgene Corporation: Employment. Jaccard:Celgene Corporation: Consultancy.

Description: The t(4;14)(p16.3;q32) leads to the ectopic expression of two oncogenes, the Multiple Myeloma Set Gene (MMSET) and the Fibroblast Growth Factor 3 (FGFR3). It is found in 15% of patients with multiple myeloma (MM) and indicates a poor prognosis. To identify the clinico-biological features associated with this adverse prognosis, we prospectively studied a series of 79 patients with t(4;14) MM.Between March 2002 and July 2007, a t(4;14) was detected by real time quantitative PCR of the IGH/MMSET and FGFR3 transcripts in 79 patients. The clinico-biological data were analysed at diagnosis and at relapse. Response rate and time to progression (TTP) after successive lines of chemotherapy, and overall survival (OS), according to beta2m and haemoglobin level, and expression of FGFR3, were evaluated. Among the 79 patients (median age:55 years), 18 (22.8%) had a MGUS or smouldering myeloma and 61 (77.2%) had a symptomatic MM. At diagnosis, no clinical or radiological feature was significantly associated. As expected, 15 patients (18%) had a t(4;14) without expression of FGFR3. IgA isotype was found in 41% and del(13) in 90% of patients. Contrasting with previous studies, only 52% of symptomatic MM had elevated beta2m (〉3mg/L). Fourty-two patients (53.1%) received autologous stem cell transplantation (ASCT). In those, the overall response (OR) was 90%. Among those responders, 16% had a complete response (CR) and 53% had a very good partial response (VGPR). Median TTP after ASCT was only 12 months. At relapse, aggressive features (plasmocytoma, cytopenias, acute renal failure, circulating plasma cells) were observed in 23% of cases. After 2nd line chemotherapy, response rate was only 49% and TTP was 6.4 months. Noteworthy, there was a trend toward a better TTP in patients treated with bortezomib as compared to thalidomide in 2nd line therapy (p=0.06). Median OS after ASCT was 31 months, independently of FGFR3 expression and isotype. OS was not significantly different in patients with and without high beta2m (〉3mg/L) or low hemoglobin (

Description: Abstract 1344 In September 2007 we published the results of a prospective randomized trial comparing in 100 AL amyloidosis patients, enrolled between January 2000 and January 2005, high dose melphalan with ASCT and the oral regimen M-Dex (melphalan 10 mg per square meter of body-surface area and dexamethasone 40 mg per day, on days 1 to 4). With a median follow-up of 3 years the median survival was better in the M-Dex arm (56.9 months) than in the ASCT arm (22.2) months (p=0.04). The hematological responses were not statistically different between the 2 arms and the higher toxicity of the ASCT arm was responsible for the shorter median survival. This study has been criticised because of the high treatment related mortality (TRM) in the ASCT arm but a landmark analysis of patients who survived for at least 6 months and who received their assigned treatment, did not show any difference in survival. A second frequent criticism was that too severe patients, who were not able to go through the high dose procedure, have been included. A separate analysis done within the 59 good risk patients showed a nonsignificant difference between the two groups in overall survival at 3 years (58% in the group assigned to receive ASCT vs. 80% in the group assigned to receive M-Dex; P = 0.13). A third concern was related to the duration of response, should high dose treatment, giving slightly more complete responses, results in more sustained responses and, with a prolonged follow-up, in a better long term survival ? To answer this question we extended the follow-up of the surviving patients. The new cut off date was August 1st, 2010, more than 5 and a half years after the last inclusion. Only 1 patient has been lost to follow-up. We did again the landmark analysis with the longer follow-up and we looked, in this population of 65 patients with 100% feasibility and 0 % TRM, at survival and remission duration. As the follow-up was very long and the biologic surveillance not planned after 2006 we took unequivocal events as censor points for the event-free survival analysis: deaths and second line treatment. At the first cutoff date, in 2006, 49 patients were alive, 30 in the M-Dex arm and 19 in the HDT arm. At the new cutoff date in 2010, 38 patients are alive, 22 in the M-Dex arm and 16 in the intensive arm, with a median follow-up of 49 months for the entire cohort and 86 months for surviving patients (figure 1). The majority of late deaths were amyloid related, but 3 patients in the M-Dex arm died of unrelated lung and digestive cancer. The median survival in the 2 arms has not been modified (56.9 month in the M-Dex arm and 22.2 month in ASCT arm, p=0.15). For the 65 patients included in the landmark analysis the median survival is not different in the 2 arms (103 month in the M-Dex arm and 97 month in ASCT arm) and the median event free survival is 56 months in the M-Dex arm and 26 months in the intensive arm (p=0.3, figure 2). Eleven surviving patients in the M-Dex arm and 6 in the intensive have not received a second treatment, 9 of these patients in the M-Dex arm and 5 in the ASCT arm have normal free light chain measurement at their last visit. Only 1 patient, assigned to receive ASCT, has been diagnosed with myelodysplasia. With a longer follow-up we did not found any superiority in the intensive arm in survival or remission duration even in the landmark analysis eliminating treatment related mortality. In the area of very efficient new drugs this analysis reinforces our choice to propose conventional treatment to amyloidosis patient avoiding the risk of intensive treatment.Figure 1.Survival according to treatment groupFigure 1. Survival according to treatment groupFigure 2.Event-Free Survival According to Treatment Group in the Landmark AnalysisFigure 2. Event-Free Survival According to Treatment Group in the Landmark Analysis Disclosures: Leblond: roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; mundipharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; genzyme: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees. Leleu:Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy, Research Funding; Leo Pharma: Consultancy; Amgen: Consultancy; Chugai: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Description: Abstract 812FN2 On behalf of IFM (Intergroupe Francophone du Myélome) Background. The interim analysis of this phase 2 randomized open label trial was presented at ASH last year. It aimed to determine the impact of the combination of pomalidomide (oral 4 mg daily) and dexamethasone (oral 40 mg weekly) in pts characterized with advanced myeloma (MM) following lenalidomide and bortezomib. The response rate (ORR, PR and better), and the median PFS were similar in the 2 arms, pomalidomide on days 1–21 vs. 1–28 of each 28-day cycle. The final analysis of IFM 2009-02 will be fully presented at ASH 2011. We have also studied subgroups characterized with refractory MM, in order to further demonstrate that the combination of pomalidomide and dexamethasone might benefit pts that have progressed after multiple novel agents. Method. This study was addressed to MM pts who had at best a stable disease with the last course of bortezomib and the last course of lenalidomide, or who were refractory to bortezomib and lenalidomide (as per IMWG criteria). The primary objective was ORR (PR and better). The responses were assessed centrally in Lille, and reviewed by an independent committee (all data reported herein are based on the IRC). FISH cytogenetic analysis was performed in Nantes on bone marrow plasma cells. All pts had received prophylaxis against venous thromboembolism. Data are presented for the overall population when there was no difference between the 2 arms. The analysis is performed on ITT. Results. Eighty four pts (57 male and 27 female) were enrolled; 43 in arm 21/28 and 41 in arm 28/28. The median (min-max) age was 60 (42–83) years. The median time from diagnosis to enrolment in IFM 2009-02 was 70.5 months (9–277). The median number of prior lines of therapy was 5 (1–13), and 100% of the pts had received bortezomib and lenalidomide as per protocol, 70% had received alkylating agents and 71% thalidomide. Overall, 21 (37.5%) pts had loss of 17p (n=15) or t(4;14) (n=6). At the cut-off of March 1st 2011 the median follow-up for alive pts was 10.4 months (1.6–14.3), the median number of cycles administered was 8 (1–18) in arm 21/28 and 6 (1–18) in arm 28/28. The ORR was 34.9% in arm 21/28 and 34.1% in arm 28/28, including 4.7% and 7.3% VGPR, respectively. Overall, 40 (47.6%) pts had stable disease (including minor response) and 3 pts reached CR. The median (95%CI) PFS was 6.3 (4.1–9.1) months in either arm, and the median duration of response was 11.4 (3.7–13.6) months and 7.9 (4.0–) months in arm 21/28 and 28/28, respectively. The median PFS was 4.2 (3.3–6.9) months for pts with SD as compared to 12.6 (9.9–14.8) months in pts that had a response. A summary of subgroups characterized with refractory MM is presented in the table below. Survival and toxicity will be updated at ASH 2011. Conclusion. Pomalidomide and dexamethasone is active and well tolerated in these heavily pre-treated MM pts. This study provides further evidence that pomalidomide has no-cross resistance with lenalidomide and suggests that it can provide benefit for pts who have relapsed after other novel therapies. Disclosures: Leleu: LeoPharma: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Research Funding; Amgen: Honoraria; Novartis: Research Funding. Roussel:Celgène: Honoraria; Janssen: Honoraria. Hulin:Celgene: Honoraria; Janssen: Honoraria. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Description: High dose chemotherapy plus autologous transplantation (ASCT) is considered a standard of care for newly diagnosed myeloma patients younger than 65 years of age. The high complete response rate (CR) achieved with the triplet combination of immunomodulatory drugs + proteasome inhibitors + dexamethasone has led investigators to propose this strategy upfront without immediate ASCT. The aim of this study was to determine if, in the era of new drugs, ASCT was still required in the initial management of young patients. We conducted a randomized trial comparing conventional dose treatment (RVD arm= 8 cycles of Lenalidomide, Bortezomib and Dexamethasone, plus stem cell mobilization after 3 cycles of RVD utilizing high dose cyclophosphamide and G-CSF) to RVD with ASCT (Transplant arm= 3 induction cycles of RVD, followed by stem cell collection, and then ASCT conditioned with Melphalan 200 mg/m2, followed by 2 cycles of RVD as consolidation). Maintenance treatment with Lenalidomide (10 to 15 mg/d) was used in both arms for one year. In the RVD arm, ASCT was planned at time of relapse. From November 2010 to November 2012, 700 previously untreated French and Belgian patients were equally randomized between arms. Randomization was stratified according to ISS stage (I vs II vs III) and FISH analysis (standard vs high risk = del 17p or t(4;14) or t(14;16)). The primary study end point was progression-free survival (PFS). Two pre-specified interim analysis were to be performed at 33% and 69% of the estimated total number of events. The second interim analysis was performed in June 2015 (346 events= 197 in the RVD arm, 149 in the transplant arm). These results were submitted to an independent data management and safety committee, who recommended completing the trial, and continuing follow-up (without cross over before progression), since the difference in PFS between the 2 groups had reached the pre-specified level of significance for stopping the study. As of June 8, 2015, median follow up was 39 months. All patients had discontinued treatment (completion of planned therapy= 66%, disease progression= 16%, adverse events= 10%). Patient characteristics of each group were similar and no significant differences were found with regard to age (median=58 years), ISS stage (I=233, II=341, III=126), Ig isotype, beta-2-microglobulin (median=3.5 mg/L), and cytogenetics (high risk=90 patients). In the transplant arm, 93% of patients underwent ASCT and 5 toxic deaths occurred during mobilization or in the actual transplant phase (1.4%). ASCT was found to improve PFS (stratified p value for log-rank test 〈 0.0002; HR= 1.5, 95% CI= 1.2-1.9). The 3-year post-randomization PFS rate was 61% in the transplant arm versus 48% in the RVD arm. The PFS benefit observed in the transplant arm was uniform across all the following subgroups: age (≤ or 〉 60 years), sex, Ig isotype (IgG or others), ISS stage (I or II or III), cytogenetics (standard or high risk), and response after the 3 first cycles of RVD (complete response or not). The 3-year post randomization rate of overall survival was extremely high (88%) and similar between the 2 study groups (stratified p value for log rank test=0.25). The complete response rate was significantly higher in the transplant arm compared to the RVD arm: 58% versus 46%, respectively (p