Targeted radioimmunotherapy with 90Y-labeled ibritumomab tiuxetan is a novel therapeutic approach for CD20-positive relapsed or refractory non-Hodgkin lymphoma (NHL). Methods: Seven consecutive patients with CD20-positive aggressive NHL who did not fully respond to prior myeloablative chemotherapy were enrolled. A 14.8 MBq (0.4 mCi)/kg dose of 90Y-ibritumomab tiuxetan was administered to all patients, and approximately 100 d afterward 18F-FDG PET/CT was performed to assess response. Results: PET/CT showed a complete response in 5 of 7 patients. Of the 2 nonresponsive patients, 1 showed persistent disease and the other progression. Toxicity included thrombocytopenia in all 7 patients and grade IV neutropenic fever in 1 patient. Conclusion: Despite the small series studied, we suggest that radioimmunotherapy is safe for consolidation in patients treated with high-dose chemotherapy for aggressive NHL and may provide clinical benefit in extensively pretreated patients.

Angiogenesis is a constant hallmark of multiple myeloma progression and has prognostic potential. Multiple myeloma cells interact with surrounding host cells and extracellular matrix, this crosstalk affecting the most important aspects of the malignant phenotype, both at primary and secondary tumor sites. The pathophysiology of multiple myeloma-induced angiogenesis involves both direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment cells. A direct involvement of bone marrow macrophages and mast cells in vasculogenic mimicry has been demonstrated, thus contributing together with circulating endothelial cells and endothelial precursor cells to the multiple myeloma neovascularization. The role of host cells or the niche microenvironment and extracellular matrix represents an intense area of research, finalized at a better understanding of the pathophysiological modifications of the complete tumor entity, i.e. malignant cells and microenvironment

Multiple myeloma plasma cells home and expand in the bone marrow where cause an unbalanced bone remodelling with increased bone resorption and low bone formation that represent the typical feature in the majority of patients. A clinically relevant aspect of the interactions of multiple myeloma plasma cells in the bone marrow microenvironment is neovascularization, a constant hallmark of disease progression. This process is only partially supported by factors such as vascular endothelial growth factor, fibroblast growth factor-2 and metalloproteinases, which are directly secreted by the tumor cells. In fact, the presence in the bone marrow microenvironment of cytokines, in particular interleukin-6, as a consequence of plasma cell-stromal cell interactions, induces the production and secretion of angiogenic factors by other cells present in the bone microenvironment, thus contributing to the angiogenic switch during the progression of the disease. Near angiogenesis vasculogenesis occur in the bone marrow of myeloma patients and contribute to the vascular three formation. In the bone marrow of myeloma patients haematopoietic stem cells are recruited and induced to differentiate into endothelial cells by the angiogenic cytokines present in the microenvironment. Myeloma plasma cells also induce angiogenesis indirectly via recruitment and activation of stromal inflammatory cells (i.e.: macrophages and mast cells) to secrete their own angiogenic factors. They are recruited and activated by tumor plasma cells through the secretion of fibroblast growth factor-2, interleukin-8, and other chemokines, such as ITAC, Mig, IP-10. When macrophages and mast cells are activated they secrete their angiogenic factors: fibroblast growth factor-2, vascular endothelial growth factor, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, which contribute to enhance the tumor neovascularization. Finally, myeloma macrophages when exposed to vascular endothelial growth factor and fibroblast growth factor-2 secreted by plasma cells shows vasculogenic ability and acquire endothelial cell markers and transform into cells functionally and phenotypically similar to paired bone marrow endothelial cells. So they participate to the formation of the bone marrow capillary network (vasculogenic mimicry).

N/A

Multiple myeloma is a plasma cell tumor that homes to and expands in the bone marrow and that, despite the new available drugs, remains incurable. Extramedullary plasmacytoma is a not frequent manifestation during the natural history of multiple myeloma and is frequently associated with plasma cell bone marrow infiltration. The most common locations for an EMP include the gastrointestinal tract, pleura, testis, skin, peritoneum, liver, endocrine glands, and lymph nodes. Primary involvement of the gallbladder fossa is exceedingly rare. In this report, we describe a patient with multiple myeloma who achieved a clinical and serological remission after autologous transplant but progressed rapidly at extramedullary site mimicking a second cancer (i.e., pancreatic or biliary cancer). In this case, the extramedullary localization was refractory to standard therapy, differently from bone marrow localization, but responded to lymphoma-like therapy. In this patient (i) the particular site of developing plasmacytoma is the gallbladder fossa, (ii) the timing of onset of this neoplasm is immediately after autologous transplant, and (iii) its disjunction from primary myeloma is that it appears in clinical and serological remission phase which may be confounding during the diagnostic approach simulating a different tumor (solid tumor).

Multiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells (CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activates stemness signaling (Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs.

Therapeutic re-challenge is currently a debated issue in the field of multiple myeloma (MM), given the recent availability of several new drugs and combinations. However, very few specific evidences are available about bortezomib re-use at first relapse. This multicenter, observational, retrospective study enrolled 134 MM patients with significant response after bortezomib-based frontline regimens and who had received a first salvage treatment containing bortezomib at relapse. The overall response rate was 71%, including 40% partial responses, 24% very good partial responses, and 7% complete responses. Re-treatment was well-tolerated, with no significant new or unexpected toxicities observed. The median duration of second progression-free survival (PFS) was 15 months, while median PFS2 was 55 months. With a median follow-up of 56 months, overall survival was 94 months for the entire series, without significant differences between patients undergoing or not undergoing transplant procedures. This real-life survey indicates that re-treatment including bortezomib as a first salvage therapy could be still considered in MM patients achieving durable response after initial exposure to bortezomib.

Multiple myeloma still remains an incurable disease with a high incidence rate in the elderly. Near the old active classes of drugs: alkylators (e.g., melphalan and cyclophosphamide), corticosteroids (e.g., prednisone and dexamethasone), and anthracyclines (e.g., doxorubicin), new drug formulations (e.g., liposomal doxorubicin) and new active classes of drugs such as proteasome inhibitors (e.g., bortezomib) and immunomodulatory drugs (e.g., thalidomide and lenalidomide) have been introduced in myeloma therapy. The high heterogeneity of this disease leads to large differences in clinical responses to treatments. High response rates and good quality responses with a long-term disease control can be observed with the introduction of new drugs. Changes in treatment strategies due to the introduction of novel drugs have been able to improve significantly the quality of responses. In fact, if in the past, Complete Remission (CR) in MM was rare to achieve, while the introduction of new treatments have increased the rate in younger patients as well as in non-transplant setting. CR represents a surrogated marker of long survival. It correlates with the long-term Progression-Free Survival (PFS) and Overall Survival (OS). Achieving CR and sustaining CR within a 3-year landmark from the treatment initiation is associated with highly superior survival. Actually, we agree that ―The more profound the remission, the longer the duration of response‖. Moreover, the interactions between tumor cells and their bone marrow microenvironment play a pivotal role in myeloma progression, inducing also drug resistance. This knowledge has improved treatment options leading to the approval of new drugs which target the malignant cell itself and also its microenvironment. These agents are in preclinical/early clinical evaluation and they appear to further improve disease control but their use is still not approved outside of clinical trials.

This review summarizes the therapeutic strategies and the drugs actually in development for the management of myeloma patients. Multiple myeloma is caused by the expansion of monoclonal plasma cells and secretion of M-protein (immunoglobulins, Bence Jones protein and free light chains). Multiple myeloma still remains an incurable disease with a high incidence rate in the elderly, despite the introduction of several new therapeutic agents (bortezomib, lenalidomide and thalidomide) which have changed its natural history. The high heterogeneity of this disease leads to large differences in clinical responses to treatments. Thus, the choice of the best treatment is a difficult issue. However, the introduction of new drugs has made it possible to achieve high response rates and good quality responses with long-term disease control. Interactions between tumor cells and their bone marrow microenvironment play a pivotal role in the development, maintenance, and progression of myeloma, inducing also drug resistance. These knowledges have improved treatment options, leading to the approval of new drugs which not only target the malignant cell itself, but also its microenvironment. These agents are in preclinical/early clinical evaluation and they appear to further improve disease control, but their use is still not approved outside of clinical trials.

Pentraxin 3 (PTX3) is a soluble pattern recognition receptor that binds with high affinity and selectivity to fibroblast growth factor-2 (FGF2), thus inhibiting its pro-angiogenic activity. Here we investigated the effects of PTX3 on monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patient-derived bone marrow (BM) plasma cells (PCs), endothelial cells (ECs), and fibroblasts (FBs), and assessed whether PTX3 can modulate the cross-talk between PCs and those microenvironment cells. PTX3 and FGF2 expression was evaluated by ELISA. Functional studies, including cell viability, wound healing, chemotaxis, and Matrigel(®) assays, were performed on MGUS and MM ECs and FBs upon the PTX3 treatment. Through western blot PTX3-induced modulation in FGF2/FGF receptor signalling pathways was evaluated in MGUS and MM ECs and FBs through western blot. Co-cultures between MM ECs/FBs and human PC lines were used to evaluate possible PTX3 indirect effects on MM PCs. Adhesion molecules were studied by flow cytometry. PTX3 provides a direct time- and dose-dependent apoptotic effect on MM ECs and FBs, but not on either MM primary PCs or human PC lines. PTX3 inhibits migration of MM ECs and FBs in a dose-dependent manner, and impacts in vitro and in vivo FGF2-mediated MM angiogenesis. Co-cultures of PCs and ECs/FBs show that PTX3 treatment indirectly impairs PC viability and adhesion. We conclude that PTX3 is an anti-angiogenic factor in MM and behaves as a cytotoxic molecule on MM cells by inhibiting the cross-talk between PCs and ECs/FBs

Autologous stem cell transplantation (ASCT) is considered the standard therapy for younger patients with newly diagnosed symptomatic multiple myeloma (MM). The introduction into clinical practice of novel agents (i.e.: proteasome inhibitors and immunomodulatory derivatives [IMiDs]) has significantly contributed to major advances in MM therapy and prognosis. These novel agents are incorporated into induction regimens to enhance the depth of response before ASCT and further improve post-ASCT outcomes. Collection of adequate hematopoietic stem cells (HSCs) is necessary for successful autologous transplantation. The mobilizing regimen usually consists of cyclophosphamide or disease-specific agents, in combination with a hematopoietic cytokine, usually G-CSF, which mobilizes HPSCs into the bloodstream, in particular when administered after myelosuppressive chemotherapy. In some patients, the number of mobilized CD34+ cells is not sufficient to perform successful stem cell transplantation due to bone marrow damage by neoplastic proliferation and/or chemoradiotherapy. To improve the collection of CD34+ cells, the mobilization procedure can be repeated or an alternative chemotherapy regimen can be chosen. Recently, the new drug plerixafor (Mozobil®) has been introduced to increase the number of circulating CD34+ cells. Its use increases the level of functional HPCs in the peripheral blood, with long-term resettlement

We assessed efficacy, safety, and reversal of renal impairment (RI) in untreated patients with multiple myeloma given bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide (VMPT-VT) maintenance or bortezomib-melphalan-prednisone (VMP). Exclusion criteria included serum creatinine ≥ 2.5 mg/dL. In the VMPT-VT/VMP arms, severe RI (estimated glomerular filtration rate [eGFR] ≤ 30 mL/min), moderate RI (eGFR 31-50 mL/min), and normal renal function (eGFR > 50 mL/min), were 6%/7.9%, 24.1%/24.9%, and 69.8%/67.2%, respectively. Statistically significant improvements in overall response rates and progression-free survival were observed in VMPT-VT versus VMP arms across renal cohorts, except in severe RI patients. In the VMPT group, severe RI reduced overall survival (OS). RI was reversed in 16/63 (25.4%) patients receiving VMPT-VT versus 31/77 (40.3%) receiving VMP. Multivariate analysis showed male sex (P = .022) and moderate RI (P = .003) significantly predicted RI recovery. VMP patients achieving renal response showed longer OS. In both arms, greater rates of severe hematologic adverse events were associated with RI (eGFR < 50 mL/min), however, therapy discontinuation rates were unaffected. VMPT-VT was superior to VMP for cases with normal renal function and moderate RI, whereas VMPT-VT failed to outperform VMP in patients with severe RI, although the relatively low number of cases analyzed preclude drawing definitive conclusions. VMPT-VT had no advantage in terms of RI reversal over VMP

The growth, survival and proliferation of cancer cells are guaranteed by a crosstalk between cancer cells themselves and surrounding host cells and extracellular matrix. An intense area of research has contributed to a better understanding of the pathophysiological modification of tumor progression, e.g., the role of microenvironment. Multiple Myeloma (MM) is a malignancy of immunoglobulin-synthesizing plasma cells with symptoms mainly related to imbalance of bone homeostasis, kidney damage, anemia, impaired humoral immunity, and sometimes nervous system dysfunctions. Plasma cells home and expand in the bone marrow where cause an unbalanced bone remodelling with increased bone resorption and low bone formation that represent the typical feature in the majority of patients. MM plasma cells are thought to be responsible for the osteolytic bone lesions, which occur by increased osteoclast formation/activity and inhibition of osteoblast formation/differentiation. In physiological conditions, this process is critically regulated by the transcription factor Runx2 and by the Wnt signaling pathway. Moreover, MM plasma cells accelerate the differentiation of resident macrophages to osteoclasts. Finally, plasma cells themselves can transdifferentiate to functional osteoclasts. Another relevant aspect of the interactions of MM plasma cells with stromal cells in the bone marrow microenvironment is neovascularization, a constant hallmark of disease progression. MM plasma cells induce angiogenesis both directly, via their own factors (vascular endothelial growth factor [VEGF], fibroblast growth factor-2 [FGF-2], hepatocyte growth factor [HGF] and metalloproteinases), and indirectly via recruitment and activation of stromal inflammatory cells to secrete their own angiogenic factors. Macrophages and mast cells play an important role in this sense. They are recruited and activated by tumor plasma cells through the secretion of FGF-2, interleukin-8 (IL-8) and chemokines, such as ITAC, Mig, IP-10. When macrophages and mast cells are activated they secrete potent angiogenic factors (FGF-2, VEGF, granulocyte-colony stimulating factor [G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF]), which contribute to the tumor neovascularization. Recent evidence demonstrates the vasculogenic ability of active MM macrophages exposed to VEGF and FGF-2, the major angiogenic cytokines secreted by plasma cells, and present in the bone marrow microenvironment at four-to five-fold higher levels than in peripheral blood. Under these stimuli, bone marrow macrophages acquire endothelial cell (EC) markers and transform into cells functionally and phenotypically similar to paired bone marrow ECs (MM patient-derived endothelial cells, MMECs). So they generate capillary-like networks mimicking those of MMECs. Thus, MM macrophages contribute to build the neovessel wall via a “vasculogenic mimicry”, hence helping MM progression by this way.