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>> for those of you who haven't met me, myname is ajai chari. i'm associate professor of medicine at mount sinai and i'm actuallydirector of clinical research. but right today i'm tasked with talking about relapsed andrefractory disease aside from research. and part of reason is there's so much interestin immunology that the clinical trials portion will be done by my colleague, hyung cho, whohis main interest is translational work going from the lab to patient care will all thenew immunologic approaches. so very exciting work. stay tuned for that. okay, so here'sa patient case that kind of will set the stage for this particular topic. a 67 year old manpresents with anemia and back pain and has multiple myeloma. and is treated with thetriplet regiment most commonly used in the

u.s., bortezomib, lenalidomide and dex followedby high dose melphalan, chemo and [inaudible] stem cell rescue. and a day 100 after transplanthe has a very good partial response and elects to start lenalidomide or revlimid maintenanceand then chose a complete remission. three and a half years later while on lenalidomidemaintenance his myeloma relapses and he has anemia, moderately low platelet count andkidney failure. and he wants to know what his treatment options are. by the way i shouldmention some of these slides are main, most of the slides are in your handout. the one'sthat aren't will be again available online. so this case illustrates two concepts. whenwe talk about relapse and refractory disease, if you ever go the nci and mmrf or both websitesif you're a patient or caregiver and interest

in clinical trials you can go there and one,some of the jargon you'll see is relapse and refractory myeloma. so relapse just meansrecurrence after responsive therapies. so this patient has relapsed. refractory meansthat his disease is progressing despite ongoing therapy. and this gentleman as we learned,not only has he relapsed but because he was on lenalidomide maintenance he's actuallyrefractory to lenalidomide a well. so he encompasses both of those definitions. and this chartis what i actually, many of my patients have seen this, i literally bring this to our visitsin clinic. every time we have to make a decision about changing treatment the first questionis clinical trials, non-clinical trials. and we'll talk about when you might want to doone versus the other. but if you're not going

to do clinical trials these are the main drugcategories that we talk about. so i was told about having to point at one or the otherbut basically we have five drug classes. cortical steroids which are dex and prednisone. theimmunomodulatory drug which are thalidomide, lenalidomide or pomalidomide, two proteasomeinhibitors, bortezmib and carfilzomib, the conventional chemotherapeutics, melphalan.you heard about the high dose melphalan with stem cell from dr. geralt [assumed spelling].but you can also give melphalan orally and that's done in many parts of the world becauseof its cost. there's a 96 hour chemotherapy called dcep or dpace, cyclophosphamide whichcan be given orally or iv, bendamustine also known as treanda which is intravenous, liposomaldoxorubicin also known as doxil which is intravenous,

carmustine or bcnu, an old drug typicallygiven in the setting of transplant with melphalan. and lastly the most recently approved category,the hdac inhibitor panobinostat. so we basically have five drug classes with many drugs ineach class. and the reason i mention this table is because while we have made a lotof progress in myeloma we haven't yet gotten to a cure and we're trying to there, to getthere. the flip side of that means that every treatment works for a while then it stopsworking. so we're going to eventually cycle through all of these drugs in a given patient.and the question is what sequence, what combination and when do you use different drug combinations?and the other point again applied for clinical trials, every treatment on here was only possiblebecause patients participated in clinical

trials. i'm sure if people know the, if iwanted to take a medication that was sitting in the laboratory and saying i want to testthis in myeloma, first you have to show in the laboratory that it kills myeloma cells.then you have to show that it's safe to give in animal models. then you have to test what'sthe right dose to give in humans. then you have to see how well it works. so by the timea drug goes through that process it typically takes minimum of about eight to ten yearsand many, many millions of dollars. and so every drug on here has had to go through thiskind of a clinical trial. and that's why we're all united here with the mmrc and mmrf andall of our collaborating institutions to really try to add more drugs in each class as wellas whole new classes of drugs. but again putting

aside the clinical trial, what are the considerationswhen somebody does have relapse disease like our patient scenario? one of the questionsis when did the disease relapse occur? what it within six months? and this was broughtup earlier by a patient question about potentially retreating. so if it was within six monthswe might want to switch because that's a relatively short remission. stem cell transplant wouldbe another option. if it's more than six months you could consider going back to the old treatment,switching classes, trying a transplant and of course clinical trial could always be considered.so how do we decide which treatment to pick? i mean, we have that huge toolbox or as mycolleague dr. jagannath likes to call it, somebody just brought it up this, at lunch,he calls it the box of chocolates. so we have

these chocolates that we play with. so whichchocolate do you pick and what combination? and part of it is what are the prior therapiesthat a patient has had? how deep is that response? did they get to a complete remission or partialremission? and what was the duration of that response? this is particularly important.we've been talking a little bit in this morning about high risk disease versus low risk disease.what's interesting in myeloma is that it's not that the high risk patients don't respondto questions of the duration, so. and, but the fda is approving new drugs. they're actuallymuch more interested in the duration of response. because you can a great response but if itlasts a month what is that adding to the patient quality of life and overall life experience?so the question really is the, both the depth

as well as duration of response. side effects,super important. this is a big segway into the next topic, you know. we all strugglewith quantity and quality of life. and sometimes we go in medicine so much to the quantitythat we forget about the quality. and all these drugs will have some side effects. andevery patient has a different experience with each drug. and one of the goals of oncologyand i always tell patients why are we seeing you more often than say your diabetes or bloodpressure doctor? and it's because oncology drugs have what we call in medicine a narrowtherapeutic index. too little, you don't get an effect. too much, the patient has sideeffects. and how to keep that sweet spot of risk benefit is one of the main reasons wehave oncology as a specialty and why internal

medicine doctors aren't prescribing chemo.time sensitive therapy we talked about. myeloma genomics, so we have many ways of determiningthe genetic profile of a disease. one of the best ways of explaining why this is so importantis comparing myeloma to lymphoma. lymphoma is a also b-cell cancer. but we don't justthink of lymphoma as a basket case. it's 50 different types of subtypes of lymphoma. andeach of those subtypes has different natural history and treatment interventions. we thinkmyeloma is going to be just as complicated. it's just we haven't gotten to the point ofmaking all of those different subtypes and assigning individual therapy. but the onlyway we're going to get there is with study like commpass. this is a huge effort thatyou've heard about repeatedly. it's extremely

important. patients have to participate. physicianshave to encourage the participation. and there's a huge cost to profiling these patients sequentiallyover time. but that's what's going to tell us when a patient relapses. why did they relapse?why do some patients do better with certain drugs? all of that kind of information's goingto help us move past the current five, the current toolbox that we have. the generalhealth of the patient is super important. diabetes, we all know in this room the sideeffects of dexamethasone. and believe it or not it was a patient advocate who lobbiedfor a large u.s. study to compare high dose dexamethasone to weekly dexamethasone. soif you think 40 milligrams of dex once a week is bad, we used to be giving 30 milligramsfour days on and off three times per month.

and that was what was being done. and it wasa patient who said, you know what, why are we doing this when we have all of these newdrugs? and studies show that that actually hurts patients. for the, so for the most partother than spinal cord compression or renal failure, very patients will be getting fourdays of dex in a row because of that study. and again, it was a patient intervention.yes, these, that's what i was, yes that's why i apologize but yeah these are going tobe on the website. yep, no problem. so diabetes because of steroids causing elevation in bloodsugar is a big problem. blood counts, this is a big issue. if somebody has a lot of myelomain the marrow, their blood counts will likely be low. and that's going to affect which drugsyou use and also their eligibility for a clinical

trial. and the organ function is very important.heart, liver, kidney function, why is this so important? if you're going to do a newclinical trial drug and the patient already has liver or kidney dysfunction and experiencessome toxicity on the drug, how do you know if it's because of the drug or because thepatient has these abnormal liver and kidney function? so whenever we test new drugs wewant to test it with essentially healthy patients, healthy myeloma patients whose only problemis myeloma and not a lot of other confounding issues that could cloud the picture. neuropathyobviously is a big issue for patients with particular drugs and there's ways to modulatethat. blood clots, the entire imid category of drugs when given with steroids can increasethe risk of blood clots. so it's depending

on how active a patient is, whether there'sany, i always tell our patients when you travel, please get travel insurance and let us knowif you're having long plane flights. because if you're on an imid taking dex and you'reon a long plane flight, that's a very high risk for clotting. and we often recommendadditional medications to prevent clots in that setting. personal lifestyle and preferencesis super important. some of our patients who come to our mount sinai live far away andthey're not able to come every week or twice a week for some of the treatments. and thatwould potentially be a big issue for what kind of option we pick and of course clinicaltrials. so part of the reason we would pick a particular treatment is also the amountof myeloma. so you've heard about the crab

mnemonic and i've illustrated here just threerepresentative time points in a patient's disease course to identify what might be thebest time to do a clinical trial. time point one might not be a good time because there'sno disease to measure at this point. so this patient had a lot of and for sake of discussionwe can call it an m-spike here about six. when you debulk the disease and it's eradicatedthere's no protein left to follow. so this patient wouldn't be eligible for a clinicaltrial typically. time point two is, we'll come back to that because that's a littlebit of disease. time point three, there's a pretty high disease burden. this patientmight very well have some of those crab systems. and you could argue if the patient is sickthat might not be a good time to do a clinical

trial. time point two is ideally the besttime to do a clinical trial. so if you can intervene here, there's a little bit of disease,you can monitor the patient, they'll be eligible for the study. but they're not so sick thatby the time you do what's called a screening, which is all the testing to go on a studybone marrow, and then register the patient, start the patient. and you need to make surethat the treatment's active. so this is why in our program we try to steer patients inthis group towards clinical trial. and this group we tend to use the treatments that i'mgoing to talk about in the rest of this talk. so one of common treatment options is a proteasomeinhibitor such as bortezomib or velcade or carfilzomib with an imid such revlimid orpomalidomide. and they often get combined

with corticosteroids and that would be calleda triplet regiment. you can also use additional drugs that are listed here, as i mentionedkyprolis or carfilzomib, pomalyst or pomalidomide and farydak panobinostat. so i'll just brieflygo through these drugs. many of you are familiar with them so i'm going to and these slidesare in your handout. so i think just the salient points. revlimid is an oral agent and it'sapproved for combination with dexamethasone. response rate in the initial studies thatled to its approval was 61%. and i should just mention when we talk about response inmyeloma we're talking about the, what dr. thismikthe [assumed spelling] showed you thatslide. this is the drop in the paraprotein. so 50% higher or drop in the protein's what'sconsidered a response. and i mention that

only because sometimes in the newer drugsyou may not get an official response by that criteria but patients can still benefit. inother words the myeloma was rising and then the disease can be stabilized or the crabsymptoms have been resolved. so but when we talk about response these are standard whatwe call imwg response criteria which is that 50% drop in a protein. the typical patientwho was given revlimid when it was first approved was, stayed on for 16 months. and we knowthat it can be combined with many other drugs. ideally for somebody who's not had it, who'snever progressed while taking revlimid, one of the tricky parts is we're having more andmore patients on lenalidomide or revlimid maintenance and so they're often getting theselow doses. and one of the questions out there

is well are they going to benefit from a higherdose. and the jury's not back on that one. i mean, there may be some benefit to try tradingup the dose and adding steroids but again it depends on the disease burden. if you'rehaving a little bit of protein rise that might be something to try. but if the disease isreally exploding you may not want to just depend on a higher dose of rev in somebodywho was on revlimid maintenance. and as you see in the last combinations, it's being combinedwith basically all the drug classes that we listed there including the proteasome inhibitors,the novel monoclonal antibodies including daratumumab, the cd38 antibody and elotuzumabas a cs1 monoclonal antibody as well. sar650984 similar to daratumumab, another cd38 antibodyand ixazomib is the oral [inaudible] proteasome

inhibitor similar to bortezomib or velcade.so revlimid can be combined with all of them. that's another one of the reasons why we hadthat table because usually we don't pair up two drugs within the same column. and we tryto pick drugs from different classes because we know that there's synergy when you combinethose both in the laboratory as well as in the patient. and it's not uncommon that youcan have progression on a doublet or two drug regiment and the third drug addition can actuallyrescue that patient. proteasome inhibitor, velcade approved for myeloma as well. initially43% response rate. responding patients initially in the pivotal studies stayed on treatmentfor 31 months. again combinations are better. similar messages if you haven't had it beforeor progressed on it obviously you can go back.

you heard a little bit about the high riskof business. there are studies that now show that translocation 414 which is present ina fair number of myeloma patients can be overcome with the proteasome inhibitor. which, andso one of the ways we think about is risk has to be considered in the context of therapy.so for example on none of the current slides in myeloma do you see deletion 13 which weused to talk about a lot five, ten years ago. and the reason is in the current era of drugsthat doesn't matter. and so similarly translocation 414 five years ago we used to call right risk.but now with the proteasome inhibitor therapies that seemed to overcome them, they've beenmoved to standard risk. so risk always needs to be considered in the context of the treatmentsthat are available when you're evaluating

that risk factor. one of the nice things aboutthe proteasome inhibitors including velcade is that can be used in kidney dysfunction.this is very important as you all know for myeloma patients because of the crab, therenal insufficiency. oncologists, we need to be very familiar with every drug's clearance.so much more so than perhaps our internal medicine and other colleagues because, because1/3 of patients with myeloma have renal dysfunction. and if a patient has an impaired clearanceof a drug the dose of that drug has to be adjusted or we may need to pick a drug, anentirely different drug that is not affected. so that's, there's also a big need for clinicaltrials for patients with renal dysfunction because they're often not represented well.the combinations again just like with revlimid

you can basically combine it with all theother drug classes. you can combine it with the imid's, you can combine with conventionalchemotherapies like cyclophosphamide and also with the novel drug categories as well. kyprolisor carfilzomib is the same class as velcade. the official label is for at least two linesof prior therapies including velcade and imid, either thalomid or revlimid. and that they'veprogressed within 60 days or while on therapy. you'll see that this response rate is now23% in comparison to the previous studies. what happens is and it's kind of an interestingnumber to think about. as we're getting more and more drugs, as our toolbox is gettingbigger and bigger, it's getting harder and harder for new drugs to come in and show singleagent activity. so when for example, revlimid

and velcade were first approved there wereno prior revlimid treated or velcade treated patients. and so you'll see that those responserates were higher than this number and the remissions were longer. and that's becausethose patients were typically less heavily pretreated. now we're seeing patients who'vehad many of those drugs and to ask a new drug to come in there and show gangbuster activityis much more hard, much more difficult. and so this is why a lot of new drugs either haveto be, have a really novel [inaudible] of action or have to be combined with other agents.elotuzumab is a great example of something that didn't show any single agent activitybut it seems to show a lot more promise when combined with revlimid. so it's an importantpart of drug development in myeloma. and it's

important to talk about that because a lotof drug companies are a little reluctant to dip their feet into the myeloma space becauseit is getting so competitive with all of these drugs. and you heard how long it takes toget a drug approved and the costs. so we have to encourage these drug companies to continuein partnership with mmrc, mmrf to continue committing to these novel agents for theseunmet medical needs that we still obviously have. the response typically lasted 7.8 monthsin the initial studies with carfilzomib. and what you see here, what i was just eludingto in people who did not have prior velcade the response rate goes up from the 23% to42%. so less heavily pretreated patients are going to do better. on average those responseswere also lasted longer, 13 months. same stuff

about the high risk. there's some studiesthat show again translocation 414 with both proteasome inhibitors no longer consideredhigh risk. deletion 17p's a little bit more complicated and it's probably beyond the scopeof this time to talk about it. but there are some studies that show that maybe proteasomeinhibitors can help mitigate some of the risks but not completely eliminate that risk. carfilzomibis a more potent second generation inhibitor but interestingly it does not have any neuropathyassociated with it for the most part. so it's a nice option for people who need a proteasomeinhibitor but have had significant neuropathy. and to that point bortezomib most people orvelcade should be getting it subq instead of iv. in other words skin injection insteadof intravenous because that really diminishes

the risk of neuropathy. although there maybe a little bit of redness at the injection sites, it's well worth it to minimize therisk of the neuropathy. can be used in kidney dysfunction and again being combined withall of those other columns that we mentioned. and so the schedule for this is a intravenouslydays 1, 2, 8, 9, 15, 16 and then a week off. and so two days back to back. there's someinteresting studies with this agent being exploring novel schedules. because we understandthat this is cumbersome for patients to be coming to the doctor's office two days everyweek. so at this year's hematology meeting in 2014, there was a publication or presentationto do weekly carfilzomib at much higher dose. so instead of giving small doses twice perweek, giving a higher dose once per week.

so that's an option that, if those of youwho are interested or on it may want to discuss with your doctor. side effects of this drug,fatigue, anemia, nausea, usually well tolerated low platelet count. patients can experienceshortness of breath, 30% or so in the label but most people are able to tolerate thiswell, diarrhea, fever. one of the reasons a little bit of dex is given with carfilzomibis there can be what we call infusional toxicities like fevers or chills. and that really isminimized with the dex premedication. pomalyst is a fda approved for patients who've hadat least two prior therapies including revlamid and velcade. and have had disease progressioneither on it or within 60 days. the response rate was 29% and the patients who respondedwere on treatment for 7.4 months and so there's

some data that again preliminary data indicatingeffectiveness. one of the, our fellow who graduated last year, we wrote a review paperabout risk stratification of myeloma. and it's kind of a semantic [inaudible] complexpoint to convey but there's, the difference between overcoming a risk and improving arisk. so translocation 414 is a good example of overcoming that risk completely becauseit's no longer high risk with the proteasome inhibitors. improving means that if you didn'thave that risk you still, so for example, pomalidomide with deletion 17p, patients withdeletion 17p who get pomalidomide will respond and do better than those who don't. but itdoesn't mean that they do as well as those who didn't have deletion 17p. so it's kindof a semantic but complicated point to explain.

and it really, to really overcome high riskwe need to do phase iii studies with two different groups, people who have it and don't havethe risk as well as people who get the drug and don't get the drug. so stay tuned forbetter risk stratification, risk adaptive therapy. because that's really, we hope thatthe future of myeloma and medicine in general is personalized therapy that, you know, patientswho have a particular profile will be treated with a particular combination. and hopefullythat, the commpass study will help us get there. and pomalidomide also is being combinedwith all the other drug classes that are listed. its schedule is similar to revlimid. one dailyone day for 21 days and then a week off. as we talked about blood thinners are neededto prevent the risk of blood clots. about

20% of patients who get these imid drugs withsteroids will have a blood clot. however with aspirin that can be reduced less than 5%.and some patients who are very high risk of having a clot either because of having priorclots or long plane flights, etc. or family history might benefit from more than justaspirin. the side effects are listed here. basically lowering of counts as you can see.anytime you see constipation and diarrhea you see that it's going to be patient specific,shortness of breath, all these are pretty, these drugs are pretty well managed side effects.of course there's going to be idiosyncratic or individual patient experiences. the newestdrug that you may have heard about, that got approved is farydak, panobinostat. it's approvedto be given in combination with velcade and

dexamethasone and in the treatment of myelomapatients who've had at least two prior regiments including velcade and an imid. the responserate was 61% overall. and it's for people who've had prior therapies as listed there.one of the side effects i think which will be mentioned here, so the schedule is orally.it's given every other day. so for typical schedule as mentioned there might be monday,wednesday, friday, week one and week two. and so when this study was done with velcadedex and panobinostat, one of the biggest issues was diarrhea. and so the way this pivotalstudy was done is everybody got velcade and dex and half got panobinostat, half got placebo.and what we found was that the three drug regiment was superior in terms of gettingbetter responses but it came at the cost of

increased diarrhea. so the placebo arm thatvelcade, dex, placebo had about an 8% risk of severe diarrhea. and the treatment armwith the panobinostat went up to 25%. so about three fold increase. however, one of the caveatsto that study is that velcade was given intravenously there. and as we discussed when you give velcadein the skin it's much better tolerated. and it has to do with the fact that when you givea drug subcutaneously the drug is released slowly into the system as opposed to iv whereyou give it as an iv push you get a very high level. and so side effects are often correlatedto the level of the drug as opposed to the slow and study release. so we think that willbe mitigated by giving velcade subcutaneously. and we actually have a clinical trial at mountsinai where we're giving this drug with revlimid

and dex. and we've actually seen no diarrhea.and we've seen responses even in people who didn't respond to revlimid before, the additionof panobinostat has really worked beautifully. so we have that presentation coming up atthis year's asco. and it's being combined also with carfilzomib without the diarrhea.so i think it's a good example of how you do your initial clinical trial might resultin the drug getting attributed to have certain side effects when it may really be the combinationthat's giving that toxicity. so what are the big clinical trials out there for phase iii?we have, i'm sorry, this here, revlimid [inaudible] with ixazomib. so this would be a completelyoral regimen with ixazomib being the oral proteasome inhibitor. rev, dex, elotuzumab,this is the one that was the cs1 monoclonal

antibody. the remission seemed to be veryimpressive duration. we have some patients, we call them the bridge club. they've beena clinical trial and it's been, they've been together for so long that they play bridgeevery week when they come in. we have velcade, dex, daratumumab, revlimid, dex dara, whichis the cd38 monoclonal antibody. kyprolis with dex verus velcade, dex as a comparisonto see, it's a head to head study. pomalidomide with velcade, dex, so all the permutationsthat you would expect here. and this is a more complicated slide. this is i think whywe're hopeful and encouraged with all the progress in myeloma. so what i've shown youhere is the same drugs that we saw at the beginning in black and we've added all thehot new and interesting drugs to show you

where work is being done. so there's threeadditional proteasome inhibitors here. so ixazomib, prozumib, marizomib, these are thenext generation proteasome inhibitors. there's also two other [inaudible] inhibitors. voinostat'salready fda approved for another type of cancer but ricolinostat is a specific hdac6 inhibitor.this category of drugs, the [inaudible] inhibitor at last year's hemotology meeting showed singleagent activity. so this class of drugs is basically what we call signal transductioninibitors which mean the cell basically has signals from the outside of the cell intoit to make it grow and stimulate proliferation. and these block those pathways. so [inaudible]is a good example. we have a couple of clinical trials with ibrutinib which is fda approvedfor other b cell cancers but it's being combined

with carfilzomib. filanocit [phonetic] sothis, this next category is drugs that interfere with the ability of the cell to divide becausecancer cells are undergoing division more than typical cells in the body. and so kinaseand [inaudible] protein inhibitor called filanesib has shown some single agent activity. thisis a really interesting drug that we also have at mount sinai, selinexor. it's a nucleartransport inhibitor which basically, the importance of this drug is those of you who saw the emperorof maladies show you heard about the break in the accelerator for cancer. so you havegenes that are the accelerator that make them grow and the breaks that stop them, this drugis basically increases the break to the nucleus to prevent cancer cells from continuing todivide. so it's a really interested molecule

that's showed in a lot of activity, many differenttumor types, not just myeloma. and then we have the monoclonal antibodies which is reallythe hot new thing. you know, it's kind of amazing that we give all these drugs to patientsbut why don't they kill the rest of the body? you know, why is it that when you take a pilllike an imid, why are you having all these other medical problems like hair loss andskin changes and all those other things? we don't know. that's the short answer. the longeranswer's these, this class of drug is going to get away from that nonspecific approachand really hit the target that you want. for example cd38 with the daratumumab. and there'salso work being done with new bone targeting agents. you'll be hearing in the next talkabout bone diseases, super important from

patient experience point of view. how canwe do more than just [inaudible] so a lot of interesting work. so going back to ourpatient case, the guy who had initially myeloma, got triplet rvd therapy, got transplant, revlimidmaintenance and was in a complete remission. then he relapses three and a half years laterand he has anemia, moderately low platelets and kidney failure. and so the reason thisis why he's not necessarily the best clinical trial candidate. he's a pretty sick guy. kidneysare not working. his blood counts are low. he may not even meet eligibility criteriafor clinical trials. and so this patient would be better served at this moment in time witha conventional approach with drugs that are not going to be renally clear. and so bortezomib,cyclosphosphamide and dex or cybord would

be a perfectly good combination for this guy.and it would bring him, and he responds well to the treatment. and then at the next relapsewhenever that may occur, that may be a better time to do a clinical trial rather than atthis moment in time. and so to summarize we've made a lot of progress in treating relapseand refracting myeloma. people can get multiple lines of therapy, basically we're going togo through that whole box of chocolates. treatment can sometimes be continued for extended periodsof time. we generally at mount sinai prefer to start with three drug approaches. the ideais if you have a high disease burden, knock it down quickly and then you can deescalateto two drugs, one drug and go to maintenance as opposed to sometimes the community physiciansstart with two drugs and then try to catch

up. so particularly when you have somebodywith renal failure time is important, time is kidneys, so you want to act quickly. andwith each drug there's all these different combinations. and you're going to hear evenmore about clinical trials in the future. so with that i'll stop and happy to take anyquestions. thank you. [ audience applause ] yes [inaudible]. >> there's a lot of information about viruses,treating myeloma, a lot of publicity on that. you [inaudible] you mention anything aboutthat today. what is your feeling on that? >> yeah, because i was trying to stay to metask assignment which is approved drugs. so

you'll be getting more about that from theclinical trials. but i think viruses are like with all immunologic approaches it's goingto be an interesting area of research. probably the biggest thing that people have heard aboutwould be the measles virus. but one of the limitations in that study was, you know, it'sa typical phase i dose escalation study where you start with low doses and you have to keeptitrating up, titrating up. and really there were no response, no response, no responseand in then just at the very, very high maximal dose there was a patient that responded. andwhen expanded it looked like the only people that really might have that benefit wouldbe people who are not immune to measles. which is very uncommon in the u.s. so it speaksto the generalizability of that particular

approach. i think the mayo group which presentedthat data is moving on with other approaches and other viruses. but the broader categorywould be called oncolytic viruses. basically using viruses to attack cells that are rapidlydividing. but stay tuned. right now i don't think we have prime time candidate yet forthe typical myeloma patient. any other, yes. [ inaudible audience question ] >> can you talk a little bit about that andalso if the renal issues are revolved, are those patients more likely to have the renalproblems come back and how do you deal with that? >> so the basically the question's about renalfailure patients. so in a [inaudible] important

generalizable message here for everyone ismyeloma kidneys are precious and we try to protect them. so we tell every patient thatcomes in our door avoid nonsteroidal anti-inflammatory drugs like motrin, advil, ibuprofen, all ofthose are kidney damaging agents. tylenol is much safer. secondly avoid all intravenouscontrast with ct scans. while mri's and pet's are okay, intravenous ct scans should be avoided.and there's a lot of technology, mri, pet, ultrasounds, you really shouldn't do that.so those are general applicable for everyone. for the patient with newly diagnose myelomawho has renal failure there's actually data showing that the, if you treat effectivelyand you, the patient responds, these patients have a comparable of course to patients whopresent without renal failure. and that's

a testament to all the novel drugs that havebeen approved. but if we were to go through that table, pretty much you could use allthe drugs there and the drugs that would have to be modified for a kidney dysfunction andoh, there we go. so, oops, go, okay, so. steroids very easily to use in renal failure. no dosereduction required. thalomid and pomalidomide, no significant reduction. lenalidomide isrenally clear so you have to adjust the dose. these two drugs, you don't need to adjustand can be used. melphalan has to be adjusted. this is why dialysis patients for examplecan get a transplant but you have to reduce the dose of the melphalan. cyclophosphamide,very easy to use in renal failure. our colleagues in nephology use i a lot. doxil can be used.[inaudible] can be used but has to be modulated.

these two drugs do not require significantmodification. we don't have yet much data for this drug. so but basically you can againgo through all of these drugs in different combinations and permutations but would haveto adjust the drug. and the earlier you can reverse the renal dysfunction, the better.and people just because they have initial renal dysfunction it doesn't mean that they'regoing to keep relapsing every time. and one of the reasons we're also getting better atpreventing renal dysfunction is because historically we used to have to put all of you throughthose repeated 24 hour urines which we still do periodically. but the serum free life chainis really good surrogate and in some ways is more reliable than the urine collectionbecause the urine collection is subject to,

you know, degradation and the warmer temperature.you have to do a full collection, depends on the volume status. whereas the free lifechain tends to be more reliable. so in somebody who has renal dysfunction the first uptickin the free life chain might, you know, you want to jump ahead and keep ahead of that.but we do need more data. and in fact every drug that gets approved, the way it worksis first tested in normal patients with normal renal function. and then if you want to geta label from the fda to use it in renal dysfunction and we have a study, some of our patientsin the room have participated in this study. for example, ixazomib we are, our center'sthe [inaudible] to that drug because it's a great thing for our dialysis patients. imagineyou spent three days of the week already getting

dialyzed. and now you have to go to the doctor'soffice the other two days. it's really miserable for the patients. and this drug would reallychange that because it's orally, it's an oral proteasome inhibitor. and but we're doingthe formal what we call pharmacokinetics which is how does this drug get cleared by the body.and that'll allow the label to have renal dosing guidelines. so it's really important.and lastly i would mention that these monoclonal antibodies, antibodies are not cleared bythe kidney. so it's a great class of drugs to add to the arsenal. so a lot of interestedwork in renal failure. >> are there are studies about, let's assumeyou have multiple myeloma and you're on a maintenance revlimid, low dose dex and thentotally apart you're diagnosed with another

cancer. and the doctor says oh for that ineed to put you on chemo. well wait, i'm already on chemo. are there, can you take two chemo'sat the same time or does one size fill? >> and this came up a little bit earlier aboutthe whole issue of secondary malignancies. we do know that these imid drugs do increasethe risk of cancer somewhat. but we also know from the swedish studies that even peoplebefore they get any treatment, [inaudible] patients have a higher risk of getting secondarycancer. so there's an inherent genetic probably instability that predisposes to patients tomyeloma. it's uncommon but it's known compared to the general population. with that saidthen it comes back to the specific of the drug, the patient. so for example i have apatient who has breast cancer that's active

with concurrent myeloma. and two of the drugson here have very good activity for breast cancer, cyclophosphamide and doxil. so wecan combine those and try to hit two cancers at once. so we work with the other oncologisttreating the other tumor types to try to find the best cocktail of drugs. yep? >> could you talk about how you keep up withthe research? it seems overwhelming certainly to me. >> you know, i would say it's even harderto be a general oncologist. at least i have a disease that i focus on. but i don't knowhow the community docs keep up with all the different tumors. which is why i think wehave to work as a collaborative fashion, right.

not every patient can come to manhattan andget all the treatments here. so what we try to do is partner with the local oncologistand guide them and hold their hands, say here's the regimen, here's the doses, here's theschedule. you give it and it's good for the patient and the doc and then they come back.so by no means am i an expert or any of us in the room who are specializing in myelomaexperts in all cancers. but, you know, that's the tradeoff. either you're a generalist ora specialist. so you know a lot about one thing or a little about a lot. you've gotto pick your poison. well you see that, you know, i think that's one of real testamentsto the mmrc is the fact that we could have filled this entire panel with just one institution.but and in some ways you could consider this

completing institutions. but we're all inthe same boat here. we're all trying to help advance myeloma care. and i think it willreally is collaborative. and we sit on the international myeloma working group meetings.and we've all seen each other ad nauseam and many, many meetings so i think it's really,it is a collaborative effort. and i think the europeans do a much better job in partbecause of drug access. they're forced to work together. i think, you know, one, atthe rates of clinical trial participation in the u.s. are dismal. you know, probablyless than 10%, 5%. europeans 30, 30 to 40% of european patients are participating inclinical trials. and in contrast american pediatric oncologists, 90 to 95% of pediatriconcology's on a clinical trial. i think it's

because it's so rare that they know that inorder to really advance pediatric oncology they have to collaborate. oh, drug access.the dean of stanford's school of medicine said that you can divide healthcare into qualityaccess and cost. and you can have two out of those three but you will never have allthree. and i think in the u.s. we don't, in some ways we do not have universal accessyet. we do not have low cost by any means. we spend far more than most western countries.but if you define quality as getting these hot new drugs when you want them, yeah. butif you define quality as like low neonatal or maternal mortality, we're horrible. andin contrast in europe you have universal access, low cost, but if you want quality which ishot new drugs, you're not going to get it.

the only way to get them is in a clinicaltrial. so it's socialized medicine versus non-socialized medicine. yeah. >> yeah, you mentioned neuropathy particularlywith velcade and there are ways to modulate that. hoping you can expand on that in particular,you know, what can i do to modulate neuropathy and stay on velcade? >> so i'm going to briefly mention that becausethat's going to be a great segway to dr. scarborough's talk. that, so you can modulate the dose ofbortezomib, less, lower dosing will help. there's frequency, instead of twice weekly,weekly, the route, instead of ivs, subq. look for other causes of neuropathy so b12 andcarnitine deficiencies are easy to fix. those

are nutritional supplements. and there's somedata that alph lipoic acid, vitamin e can also be helpful. so those are the main strategiesto try to help with neuropathy and dr. scarborough who's our colleague in palliative care medicinewill be able to comment further. sorry, oh i'm told we have one more question, okay.yes? >> hi, you mentioned the importance of genomicanalysis in when somebody has relapsed. what i'm wondering is how far along are we withmultiple myeloma in being able to say okay, if you've got this genomic profile then thisis the drug combination that's right for you? >> that's a really good question. we definitelydon't have, we're not at the point where we can do this for every patient in the u.s.across the board in myeloma. but i can tell

you that, you know, the translocation 414is one example of a specific mutation that might affect therapy. unfortunately, you know,if you look at this table of drugs, we really don't have any biomarkers that say okay, ifyou have a low level of this or a high level of that you should get this drug. and that'swhere we need to get. but i can tell you some of the interesting work that we've been doingat mount sinai. we have one of the largest, eric shot [assumed spelling] is a world renownedinformatics person and he was recruited from california from a biotech, informatics. andi'll get to what that means in a second. but basically what they did was really cool. theytook for example, inflammatory bowel disease and the patients weren't responding, theyscreened, they took the genetic profile of

the cells and screened it against a batteryof drugs that are available already commercially to try and predict where you might see anactivity. and interestingly they found anti-seizure medication which had no previous use or activityin that disease and found that it seemed to help. and that's now moved to clinical trialsand shown a clinical benefit. we're doing the similar thing on a case by case basis.it's basically called drug repurposing where you, a patient who has relapsed myeloma, wewould take their bone marrow aspirate and work with our informatics colleagues to tryto get a personalized output for that patient about maybe drugs that not, may not even beon this table. it may completely unheard of and maybe, you know, scleroderma or lupusand it seems to have a signal. and, and obviously

this has to be in tightly, you know, has tobe done under supervised clinical trial setting. i sit on the irb where institutional reviewboard, we can't just go testing any drug willy nilly. so you have to show that there's ascientific rational, the drug's approved and then you could try these [inaudible] uses.