[Music] my name is maria choudry i am a myeloma doctor and researcher at the ohio state university comprehensive cancer center my research and my clinic is focused on the care of multiple myeloma patients i will first talk to you about linoleramide so linalidamide is a oral agent it's oral drug that is uh sold in the us under the trade name revlimid and it is uh it was actually fda approved for the first time in 2006. now it is used as a part of a regimen um for newly diagnosed multiple myeloma patient as frontline therapy in both transplant eligible as well as transplant ineligible patients when it is used as a frontline therapy it is combined with botismi and dexamethasone in transplant eligible patients while in patients who are not transplant and if they are fragile and have co-morbidities which means other medical conditions then it can be used alone with dexamethasone while in patients who can tolerate three drug regimens it is uh used in combination with buddhism and dexamethasone as well as in combination with daratumumab and dexamethasone again in transplant ineligible patient linalidamide is also used as maintenance therapy after autologous stem cell transplant in patients who are not um linolidamide refractory or patients who tolerate linolenide well as a part of frontline therapy it can be used again in relapsed and refractory setting and in those situations in these patients it is combined with the proteosome inhibitors like carpholizimab or exacerb or immunotherapy drugs like daratumumab or ilotusa map linalidamide is taken as is taken orally and the schedule is when it is used as a part of combination regimens um it is used at a dose of 25 milligrams every day days 1 through 21 of a 28-day cycle which means you take it every day for three weeks then you have a week break and when linalidomide is used as a part of maintenance therapy after autologous stem cell transplant it is uh taken as 10 milligrams every day we have to be careful um using this drug in elderly patients and fragile patients um in these patients i start with a modified dose i start with a lower dose which is 15 milligrams just to make sure that they don't get into trouble with side effects and toxicities of this drug we have to be careful while prescribing this medication to patients who have kidney disease kidney problems in these patients i start at a lower dose because these patients tend to get into trouble with more cytopenias like neutropenia so i start with anywhere between five milligrams to 15 milligrams and if the patient tolerates okay then always consider going up to the maximum dose of 25 milligrams orally in terms of side effects the most common side effect that patients have or trouble with is a feeling fatigued and tired another side effect that bothers them is diarrhea patients can have malgias joint pains generalized body aches and pains patients can have pluridis or rash as well linoleumite also causes uh bone marrow suppression which means it can lower the cell blood cell count and can cause anemia um low platelet counts um and uh low white cell count some other rare side effects but adverse events that can happen are incidents of clots we have seen patients who get linoleumite especially in combination have higher incidence of getting arterial as well as venous blood clots and there is also an increased incidence of having other malignancies so how to deal with these toxicities and these side effects so i always tell my patients report each and every symptom even if you are thinking that it's not related to drug but always report make a diary report these symptoms to your doctor because your quality of life is important and we want patients to be able to do every day what they like to do and avoid treatment discontinuations and interruptions but at the same time maintain quality of life as i said so in terms of major side effects like fatigue if the patient is having what we call grade three or grade four fatigue which means that they are um at a point where they are not able to do what they like to do every day and are spending more time in couch and bed than those modification is indicated and we slightly go down on the dose and it helps the patient and they're able to continue with the therapy diarrhea is another bothersome side effect that can of course affect the quality of your life so it we i always tell patients make sure that you hydrate yourself well uh patients can use over-the-counter anti-diarrheal agents like immodium and there is a hypothesis that linalidomide interferes with the absorption of bile acids in the intestine uh bile acids are the are the secretions from liver um that go into the intestine and they help in the absorption of lipids um so linoleimide affects the reabsorption of those pile acids and this leads to diarrhea so in my patients i have success in controlling the diarrhea by giving them bile acid sequestrants like cholesterol so that's another drug that your doctor can prescribe and again if the diarrhea is aware then those modification is indicated at that point patients can have a rash and pruritus and this can be treated with over-the-counter anti-stamin drugs like benadryl or citrizine if the rash is aware and is generalized all over your body then we have to do a treatment discontinuation for a short period of time and treat the patients with steroids i never had to stop the treatment because of rash because we are able to control it with these agents and eventually patient becomes becomes tolerant and do not get rash again and then it can lower your cell count by causing the bone marrow suppression so the patients get frequent blood count monitoring and if needed especially in patients who have relapse refractory disease they get blood transfusions and growth factors we have to monitor our patients closely for infections and the infections are monitored and if needed we do some prophylactic measures for example in patients who are on front line therapy and then fragile antibiotic prophylaxis for first few months of treatment is indicated um to decrease the risk of infection in patients who are developing severe infections needing hospitalizations we do intravenous immunoglobulins which is a blood product composed of antibodies and they help and this product help decrease the risk of infections in myeloma patients and always get immunizations vaccinations our patients should get yearly flu shot and before they start the treatment with the anti-myeloma therapy we always give them pneumonia vaccination and then um there's a risk of uh blood clot blood clots arterial as well as venous so always talk to your doctor about profile exercise which is which means um medications to prevent the blood clot we always do um aspirin which is an anti-platelet agent in patients who are at high risk of having a blood clot for example the patients who have significant cardiac history patients who have history of stroke or blood clots in past we um do prophylaxis with anticoagulation agents like lobinox or aliquips or other oral anticoagulants there is a risk of developing other malignancies so patients should always get their age-appropriate cancer screening and their blood work is monitored periodically while they are on linolenidamide for any other hematological malignancy um another um what else do i need to mention um linolenidamide the prolonged use of linolenide can impact the ability to collect the stem cells so if the patients decide not to get the upfront or early autologous stem cell transplant then always discuss with the doctor about the collection and harvesting the stem cells and keeping them for future use and then linoleridamide is also teratogenic which means it can cause harm to the fetus so patients who are prescribed lena lena might have to go through rams program patients actually pharmacy as well as a provider have to go through this program to make sure that adequate patient is aware and they are taking adequate precautions to avoid pregnancy so mechanism of action so linalidamide is what we call an image molecule immunomodulating agent um this uh pretty much uh defines the mechanism of action of this drug um so this medication has a direct effect on myeloma cells and causes cell death um the tar i'm still doing i'm sorry the target of linoleida is a receptor protein which is called cerebron linolenidamide binds to the cerebellum and increases its affinity for certain transcription factors and when cerebral binds to those transcription factors it leads to degradation of those transcription factors and eventually um interrupts the pathways that are needed for cell survival eventually leading to cell death so lenovite has this effect direct effect on myeloma cells and causes cell death it also modulates the immune system which means that it enhances the ability of immune system to recognize the malignant cells and inactivates the immune system as well and it literally does so by um causing the activation and proliferation of t cells and nk cells which are immune cells as well as causing the inhibition of some pro-inflammatory cytokines which are the substances in the body that cause inflammation linda might also have anti-angiogenesis effect which means that it decreases the blood supply to the tumor cells by decreasing certain substances like wedge f um tnf alpha and interleukin-6 and it and as a result of this effect you can say that the tumor is starved um so this is the mechanism of action of this drug which is imid or lenalidomide cereblon is a receptor protein ligase and it is expressed in immune cells like b cells and t cells um and the it binds with the certain transcription factors and keeps them under check um when uh linalidamide binds to cereblon it increases its affinity its ability to bind to those transcription factors and cereblon is a ligase protein it causes a degradation of those transcription factor linalidomide potentiates that effect and eventually it interferes with a cell cycle which is needed for cell survival and cell growth and eventually leading to what we call apoptosis or cell death myeloma cells do express cerebellum um the degree of expression does varies uh uh but they do express that like how do you know if you still have a test for that or that's a yeah that's a great question um and i'm glad that you asked this question because this question makes sense that if we know a molecular target for a drug can we develop a test to um quantify that target and use that test to as a predictive biomarker to know if the drug is going to work or if the patient is going to be resistant to that drug so it's a great question so there are two uh parts of answer uh part of part number one is uh there is no validated test that can measure the uh for now that can measure the expression protein expression of cerebrum or the gene expression various studies have been published over the last few years that has looked at this again protein expression as well as gene expression but the results of these studies are very inconsistent a part of it the part of the rationale reason is that there are various gene variations in in gene expression that also limits the ability of this essay so there is no validated test right now the second part of the answer is as i told you before as i mentioned that revlimid or linoleidamide again causes this immune modulating effect okay and it is combined with some other anti-myeloma therapies and it has synergistic activity um so um using the cerebellum assay might not be consistent might not give us a consistent result because of some other mechanism of actions of linolenidomide uh this drug increases the risk of having other malignancies so it's important that your doctor monitor you for that and get periodic blood work for the monitoring of any other hematological malignancy and you should always get age-appropriate cancer screening other second malignancies include hematological malignancies there is increased risk of developing leukemias and mds as well as solid tumors like colon cancer and breast cancer i have patients in my clinic who got all of these the percentage is small but this is still something that we need to look for and be careful about if you are susceptible to having skin cancer because of ethnicity or a family history or your geographical location lenalidomide can increase that risk as well so you need to have your skin checked as well that's a very good question i um emit linolenidamide or pomalidomide can make you feel fatigued and tired uh so i always tell my patients take it at night before you go to bed if you are taking steroids with image you can take steroids during the day time early morning because steroids can interfere with sleep one of the most common side effects of image is rash and itching so this is a side effect that can scare the patients rash appears as reddish spots it can start from your body or it can start on your arms or legs and it can spread there can be itching associated with rash sometimes patients have a rash as bad as full skin involvement so um it has something to do with immunomodulating action of image in my patients i never give up on image because of rash if the patient has mild rash which means that you have some spots on your arms and your body then i add antihistamine drugs like citrusine during the daytime or benadryl at night and able to control the rash if the rash is swear which means that it involves most of your body and is itching a lot then i hold emit a drug for a week or so until the rash improves and adds citrusine or benadryl at night as well as steroids like um short course of renaissance once the rash improves i'd re-challenge with the same drug i rechallenge within elidamite or pomalidamite and tell the patient that when you restart your imid molecule drug add citrusine or banana drill with it and take it together for a few weeks and then see what happens some patients develop rash again and i go to the same cycle again but eventually patients develop tolerance and are able to take the drug without rash