 Hello to everyone, and first of all, thank you very much to the Myloma Patients Europe Organization for inviting me to this meeting with the patients. And my name is Maria Victoria Mateos. I work as a dermatologist at the University Hospital of Salamanca, Spain. And I will address the topic of monoclonalganopathy, as well as the smoldering Myloma. In the next slide, you can see my conflict of interest. And here, you can see a clinical case, the most common way in which we do the diagnosis of either monoclonalganopathy or smoldering Myloma. Asymptomatic patients that in routine analysis, the total serum proteins are elevated with a normal albumin. The hemogram and the biochemistry are usually normal. And the general practitioners usually perform serum protein electrophoresis in order to identify what you see here in the slide, AM component. The next step is to go to the bone marrow, because you know it's in the bone marrow when the plasma cells are produced. And these plasma cells are responsible of the production of this monoclonal component. And if we consider these two features, plasma cell proliferating into the bone marrow together with the end component, we are going to be able to do the diagnosis of monoclonalganopathy or smoldering Myloma or multiple Myloma. Monoclonalganopathy is defined by the presence of a monoclonal component inferior to 3 grams per deciliter. And the plasma cell bone marrow infiltration is quite low, less than 10%. But important comment is there is not any Myloma-defined event. Patients are completely asymptomatic. Smoldering Myloma is defined by the presence of a monoclonal component, higher than 3 grams per deciliter in serum, and the plasma cell bone marrow infiltration is between 10% and 60%. But again, there is not any Myloma-defined event. And this is the main difference between M-Gas smoldering and Myloma, because multiple Myloma is basically characterized by the presence of Myloma-defined events clinical symptomatology. One important comment, when we have in front of us patients in which we suspect the monoclonalganopathy smoldering or multiple Myloma, you have to know that there are some other concomitant diseases that sometimes can mimic the Myloma-related symptomatology. Smoldering, monoclonalganopathy, and even Myloma usually affected to the elderly population. And it's quite common to have in front of us patients with some degree of anemia or some degree of renal infirmation because of hypertension or diabetes. We have to be very sure that this symptomatology is or not related with the plasma cell bone marrow infiltration because the management of monoclonalganopathy smoldering and multiple Myloma is completely different. And a second important consideration before doing the diagnosis of monoclonalganopathy or smoldering is the confirmation of the results. And we have to repeat the hemogram, the biochemistry, the certain protein electrophoresis, the urine protein electrophoresis in approximately two or three months times in order to confirm that everything remains stable. And if this is the case, we do the diagnosis of hemgas smoldering. And the next step is to inform to the patients about the diagnosis. Monoclonalganopathy is basically divided in three different subtypes, known IgM, Emgas, IgM, Light Chain, Emgas. But maybe this is not important for you. What is important to see is that the Emgas is a very frequent disease and over 5% of the population older than 70 years can present a monoclonalganopathy. And this is the workappa recommended when we have in front of us a patient with monoclonalganopathy. And together with the medical history, hemogram, biochemistry, what is very relevant because we have to be sure that you don't present any anemia, renalin, Burman, hypocalcinia. We have to do the protein studies in order to very well characterize the type and the size of the monoclonal component. It is also possible to do the serum-free light chain and the serum-free light chain ratio because they are going to help us to evaluate the prognosis and the potential risk of progression to multiple myeloma. It is recommended to do bone marrow aspirated plus minus biopsy in order to evaluate how many plasma cells are infiltrating the bone marrow. And definitely we need to evaluate the bone disease. And for doing this, the optimal assessment is to do low-dose CT or PET CT or MRI and only to reserve X-ray if there is not any other possibility. Important consideration, when we do the diagnosis of a monoclonal organopathy and the M protein is lower than 1.5 grams per deciliter, so very low M component. And the type of monoclonal component is IgG. In principle, the risk of progression to multiple myeloma for this patient is extremely low and it would not be recommended to do bone marrow or bone disease evaluation. Of course, this is what the guidelines recommend us but we have to consider another important information and it's the discussion with the patient. And if the patient is down and the patient is anxious and nervous because of the diagnosis of monoclonal organopathy, maybe it is appropriated to do the bone marrow as well as the bone disease evaluation in order to be sure about the diagnosis. And when the M gas decides the type of the monoclonal component is IgM, your physician will usually order a CT in order to evaluate if you have adenomegalitis, adenopathy because the probability of progression to another different type of disease the baldestrone macroglobulinemia. Overall, and this message, I think that is very important for the patients. The risk of progression to multiple myeloma for patients with monoclonal organopathy is very low, 1% per year. And this means that the risk of progression to myeloma is 10% at 10 years, 20% at 20 years and most patients will never progress to multiple myeloma. Anyway, we can utilize and I think that this is not important for you some specific features like the size of the monoclonal component or the free light chain ratio or the bone marrow compartment to evaluate very well the plasma cells in order to establish different models and in order to accurate the risk of progression to multiple myeloma. But overall, you have to know that the risk of progression to myeloma is quite low. It is recommended to do a follow up because if patients with M gas are followed by the hematologist or even the general practitioner for patients with a very low risk of progression to multiple myeloma, they are going to be able to detect another potential concomitant disease in these follow ups and definitely the benefit in overall survival is going to be greater. So low risk M gas can be followed every two or every three years. If after the first year, the M component remains stable, if the risk of progression to multiple myeloma is a bit higher, it is recommended to follow patients with M gas at least once per year in order to evaluate the M component, hemogram and biochemistry and in principle, it is not necessary to do anything else. What happens with smoldering myeloma? Smoldering myeloma is between M gas and multiple myeloma and the diseases are a bit different because the M component is higher than three grams and the plasma cell bone marrow infiltration is also higher than 10% but lower than 60%. But myeloma defining events are not present. Patients are completely asymptomatic. The workup is a bit more complex and it requires the medical history, hemogram, biochemistry, protein studies but I decided to remark here in blue some approaches is some techniques that are mandatory in patients with M gas. Serum-free light chain measurement, bone marrow aspirate plus minus biopsy as well as MRI of the spine and pelvis or ideally whole body MRI together with low-dose CT or PET CT in order to evaluate the possibility of bone disease. Why I decided to remark these three assessments, serum-free light chain, plasma cell bone marrow infiltration and MRI at least of the spine and pelvis? Because the definition of multiple myeloma, those patients who required immediate active therapy was updated at the end of 2014 because when asymptomatic myeloma, a asymptomatic patient, so patient with a smoldering myeloma, presenting with any one or more of the biomarkers that you can see here in a red square, the probability of progression to multiple myeloma is extremely higher. And we had the opportunity to see that asymptomatic smoldering myeloma patient with more than 60% of plasma cell in the bone marrow, these patients were going to progress to myeloma within the next year. And the same is applicable for smoldering myeloma with a serum-free light chain ratio higher than 100. And the same is applicable to smoldering myeloma and in MRI when more than two focal lesions were presented. The International Myeloma Working Group considered these biomarkers and they decided to incorporate this to the definition of myeloma. And this means that the definition of myeloma was expanded and some patients considered as asymptomatic myeloma patients smoldering myeloma patients in the past are now considered as multiple myeloma. These patients do not present any crab symptomatology, but we know that they were going to develop this crab symptomatology in the next year. And this is the reason why we decided to remove this smoldering myeloma into the definition of multiple myeloma. You have to know that this proportion of new patients with multiple myeloma is rather small and we have to consider again what happens with the rest of patients with the smoldering myeloma when they are not included within the definition of multiple myeloma. And here you can see a small monoclonal monopathy smoldering myeloma. And I think that this slide is very illustrative. Smoldering is a born disease and we can found here some patients in which it is going to be very difficult to move to the overt fire. These patients are comparable to the low risk smoldering myeloma. We are going to have patients that they are going to move rapidly to the over fire. So to the multiple myeloma and in the middle we are going to have intermediate risk smoldering myeloma patients. You can understand that when we have in the clinic a patient with smoldering myeloma the first thing the ematologist must do is to evaluate in which group you are in order to evaluate the risk of progression to multiple myeloma. And there are different models and different approaches in order to evaluate the risk of progression to multiple myeloma. But you have to know that the international myeloma working group evaluated more than 1,000 patients with smoldering in order to establish this model. And it's very simple because this model includes the serum M spike, two grams, free light chain ratio 20, plasma cell bone marrow infiltration 20. When a patient with a smoldering myeloma presents known of these factors the risk of progression to multiple myeloma is going to be very low, 5% at two years. When a smoldering myeloma presents just one of these three risk factors the risk is intermediate 17% at two years. And when the patient presents two or three of these risk factors the probability of progression to multiple myeloma is higher approximately 50% at two years. And this is the high risk group of patients with smoldering myeloma and your physician can incorporate also the presence of cytogenetic abnormalities. It's true that there are other different models available to evaluate the risk of progression to multiple myeloma. And a practical approach is to follow how the M component evolves over time. And if your physician see that the M component is increasing over time definitely the probability of progression to multiple myeloma is going to be higher than in those patients in which the M component remains stable over time. But how to manage this information? From my point of view, the most relevant information is that every physician with a smoldering myeloma patient in front of him or her the first thing is to evaluate these biomarkers I previously showed you in order to see if the diagnosis is smoldering or myeloma. And the next step is to evaluate the risk of progression to multiple myeloma. Because the management is definitely going to be risk-adapted and it is very appropriate to identify especially those patients in which we know that the risk of progression to multiple myeloma is going to be of approximately 50% at the two years. The management risk adapter as I previously told you and this is a example 56 year old mama with M component 1.8 plasma cell bone marrow infiltration 12% certain free light chain ratio nine no myeloma defined in the event risk of progression to multiple myeloma 5% at two years. I would not treat this patient and this patient should be followed once per year. A second patient 68 year old woman with M component 1.8 plasma cell bone marrow infiltration 22 certain free light chain ratio 10. According to this model, the risk of progression to multiple myeloma would be 17% at two years. I would not treat to this patient and I would follow this patient every four, six months during the first two years in order to see how the component evolves and in everything is stable. I would follow this patient just once per year. Which evaluations your physician has to do every visit at least emogram and biochemistry protein studies and the imagine techniques like PECCP or MRI can be done just once per year especially during the first years. This is a third patient 38 year old woman M protein 3.8 plasma cell bone marrow infiltration 39 certain free light chain ratio 79. This patient has a higher risk of progression to multiple myeloma 46% at two years. I would discuss with this lady and I would treat to this young lady with a high risk of smoldering myeloma. And the same is applicable to this 50 year old man with AM component 3.5 plasma cell bone marrow infiltration 25 certain free light chain ratio 46. Everything is higher and in addition this patient presented a chromosomal abnormality plus one Q. The progression risk at the two years would be approximately 60%. And even you have to know that new molecular markers and new genetic analysis are being done in patients with a smoldering myeloma in order to gain much more information about the biology of the disease. And it is possible to see in front of us this patient with a intermediate risk of progression to multiple myeloma 17% progression risk at two years with an abnormality in the gene CEMIC. And this is feasible. We know that the risk of progression to multiple myeloma in this case would be higher than expected. And maybe I would treat to this patient. This is just to inform you about the further investigations we are doing in the patients with a smoldering myeloma and definitely is based on genomic studies in order to evaluate genomic abnormalities that we know that they are going to confer a higher risk of progression to patients with a smoldering myeloma. Anna, maybe you can ask me why did you plan early treatment to these patients with a high risk smoldering myeloma? Because point number one, if we go to the oncology perspective, maybe you know that in oncology, the early intervention is something very common to almost all malignancies in order to try to cure eradicated the disease or at least to delay the progression to active myeloma. Anna, when a patient is diagnosed over a polypus and the diagnosis is colon cancer, oncologists don't wait to see metastasis in the liver in order to treat this patient. By contrast, this is what we do, basically in patients with a smoldering. But the second important comment and the second important consideration in order to plan an early treatment is that we are going to prevent myeloma related symptomatology. And you know that the myeloma related symptomatology is clearly impacting in the quality of life of the patients. But in addition, we are going to treat the disease less complex from the molecular point of view and maybe the cure or at least the control is going to be easier to be achieved. Anna, there are some evidence about the role of early treatment in high-risk smoldering myeloma patients. This is the first study conducted by the Spanish myeloma group more than 10 years ago. Anna, when we treat high-risk smoldering myeloma patients with a lenal edomide and examedasone, we observe a significant benefit in terms of time to progression to myeloma two years versus nine years with a benefit also in overall survival. And this data were confirmed later on by another study conducted in the US in this case with a lenal edomide versus observation but the same magnitude of the benefit especially in patients with a high-risk smoldering myeloma. And under the platform of lenal edomide and examedasone, you have to know that if you go to clinicaltrials.gov, there are more than 50 clinical trials ongoing conducted in this specific population. Some of these trials are based on lenal edomide and examedasone plus a third drug like ilotusumabacarthylsomide exasomide. There are some trials evaluating the role of the monoclonal antibodies anti-CD38 with very promising efficacy data, but also there are some curative approaches and this is the curative approach planted by the Spanish myeloma group in 90 high-risk smoldering myeloma patients to which we have treated them with induction, transplant, consolidation and maintenance. And the preliminary data are quite promising in terms of efficacy, in terms of safety, PFS and overall survival, although it's true that we need more data in order to see how these patients evolve over time. And in summary, and this is the conclusion for smoldering myeloma is a heterogeneous disease is different to monoclonal gamopathy and it is very important to identify the risk of progression to multiple myeloma. Personally, I consider that there are a couple of phase three clinical studies confirming the superiority of Lendex versus observation as early treatment in these patients, although I have to recognize and this would be my first recommendation if you are diagnosed of high-risk smoldering and there is a clinical trial active, this is going definitely the best way in order to increase and in order to move forward with further investigations in these asymptomatic diseases. And I stop here. Thank you very much for your attention.