Isatuximab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma patients with renal impairment: ICARIA-MM subgroup analysis

The randomized, phase 3 ICARIA-MM study investigated isatuximab (Isa) with pomalidomide and dexamethasone (Pd) versus Pd in patients with relapsed/refractory multiple myeloma and ?2 prior lines. This prespecified subgroup analysis examined efficacy in patients with renal impairment (RI; estimated glomerular filtration rate <60 mL/min/1.73 m²). Isa 10 mg/kg was given intravenously once weekly in cycle 1, and every 2 weeks in subsequent 28-day cycles. Patients received standard doses of Pd. Median progression-free survival (PFS) for patients with RI was 9.5 months with Isa-Pd (n = 55) and 3.7 months with Pd (n = 49; hazard ratio [HR] 0.50; 95% confidence interval [CI], 0.30-0.85). Without RI, median PFS was 12.7 months with Isa-Pd (n = 87) and 7.9 months with Pd (n = 96; HR 0.58; 95% CI, 0.38-0.88). The overall response rate (ORR) with and without RI was higher with Isa-Pd (56 and 68%) than Pd (25 and 43%). Complete renal response rates were 71.9% (23/32) with Isa-Pd and 38.1% (8/21) with Pd; these lasted ?60 days in 31.3% (10/32) and 19.0% (4/21) of patients, respectively. Isa pharmacokinetics were comparable between the subgroups, suggesting no need for dose adjustment in patients with RI. In summary, the addition of Isa to Pd improved PFS, ORR and renal response rates

Impact of minimal residual disease detection by next-generation flow cytometry in multiple myeloma patients with sustained complete remission after frontline therapy

Minimal residual disease (MRD) was monitored in 52 patients with sustained CR (≥2 years) after frontline therapy using next-generation flow (NGF) cytometry. 25% of patients initially MRD- reversed to MRD+. 56% of patients in sustained CR were MRD+; 45% at the level of 10−5; 17% at 10−6. All patients who relapsed during follow-up were MRD+ at the latest MRD assessment, including those with ultra-low tumor burden. MRD persistence was associated with specific phenotypic profiles: higher erythroblasts’ and tumor-associated monocytes/macrophages’ predominance in the bone marrow niche. NGF emerges as a suitable method for periodic, reproducible, highly-sensitive MRD-detection at the level of 10−6

Low pre-transplant levels of mannosebinding lectin are associated with viral infections and mortality after haematopoietic allogeneic stem cell transplantation

Background: Mannose-binding lectin (MBL) is a key component of innate immunity. Low serum MBL levels, related to promoter polymorphism and structural variants, have been associated with an increased risk of infection. The aim of this work was to analyse the incidence and severity of infections and mortality in relation to the MBL2 genotype and MBL levels in patients underwent allogeneic haematopoietic stem cell transplantation (Allo-HSCT). Results: This was a prospective cohort study of 72 consecutive patients underwent Allo-HSCT between January 2007 and June 2009 in a tertiary referral centre. Three periods were considered in the patients? follow-up: the early period (0?30 days after Allo-HSCT), the intermediate period (30?100 days after Allo-HSCT) and the late period (> 100 days after Allo-HSCT). A commercial line probe assay for MBL2 genotyping and an ELISA Kit were used to measure MBL levels. A total of 220 episodes of infection were collected in the 72 patients. No association between donor or recipient MBL2 genotype and infection was found. The first episode of infection presented earlier in patients with pre-transplant MBL levels of < 1000 ng/ml (median 6d vs 8d, p = 0.036). MBL levels < 1000 ng/ml in the pre-transplant period (risk ratio (RR) 2.48, 95% CI 1.00?6.13), neutropenic period (0?30 days, RR 3.28, 95% CI 1.53?7.06) and intermediate period (30?100 days, RR 2.37, 95% CI 1.15?4.90) were associated with increased risk of virus infection. No association with bacterial or fungal disease was found. Mortality was associated with pre-transplant MBL levels < 1000 ng/ml (hazard ratio 5.55, 95% CI 1.17?26.30, p = 0.03) but not with MBL2 genotype. Conclusions: Patients who underwent Allo-HSCT with low pre-transplant MBL levels presented the first episode of infection earlier and had an increased risk of viral infections and mortality in the first 6 months post-transplant. Thus, pre-transplant MBL levels would be important in predicting susceptibility to viral infections and mortality and might be considered a biomarker to be included in the pre-transplantation risk assessment.This work was supported by grants from the Fondo de Investigaciones Sanitarias (Ministry of Health of Spain) PI04/0492 to MC Fariñas and Instituto de Investigación Sanitaria Valdecilla (IDIVAL) API 06/01. The content of the paper is solely the responsibility of the authors and does not necessarily represent the official views. The funding body was not involved in the design of the study, collection or analysis of the data, interpretation of the data, or in the writing of the manuscript

Comorbidity as a prognostic variable in multiple myeloma: comparative evaluation of common comorbidity scores and use of a novel MM–comorbidity score

Comorbidities have been demonstrated to affect progression-free survival (PFS) and overall survival (OS), although their impact in multiple myeloma (MM) patients is as yet unsettled. We (1) assessed various comorbidities, (2) compared established comorbidity indices (CIs; Charlson comorbidity index (CCI), hematopoietic cell transplantation-specific comorbidity index (HCT-CI)), Kaplan Feinstein (KF) and Satariano index (SI) and (3) developed a MM-CI (Freiburger comorbidity index, FCI) in 127 MM patients. Univariate analysis determined moderate or severe pulmonary disease (hazard ratio (HR): 3.5, P<0.0001), renal impairment (via estimated glomerular filtration rate (eGFR); HR: 3.4, P=0.0018), decreased Karnofsky Performance Status (KPS, HR: 2.7, P=0.0004) and age (HR: 2, P=0.0114) as most important variables for diminished OS. Through multivariate analysis, the eGFR ⩽30 ml/min/1.73m2, impaired lung function and KPS ⩽70% were significant for decreased OS, with HRs of 2.9, 2.8 and 2.2, respectively. Combination of these risk factors within the FCI identified significantly different median OS rates of 118, 53 and 25 months with 0, 1 and 2 or 3 risk factors, respectively, (P<0.005). In light of our study, comorbidities are critical prognostic determinants for diminished PFS and OS. Moreover, comorbidity scores are important treatment decision tools and will be valuable to implement into future analyses and clinical trials in MM

Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production

Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide, an anti-helminthic. Niclosamide, at clinically achievable non-toxic concentrations, killed MM cell lines and primary MM cells as efficiently as or better than standard chemotherapy and existing anti-myeloma drugs individually or in combinations, with little impact on normal donor cells. Cell death was associated with markers of both apoptosis and autophagy. Importantly, niclosamide rapidly reduced free light chain (FLC) production by MM cell lines and primary MM. FLCs are a major cause of renal impairment in MM patients and light chain amyloid and FLC reduction is associated with reversal of tissue damage. Our data indicate that niclosamides anti-MM activity was mediated through the mitochondria with rapid loss of mitochondrial membrane potential, uncoupling of oxidative phosphorylation and production of mitochondrial superoxide. Niclosamide also modulated the nuclear factor-κB and STAT3 pathways in MM cells. In conclusion, our data indicate that MM cells can be selectively targeted using niclosamide while also reducing FLC secretion. Importantly, niclosamide is widely used at these concentrations with minimal toxicity

Adverse effects of thalidomide administration in patients with neoplastic diseases

Thalidomide, a glutamic acid derivative, was withdrawn from clinical use in 1962 due to its severe teratogenic effects. Its recent reinstitution in clinical practice was related to its benefits in leprosy and multiple myeloma. Moreover, the antiangiogenic and immunomodulatory properties of thalidomide have led to its evaluation in several malignant diseases, including myelofibrosis, renal cell cancer, prostate cancer, and Kaposi sarcoma. However, thalidomide use is associated with several side effects: somnolence and constipation are the most common, while deep vein thrombosis and peripheral neuropathy are the most serious. A combination of thalidomide with steroids or chemotherapy is being evaluated in several phase 2 studies. While it is not yet clear whether these combinations will enhance efficacy, they appear to increase the toxicity of thalidomide, and thalidomide analogs are being developed to minimize this toxicity. Ongoing studies will clarify the potential advantages of these agents in the treatment of neoplastic diseases

Thalidomide in cancer medicine

Thalidomide, an oral agent with antiangiogenic and immunomodulatory properties, is being investigated extensively in the management of advanced cancer. Multiple studies with large numbers of patients have confirmed that this drug has significant activity in multiple myeloma. Some patients with myelofibrosis or myeodysplatic syndromes may reduce their need for transfusions after thalidomide treatment. The activity of thalidomide in solid tumors is less prominent. Studies in Kaposi’s sarcoma, malignant melanoma, renal cell carcinoma and prostate cancer appear more promising especially when thalidomide is combined with biological agents or with chemotherapy. Limited activity was demonstrated in patients with glioma, while thalidomide appears to be inactive in patients with head and neck cancer, breast or ovarian cancer

Thalidomide in cancer medicine

Thalidomide, an oral agent with antiangiogenic and immunomodulatory properties, is being investigated extensively in the management of advanced cancer. Multiple studies with large numbers of patients have confirmed that this drug has significant activity in multiple myeloma. Some patients with myelofibrosis or myeodysplatic syndromes may reduce their need for transfusions after thalidomide treatment. The activity of thalidomide in solid tumors is less prominent. Studies in Kaposi’s sarcoma, malignant melanoma, renal cell carcinoma and prostate cancer appear more promising especially when thalidomide is combined with biological agents or with chemotherapy. Limited activity was demonstrated in patients with glioma, while thalidomide appears to be inactive in patients with head and neck cancer, breast or ovarian cancer

Clinical implications of chromosomal abnormalities in multiple myeloma

The adverse prognostic role of cytogenetic abnormalities has recently been established in plasma cell dyscrasias. Modern techniques such as fluorescence in situ hybridization and comparative genomic hybridization have revealed a higher incidence of cytogenetic abnormalities in patients with multiple myeloma (MM) compared to conventional cytogenetics. Hypodiploidy and chromosome 13 abnormalities are found in more than 50% of myeloma patients, representing well known factors with adverse prognosis. Rearrangements involving the switch regions of immunoglobulin heavy chain (IgH) gene at 14q32 with various partner genes represent the most common structural abnormalities, having an incidence of 70% in MM. Structural abnormalities of chromosomes 17 and 8 involving the p53 and c-myc genes are considered to be less frequent events, but carry a poor prognosis. New therapeutic approaches such as non-myeloablative allotransplantation and modern therapeutic agents (thalidomide, lenalidomide, and bortezomib) and their combinations give promise for an improved therapeutic management of patients with MM. The detection of t(4; 14), t(14; 16), deletion of chromosome 13 on metaphase analysis, or deletion of p53 by FISH will define high-risk prognostic groups that are not generally controlled with high-dose melphalan and autologous stem cell transplantation (ASCT), and should therefore be treated with more investigational therapies. Alternatively, eligible patients who do not have these poor risk factors are more likely to benefit from a high-dose, melphalan-based, regimen followed by ASCT