 Hello to everybody. I am Roman Hayek, Head of Department of Oncology and Chairman of Czech Myelma Group. First of all, I want to thank the organizers for inviting me. It's really nice to participate in this excellent Masterclass meeting. You can see the title of my presentation. I did not realize how difficult it will be to prepare such presentation as I accept the invitation. This is my disclosure and here is my agenda and I will start with a short introduction. It's no doubt the treatment option in multiple Myeloma. Very significantly changed during the last 10 years. We have so many treatment possibilities and modalities and of course we can achieve excellent outcome. We have excellent opportunities for improving outcome but we also need guidance on how to choose the right treatment for our patients. You are familiar that recently two guidelines were just published. This is the International Guidelines. I highlighted two names which are actually present on this meeting and this is IHA-SMO Guidelines. Again, Marivi and me participating on these guidelines and what simplifying very simple guidelines was a guideline set. For newly diagnosed setting they recommend especially DARA-VMP, DARA-RDOVRD regimens is implemented and for transplant-illegible patients you can see the DARA-VTD regimen which is already approved in Europe is recommended. But to be honest in our setting we are more happy that we switch from very conservative European VMP approach to we are the approach in newly diagnosed setting especially for patients not eligible for transplantation. This regimen is approved in Europe. So if I summarize briefly newly diagnosed setting I want to highlight that choice of upfront treatment can influence the therapeutic approach in later lines. Transplants are remaining still as standard and RVD seems to be achievable treatment in our region if DARA-TUMMA based regimen are not yet available. What about relapse? First relapse. This is four years old guidelines focusing on relapse and I just highlighted by yellow which regimen and combinations are available in Czech Republic. We are actually not doing bad. So we have so many choices for first relapse and new guidelines just publishes a complicated situation but I think it's understandable. They are working already with treatment given to patients in a newly diagnosed setting via the DARA-ADIO-DARA-VMP and then with subcategories lenalidomide or bortazomid sensitive or refractory and I highlighted with red color which regimens are not yet available. So it's a challenge for the future. If you're thinking about which regimen should be used in first relapse, so to me DARA-ADIO-DARA achieve really impressive Median of progression of free survival. Definitely better than Median of progression of free survival for all other triplets. So even if you can see data for standard risk patients it's 52 months and for exactly first relapse it's 53 months of Median of progression of free survival. So this is the really incredible super data. So this is clear reason and advocacy as first choice if DARA-ADIO-DARA is available and there is no other conditions or contraindication for this regimen. This is the first choice. Quite difficult situation is for patients who are already treated with VRD. In fact in our hand now we have effective only carfazomidexamethasone. And for more advanced disease I always try to emphasize that we have used the proactive approach and to try find sensitive drugs for individual patients. I think we have thinking this way if response is not good enough we can discuss if the PR is enough or VGPR is enough then we have three possibilities. In the middle one treat until progression this is typical clinical study approach but it's not good approach for real work. So we have in this case to switch to other regimen if this regimen are available or probably thinking about use retransplantation as consolidation. If we use this strategy we probably really achieve better outcomes then in clinical trials when you can treat patients independently on the on the response achieve except progression until the end of trial. So we also adopted into our check myeloma guidelines three years ago and what new guidelines saying? Okay again working with refractory sensitive subgroup adding the subgroup triple class refractory patients and I again highlighted by red which are regimen are not yet approved in Europe or not reimbursed in most country in Europe and you can see the situation is not so optimistic. So we have to work on it. What is the reimbursed situation in central Europe and Balkan countries? This is a map for your orientation and I just have acknowledgement I thank you myeloma patients Europe kindly providing me with this map and I announced that this information will be transferred to MPA Access Atlas which definitely will be one practical tool and really congratulations and thanks for this activity. Then our regimen which will be reviewed in the survey which were reviewed in the survey some of regimen still missing like and you can you can see the reimbursement is color for reimbursement is green, reimbursement restriction orange, no reimbursement red, dark red and gray awaiting decision on our data. So we start with Darzalex. This is Darzalex monotherapy for advanced disease eucosne. Still there are some red colors and orange colors especially in our regions otherwise is approved across Europe. Then here is the most effective quality and I see that it's still a lot of countries in which this combination is not rainbows. Okay it's expensive but it's the most effective combination which we can offer to our patients. Better situation is in relapse setting for data VD and here is data for newly diagnosed setting and use data of course this was just introduced so it's limited access across Europe. I just want have one command is always by green for Russia. Green is always green for Russia so it's probably should be rechecked because it's definitely not true at all. So and Darzalex combination for transplant eligible patients that are VTD again limited access across all Europe is too soon and another anti-CDC 38 monoclonal antibody eczesomyp this same situation was just introduced and proofed so you can see just few countries of course Russia can be can use it. Combinations proteasome inhibitor and lenalidomide on the left-hand side carphazomidexametazone and your right-hand side carphazomide revlimidexametazone actually it was the first from the new agent introduced several years ago so the situation is quite good in Europe and also in our regions eczesomyp Rd. I think very similar situation a little bit more red and here is well Kate okay you can see in relapse setting newly diagnosed transplant eligible and non-eligible the situation across Europe and also our region is really good okay this drug is here for 15 years what about emits relapse setting on your left hand side newly diagnosed on your right hand side for relapse setting quite nice situation just few red and few orange it's quite more difficult to introduce the revlimidexametazone in newly diagnosed setting a lot of red and orange color in our region it was surprised for me to see the lenalidomide maintenance is not rainbows in most country in Europe it's amazing it's fast for check because it's here rainbows in check for more than one and a half year but okay nevertheless the situation is surprising to me because we know that the lenalidomide maintenance a matter for almost decade and here is him novit in relapse setting quite okay intermediate situation not good not too bad so this is the overview okay we have no problem with old-fashioned style drug in newly diagnosed setting and lenalidomide relapse setting then the situation varied country from country and definitely this is the good for carfuzomib, lenalidomide, exasamid, lenalidomide, deratum, bortezomidexametazone more difficult for deraardi and of course some drug was just introduced and just approved so we have to evaluate this in the near future so summary for reimbursement situation in our regions too many of novel triplets effective but also expensive some drugs like lenalidomide maintenance despite clear clinical benefit are not in remorse although random trials the results are now 10 years there has seen some limited access to novel triplets in central euro and balkan countries and current guidelines are very ambitious but can help do more speedy approval in some countries across the world not to not only in euro so what's our common access challenge which we are facing I just highlight some of them and I think this is the matter for discussion so availability in a comic situation but also unreal request hopes from physicians significant deformation of indication approved by Emma on the national level by national regulators significant delay of approvals and then risk of unsuccessful transformation or overturn from temporary approval to permanent approval and reimbursement so I will use few examples and then we can discuss it during discussion part first example typical for our national regulators they play game with status performance so you can see six different variants of eco and just patients with these eco status can achieve on the sum drugs and they are covered so for instance for xrd it should be eco 1 or 0 for rd it should be 0 to 0 to 2 you know it's not understandable because this is full euro regiments for data vdu you can see 0 1 2 only if myeloma related which is perfect for kd 0 1 2 or 3 only if myeloma related and a variant 0 1 and 2 plus only if i'm related so you can see the six variants so it's really difficult for our physicians just check every conditions every every day every time in our patient clinic if it's fit otherwise it's not reinforced so it's serving as exclusion criteria for reimbursement and of course and directly it's the strategy is focused to minimize budget impact another example additional criteria this is in check but not to be confused it's simplifying things this is the criteria for reimbursement of combination a lot to sum up linolego with dexamethasone irrep is highlighted what emas says we've been approved lrd for for patients who were treated with at least one prior line that's it and then you can see in all white part of this cartoon that there are a lot of restrictions on national level which are sometimes confusing even for us and it's very difficult to to really take care about this this restriction criteria because the similar restrictions are seen for all triplets consequently it's leading to very limited indication of this regiment and definitely transformation to permanent approval and reimbursement will be serious challenging issue what's our clinical consequence of limited treatment access for patients again i will use some examples standard versus high risk relapse setting so standard risk we discuss that we always using data rd for because the benefit is mostly seen in standard risk patients it's incredible 53 median of progression free survival so to me for patients with standard risk in first relapse i think it's a leading to some consequence if worsening prognosis if such regimen is not available for high risk we learn we have learned that two combination in newly diagnosed setting not working properly like rd and we think it's also true for relapse setting for high risk i just highlighted the the difference between carphesimidexamethosone and bortesimidexamethone for high risk in candor trial 8.8 versus 6 it's definitely not clinically meaningful if we talk about data rd which nicely working in in standard risk patients it's significantly better that control arm in in for high risk but as you could see clinically in not so it's not so magnificent 22.6 months and if we compare with combination proteosamethone and and lenalidomine k rd 23 months x rd 21.4 months of course this is in direct comparison but for patients with similar pretreatment so i think these regimens are doing very similar so it's no significant difference and consequence so we can choose so if some of this regimen is missing it has no probably any consequence for patients so for this example on this example i want to say that for standard risk limited access to the rd has probably negative consequence for patients but for high risk such limited access have no negative consequence if some other replets are in boost clinical consequence example two refractory patients to lenalidomine there is summary busy slide with all regimen evaluated in lenalidomide refractory patients i will not talk about these two t candor ik ikikema trials with backbone kd and darao isa tuximac adding because the proportion of lenalidoma the refractory patient was only 32 person and it was not designed clinical trial exactly for lenalidomide refractory patients but for all these four trials with backbone pomalidomide dexamethasone the proportion of lenalidomide refractory patients is significant is highlighted by 79 94 71 90 percent for this regiment and you can see mediano of progression for survival between 10 up to 12 months and you can see also control arm between 5 up to 7 7 months so the difference between regiment in indirect comparison is definitely not clinical clinically meaningful despite this indirect comparison and we have to discuss if the benefit for five months of such expensive regimen is clinically meaningful and it's enough advocacy to achieve reimbursement it's very difficult so on in this conclusion in this example i showed the mediano progression for survivor which range in clinical trials with pomalidomide dex backbone focusing on len refractory relapsed multi pomalidoma patients between 10 up to 12.4 months 79 up to 94 percent of patients were refractory to lenalidomide and although it is a direct comparison it seems that different is not clinically meaningful otherwise it's very difficult to treat patients lenalidomide refractory despite we we using the really really good triplets but but it's not advocacy that we don't need more treatment options i just remind you what i already said with this strategy we definitely if the if the response is not good enough then we need other regimen with different mechanisms of action switching to achieve better results so clinical consequences for limited treatment access for patients is related to limitation of individual approach lower chance to find sensitive treatment for individual patients i always use this slide as just example it's krd versus kd aspire and this is the krd arm median 26.3 months was achieved but if you compare patients with vgpr versus minimal response patients you can see three years versus one year so this is the clinically significant clinically meaningfully difference and that's that's the reason why you need more regimens to find sensitive regimen for individual patients conclusion new therapies for relapse refractory multiple might provide excellent opportunities for improving outcomes of course we need guidelines new guidelines seems to be challenged for many countries because limited access to novel triplets but they can help to more speedy approval in some countries across the world limited access to novel therapies are seen in the most central european balcan countries and common access challenge which in this region is delay of approval restriction of treatment window applied by national regulators clinical consequences of limited treatment access for patients are not always clearly seen however more treatment options increasing a change to find sensitive chance to find sensitive regimen for individual patients and of course cooperation with patients organization can improve situation although it is difficult task thank you for attention and thank you for listening