Tamara Berno

Alkaline phosphatase variation during carfilzomib treatment is associated with best response in multiple myeloma patients

The ubiquitin–proteasome pathway regulates bone formation through osteoblast differentiation. We analyzed variation alkaline phosphatase (ALP) during carfilzomib treatment. Data from 38 patients enrolled in the PX‐171‐003 and 29 patients in PX‐171‐004 studies, for patients with relapsed/refractory myeloma, were analyzed. All patients received 20 mg/m2 of carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28‐day cycle. Sixty‐seven patients from ALP data were evaluable. In PX‐171‐003, the ORR (>PR) was 18% and the clinical benefit response (CBR; >MR) was 26%, while in PX‐171‐004, the ORR was 35.5% overall and 57% in bortezomib‐naive patients. ALP increment from baseline was statistically different in patients who achieved ≥VGPR compared with all others on Days 1 (P = 0.0049) and 8 (P = 0.006) of Cycle 2. In patients achieving a VGPR or better, ALP increased more than 15 units per liter at Cycle 2 Day 1 over baseline. An ALP increase over the same period of time was seen in 26%, 13% and 11% of patients achieving PR, MR, and SD, respectively. This retrospective analysis of patients with relapsed or refractory myeloma treated with single‐agent carfilzomib indicates that early elevation in ALP is associated with subsequent myeloma response.

Lenalidomide in patients with chemotherapy-induced polyneuropathy and relapsed or refractory multiple myeloma: results from a single-centre prospective study.

Lenalidomide, an immunomodulatory drug used in myeloma therapy, has been claimed to be less neurotoxic than thalidomide, but evidence is still weak. We prospectively assessed lenalidomide safety in myeloma patients to evaluate whether it would induce or modify a previously ensued chemotherapy‐induced peripheral neuropathy (CIPN). Thirty consecutive patients (17 men, mean age 63.7 ± 9.4) previously treated with bortezomib and/or thalidomide and starting on lenalidomide (25 mg/day for 21‐day cycles) for relapsed or refractory myeloma were assessed at baseline, 6, and 12 months from the beginning of lenalidomide with Total Neuropathy Score clinical version (TNSc), Eastern Cooperative Oncology Group (ECOG) performance status, and numeric rating scale (NRS) for pain. TNSc >2 was considered significant for CIPN. TNSc changes of at least 4 points from baseline value were considered clinically relevant. At baseline 16 of the 30 patients (53.3%) had CIPN (mean TNSc 5.8, range 3–15). After 6 months, 13 patients were unchanged, 1 improved, and 2 worsened. After 12 months the patient who had improved persisted stable, and the two who had worsened returned to TNSc baseline value. The 14 patients without CIPN at baseline did not develop neuropathy. NRS and ECOG performance status persisted unchanged. Our results demonstrate lenalidomide safety and very low neurotoxicity also in patients with pre‐existing CIPN treated for 1 year.

Parathyroid hormone receptor mediates the anti-myeloma effect of proteasome inhibitors.

Clinically significant serum parathyroid hormone (PTH) variations have been reported in multiple myeloma (MM) patients treated with proteasome inhibitors. To elucidate the association between serum PTH variations and proteasome inhibition in MM, the effect of PTH and PTHR1 ligands on the proteasome inhibitors bortezomib and carfilzomib in vitro and in vivo was determined. The MM cell lines ARP1, OC1 and 5TGM1 expressed mRNA and protein encoding PTH receptor 1 (PTHR1). Treatment of 5TGM1 cells with either PTH(1-34), bortezomib or carfilzomib alone dose-dependently inhibited 5TGM1 cell proliferation. However, treatment with the potent PTHR1 antagonist [TYR34]PTH(7-34) (PTH(7-34)) had no significant effect on myeloma cell proliferation and cell viability. In contrast, when used in combination with bortezomib or carfilzomib, PTH(7-34) treatment significantly reduced the bortezomib or carfilzomib-associated decrease in cell proliferation. Treatment of the C57BL/KaLwRij mouse myeloma model with either bortezomib or carfilzomib provided a significantly prolonged survival benefit compared to controls (p=0.04; p=0.01 respectfully). This potent anti-myeloma effect was completely abrogated by concomitant treatment with PTH(7-34). These results suggest an important role of the PTHR1 in the anti-myeloma effect of proteosome inhibition.

Low-risk identification in multiple myeloma using a new 14-gene model

Identifying the best gene expression pattern associated with low‐risk disease in patients with newly diagnosed multiple myeloma (MM) is important to direct clinical treatments. The MM Survival Index14 (MMSI14) was developed from GEP data sets of 22 normal plasma cells (NPC), 5 MM cell lines (MMCL), 44 monoclonal gammopathy of undetermined significance (MGUS), and 351 newly diagnosed MM patients. R/bioconductor and siggenes package were used to obtain heatmap, boxplot and histogram whose results were then analyzed by Kaplan–Meier analysis. Fourteen genes associated with low‐risk disease in MM were identified. We validated the disease prognostic power of MMSI14 with an independent data set of other 214 newly diagnosed MM patients and also compared our model with the 70‐gene, the 8‐subgroup, IFM15, and HMCLs7 models. Survival analysis showed that a low MMSI14 signature was associated with longer survival. Applying MMSI14 to independent data sets, we were able to classify 39% of patients as low‐risk, with a survival probability of more than 90% at 60 months. Multiple clinical parameters confirmed significant correlation between low‐ and high‐risk subgroups defined by MMSI14. Comparing previously published models to the same data sets the MMSI14 model retained the best prognostic value. We have developed a new gene model (MMSI14) for defining low‐risk, newly diagnosed MM. The multivariate comparative analysis confirmed that MMSI14 is the best available model to predict clinical outcome in MM patients.

Lenalidomide long-term neurotoxicity Clinical and neurophysiologic prospective study

Objective: To evaluate long-term lenalidomide neurotoxicity and correlation with cumulative dose and hematologic response. Methods: Nineteen myeloma patients (7 men, mean age 63.2 years) underwent clinical and neurophysiologic assessment at baseline and at 2 (8 patients, group A) or 5 years (11 patients, group B) after starting lenalidomide therapy for relapsed/refractory multiple myeloma. Neuropathy was scored with Total Neuropathy Score clinical version (TNSc). Lenalidomide cumulative dose was correlated with severity of neuropathy and hematologic response. Results: At enrollment, 7/19 patients (3 in group A, 4 in group B) had neurophysiologic signs of neuropathy secondary to previous chemotherapy, in 2 of them subclinical. Neurophysiologic evidence of sensory axonal neuropathy occurred in 4/8 patients at 2 years follow-up (group A) and in 3/11 patients at 5 years follow-up (group B). Dorsal sural nerve sensory action potential amplitude was the earliest neurophysiologic abnormality. No relevant (≥4) clinical changes were found in TNSc score. Hematologic overall response was 62% in group A and 100% in group B. No correlation was found between lenalidomide cumulative dose and neuropathy or between neuropathy and hematologic response. Conclusions: In our study, up to 50% of myeloma patients on long-term lenalidomide therapy developed sensory axonal neuropathy. Reduced dorsal sural nerve sensory action potential amplitude was the first neurophysiologic alteration. Neuropathy was usually subclinical or mild, however. Neurotoxicity was independent of lenalidomide cumulative dose and hematologic response.

NK cells and their receptors in naive and rituximab-treated patients with anti-MAG polyneuropathy

BACKGROUND Natural killer (NK) cells can bridge innate and acquired immunity, and play a role in autoimmunity. A few studies evaluated the distribution of NK cells and the expression of their receptors in chronic immune-mediated demyelinating polyneuropathies. We investigated NK cell distribution and NK cell receptor expression in 20 naïve patients with anti-MAG polyneuropathy (MAG-PN). METHODS Using flow cytometry, we analysed NK cells and a series of NK cell receptors in the peripheral blood of patients with MAG-PN, and, as controls, in patients with chronic inflammatory demyelinating peripheral polyradiculoneuropathy (CIDP) and in healthy subjects. Six MAG-PN patients were also tested after rituximab treatment. RESULTS At baseline the percentage of NK cells did not differ among the groups. KIR2DL2 receptor expression in MAG-PN patients was higher, andCD94/NKG2A receptor expression in both MAG-PN and CIDP patients was lower than in healthy controls. These abnormalities did not correlate with any clinical or demographic variable. No modification was found after rituximab therapy. CONCLUSIONS The data suggest that MAG-PN shows abnormalities in NK cell receptors that characterise other autoimmune diseases, and cannot help in differential diagnosis with CIDP. The impairment of the relevant CD94/NKG2A inhibitory pathway, which might play a central role in the development and perpetuation of MAG-PN, warrants further functional investigations.

Mechanisms of Thrombosis in Paraproteinemias: The Effects of Immunomodulatory Drugs

The introduction of immunomodulatory drugs (IMiDs) has improved clinical outcome in patients with multiple myeloma (MM). However, their use has been associated with a higher risk of cardiovascular complications. The use of IMiDs with dexamethasone, chemotherapy, or in combination with erythropoietic agents enhances the risk of venous thromboembolism (VTE) up to 25%. The pathogenesis of this increased risk of VTE seen with IMiD-based combination therapy is not yet fully understood, but several mechanisms have been proposed to explain the development of this hypercoagulable state. In cancer patients, prothrombotic factors include age, chemotherapy, immobility, enhanced expression of tissue factor of malignant cells, circulating microparticles, and increased vascular endothelial growth factor (VEGF). In patients with paraproteinemias, immunoglobulin-specific mechanisms may also be involved and include hypofibrinolysis, hyperviscosity, procoagulant autoantibody production, effects of inflammatory cytokines, and acquired activated protein C resistance (APCR). In this review we will focus on IMiD-associated effects on specific thrombotic mechanisms.

Lenalidomide for bortezomib-resistant multiple myeloma.

we thank Briani et al.1 and Gozzetti et al.2 for their additional comments to the topics discussed in our Case study.3 Briani and colleagues report on their experience with lenalidomide treatment in patients with relapsed or refractory disease after previous bortezomib and/or thalidomide therapy and chemotherapy-induced peripheral neuropathy.1 they observed a significant improvement in neurological symptoms and total neuropathy score clinical version (tnsc). the improvement was most pronounced in patients with a high baseline tnsc. Bortezomib induces sensory neuropathy, which usually resolves in about two-thirds of patients within a median time of 2–3 months after discontinuation of therapy.4 the likelihood of sensory neuropathy normalization is improved when guidelines for treatment modifications are followed and dose reductions implemented or treatment discontinued at early grades of neurotoxicity. By contrast, thalidomide induces a sensory neuropathy in most patients and in 30–40% of affected patients a mixed sensory-motor neuropathy with low potential for complete resolution. improvements or resolutions are seen in about one-quarter of patients, mostly after long follow-up, ranging between 4 and 6 years.4 in the future, other drugs such as carfilzomib with no or very limited neurological adverse effects may provide additional treatment alternatives for patients with pre-existing neuropathy. Gozzetti and colleagues report on two patients with light-chain induced renal failure.2 Both patients were started with a bortezomib-based regimen. One patient, with a deletion of 13q identified by fluorescence in situ hybridization analysis, responded to this treatment and was re-exposed to bortezomib therapy after relapse. at a subsequent second relapse the same regimen was applied but was found to be ineffective, while rescue therapy with lenalidomide (dose adapted to the glomerular filtration rate) induced a very good partial response. this finding motivated the authors to continue therapy with lenalidomide maintenance treatment. three trials presented at cancer meetings support this concept; all three reported a significant increase in progression-free survival with lenalidomide maintenance therapy.5–7 a substantial survival benefit, however, has not been demonstrated as yet. we fully agree with Gozzetti and colleagues regarding the importance of cytogenetic testing for prognostication in myeloma. approximately 15–20% of all myeloma patients present with highrisk disease8 and these patients are clear candidates for treatment with potent multidrug combinations upfront. in addition to cytogenetic data, gene arrays and molecular markers (such as interferon regulatory factor 4)9 could be helpful in designing rational treatment strategies for individual myeloma patients. Gozzetti and colleagues report on another patient with renal failure, with a deletion of 17p and a t(4;14) detectable by cytogenetic analysis.2 this patient was refractory to bortezomib and did not respond to lenalidomide rescue treatment. recent data show that both bortezomib and—to a lesser extent—lenalidomide can overcome the negative prognostic impact of poor cytogenetics such as loss of 13q or a t(4;14). Loss of p53, which occurs with a deletion of 17p, seems to be associated with a poor response to all drugs presently approved for treatment of myeloma and is linked to a very short survival. Hopefully, new drugs in clinical development will overcome this therapeutic dilemma.

Detection of monoclonal T populations in patients with KIR-restricted chronic lymphoproliferative disorder of NK cells

The etiology of chronic large granular lymphocyte proliferations is largely unknown. Although these disorders are characterized by the expansion of different cell types (T and natural killer) with specific genetic features and abnormalities, several lines of evidence suggest a common pathogenetic mechanism. According to this interpretation, we speculated that in patients with natural killer-type chronic lymphoproliferative disorder, together with natural killer cells, also T lymphocytes undergo a persistent antigenic pressure, possibly resulting in an ultimate clonal T-cell selection. To strengthen this hypothesis, we evaluated whether clonal T-cell populations were detectable in 48 patients with killer immunoglobulin-like receptor-restricted natural killer-type chronic lymphoproliferative disorder. At diagnosis, in half of the patients studied, we found a clearly defined clonal T-cell population, despite the fact that all cases presented with a well-characterized natural killer disorder. Follow-up analysis confirmed that the TCR gamma rearrangements were stable over the time period evaluated; furthermore, in 7 patients we demonstrated the appearance of a clonal T subset that progressively matures, leading to a switch between killer immunoglobulin-like receptor-restricted natural killer-type disorder to a monoclonal T-cell large granular lymphocytic leukemia. Our results support the hypothesis that a common mechanism is involved in the pathogenesis of these disorders.

Activated protein C resistance as measured by residual factor V after Russell's Viper Venom and activated protein C treatment analyzed as a continuous variable in multiple myeloma and normal controls

Increased risk of venous thromboembolism (VTE) has been described in multiple myeloma patients, particularly when exposed to immunomodulatory drugs. Epidemiological studies have shown that monoclonal gammopathy of undetermined significance (MGUS) patients also have an increased risk of VTE compared with normal individuals. Acquired activated protein C resistance (APC-R) is an independent risk factor for VTE in hematologic malignancies. We reviewed the records of patients with multiple myeloma and MGUS for APC-R by PEFAKIT APC-R test and compared them to normal individuals. We excluded from the analysis patients with a documented factor V Leiden mutation. The PEFAKIT APC-R is a plasma-based functional prothrombin assay based on ratio of patient clotting time with and without APC. Thirty-three MGUS and 93 multiple myeloma patients were compared with 39 normal individuals. Baseline characteristics from the three groups were similar in terms of age, sex, and performance status. The median APC-R for multiple myeloma, MGUS, and controls were 1, 1.06, and 1.1, respectively. Multiple myeloma patients compared to normal individuals had significantly shorter APC-R (P = 0.0012). No significant difference was observed between MGUS and normal individuals (P = 0.17). After analyzing APC-R values and multiple coagulation parameters, a significant inverse correlation was found between APC-R and fibrinogen (P = 0.0000001) and D-dimer (P = 0.045) serum levels and a direct correlation with prothrombin time value (P = 0.034). The Pefakit APC-R test measured as continuous variable shows a statistically significant decrease in patients with myeloma compared to normal individuals.