 Buongiorni. I'd like to thank the organiser for the opportunity to be here today with you. I'm Paolo Milani and I'm consultant at the Amilioidosis Research and Treatment Centre of Pavia, Italy. And I'm going to talk with you about myeloma-related diseases. So, thank you again. Those are my main disclosure. So, we have to talk about myeloma-related diseases. And so, I would like to start with the definition of the so-called monoclonal gamopathy of clinical significance. This is an important emerging field in the plasma-cell dyscrasia field, in the plasma-cell disc amongst the plasma-cell dyscrasia experts and so also patients. Those conditions are characterized by the fact that they are small, dangerous, greeting-be-cell clone as proposed by mentor-professor Milani late in 2006. Plus, related symptoms. Three are the main characteristics, the presence of monoclonal gamopathy, the presence of no over-associated cancers or lympho or plasma-cell proliferation. And associated symptoms. And we will look into that closely. In the last few years, many papers reported, first of all, the importance of the so-called monoclonal gamopathy of renal significance, the so-called MGRS. And then, the most founded, the International Kidney, a monoclonal gamopathy research group that involves clinicians, but also pathologists, nephrologists, hematologists, and all the experts involved in the diagnosis and treatment in those myeloma-related disorders. And Professor Ferman, few years ago, defined the monoclonal gamopathy of clinical significance, so the definition of those different conditions. The first definition is related to the presence of renal involvement only, so those conditions that are mainly monoclonal gamopathy of renal significance, those with renal, but also systemic involvement, so the presence of also other organs involved, and those with usually without renal involvement, so those conditions with only extra-renal manifestation. We will look through most of those conditions that are all myeloma-related disorders. And Dr. Angela Dispencieri, my mentor when I was in U.S. a few years ago, had an extraordinary lecture at the last American Society ofematology meeting in 2020. She described the monoclonal gamopathies of clinical significance, and we are going to talk of most of those conditions. We, I will not focus on the light-chain AL amyloidosis in my presentation because Professor Minema already gave us extraordinary lecture. And so I would like to focus about the kidney-related disease, so the so-called monoclonal gamopathy of renal significant disease, the MGRS. Those situations have plasma cell disorder or a B cell disorder that does not meet the current criteria for immediate treatment, so in all those situations patients will not require immediate chemotherapy. But this clone produces a nephrotoxic light-chain, a nephrotoxic monoclonal immunoglobulin that could create direct damage to the kidney or other organs. Those conditions are characterized by the presence of a non-response to immunosuppressive regimens or other regimens that are usually used for other gomerulopathies. All the affected patients have a very high rate of recurrence after kidney transplant. Obviously, in those cases in which the disease is not recognized and the patient received immediate transplant without an effective chemotherapy. And lastly, affected patients are at risk for progression to the corresponding immunological cancer. So all of them needs to be tested and followed by immunologists in order to exclude the presence of a progression to the corresponding immunological diseases. This is the histological classification proposed by the EMG group based on the fact that immunoglobulins are deposited in different homes in organized deposits or non-organized deposits. And here we have the main clinical picture of those conditions. As mentioned, I will not focus on AL amyloidosis that is probably one of the most important MGRS in characterized with the so-called organized deposits. The other forms are much rarer and are the monoclonally monocloctal gomerulopathies and the type 1 crealglobulinemic gomerulopathies, characterized by different behavioral proteinuria, nephrotic syndrome in different personages, and extremely rarer extra-renal manifestations. For those MGRS with non-organized deposits, the most important are the so-called MITD, monoclonal immunoglobulin deposition diseases. Most important of this group is the light chain deposition disease, and then we have heavy chain or light and heavy chain deposition disease. This condition is characterized by the presence of a proteinuria that is less abundant compared to light chain AL amyloidosis, a nephrotic syndrome that is less important, and the presence of hypertension and imaturia in most of the patients. Extra-renal manifestations are rare, but really important to be defined, and they are mostly related to hepatic and cardiac manifestations. MGRS represent the majority of patients, approximately 80% of patients have a monoclonal gamapathy of ring, a significant so-known myeloma clone, but almost 30% of patients could have a myeloma. Then we have also a rarer condition, the PGN-MID, with an heavier proteinuria compared to LCDD and known extra-renal manifestations, and also the C-triegel myelopathy that also have no extra-renal diseases. Looking particularly at LCDD, I had the pleasure to guide an international effort in order to collect data about patients with LCDD all around the globe. At ASH last year, I presented a poster with the first data analysis of 359 patients with light chain deposition disease. This is the larger, serious report so far. The main characteristics are that patients have a low plasma cell burden, a median of plasma cell infiltration of 10%, and in most of the cases, the patients had already had diagnosis of advanced renal disease. The most frequent treatment type is vortex-me-base in approximately 50% of patients. The overall survival of this patient is quite good, and it is important to note that predicting factors on survivors are the presence of end-stage renal diseases and the presence of a high plasma cell burden, a diagnosis. Most important is the renal survival, so the time to dialysis in those patients. And the most important predictors and independent predictors of renal survival are the presence of a heavy proteinuria in the nephrotic range and an advanced renal disease and diagnosis is not. So, in addition, we also found that obtaining a complete remission or a very good partial remission that our goal of treatment that represent the profound reduction of pre-light chain of monoclonal component is associated with a significantly better overall survival in our patient's core compared to obtaining only a mild reduction or a non-response to therapy. Renal survival is also associated with obtaining a complete remission or a very good partial remission. So, the conclusion of this first analysis was that the degree of proteinuria and bone marrow plasma cell infiltration predict renal and overall survival and that obtaining a profound reduction of the monotoxic immunoglobulin defined by the complete remission or very good partial response after treatment could predict renal and organ survival. Now, I'm going to have the final results, final analysis of more than 460 patients and I hope to do this analysis soon. Moving to other myeloma-related diseases, we have to look at those related to peripheral neuropathy, peripheral nervous system involved. One of the most important is the so-called palm syndrome characterized by the presence of follinear apathy, organomegaly, endocrinopathy, monoclonal component and skin changes. Those are the mandatory criteria defined every year by doctor dispensary. A combination of those criteria allow you to gain the final diagnosis. Neuropathy is characterized as a subacute distal symmetric sensory motor neuropathy. Sensory syndrome usually precede motor symptoms and many patients quickly unfortunately become wheelchair or bed bound dependent. So it is important to rapidly recognize these diseases. Another important issue is the presence of osteosclerotic bone lesions, so a skeletal survey is mandatory. And we have several minor criteria as mentioned, the organomegaly, the presence of endocrinopathy and the presence of thrombocytosis that are also important minor criteria that have to be combined with the mandatory and major criteria. And we could have specific skin changes related to this condition. This is a picture of one of our recent patient diagnosed with thrombos syndrome here in Padilla. So this condition is really difficult to identify, but we could use this important criteria in order to get the final diagnosis and specific therapy. Moving to other diseases are those related to the skin. These are rare condition. Scleromixedema is important. Build 4 for criteria are mandatory. Presence of popular cutaneous erection-specific histological manifestation, the presence of monoclonal gamopathy obviously in the absence of thyroid dysfunction. Another important but rare condition is this Knitzler syndrome characterized by the presence of othicaria rash in the IgM monoclonal component with other two signs that mostly are related to thiva and increase the seriative protein. Another important skin-related disorder is the Tempi syndrome defined by the presence of Terengectasia-elevated aerotropolthane, monoclonal gamopathy and periphery necrotic fluid collection. A rare condition is acquired crutic slaksa, characterized by loose redundant hypoelastic skin and other manifestation. Obviously for those conditions a specific dermatologic consultation is mandatory and also specific histological evaluation. For all the monoclonal gamopathy of clinical significance, earleg diagnosis has a key role. So a careful clinical work cut at the baseline evaluation of all those patients with the monoclonal gamopathy of undetermined significance is really important. We have to look at renal and extra renal manifestation. We have to search for proteinuria in all our patients with amgas. We have to check for renal function and serum cardiac biomarkers that are important in order to exclude cardiac diseases, but also cardiac amyloidosis and cardiac disease related to LCDD, for example. Cardiac imaging will be required in suspected cases. Laboratory is important. We have obviously to identify our monoclonal component with serum and urine immunofixation and free light chain measurement that are mandatory. It is not detected monoclonal protein, but we may now use more sensitive techniques. Mass spectrometry of serum and urine, we hope to have this technique here in Padilla soon and this already used in some centers around the globe. Or we might test for bone marrow evaluation with next-generation flow or next-generation sequencing. All those patients with disease or really suspected disease must be tested with CT or Percity scan in order to search for singles plasmocytoma or osteosclerotic syndrome as mentioned. Treatment. The treatment of M-G-C-S is the treatment of renal and dixtra renal manifestation, but those treatment is related to the treatment of the clone. So we have to try to eradicate the non-malignant clone that produces toxic light chains. If the clone is plasmocytic, we have to move with bortezomy-based regimen, autologous tents and transfer obviously only in those eligible and probably anti-CD38 monoclonal antibodies will play a role also in those rare conditions. In the presence of a lymphoplasmocytic or lymphoplasmoblast disease, we need specific therapy and also in this setting we will see the role of newer agent. So we have new emerging options for the treatment of the underlying clone in order to reduce the renal and dixtra renal manifestation. The primary objective is to preserve the organ dysfunction. And we saw in light chain amyloidosis and now also in LCDD that the complete elimination of the toxic monoclonal protein, v-monoclonal immunoglobulins is the goal of treatment. Because if you reach a profound reduction of the toxic light chain, these will be associated with an improvement in terms of survival but also an improvement in terms of the organ dysfunction. This is the goal for amyloidosis but also for those conditions. And probably in the upcoming months we will see studies about the role of the minimal residual disease evaluation also in this rare condition. With that, I'd like to invite all of you to in the international the monoclonal gamopathy research group workshop that will be held in Milano next year. It was planned for 2021 but unfortunately due to the pandemic we decided to move to next year and hopefully it will be a live meeting. And again I'd like to thank all my mentors and all my colleagues from the Pavia unit. Thank you so much for your attention. I will be happy to take all your questions.