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Introduction: A significant unmet need exists in patients with relapsed or refractory multiple myeloma (MM), which remains an incurable disease despite recent advances in the field. One such development was the use of deacetylase inhibitors (DACi), which exert unique antimyeloma effects through targeting of epigenetic and protein metabolism pathways. The pan-DACi panobinostat was recently approved in combination with bortezomib and dexamethasone for use in patients with relapsed or relapsed and refractory MM. Results of a phase 3 trial showed that the panobinostat-containing regimen improved the overall response rate and progression-free survival. Panobinostat-associated adverse events included thrombocytopenia, diarrhea, fatigue, and peripheral neuropathy. Research into how to maintain the benefits of DACi while improving tolerability is ongoing. Areas covered: This review focuses on the efficacy and safety of panobinostat and panobinostat-based combinations for MM. Early data from clinical trials investigating the HDAC6 inhibitor ricolinostat are also discussed. Expert commentary: DACi are a unique and effective new class of agents for the treatment of MM, with panobinostat being the first to have clinically meaningful benefit for patients with relapsed or refractory MM. Optimization of dose and schedule, novel combination strategies, and introduction of selective DACi may improve the risk-benefit profile of DACi-based regimens.

Renal impairment (RI) is a major comorbidity in patients with multiple myeloma (MM). Here we present the pooled safety and efficacy analysis of three clinical trials (MM-002, MM-003, and MM-010) of pomalidomide + low-dose dexamethasone (POM + LoDEX) in patients with moderate RI (creatinine clearance [CrCl] ≥ 30 to <60 mL/min) and without RI (≥ 60 mL/min). Trial protocols were approved by the institutional review board of each site involved. Patients with RI were older than patients without RI, although other baseline characteristics were similar. The dosing and safety profile of POM + LoDEX was similar across RI subgroups. Median overall response rate, progression-free survival, time to progression, and duration of response were not significantly different between RI subgroups. However, patients with vs. without RI had significantly shorter median overall survival (10.5 vs. 14.0 months, respectively; p = .004). This analysis demonstrates that POM + LoDEX is a safe and effective treatment for patients with moderate RI. The trials were registered at ClinicalTrials.gov as NCT00833833 (MM-002), NCT01311687 (MM-003), and NCT01712789 (MM-010) and at EudraCT as 2010-019820-30 (MM-003) and 2012-001888-78 (MM-010).

Recently, outcomes for patients with multiple myeloma have improved dramatically due to improved and innovative therapies. However, most patients will either relapse or become refractory to current therapy. Thus, a significant unmet need remains for novel agents to treat this patient population. Panobinostat, a potent pan-deacetylase inhibitor with a unique mechanism of action targeting both epigenetic regulation of gene expression and protein metabolism, has preclinical synergy with a number of agents, including the proteasome inhibitor bortezomib. In a phase 3 trial of panobinostat with bortezomib and dexamethasone, addition of panobinostat significantly prolonged the median progression-free survival of patients with relapsed or relapsed and refractory multiple myeloma. This review focuses on clinical development of panobinostat, with particular emphasis on pharmacokinetics and adverse event management.

Outcomes for patients with multiple myeloma (MM) have improved significantly over the past decade. Despite these advances, MM remains incurable and an unmet medical need remains for patients who are relapsed and/or refractory. Panobinostat is a potent, oral pan-deacetylase inhibitor that elicits anti-myeloma activity through epigenetic modulation of gene expression and disruption of protein metabolism. Preclinical data demonstrated that panobinostat has synergistic effects on myeloma cells when combined with bortezomib and dexamethasone. In a Phase III clinical trial evaluating bortezomib and dexamethasone in combination with panobinostat or placebo in patients with relapsed or relapsed and refractory MM (PANORAMA 1), panobinostat led to a significant increase in median progression-free survival. Panobinostat is currently under regulatory review with a recent accelerated approval granted for the treatment of relapsed disease, in which both bortezomib and immunomodulatory drugs have failed. Here, we summarize the preclinical, pharmacokinetic and clinical data for panobinostat in MM.

Over two-thirds of newly diagnosed multiple myeloma are over 65 years. The treatment goals for the non-transplant-eligible patients should be to prolong survival by achieving the best response, while ensuring quality of life. New upfront treatment combinations based on first generation of novel proteasome inhibitors and immunomodulatory drugs plus alkylating agents, the historical platform, have significantly improved outcomes in the past 10 years. Other non-alkylator induction regimens, essentially lenalidomide plus low-dose dexamethasone are also available and provide a novel backbone that may be combined with novel second- and third-generation drugs. Data indicate that prolonged treatment extends the progression-free survival. In summary, this group requires individualized and dose-modified regimens to improve tolerability and efficacy, while maintaining their quality of life.

Introduction: Several novel proteasome inhibitors (PIs) and immunomodulatory agents (IMIDs) with similar, but not exactly the same, mechanisms of action than their predecessors have been developed in the last years with three different aims: to increase the efficacy; to overcome the resistance and to exhibit a better toxicity profile., Areas Covered: This review summarizes the mechanism of action of novel PIs (carfilzomib, ONX-0912, MLN-9708, marizomib and CEP-18770) and IMIDs (pomalidomide), stressing the similarities and differences with their parental drugs. It also reviews their most updated clinical results. A search of the recent literature in published papers and abstracts from the most important oncology scientific meetings (ASCO and ASH) has been performed., Expert Opinion: Novel PIs and IMIDs show clinical activity as single agents and in combination with dexamethasone, with similar or even higher efficacy than their predecessors; moreover, they may even overcome resistance to their parental drugs, indicating that there are some differences in their mechanisms of action and resistance. The investigation of these mechanisms of resistance and ways to overcome it would allow the optimization of the sequential use of these agents, and the design of novel therapeutic strategies and more appropriate scientifically based combinations.

Melphalan-prednisone (MP) was introduced for the treatment of MM in late 1960s. In the subsequent 30 years, the treatment improvements remained stagnant, since more complex chemotherapy combinations, such as vincristine, doxorubicin, and dexamethasone (VAD), or with the addition of BCNU (VBAD) or melphalan and cyclophosphamide (VCMP), only led to small increases in the overall response rate but without differences in survival, as assessed in a large meta-analysis that included over 6000 patients. The next step forward was the use of high-dose melphalan followed by stem cell support (autologous stem cell transplant - ASCT) for young myeloma patients, which resulted in a significant improvement in disease free survival and overall survival. However, for elderly patients MP remained as the standard of care. From year 2000, a revolution in the treatment armamentarium of MM has emerged with the availability of new agents with singular mechanism of action such as thalidomide and lenalidomide (Revlimid®), both immunomodulatory drugs and the proteasome inhibitor bortezomib (Velcade®).

While in bone marrow allogeneic transplantation the infusion of high doses of progenitor stem cells has a favourable impact on outcome, due to a faster hematopoietic and immune recovery, in the peripheral blood allo-setting the infusion of a high number of CD34 cells increases the risk of extensive chronic graft vs. host disease (cGVHD). This higher incidence of extensive cGVHD has an adverse impact on outcome due to a higher transplant related mortality, specially among patients receiving T-cell depleted allogeneic transplantation with myeloablative conditioning. By contrast, patients undergoing reduced intensity conditioning regimen may benefit from increasing higher CD34 + cell doses, especially those categorized as high risk according to disease status at transplant. Thus, the source of progenitors cells, type of conditioning and GVHD prophylaxis, among other factors, may influence the effect of the progenitor cell dose on outcome after allogeneic transplant.

For many years progress in event free and overall survival in patients diagnosed with multiple myeloma have been modest, however recently newer therapeutic options have become available and, for a small but increasing subset of patients, an "operational cure" can be offered. Although autologous transplantation is associated with a prolongation in event free and overall survival as compared to conventional chemotherapy, there is no plateau in the survival curves. By contrast, the use of allogeneic hematopoietic stem cells provides a tumor-free stem cell source and graft-vs.-myeloma activity leading to a higher frequency of long term survivors in molecular remission. Unfortunately, allogeneic transplantation has been associated with high transplant-related mortality (TRM). Non-myeloablative or reduced intensity conditioning (RIC) regimens, designed to be immunosuppressive rather than myeloablative, in an effort to reduce the toxicity and TRM associated with high dose chemotherapy, but maintaining the GVM effect, have been developed showing up to 90% overall response rate and low TRM. Interestingly, in a significant proportion of patients disease response is preceded by GVHD, suggesting a clear relationship between GVHD and graft vs. myeloma effect. Nevertheless these patients are at risk of developing life threatening complications and, on the contrary, some patients who reach disease control after GVHD and respond to GVHD therapy may finally relapse. Thus, efforts to separate GVM and GVHD are still required in order to improve the outcome of myeloma patients receiving allogeneic transplantation., (Copyright 2004 Taylor and Francis Ltd)

In the present review we analyse the current knowledge about the growth properties of AML progenitor cells and their relationship with other clinico-biological characteristics of the disease. Leukaemic colony forming unit L-CFU is considered to be the clonogenic cell in AML and more immature than the blast cell population. Our studies have shown that in leukaemic hematopoiesis colony forming cells can exist among both cell fractions CD34+ and CD34-. Optimal "in vitro" proliferation of L-CFU is dependent upon the addition of exogenous growth factors. However, it has been observed that leukaemic progenitor cells frequently display a certain degree of autonomous proliferation. In order to quantify the "in vitro" behaviour of L-CFU, we have explored 3 parameters: 1) plating efficiency (PE); 2) autonomous growth (AG); and 3) autonomous proliferative index (API) which was calculated as AG divided by PE and we have correlated them with other clinico-biological data. According to the FAB classification we could observe that patients with M3 subtype showed an higher PE than other AML subgroups and a significantly lower API. Regarding CD34 expression we observed that AG was enhanced in CD34+ cases and also in those showing a higher rh123 elimination. In order to determine whether PE could condition clinical evolution, we analysed this parameter in a large series of patients but failed to demonstrate any relationship. By contrast, we observed that patients who displayed a higher API showed a shorter survival than patients with lower API (18% vs 48% surviving at 3 years). We have also shown that abnormalities in the CFU-GM growth pattern could be associated with risk the of relapse in AML patients; a switch from normal to abnormal "in vitro" growth should alert us. But for the assessment of the real value of these analyses sequential follow-up studies are mandatory. In summary, cell culture studies contribute not only to a better understanding of leukaemic hematopoiesis but may also contribute to better disease monitoring.

The c-kit proto-oncogen (CD 117) has been shown to be present in several cell types including normal and neoplastic hemopoietic cells. Among normal BM cells, CD117 expression has been found in about half of the CD34+ precursors including progenitors committed to the erythroid, granulo-monocytic, and megakaryocytic cell lineages. In addition, strong CD117 expression is detected in bone marrow mast cells as well as in a small subset of NK cells displaying strong reactivity for CD56, and in a relatively important proportion of CD3 /CD4 /CD8 prothymocytes. These results suggest that CD117 expression can be detected in both myeloid and lymphoid lineages although for the lymphoid lineage it would be restricted to a small NK-cell subset and early T-cell precursors. In acute leukemias CD117 expression was initially associated with AML. Nevertheless, at present it is well established that CD 117 expression may also be found in a relatively important proportion of T-ALL while it is usually absent in B-lineage ALL. Moreover, recent studies have shown that in about one-third of multiple myeloma cases and patients with monoclonal gammopathy of undetermined significance plasma cells display reactivity for CD1117. The prognostic influence of CD117 expression has not yet been clearly established. The analysis of this marker may also be of value for the investigation of minimal residual disease (MRD). It has been suggested that CD117 in combination with other antigens may be of great help for the identification of leukemia-associated phenotypes that could be used to monitor MRD in both acute myeloid leukemias and multiple myeloma patients achieving morphological complete remission.

Here the current studies in cell DNA content of plasma cells (PC), from multiple myeloma (MM) patients is reviewed, focusing on two complementary aspects the detection of clonal abnormalities and the identification of the proliferative rate of PC. There is accumulating evidence that the measurement of cell DNA content by flow cytometry (FCM) is a useful parameter in the clinical evaluation of MM patients. Between 50 and 70% of MM patients display DNA aneuploidy, the majority of them being hyperdiploid. Comparing hyperdiploid with diploid patients, the former seem to display a better prognosis. Fluorescence in situ hybridization studies have confirmed that there is a high incidence of numerical chromosome abnormalities in MM and that trisomies are significantly more common than monosomies (84% vs 14%). The most frequent gains can be seen in chromosome 9 and 15 while the most common monosomies are those of chromosome 13 and X in females. The possibility of analysing the cell cycle distribution by using a propidium iodide (PI)/CD38 double staining technique may be an alternative to other more laborious methods of assessing the PC labelling index. Thus, patients with > 3% S-phase PC detected by FCM have an adverse prognosis and this parameter is one of the most important independent prognostic criteria for predicting survival in MM patients. Moreover, the number of S-phase PC, together with other prognostic factors, such as beta 2microglobulin, age and performance status can be a very useful tool for stratifying patients into groups in order to establish risk-directed therapeutic protocols.

Flow cytometry has rapidly expanded from basic research to clinical laboratories mainly due to its unique characteristics regarding cell analysis. Among the clinical uses of flow cytometry cancer represents one of the most relevant. Several applications of flow cytometry can currently be applied to the study of cancer, including the detection of tumour cell DNA aneuploidy, the analysis of tumour cell proliferation and the immunophenotyping of leukemias. Although standardized flow cytometry protocols for these applications are scanty, the clinical value has been clearly established. The presence of DNA aneuploidy and a high proportion of S-phase tumour cells have been associated with tumour malignancy and a poor prognosis. The immunophenotype of leukaemia is of great help both for the diagnosis and classification of chronic lymphoproliferative disorders and acute leukaemias, especially in acute lymphoblastic leukemia cases and the M0, M3-variant, M6 and M7 acute myeloblastic leukaemia subtypes. In addition, it allows the identification of relatively rare leukemia cases such as the biphenotypic and the Nk-cell lineage leukemias. The development of flow cytometry is continuously bringing new applications into the clinical laboratory in the area of cancer diagnosis.

In the present study the usefulness of a method combining multiple staining direct immunofluorescence technique together with flow cytometry in order to predict relapse in ALL is analyzed in a group of 47 patients (11 T-ALL and 36 B-ALL). Results show that this method can be applied to at least two-thirds of all ALL patients being specially useful for the T-ALL cases (100% vs 56%) as this corresponding to the incidence of "aberrant" phenotypes. The detection of an increase in the percentage of bone marrow cells displaying "aberrant" phenotypes in two consecutive samples from the same patient is of great help on predicting relapse (sensitivity of 92% and specificity of 75%).