Bernadette Hennache

Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide–refractory multiple myeloma: Intergroupe Francophone du Myélome 2009-02

The combination of pomalidomide and dexamethasone can be safely administered to patients with multiple myeloma (MM) and has significant efficacy, although the optimal regimen remains to be determined. Patients with MM whose disease progressed after multiple lines of therapy have limited treatment options. We designed a multicenter, phase 2 randomized study assessing two different dose regimens of pomalidomide and dexamethasone in advanced MM. Treatment response was assessed centrally. Pomalidomide (4 mg) was given orally on days 1 to 21 (arm 21/28) or continuously (arm 28/28) over a 28-day cycle, plus dexamethasone given weekly. Eighty-four patients (43, arm 21/28 and 41, arm 28/28) were randomized. The median number of prior lines was 5. Overall response rate was 35% (arm 21/28) and 34% (arm 28/28), independent of the number of prior lines and level of refractoriness. Median duration of response, time to disease progression, and progression-free survival was 7.3, 5.4, and 4.6 months, respectively, which was similar across cohorts. At 23 months follow-up, median overall survival was 14.9 months, with 44% of the patients alive at 18 months. Toxicity consisted primarily of myelosuppression, which was manageable. The efficacy and safety data presented here, along with data from other phase 2 trials, suggest that pomalidomide 4 mg per day on days 1 to 21 of 28 with dexamethasone should be investigated in future trials. This trial is registered at ClinicalTrials.gov (No. NCT01053949).

Total soluble HLA class I and soluble HLA-G in multiple myeloma and monoclonal gammopathy of undetermined significance.

Serum β2-microglobulin, the light chain of the HLA class I molecular complex, remains one of the best survival prognostic factors in multiple myeloma, but other HLA class I molecules might be of interest in monoclonal gammopathies. In this study, we evaluate total soluble HLA class I (HLA-Is) and soluble HLA-G (HLA-Gs) in 103 patients with newly diagnosed multiple myeloma, 30 patients with monoclonal gammopathy of undetermined significance (MGUS), and 30 healthy subjects, studying their prognostic value in multiple myeloma. In multiple myeloma patients, HLA-Is and HLA-Gs median values were 0.8 μg/mL and 28 ng/mL, respectively. Median HLA-Is concentration was higher in stage II and III multiple myeloma patients than in stage I multiple myeloma, MGUS, and control patients. Median HLA-Gs was significantly lower in healthy controls than in MGUS and multiple myeloma patients. A high level of HLA-Is (≥2.1 μg/mL) was predictive of short survival (P = 0.017). For each given level of β2-microglobulin, the relative risk of death was higher for patients with HLA-Is ≥ 2.1 μg/mL than in patients with a lower level (P = 0.047). HLA-Gs, a marker of monoclonal gammopathy, was of no prognostic value, but the addition of HLA-Is to β2-microglobulin produced an efficient prognostic score (P < 0.0001). HLA-Is is a new marker of multiple myeloma tumor load and provides additional survival prognostic information to β2-microglobulin.

Serum immunoglobulin free light chain correlates with tumor burden markers in Waldenstrom macroglobulinemia.

The serum IgM level has been utilised as a marker of tumor progression and to assess response to therapy in patients with Waldenstrom macroglobulinemia (WM). However, there are many limitations to the IgM protein level. The objective of this study was to evaluate the association of known tumor burden markers and prognostic factors with serum free light chain (sFLC) in 98 patients with WM. We demonstrated that sFLC measurement accurately differentiated IgM-MGUS compared with WM reflecting a measurement of tumor burden. In univariate and multivariate analysis, median sFLC at the cut-off at 60 mg/L was higher for WM patients with low hemoglobin and high β2M, when we applied the WM-IPSS cut-offs, but showed no association with IgM level. This study demonstrates that sFLC is a new marker in WM disease. Further analysis is required to prospectively study the role of sFLC in monitoring response to therapy and as a prognostic marker in WM patients.

IgA kappa/IgA lambda heavy/light chain assessment in the management of patients with IgA myeloma

Accurate quantification of immunoglobulin A (IgA) monoclonal immunoglobulins by serum protein electrophoresis (SPEP) can be difficult and can impact the assessment of response among patients with multiple myeloma (MM). Therefore, there is a need to identify new assays that better reflect disease burden and response to treatment, and correlate with patient outcome. IgA Hevylite (HLC) measures IgA kappa and IgA lambda separately and provides precise quantitative measurements of the monoclonal IgA expression and polyclonal‐isotype matched suppression. In the current study, the authors assessed the usefulness of these assays in the diagnosis of IgA MM and sought to comment on the prognostic value of the assays.

Prognostic value of PINI index in patients with multiple myeloma.

Background:  The Prognostic Inflammatory and Nutritional Index (PINI) is a simple scoring system that aggregates two blood markers of inflammatory [C‐reactive protein (CRP) and orosomucoid] and of nutritional (albumin and prealbumin) states. It is used in routine practice in geriatric medicine, especially in hospitalized elderly patients. This study was undertaken to evaluate the usefulness of PINI index in multiple myeloma (MM), a malignancy of the elderly.

Evaluation and prognostic value of serum osteoprotegerin in multiple myeloma

An essential cytokine system for osteoclast biology consists of the receptor activator of nuclear factor (NF)-B ligand (RANKL), its receptor RANK, and the soluble decoy receptor osteoprotegerin (OPG). Myeloma plasma cells have been shown to increase RANKL expression and to decrease OPG availability in the bone marrow microenvironment. These effects result in an increased RANKL:OPG ratio that favours the activation of osteoclasts. Conflicting reports exist regarding serum OPG levels in multiple myeloma (MM) and their correlation with lytic bone disease and survival (Seidel et al, 2001; Lipton et al, 2002; Kraj et al, 2003; Terpos et al, 2003; Corso et al, 2004; Kyrtsonis et al, 2004). We evaluated the serum levels of OPG in 140 newly diagnosed MM patients and assessed its prognostic value in the 101 symptomatic patients requiring treatment. The mean (± standard deviation) OPG levels in symptomatic MM, asymptomatic MM and controls represented by 41 healthy ageand sex-matched individuals were 3.4 ± 2.5, 2.9 ± 1.1 and 2.0 ± 0.7 ng/ml respectively. The median OPG concentration in symptomatic MM, asymptomatic MM and controls were 3.0 ng/ml (range, 0.8–24), 2.6 (1.6–7.2) and 1.6 ng/ml (1.2–3), respectively. OPG levels were higher in asymptomatic and symptomatic MM compared with controls (P < 0.001 in each case). In contrast, there was no statistically significant difference between asymptomatic and symptomatic MM patients (P 1⁄4 0.28). Bone lesions were graded in three groups according to a standard radiographic evaluation: no osteolytic lesions, 1–6 lesions, >6 lesions. We found no significant differences of OPG values between the three groups. Significant correlations were found with b2-microglobulin (r 1⁄4 0.23; P 1⁄4 0.02) and creatinine (r 1⁄4 0.22; P 1⁄4 0.03) but not with haemoglobin, bone marrow plasmacytosis, M-component, albumin, lactate dehydrogenase (LDH) or C-reactive protein (CRP) levels. We assessed the prognostic value of OPG on overall survival (OS) and progression-free survival (PFS) in symptomatic patients. Median follow-up of the 101 patients was 68.4 months [95% confidence interval (CI): 60.2–76.6]. The median PFS and OS were 18.8 months (95% CI: 14.5–23.1) and 39.8 months (95% CI: 29.6–50.0) respectively. High serum levels of OPG were associated with a poorer OS and PFS in univariate analysis (P 1⁄4 0.025 and P 1⁄4 0.029 respectively) (Fig 1A,B). The other adverse prognostic factors were age >60 years (P 1⁄4 0.019), albumin <35 g/l (P 1⁄4 0.015), b2-microglobulin >2.5 mg/l (P 1⁄4 0.025), bone marrow plasmacytosis >15% (P 1⁄4 0.048), chromosome 13 deletion (P 1⁄4 0.002), CRP > 16 mg/l (P 1⁄4 0.037), IgA isotype (P 1⁄4 0.012), LDH > 350 IU/l (P 1⁄4 0.016), k light chain (P 1⁄4 0.021) for OS and b2-microglobulin >2.5 mg/l (P 1⁄4 0.01), chromosome 13 deletion (P 1⁄4 0.002), and IgA

IgMκ and IgMλ Measurements for the Assessment of Patients with Waldenström's Macroglobulinaemia

Purpose: Accurate quantification of monoclonal IgM immunoglobulins is essential for response assessment in patients with Waldenströms macroglobulinaemia (WM). The propensity of IgM to form multimers in serum makes sample evaluation by current laboratory methods particularly challenging. Experimental Design: We assessed the precision and linearity of IgMκ and IgMλ heavy/light chain (HLC, Hevylite) assays, and established reference intervals using 120 normal donor sera. We compared the quantitative performance of HLC assays with serum protein electrophoresis (SPE) and total IgM nephelometry for 78 diagnostic samples and follow-up samples from 25 patients with WM. Comparisons were made between the three methods for diagnostic sensitivity and response assessment. Results: IgMκ and IgMλ HLC assays showed low imprecision and good linearity. There was good agreement between summated HLC (IgMκ + IgMλ) and total IgM (measured nephelometrically; R2 = 0.90), but only moderate agreement between involved IgM HLC and SPE densitometry (R2 = 0.49). Analysis of 120 normal donor sera produced the following normal ranges: IgMκ: 0.29–1.82 g/L; IgMλ: 0.17–0.94 g/L; IgMκ/IgMλ ratio: 0.96–2.30. Using these ranges, IgM HLC ratios were abnormal in all WM presentation sera tested, including 15 with non-quantifiable SPE. Despite discordance in quantitation, responses assigned with HLC assays showed excellent agreement to those based on international guidelines using SPE or total IgM; although abnormal HLC ratios indicated residual disease in some patients with negative electrophoresis results. Conclusions: Nephelometric assessment of IgMκ and IgMλ HLC pairs offers a quantitative alternative to traditional laboratory techniques for the measurement of monoclonal IgM and may aid in the management of WM. Clin Cancer Res; 22(20); 5152–8. ©2016 AACR.

Clinical relevance of soluble HLA class I molecules in Waldenstrom Macroglobulinemia.

Objectives:  Waldenstrom Macroglobulinemia (WM) is a B‐cell neoplasm characterised by secretion of IgM by lymphoplasmacytic bone marrow cells and by cytopenias and hypogammaglobulinemia in a subset of patients. Beta‐2 microglobulin (b2m) is a major prognostic factor in WM and the heavy chain of HLA class I molecules, which are known to have immunosuppressive properties and have been implicated in the pathogeny of several malignancies.

IgMκ and IgMl measurements for the assessment of patients with Waldenstrӧm's macroglobulinaemia

Purpose: Accurate quantification of monoclonal IgM immunoglobulins is essential for response assessment in patients with Waldenströms macroglobulinaemia (WM). The propensity of IgM to form multimers in serum makes sample evaluation by current laboratory methods particularly challenging. Experimental Design: We assessed the precision and linearity of IgMκ and IgMλ heavy/light chain (HLC, Hevylite) assays, and established reference intervals using 120 normal donor sera. We compared the quantitative performance of HLC assays with serum protein electrophoresis (SPE) and total IgM nephelometry for 78 diagnostic samples and follow-up samples from 25 patients with WM. Comparisons were made between the three methods for diagnostic sensitivity and response assessment. Results: IgMκ and IgMλ HLC assays showed low imprecision and good linearity. There was good agreement between summated HLC (IgMκ + IgMλ) and total IgM (measured nephelometrically; R2 = 0.90), but only moderate agreement between involved IgM HLC and SPE densitometry (R2 = 0.49). Analysis of 120 normal donor sera produced the following normal ranges: IgMκ: 0.29–1.82 g/L; IgMλ: 0.17–0.94 g/L; IgMκ/IgMλ ratio: 0.96–2.30. Using these ranges, IgM HLC ratios were abnormal in all WM presentation sera tested, including 15 with non-quantifiable SPE. Despite discordance in quantitation, responses assigned with HLC assays showed excellent agreement to those based on international guidelines using SPE or total IgM; although abnormal HLC ratios indicated residual disease in some patients with negative electrophoresis results. Conclusions: Nephelometric assessment of IgMκ and IgMλ HLC pairs offers a quantitative alternative to traditional laboratory techniques for the measurement of monoclonal IgM and may aid in the management of WM. Clin Cancer Res; 22(20); 5152–8. ©2016 AACR.

Tubulopathie pseudo-myélomateuse et dépôts de chaînes légères au cours du lymphome lymphoplasmocytaire de bas grade/maladie de Waldenström

La macroglobulinemie de Waldenstrom (MW, ou lymphome lymphoplasmocytaire) est une proliferation lymphoplasmocytaire rare envahissant la moelle osseuse associee a la presence d’une immunoglobine M (IgM) monoclonale serique. L’atteinte renale, rare au cours de la maladie de Waldenstrom, est classiquement glomerulaire : glomerulopathie membranoproliferative associee a une cryoglobulinemie, depots intracapillaires monoclonaux d’IgM ou amylose AL. L’infiltration interstitielle par la proliferation lymphomateuse est egalement une presentation classique de la MW. A l’inverse, l’atteinte tubulaire comparable a celle observee au cours de la tubulopathie myelomateuse ou les maladies a depots non amyloides de chaines legeres monoclonales de type Randall sont exceptionnellement observees. Nous rapportons trois cas d’atteinte renale particuliere au cours de la MW, associant tubulopathie « pseudo-myelomateuse » et depots de type Randall, qui semblerait liee a un pronostic renal plus defavorable.