Josefina Udi

Consensus statement from European experts on the diagnosis, management, and treatment of multiple myeloma: from standard therapy to novel approaches

Treatment for multiple myeloma (MM) has changed beyond recognition over the past two decades. During the early 1980s, MM inevitably resulted in a slow progressive decline in quality of life until death after about 2 years, while today patients can expect a 50% chance of achieving a complete remission, median survival of 5 years, and a 20% chance of surviving longer than 10 years. An international expert opinion meeting (including members of the GIMEMA and DSMM study groups) was held in 2009. One of the outcomes of the meeting was the development of a consensus statement outlining contemporary optimal clinical practice for the treatment of MM. The international panel recommended that the state of the art therapy for MM should comprise: (a) evidence-based supportive care, (b) effective and well-tolerated chemotherapeutic regimens, (c) autologous hematopoietic stem cell transplant (ASCT) for patients suitable for intensive conditioning therapy, and (d) evidence-based incorporation of novel anti-MM agents. Maintenance strategies have also become increasingly important for the prolongation of remission after front-line therapies. In addition, improved understanding of the biology of MM has led to the development of novel biological therapeutic agents such as thalidomide, lenalidomide, bortezomib, and others. These agents specifically target intracellular mechanisms and interactions, such as those within the bone marrow microenvironment, and have been integrated into MM treatment. This report reviews recent clinical advances in the treatment strategies available for MM and provides an overview of the state of the art management of patients with MM.

Potent in vitro and in vivo activity of sorafenib in multiple myeloma: induction of cell death, CD138-downregulation and inhibition of migration through actin depolymerization.

Despite considerable advances, multiple myeloma (MM) remains incurable and the development of novel therapies targeting the interplay between plasma cells (PCs) and their bone marrow (BM) microenvironment remains essential. We investigated the effect of various agents in vitro on the proliferation, phenotype, morphology, actin polymerization and migration of MM cells and, in vivo, the tumour growth of L363‐bearing non‐obese diabetic severe combined immunodeficient mice with a deficient interleukin‐2 receptor gamma chain (NSG). In vitro, we observed a dose‐dependent cytotoxicity with bortezomib and sorafenib. Using RPMI8226 cells co‐expressing histone 2B‐mCherry and cytochrome c‐GFP, bortezomib‐ and sorafenib‐induced apoptosis was confirmed, and both agents combined showed synergism. Sorafenib induced CD138‐downregulation and abolished CXCL12‐induced actin polymerization. L363 cells expressed CCR4 and CCR5 and migrated to their common ligand CCL5. Chemotaxis to BM stroma cells was notable and significantly reduced by sorafenib. Downregulation of phospho‐ERK appeared relevant for the inhibition of actin polymerization and chemotaxis. Sorafenib alone, and combined with bortezomib, showed substantial antitumour activity in L363‐bearing NSG. Correspondingly, sorafenib induced clinical responses in MM‐/AL‐amyloidosis patients. We conclude that, in addition to the cytotoxic and anti‐angiogenic effects of sorafenib, blocking of MM cell migration and homing represent promising mechanisms to interrupt the interplay between PCs and their supportive microenvironment.

Prognostic Risk Factor Evaluation in Patients With Relapsed or Refractory Multiple Myeloma Receiving Lenalidomide Treatment: Analysis of Renal Function by eGFR and of Additional Comorbidities by Comorbidity Appraisal

INTRODUCTION Renal impairment (RI) is a dreaded complication in multiple myeloma (MM) and has been associated with decreased progression-free survival (PFS) and overall survival (OS). METHODS Forty-five consecutive patients with MM received lenalidomide therapy combined with either dexamethasone or standard chemotherapy, with dose modification according to current guidelines. Comorbidity indices (hematopoietic cell transplantation-specific comorbidity index [HCT-CI], Kaplan Feinstein [KF], and the Freiburg comorbidity index [FCI]) were analyzed and renal function was determined by estimated glomerular filtration rate (eGFR) before lenalidomide treatment and 1, 3, and 6 months after treatment. RESULTS The median patient age was 66 years. Pretreatment was substantial with ≥ 2 treatment lines in 71% of patients. Lenalidomide induced median PFS and OS of 13 and 25 months, respectively. The analysis of comorbidity scores identified only the FCI as significant, with different PFS for low-risk vs. high-risk patients of 20 vs. 9 months (p = .0036) and OS of not reached vs. 12.8 months (p < .0001), respectively. Although baseline renal function by serum creatinine evaluation appeared normal (median 1.0 mg/dL), mild RI was readily detectable by eGFR (median 83 mL/min/1.73 m(2)). When patients without RI were compared with those with mild, moderate, and severe RI, 1- and 2-year PFS rates were similar (hazard ratio [HR] with decreasing eGFR, 1.028; p = .6927). For OS, the HR of 1.192 indicated decreased survival probabilities with deteriorating eGFR (p = .0411), which was perceived by eGFR but not serum creatinine assessment (p = .2253). CONCLUSIONS Lenalidomide was well tolerated in intensively pretreated and elderly MM patients, including those with RI. PFS was not significantly different in patients with decreasing eGFRs, albeit RI and other comorbidities remained significant for OS.

European Myeloma Network: the 3rd Trialist Forum Consensus Statement from the European experts meeting on multiple myeloma

Over the past two decades, not only treatment options, but also the diagnosis, staging, and risk assessment of multiple myeloma (MM), have undergone significant development, partially due to a deeper understanding of MM pathogenesis. Conventional cytogenetics and fluorescence in situ hybridization are routinely assessed in MM, and when combined with ISS stage may attain an even better predictive potential. In order to achieve even more effective and individualized therapies, one crucial goal is the identification of genes and gene combinations that predict for response or resistance to chemotherapy. High-dose chemotherapy with autologous stem cell transplant (SCT) still remains the standard therapy for younger patients, with novel agents now being included in both pre-transplant regimens and post-transplant consolidation/maintenance approaches. Similarly, novel agents are also being incorporated into allogeneic SCT for selected patients. In the treatment of elderly patients with MM, novel agents have been successfully incorporated into less intensive regimens, including melphalan/prednisone, low-dose dexamethasone, and cyclophosphamide/dexamethasone. While second-generation proteasome inhibitors are currently being intensively investigated, the subcutaneous administration of bortezomib, being equivalent to the established i.v. route, is now entering clinical practice. Supportive care remains a crucial aspect in the management of MM. The European Myeloma Network Trialist Group aims to address these contemporary aspects in MM.

Challenging the current approaches to multiple myeloma- and other cancer-related bone diseases: from bisphosphonates to targeted therapy

An international myeloma meeting entitled “Challenging the current approaches to multiple myeloma- and other cancer-related bone diseases: from bisphosphonates to targeted therapy” was held in Freiburg, Germany in July 2011 to discuss novel insights into and approaches to myeloma bone disease and other bone-seeking tumors. This review briefly summarizes the most prominent data of the meeting and current literature on our understanding of bone disease, the role of imaging techniques, operative interventions and systemic bone-seeking treatment, all of which should further improve our future therapeutic choices.

Early and mature endothelial progenitors and VEGFR2+-cells in multiple myeloma: Association with disease characteristics and variation in different cell compartments

We analyzed (1) early endothelial progenitors (EPCs; CD34(+)/AC133(+)/VEGFR2(+)), mature EPCs (CD34(+)/VEGFR2(+)) and VEGFR2(+)-cells in bone marrow (BM)-specimens of multiple myeloma (MM)- vs. monoclonal gammopathy (MGUS)-patients and healthy controls; (2) differences of BM-, peripheral blood (PB)- and leukapheresis (LP)-samples; and (3) the association of EPCs and VEGFR2(+)-cells with MM-parameters. MM patients demonstrated highest early and mature EPCs and VEGFR2(+)-cells in the BM, particularly with advanced and active disease. Endothelial cells differed in BM-, PB- and LP-specimens, albeit seemed less associated with unfavorable prognostic MM-parameters. Our data suggest that especially VEGFR2(+)-cells and mature EPCs in MM are of value to explore further.

BubR1 is frequently repressed in acute myeloid leukemia and its re-expression sensitizes cells to antimitotic therapy.

Spindle poison-based therapy is of only limited benefit in acute myeloid leukemia while lymphoblastic leukemia/lymphoma responds well. In this study, we demonstrated that the spindle assembly checkpoint protein BubR1 was down-regulated in the vast majority of cases of acute myeloid leukemia whereas its expression was high in lymphoblastic cells. Correct function of the spindle assembly checkpoint is pivotal in mediating mitotic delay in response to spindle poisons. Mitotic delay by the spindle assembly checkpoint is achieved by inhibition of anaphase-promoting complex-dependent proteolysis of cyclin B and securin. We demonstrated a link between the repression of the spindle assembly checkpoint protein BubR1 in acute myeloid leukemia and the limited response to spindle poison. In accordance with its established role as an anaphase-promoting complex-inhibitor, we found that repression of BubR1 was associated with enhanced anaphase-promoting complex activity and cyclin B and securin degradation, which leads to premature sister-chromatid separation and failure to sustain a mitotic arrest. This suggests that repression of BubR1 in acute myeloid leukemia renders the spindle assembly checkpoint-mediated inhibition of the anaphase-promoting complex insufficient, which facilitates completion of mitosis in the presence of spindle poison. As both direct and BubR1-mediated restoration of cyclin B expression enhanced response to spindle poison, we propose that the downstream axis of the spindle assembly checkpoint is a promising target for tailored therapies for acute myeloid leukemia.

Does colorectal cancer in ulcerative colitis patients constitute a risk for chemotherapy refractoriness?:a systemic approach by detailed analysis via the electronic tumor base documentation system.

Background: Ulcerative colitis (UC) patients may develop colorectal cancer (CRC), especially with pancolitis and longer UC duration. The question whether CRC with underlying UC has a dismal prognosis remains unsettled. Patients and Methods: We performed an electronic tumor base documentation (eTBD) search of CRC and UC patients at our department to address whether (1) CRC prognosis is impaired and (2) defined risks can be determined. Results: With the inclusion of an index patient with UC and unresponsive CRC, 20 additional patients were identified via eTBD. Chemotherapy response was less substantial, with complete response or stable disease in 3 patients each, but rapidly progressing or refractory disease in 15/21 patients. 12 out of the 21 patients died. Our hazard ratio analysis revealed International Union against Cancer (UICC) stage IV and III disease, grade 3 tumors, longer latency from UC to CRC and age >60 years as potential risks. Median progression-free survival and overall survival were 48 and 82 months, respectively. Time from tumor dissemination to death was 10 months. Conclusions: The prognosis of CRC in UC patients is not necessarily impaired, albeit chemotherapy response with disseminated disease may be unfavorable. Our data should be enlarged by subsequent analyses to better elucidate whether response in UC and CRC is more challenging and defined risks can be confirmed.

Interplay of parathyroid hormone-related peptide (PTHrP), renal insufficiency and bulky disease in the pathogenesis of hypercalcemia in Hodgkin’s lymphoma (HL)

Hypercalcemia is most commonly attributed to malignancies with up to 30% of patients with cancer developing this complication during the course of their disease. Two mechanisms can be distinguished: metastatic and non-metastatic hypercalcemia: In metastatic hypercalcemia, bone or bone marrow (BM) are directly affected by tumor infiltration, leading to osteoclast-induced bone resorption. In non-metastatic hypercalcemia, humoral factors are secreted by tumor cells, this being predominantly observed in solid tumors (ST) or T-cell malignancies (TCM). Typical mediators of humorally induced hypercalcemia are parathyroid hormone (PTH)-like substances (PTHrP), vitamin D metabolites, and diverse lymphokines. In ST and TCM, PTHrP has been shown to be the main mediator, whereas vitamin D3 was mostly responsible in the rare cases of humorally mediated hypercalcemia in NHL and Hodgkin’s lymphoma (HL). PTHrP is widely expressed in normal and malignant tissues and may act as a paracrine or autocrine factor. PTHrP shares many actions with PTH leading to increased calcium release from bone, reduced renal calcium excretion, and reduced renal phosphate reabsorption. We illustrate the rare case of a patient with HL showing PTHrP-associated hypercalcemia without evidence of bone lesions or BM infiltration: this 55-yr-old gentleman was admitted because of rapidly deteriorating health. He complained about intense upper abdominal pain, dry cough, night sweats, but no fever. Physical examination revealed large abdominal masses and hepatosplenomegaly and laboratory findings hypercalcemia and hypophosphatemia. Notably, PTH levels were decreased, vitamin D3 was normal, and serum creatinine increased (Fig. 1A,B). Via liver biopsy, the diagnosis of classical HL was obtained, thereby allowing the PTHrP analysis in infiltrating Hodgkin and Reed-Sternberg cells (HRSC). In our patient, the prominent cytoplasmatic PTHrP expression could be identified by means of immunohistochemistry (IHC; Fig. 1C). As typically described in rare cases of hepatic HL infiltrates, HRSC were only few and far within the infiltrate of inflammatory lymphocytes and histiocytes. Of note, no PTHrP expression was detected in liver-infiltrating HRSC of normocalcemic control HL patients (Fig. 1D) and unaffected liver tissue (Fig. 1E). BM involvement was repetitively excluded (Fig. 1F,G). Magnetic resonance imaging (MRI) and computed tomography (CT) scans showed extensive HL manifestations in liver, spleen, and mesenterial, mediastinal, retromandibular and submandibular lymph nodes (Fig. 1H–J). The patient was sufficiently hydrated and received bisphosphonates which resulted in normalization of plasma calcium and phosphate levels. Renal function also improved (Fig. 1A,B). Because of high-risk, stage IVB HL, chemotherapy (CTx) was rapidly initiated (BEACOPP). While on CTx, creatinine levels dropped, albeit full normalization of renal function was not accomplished until completion of the 6th BEACOPP cycle and achievement of complete remission (Fig. 1B,K– M) which has been ongoing for 41 months. In conclusion, we provide solid support for the IHCverified PTHrP secretion of liver-infiltrating HRSC and the metabolic disorder. We believe that the IHC-assisted PTHrP detection, as well as analysis of serum PTHrP concentrations, may be helpful for the differential diagnosis of hypercalcemia in patients with lymphoma, including HL. We postulate a pathogenetic role of HLinduced cell production and secretion of PTHrP in hypercalcemia.