Multiple Myeloma (MM): Diagnosis, Treatment and Side Effects Management. Transcript. Slide Name & Number

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1 Question 1) Multiple myeloma is a disease of: a) Hematopoietic stem cells b) Reticulocytes c) Plasma cells d) Mature lymphocytes 2) What is the acronym for the criteria used to guide therapy initiation in multiple myeloma? a) POEMS b) CRAB c) FISH d) ASCT 3) Induction regimen choice is largely influenced by: a) Age b) Karyotype c) Cytogenetics d) Stem cell transplant candidacy 4) Preferred induction regimens for multiple myeloma include: a) Single-agent regimens b) Two-drug regimens c) Three-drug regimens d) Radiation therapy 5) Which agent was shown to be beneficial in two Phase III trials as maintenance therapy in multiple myeloma post autologous stem cell transplant : a) Bortezomib b) Carfilzomib c) Thalidomide d) Lenalidomide 6) Treatment options for relapsed/refractory multiple myeloma include: a) Immunomodulatory agents b) Monoclonal antibodies c) Histone deacetylase inhibitors d) All of the above 7) Which agents require venous thromboembolism prophylaxis when used in patients with multiple myeloma? a) Histone deacetylase inhibitors b) Immunomodulatory agents c) Monoclonal antibodies d) Proteasome inhibitors Slide Name & Number Overview of Multiple Myeloma (MM) Slide 5 Symptomatic Myeloma Slide 14 Induction Slide 16 Preferred Induction Regimens Slide 17 Three Drugs are Better Than Two Slide 18 Maintenance Therapy Slide 35 Relapsed/Refractory Myeloma Slide 36 Therapy Related Adverse Effects Immunomodulatory Drugs Slide 49 Page 1 of 28

2 8) Which agents require venous viral prophylaxis when used in patients with multiple myeloma? a) Histone deacetylase inhibitors b) Immunomodulatory agents c) Monoclonal antibodies d) Proteasome inhibitors 9) Which agents require electrocardiogram and electrolyte monitoring at baseline and intermittently during treatment when being used in patients with multiple myeloma? a) Histone deacetylase inhibitors b) Immunomodulatory agents c) Monoclonal antibodies d) Proteasome inhibitors 10) Multiple myeloma patients receiving high-dose steroids require anti-infective prophylaxis against: a) Herpes simplex virus b) Influenza B c) Pneumocystis pneumonia d) Pseudomonas 11) A unique side effect of bisphosphonates that requires monitoring in patients with multiple myeloma is: a) Renal insufficiency b) Osteonecrosis of the jaw c) Osteonecrosis of the hips d) Pancytopenia Therapy Related Adverse Effects Proteasome Inhibitors Slide 50 Therapy Related Adverse Effect HDAC Inhibitor Slide 52 Infections Slide 53 Bone Health Slide 62 Nursing Considerations in Caring for Multiple Myeloma Patients 12) The following are strategies for patients taking steroids: a) Take with food, take anti-viral agent, exercise b) Take in AM, take antidyspepsia medication, monitor for fever c) Take ibuprofen, take anti-bacterial, drink extra fluids d) a and b 13) Risk factors for Deep Vein Thromboses include: a) Polypharmacy and poor nutrition b) Testosterone c) Travel and smoking d) Anorexia 14) Sensory signs of peripheral neuropathy include: a) Difficulty opening things or inability to feel small objects b) Difficulty hearing, ringing or buzzing in ears c) Trouble fastening buttons d) Difficulty ambulating Managing Steroid Related Side Effects Slide 68 Learning Objective: Managing side effects and long term considerations Thromboembolic Events -DVT/PE Slide 73 Learning Objective: Managing side effects and long term considerations Peripheral Neuropathy Slide 69 Learning Objective: Managing side effects and long term considerations Page 2 of 28

3 management. SLIDE 1: Multiple Myeloma (MM): Diagnosis, Treatment and Side Effects Management Lauren Berger: Hello, everyone. On behalf of The Leukemia and Lymphoma Society, thank you for sharing your time with us for this continuing education program on multiple myeloma, diagnosis, treatment, and side effects SLIDE 2: Welcome & Introductions Describe the pathophysiology of multiple myeloma Identify tests used to diagnose disease and monitor treatment Explain the overarching goals of treatment for multiple myeloma List approved and emerging treatment options, including stem cell transplantation, and the role of clinical trials Describe strategies to manage treatment side effects as well as potential long-term and late effects of treatments We are fortunate to have as our presenters, Dr. Sagar Lonial, one of the nation s leading experts in multiple myeloma and his colleagues, Dr. Elyse Hall Panjic, a clinical oncology pharmacist and Miss Charise Gleason, a Nurse Practitioner. We appreciate their dedication and their commitment to caring for patients living with blood cancers. SLIDE 3: Faculty Dr. Sagar Lonial is Chair and Professor, Department of Hematology and Medical Oncology, and Chief Medical Officer, Winship Cancer Institute, Emory University School of Medicine. Dr. Elyse Hall Panjic is Clinical Specialist, Hematology Oncology, Emory University Hospital. Miss Charise Gleason, is Nurse Practitioner, Department of Hematology and Medical Oncology, Chief Advanced Practice Provider, at Winship Cancer Institute of Emory University, in Atlanta Georgia. Our special thanks to Dr. Lonial, Dr. Hall Panjic and Miss. Gleason for volunteering their time and expertise with us. Dr. Lonial, I am now privileged to turn the program over to you. SLIDE 4: Multiple Myeloma Diagnosis, Treatment and Side Effects Management Dr. Sagar Lonial: Thank you very much, and I appreciate the opportunity to spend the next few moments talking a little bit about some of the really amazing advances that have occurred in the management of patients with myeloma. And before we get to some of those new innovations and new drugs and talk about how to manage and use those drugs in the most optimal way, I want to start off with a little bit of an overview of myeloma in general. SLIDE 5: Overview of Multiple Myeloma (MM) So, multiple myeloma is a malignancy of plasma cells, and these are cells that live within the bone marrow. And their main function is to make antibodies, typically in response to either an infection or in response to a vaccine. And what Page 3 of 28

4 occurs with myeloma is proliferation of monoclonal plasma cells, all of the same origin, that then accumulate in the bone marrow, resulting in bone destruction as well as consequences of marrow failure. Now, one of the things that are important about myeloma is that we have biomarkers to assess overall disease status, and these include following something in the blood called a serum M protein, or a pair of proteins. And typically these proteins are of an IgG, IgA, or IgM phenotype. And so, we actually have one of the first biomarkers to assess efficacy or lack of efficacy of our treatments. And this is a really important thing to do because, unlike many other cancers, we don t always have to use CAT scans to know whether or not the patient is responding to therapy. We can use some of these biomarkers like gamma globulins or M protein. SLIDE 6: Epidemiology Now, in terms of epidemiology of myeloma, there are about 30,000 new cases per year, about 12,000 total deaths, but that makes the actual number of patients with myeloma in the U.S. somewhere over 60,000 patients at any given time point. And the risk factors are really not very well known, except that we know that African Americans seem to be a much higher incidence of developing MGUS (monoclonal gammopathy of unknown or undetermined significance 1 ) or myeloma, almost 2:1 compared to non-african American patients. The median age at diagnosis is in the mid to late 60 s, and there is some hint that perhaps chemical exposure, the same kinds of things that we see with other blood cancers, may be risk factors for developing myeloma. But, at this time point, because of the relative rarity of patients developing myeloma, there is no routine screening that is recommended for myeloma at this time point. SLIDE 7: Diagnostic Workup So, when we think about an appropriate diagnostic workup for patients, it is important to make sure that a thorough and complete workup is done at diagnosis. And the NCCN practice guidelines have very nicely outlined what we consider to be standard of care for patients with newly diagnosed myeloma. And that includes chemistries, CBC, albumin and beta-2 microglobulin that are needed for staging, assessment of the monoclonal protein in both the serum and the urine. That requires a 24-hour urine collection with urine immunofixation, as well as a serum immunofixation, as well. It also does require the use of the free light chain assay, which is a kappa and lamda assessment within the blood--not within the urine but within the blood. From a diagnostic perspective, it also requires a bone marrow (biopsy) to assess plasma cell numbers in the bone marrow as well as chromosomal and FISH (fluorescence in situ hybridization), or some form of genetic analysis to understand what the risk for a given patient is. 1 MGUS (Monoclonal Gammopathy of Undetermined Significance) is an asymptomatic condition in which there is a presence of an abnormal M protein in the blood. MGUS can evolve into a progressive B- lymphocyte malignancy such as myeloma or lymphoma in about 30 percent of patients affected over 20 years or more of observation. Source Myeloma Booklet - Page 4 of 28

5 From an imaging perspective, the baseline has included the use of a skeletal survey, which is a series of x-rays done throughout the body to look for lytic bone disease. But, more modern approaches have now used PET-CT scans, low-dose whole body CT scans, or MRIs to better understand the extent and level of bone involvement in patients at the time of initial presentation. SLIDE 8: Criteria for Diagnosis of Myeloma Now, it s important to realize that myeloma is a plasma cell disorder, as I mentioned before, but it does not occur in pure isolation. There are other plasma cell disorders that are important to be differentiated from myeloma, and that includes MGUS or monoclonal gammopathy of unknown significance, smoldering myeloma, or SMM, and, finally, active myeloma. And what distinguishes active or symptomatic myeloma from the other two categories is the absence of what we call CRAB criteria. And the CRAB criteria represent hypercalcemia, renal insufficiency, anemia, and bone disease. And in the absence of those, a patient is considered to have either MGUS or smoldering myeloma. Now, in the last two years the International Myeloma Working Group did redefine what it means to have symptomatic myeloma and, in addition to the CRAB criteria, added in three other criteria that are being used in daily practice now. And those include an abnormal free light chain ratio of greater than 100, a greater than 1 focal bone lesion by MRI, or greater than 60 percent plasma cells in the bone marrow. And those are now considered to be diagnostic for myeloma, not necessarily smoldering myeloma, which is where they may have gone in the past. SLIDE 9: Smoldering Multiple Myeloma Now, smoldering myeloma is an entity that is somewhat separate from myeloma in the sense that it has a different natural history than myeloma. Patients with symptomatic myeloma clearly need treatment because they have symptoms that require intervention to reverse. Patients with smoldering or MGUS, as you can see here, do convert to myeloma over time but at different rates and frequencies. And so, MGUS- -the teaching is basically 1 percent per year will progress versus in smoldering myeloma it s on average 10 percent per year. But, if you can get all the way out to five years with smoldering, your risk of progression then drops to 2 percent per year, so it begins to look much more like MGUS than like smoldering myeloma. And separating out the true smoldering that are going to convert to myeloma from typical MGUS, which in all likelihood will not, is a current ongoing diagnostic challenge, as we move forward in managing these diseases over time. SLIDE 10: Myeloma Progression Now, the typical story that s used in terms of the natural history of patients with myeloma is that all patients have some sort of an MGUS or smoldering myelomatype state, and that eventually progresses to an active myeloma state. Patients achieve a remission and then have subsequent relapses with shorter and shorter durations of remission. And I will tell you that this figure is actually not one of my favorite figures because I think many of the new drugs that we have are changing this paradigm. Page 5 of 28

6 We are getting longer and longer remission, even in late relapse, because we have new mechanisms and new biology that is helping to drive some of those responses over time. So, this is a schematic way to think about the disease, but in terms of time it may not always be an accurate representation of what an individual patient experiences over time. SLIDE 11: Revised ISS staging Now when we talk about staging patients with myeloma, it s important to realize that we now have the revised International Staging System (ISS) that came out about a year and a half ago now, and that revised staging system takes the old ISS, which is at the top of the table here, which looks at beta-2 microglobulin and albumin and combines it with two other known independent prognostic features. That is FISH use, with the presence or absence of 17p, 4;14, or 14;16 translocations with LDH (lactase dehydrogenase). LDH, again, is known to be an independent prognostic marker, and you amalgamate both genetics and LDH with the old ISS. And at the bottom you come up with what I m showing you here, which is the revised ISS or the R-ISS (Revised International Staging System) staging system, moving forward. And this is the staging system that should be used for all patients seen now, and going forward in the future. SLIDE 12: Risk Stratification Now, what about individual risk stratification by itself? I mentioned to you that I think genetics is really important. We know that, for instance, patients with 4;14, 14;16, or 17p deletion have high-risk disease. We know that patients with 11;14 translocation have standard risk disease, and patients with hyperdiploidy, or extra copies of odd numbered chromosomes appear to have good risk disease. And it s important to understand that in certainly in many of these situations, these are used to guide how patients are treated in either the induction therapy setting or in the post-transplant setting as well. SLIDE 13: MM Related Diagnosis Now, what are other diagnoses that may be somewhat similar or overlapping with multiple myeloma? These are other disorders that you might see in the same vernacular as myeloma, and they include MGUS, or monoclonal gammopathy, Waldenstrom s macroglobulinemia, which clinically presents differently than myeloma, although it can be similar to an IgM-type myeloma. There are patients who have primary amyloidosis, where they may not have a very large protein, but that protein can have significant impact on renal, cardiac, hepatic, or overall performance status and function. And that can be far more important than the manifestation of the plasma cell disorder, in of itself. There can be patients who have either just heavy chain or light chain-based diseases, that either impact, again, cardiac function or renal function. There is plasma cell leukemia, which is usually seen in the advanced myeloma stage, that can be present at the time of initial diagnosis--and, of course, an overlap syndrome that is actually biologically quite interesting, called POEMS (Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, where patients can have a low-level M protein. But, they have endocrinopathy, they have organomegaly, and they usually have some level of peripheral neuropathy as well. And Page 6 of 28

7 these are patients that are often treated similarly to amyloid patients and can have significant benefit from the use of high-dose therapy and autologous stem cell transplantation. SLIDE 14: Symptomatic Myeloma Now, as I mentioned before, symptomatic myeloma is really defined by the presence or absence of the CRAB criteria, and each of these CRAB criteria does have to be relatable to the plasma cell disorder. So, simply having anemia because of iron deficiency and a plasma cell disorder does not make you symptomatic. The two have to be somewhat related in order to be important. SLIDE 15: MM Treatment Now, as we think about myeloma treatment, we break it down into a couple of categories, and we re going to cover some of these categories as we go forward. The first is the induction phase, and this is how newly diagnosed myeloma patients are treated, typically with the goal of trying to minimize their current symptomatology and reduce total tumor burden. The second phase is then stem cell transplantation for suitable patients. And I will tell you that this is a moving target. Many in Europe say that if you are over the age of 65, you cannot have a transplant. That is absolutely not the approach we take in the U.S. And the oldest patients that have been transplanted in our center have been up to age 78, and there are many centers that will transplant even beyond that. So, age in and of itself is not a criteria for eligibility for transplantation. Following transplant, maintenance therapy and how maintenance therapy is tailored, based on risk, is certainly an important discussion. And then, when myeloma comes back, management of relapsed and refractory disease, as well as the supportive care approaches--that are important in how to deal with these patients over time as well. SLIDE 16: Induction Now, as we talk about induction therapy, again, symptomatic myeloma is a requirement, symptomatic myeloma meaning those CRAB criteria or those myeloma-defining events I mentioned earlier as well, including a free light chain ratio greater than 100, greater than 60 percent plasma cells, or greater than 1 bone lesion. And, again, the choice of induction regimen, in my mind, is really dependent on function and performance status. For patients that are not frail, and there is actually a true definition of frail by the International Myeloma Working Group, then they should be considered stem cell transplant candidates and should get a more aggressive induction regimen than a patient who is considered to be frail. SLIDE 17: Preferred Induction Regimens And so, as we think about preferred induction regimens, in my view a triplet is now the standard for fit patients. This includes a proteasome inhibitor and an IMid (immunomodulatory drug) drug. Proteasome inhibitors are bortezomib (Velcade ), carfilzomib (Kyprolis ), or ixazomib (Ninlaro ). IMiDs are thalidomide (Thalomid ) or lenalidomide (Revlimid ) or pomalidomide (Pomalyst ). And typically the most common regimen used is bortezomib plus lenalidomide and dexamethasone (Decadron ), or the RVD combination. Page 7 of 28

8 Second choices, or what I would consider less optimal choices, are a proteasome inhibitor with a cytotoxic agent. This typically would include bortezomib plus cyclophosphamide (Cytoxan ), or the VCD regimen. This, again, is not my first choice, and I think it s not as good as the IMiD proteasome inhibitor combination. Now, other induction regimens, in my mind, that are of some interest, include the use of either two drug regimens, using bortezomib or lenalidomide or carfilzomib or ixazomib. And these are typically retained for patients who are frail because, as I mentioned, fit patients should get a triplet as part of their initial induction. SLIDE 18: Three Drugs Are Better Than Two And the reason why I think patients should get a triplet as you can see from this figure--is that the overall response rate and very good partial response rate increases significantly when three drugs are put into the mix, compared to only using two. And we know now from head-to-head trials that the use of VCD or bortezomib with cyclo-index is inferior to the IMid proteasome inhibitor combination, as published by the French group as well as many retrospective data analyses that have been performed over time. SLIDE 19: Theoretical reason for Antagonism between PI and IMID Now, there are concerns that the IMiD proteasome inhibitor may be somewhat antagonistic. And this is a cartoon describing mechanisms of action for cereblon, which is how the IMiD classes of drugs work in combination with the proteasome inhibitor. And I think it s important to realize that these theoretical concerns of potential antagonism have been over-born by clinical evidence suggesting that these are, in fact, quite active when given in combination together. SLIDE 20: Improving induction can improve high dose therapy (HDT) And so, the summary of how to improve induction therapy and how to optimize induction therapy is that it should use modern drugs, and in my view that means an IMiD and a proteasome inhibitor together. It should use three drugs, not two drugs. And it s important to not under-treat standard risk patients. This is a mistake, I think, that many groups have made in the last decade by saying that because the patient has standard risk myeloma, we are going to give them less intensive therapy. And what I would argue is that that means you are going to offer them a lower chance of longterm remission or even cure. And I think cure is a word we can use in a small subset of patients with myeloma, and aggressive therapy for even standard risk patients is something we should do to try and maximize the benefit that patients get in terms of their initial therapy and sets them up for the use of transplant. SLIDE 21: Transplant versus Conventional Chemotherapy Now, transplant is a treatment approach that has been used for many, many years now, and it was first identified through the use of high-dose therapy in the context of the French group. And what they nicely showed was an improvement in progression-free survival (PFS) and an improvement in overall survival, favoring the group that underwent high-dose therapy and autologous transplantation. Page 8 of 28

9 SLIDE 22: MPR vs MEL200 (tandem melphalan 200 mg/m2 with stem-cell support) And this was followed up more recently by a trial from the Italian myeloma group, where patients were compared with either induction therapy with lenalidomide and dexamethasone and then randomized to MPR (melphalan (Alkeran ), prednisone (Rayos, Sterapred ), lenalidomide) versus a transplant, suggesting that PFS and overall survival was greater for the group that received the transplant than the group that did not receive the transplant. SLIDE 23: MPR vs MEL200 vs MPR-R vs MEL200-R And this was further demonstrated through the use of lenalidomide maintenance, where, again, the best outcomes were seen among the patients who received MEL 200 (tandem melphalan 200 mg/m2 with stem-cell support) as part of their transplant and lenalidomide maintenance as part of their post-transplant management care, compared to the group that either did not receive a transplant or did not receive lenalidomide maintenance. approach 2. SLIDE 24: EMN02/HO95 MM Trial: Study Design Now, more recently a trial was presented by the European group that gave everybody a triplet VCD (bortezomib, cyclophosphamide, dexamethasone) as part of their induction, and then compared VMP (bortezomib, melphalan, prednisone) versus one to two cycles of transplant, again, as part of the treatment SLIDE 25: PFS by Randomization And, as you can see here, there was a significant improvement for the group in red that had the transplant compared to the group that did not. This is progression-free survival, so duration of remission was clearly longer in the group that had the transplant compared to the group that did not. SLIDE 26: PFS by Cytogenetics (High Risk) And, even more importantly, the high risk subset of patients gained about a 10- month improvement in progression-free survival with the use of transplant compared to the group that didn t. And that s important because there are certainly groups out there suggesting that high-risk patients may not gain benefit from transplant. There have now been several studies, even with modern drugs, that continue to demonstrate the benefit of high-dose therapy for patients--even patients who have high-risk myeloma at the time of initial presentation. SLIDE 27: IFM 2009: Study Design Now, the largest study done to date, looking at what I think is the best induction regimen, is the IFM 2009 trial. This was a randomized trial where everybody got RVD (lenalidomide, bortezomib, dexamethasone) as part of their initial therapy and then were randomized to either no transplant in arm A or a transplant in arm B, followed by a couple of cycles of post-transplant consolidation. 2 HDM- high-dose melphalan. CTX-cyclophosphamide. Page 9 of 28

10 SLIDE 28: IFM 2009: Best Response 3 And what I think you see is that the response rate was clearly higher for the group that had the transplant compared to the group that did not. SLIDE 29: IFM 2009: PFS (9/2015) And this translated into an improvement in progression-free survival of almost 10 months, favoring the group that had the transplant, compared to the group that did not. So, even when the best induction regimen is used, there continues to be a benefit in terms of progression-free survival, favoring the group that had the transplant. SLIDE 30: IFM 2009: OS (9/2015) Now, with a very short follow-up of only 36 months, there was no difference in overall survival as yet. But, again, if our goal is to offer patients the best likelihood of cure or long-term disease-free survival, maximizing benefit in the context of remission is, in fact, really important. SLIDE 31: KRd outcomes by Transplant Status Now, there are people out there that would argue that the replacement of bortezomib with carfilzomib in the KRd (carfilzomib, lenalidomide, dexamethasone) regimen may represent the best regimen, going forward. And I would show you data from Andrzej Jakubowiak that suggest that even in patients that get KRdas their induction, the remission duration is clearly better for the patients that have a transplant compared to the patients that don t, again suggesting that transplant does continue to offer benefit, even for patients that are getting modern, very aggressive, very active induction regimens, going forward. SLIDE 32: Getting to Minimal Residual Disease (MRD): New Definitions for CR Now, one of the important messages that has come out in the last few years is that looking at complete remission by conventional criteria is probably not the best way to assess overall response and response duration. And so, we re talking about getting to what I call minimal residual disease, or MRD. And that is levels of disease burden well below what we typically measure in the context of complete remission. And, as an example, you can see from this cartoon that patients that achieve molecular or flow complete remission are much lower on the iceberg than patients who only achieve conventional complete remission. And so, our goal is increasingly trying to get patients lower and lower on the iceberg in order to ultimately increase the fraction of patients that are cured of their myeloma, going forward. 3 CR - complete response. VGPR-very good partial response. PR-partial response. MRD-minimal residual disease. The amounts of cancer cells that may remain after treatment. These cells are only identified by sensitive molecular techniques. source Page 10 of 28

11 SLIDE 33: Outcomes for patients are the same if they achieved MRD negativity And, just as an example, if you look back at that IFM study that I just showed you a moment ago, you can see that -their outcome for patients who achieve an MRD negativity at 10 to the -6 is really very good, compared to patients who don t achieve it or who achieve it at only 10 to the -4 or 10 to the -5, suggesting that this is a reasonable endpoint for trials, going forward. SLIDE 34: Depth of response is more important than how you got there Now, if you look at that same trial, arm A where the patients that did not have a transplant. Arm B are the patients that did have a transplant. And you can see if you got to that 10 to the -6, it didn t really matter. The outcome on both curves was the same. However, two-thirds of patients in arm B achieved an MRD negative CR (complete response), compared to only one-third in arm A, suggesting that you are more likely to get to that benchmark with a transplant than you are without a transplant. And so, I think it is important that we continue to offer patients high-dose therapy as part of their treatment approach because that treatment approach over time is really quite critical. SLIDE 35: Maintenance Therapy Now, what about post-transplant maintenance therapy? Well, there have been two trials now looking at the role of single-agent lenalidomide as maintenance therapy. The CALGB (cancer and leukemia group B) trial in the U.S. demonstrated a significant improvement in progression-free and overall survival. The French trial did not demonstrate an improvement in overall survival. But, this has now been reported out in a meta-analysis, suggesting that there is clearly an improvement in overall survival, favoring the use of lenalidomide maintenance. And I would argue that for standard risk patients, that has become a new standard, going forward, over time. SLIDE 36: Relapsed/Refractory Myeloma So, I think as we begin to summarize the role of transplantation, going forward, it s important to realize that induction with an IMiD and a proteasome inhibitor, the use of transplantation for nearly all patients, and then the use of posttransplant maintenance therapy, are what we have done to really push the field forward and ultimately improve long-term, progression-free, and overall survival. Ms. Elyse Hall Panjic: Okay, thank you. Many patients with myeloma will ultimately relapse. And there are several factors to consider when choosing a regimen to treat relapsed disease. This would include patient-specific factors, such as their co-morbid condition and how previous treatment was tolerated. The previous treatment and duration of response to that treatment also plays a large role in choosing a regimen. Patients with a response to a previous regimen that lasted six, nine months or longer may be treated with a similar regimen. However, in some cases patients may be refractory to certain types of myeloma therapy, meaning they progressed while on therapy or within 60 days of the last treatment on a regimen that they had previously responded to. Page 11 of 28

12 Here you would want to consider therapy that the patient is naive to and evaluate any drug classes that may have not been previously used and incorporating those medications into the regimen. This is where many of the novel agents for myeloma come into play. This would include the newer proteasome inhibitors, carfilzomib and ixazomib, and the newest immunomodulatory agent, pomalidomide. We now have monoclonal antibodies for the treatment of myeloma with daratumumab (Darzalex ) and elotuzumab (EMPLICITI ), as well as the histone deacetylase or HDAC inhibitor, panobinostat (Farydak ). SLIDE 37: Carfilzomib Carfilzomib is a proteasome inhibitor approved in 2012 for relapsed or refractory myeloma. The ASPIRE study evaluated carfilzomib in combination with lenalidomide and dexamethasone for lenalidomide and dexamethasone alone. Progression-free survival was significant in the carfilzomib group compared to the Revlimid (lenalidomide) and dexamethasone alone group, with an increase of 8.7 months as well as the overall response rate of 87 versus 66 percent--was also significant for the carfilzomib group. Patients in the carfilzomib group also had a longer duration of response and were able to stay on therapy longer, compared to the lenalidomide and dexamethasone alone group. A second large stage III clinical trial, the ENDEAVOR trial, compared carfilzomib and dexamethasone to bortezomib and dexamethasone in relapsed or refractory disease. Progression-free survival was also significant at 18 months in the carfilzomib group, compared to only nine months in the bortezomib group, with a median duration of response of 21 months with carfilzomib, compared to only 10 months with bortezomib. SLIDE 38: Ixazomib Ixazomib is the newest proteasome inhibitor, approved in 2015, and is an oral medication that patients are able to take at home on a weekly basis. The Phase III TOURMALINE trial compared ixazomib, lenalidomide, and dexamethasone to lenalidomide and dexamethasone alone. SLIDE 39: Final PFS analysis: A significant, 35% improvement in PFS with IRd vs placebo-rd Ixazomib added to lenalidomide and dexamethasone resulted in a significant progression-free survival of 36 percent, compared to lenalidomide and dexamethasone alone, as shown here. SLIDE 40: Daratumumab: Mechanism of Action Daratumumab is a human CD38 monoclonal antibody also approved in CD38 is a transmembrane glycoprotein that is highly expressed on myeloma cells, that works by binding to and inhibiting the growth of CD38 expressing myeloma cells by complement-mediated and antibody-dependent cell-mediated cytotoxicity effects, antibody-dependent cellular phagocytosis, apoptosis, and inhibition of the enzymatic activity of CD38. In some cases it can activate and increase T cells which also improves response in patients. Page 12 of 28

13 SLIDE 41: Daratumumab Here I will talk about three clinical trials, looking at daratumumab for relapsed or refractory multiple myeloma. The first is the SIRIUS trial that looked at daratumumab at two different doses of either 8 mg per kg or 16 mg per kg. The results here are from the 106 patients enrolled in the 16 mg per kg dose. The overall response rate for these patients was 29 percent. They had a median duration of response of around 7 months and a time to progression was 3.7 months. The CASTOR trial compared daratumumab with bortezomib and dexamethasone to bortezomib and dexamethasone alone. There was a median follow-up of 7.4 months in this trial, in which progression-free survival was not reached for the daratumumab group and was 7.2 months in the bortezomib and dexamethasone alone group. The overall response rate was also significant for the daratumumab group, at 83 percent compared to 63 percent. The POLLUX trial enrolled 569 patients that either received daratumumab, lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone. The median follow-up here was just over 13 months, and the progression-free survival at 12 months was around 83 percent for the daratumumab group versus 60 percent for the lenalidomide and dexamethasone only group. The overall response rate was also significant for daratumumab at almost 93 percent compared to only 76 percent in the lenalidomide and dexamethasone group. SLIDE 42: CASTOR trial Progression-free Survival This depicts the progression-free survival of the CASTOR trial comparing daratumumab plus bortezomib and dexamethasone with bortezomib and dexamethasone alone in the intention to treat population. The Kaplan Meier estimate of progression-free survival at one year is 60.7 percent for the daratumumab group compared to only 26.9 percent in the bortezomib and dexamethasone group. There was a 61 percent reduction in the risk of disease progression or death in the daratumumab group compared to the bortezomib and dexamethasone group. SLIDE 43: POLLUX trial: Progression-free Survival The POLLUX trial also showed improved progression-free survival, and this Kaplan Meier analysis showing that the median progression-free survival was not reached for the daratumumab-lenalidomide-dexamethasone group and was 18.4 months for the lenalidomide-dexamethasone group. The reduction in the risk of disease progression or death was 63 percent for the daratumumab group compared to the lenalidomide-dexamethasone alone group. SLIDE 44: Elotuzumab: Mechanism of Action The second monoclonal antibody approved for myeloma in 2015 is elotuzumab, and it is also approved for the treatment of relapsed and refractory myeloma. Elotuzumab is a humanized IgG1 monoclonal antibody that specifically targets the SLAMF7, or Signaling Lymphocytic Activation Molecule Family Member 7 protein, which is expressed on myeloma cells. It has a dual mechanism of action by both directly activating natural killer cells and through antibody dependent cell-mediated cytotoxicity to cause targeted myeloma cell death. Page 13 of 28

14 SLIDE 45: Elotuzumab The ELOQUENT-2 was a Phase 3 trial with 646 patients that received either elotuzumab plus lenalidomide and dexamethasone compared to lenalidomide and dexamethasone alone in relapsed or refractory disease. Progression-free survival on one and two years was better for patients receiving elotuzumab. The median progression-free survival and overall response rates were significant for patients receiving elotuzumab compared to the group that did not. SLIDE 46: ELOQUENT-2: Extended Progression-Free Survival Here, the extended progression-free survival is depicted for one, two, and three years, all favoring the elotuzumab combination, showing that benefits of this combination is maintained over time. There was a 27 percent overall reduction of risk of disease progression or death with elotuzumab combined with lenalidomide and dexamethasone compared to lenalidomide and dexamethasone alone. SLIDE 47: Relapsed/Refractory Myeloma So, to review, there are several regimens that can be used for patients with relapsed or refractory myeloma. This would include combinations of carfilzomib and lenalidomide with dexamethasone, ixazomib with lenalidomide and dexamethasone, daratumumab alone or in combination with bortezomib and dexamethasone, and elotuzumab plus lenalidomide with dexamethasone. SLIDE 48: Adverse Effects/Supportive Care Now, managing adverse effects and providing appropriate supportive care is important for properly managing myeloma patients. SLIDE 49: Therapy Related Adverse Effects: Immunomodulatory Drugs 4 Many adverse effects are related to therapy. And, first, I will discuss these based on the different drug classes. The three immunomodulatory drugs available are thalidomide, lenalidomide, and pomalidomide. All three of these drugs are oral agents that patients will be taking at home, and so it is always important, as a pharmacist, to discuss the schedule of these medications and timing of taking them to ensure proper adherence. All three drugs have a risk of venous thromboembolism and require prophylaxis, especially when used in combination with high dose steroids. Patients on thalidomide should be monitored for neuropathy while neutropenia and thrombocytopenia are more of a concern with lenalidomide and pomalidomide. Dosage adjustments for these respective adverse effects may be necessary. There is a risk of rash with lenalidomide that patients should be educated on. And, for those patients who are on it for a long period of time, may experience diarrhea. Diarrhea is often not responsive to our regular antidiarrheal agent such as loperamide (Imodium, Diamode) because it is due to bile acid malabsorption. In this case, we like to use bile acid sequestrants to manage diarrhea symptoms in these patients. Patients that are also on lenalidomide for long-term, 4 DLT - dose-limiting toxicity Page 14 of 28

15 especially in the maintenance setting, should be educated on the risk of secondary malignancies prior to initiating therapy. SLIDE 50: Therapy Related Adverse Effects Proteasome Inhibitors There are three proteasome inhibitors - bortezomib, carfilzomib, and ixazomib. Bortezomib has the highest incidence of peripheral neuropathy, and patients should be educated on this risk as well as what other medication can be given in the incident of neuropathy. Patients may also experience gastrointestinal upsets, myelosuppression, and fatigue is common. Carfilzomib has less neuropathy compared to bortezomib, but uniquely, patients may be at risk, although a low incidence of infusion reactions, when initiating therapy. Dexamethasone should be used as a premedication. And, often, patients are receiving dexamethasone as part of a regimen. So, this can be given prior to the infusion on days the patient is receiving both carfilzomib and dexamethasone. Patients should also receive hydration with this medication to ensure proper renal function as tolerated with each infusion. Ixazomib is an oral proteasome inhibitor that is taken at home by the patient on a weekly basis. So, this, again, is another area for pharmacist intervention to ensure that patients understand the schedule of the drugs that they are taking at home. It too has a much lower incidence of neuropathy compared to bortezomib. However, gastrointestinal adverse effects are common, and patients should also have blood counts monitored monthly. All patients on a proteasome inhibitor require HSV (herpes simplex virus) prophylaxis with antiviral therapy. Since many of the proteasome inhibitors - bortezomib, carfilzomib, and ixazomib - are often combined with other oral agents including lenalidomide and dexamethasone, I often give patients calendars to help them understand when they need to take different medications along with any specific instructions they would need. Patients receiving ixazomib, usually in combination with lenalidomide and dexamethasone, are taking the entire regimen at home. So, in this case, I really spend time with them and provide them the calendar to make sure they understand the schedule that they are taking since the ixazomib is given once weekly for three weeks. So, they re one week off, and the lenalidomide is usually given for 21 days in a row followed by a week off. And the dexamethasone is usually given on the same days as the ixazomib. SLIDE 51: Therapy Related Adverse Effects Monoclonal Antibodies The monoclonal antibodies daratumumab and elotuzumab are generally well tolerated with one of the most frequent adverse effects being infusion reaction. All patients should receive premedication when receiving either daratumumab or elotuzumab prior to initiating the infusion. And, for cycle one, patients receiving daratumumab should receive post-infusion reaction prophylaxis as well. Upper respiratory tract infections and fatigue are other common adverse events seen with these effects. As a pharmacist, I always make sure to educate patients on the risk and signs and symptoms of infusion reactions 5 with these agents as this can be quite scary for patients. However, with proper premedication and education, we generally can get patients through therapy without much issue. 5 Daratumumab side effects needing medical attention: Infusion reactions (such as shortness of breath or trouble breathing, headache, dizziness or lightheadedness (hypotension), rash or hives, cough, itching, wheezing, nausea, Page 15 of 28

16 SLIDE 52: Therapy Related Adverse Effects HDAC Inhibitor The histone deacetylase, or HDAC inhibitor panobinostat is also approved for relapsed or refractory myeloma. Severe diarrhea is a common and potentially serious adverse effect with this agent, which can lead to dose adjustment or discontinuation. Patients should be educated to use Imodium or loperamide for severe diarrhea, but also, understand at what point they would need to seek additional treatment for diarrhea that is lasting several days or a patient is having several times each day. Severe or fatal cardiac ischemic events and arrhythmias have been seen with this drug as well. Patients should have periodic ECGs (echocardiogram) and routine electrolyte monitoring. This, again, is where proper management of diarrhea comes into play as patients with severe diarrhea may be at more risk of electrolyte abnormalities and should be monitored closely until their diarrhea resolves. SLIDE 53: Infections Infection prophylaxis for myeloma patients is often based on the regimen a patient is receiving. Patients receiving proteasome inhibitors, as previously discussed, should all receive herpes simplex or herpes zoster virus prophylaxis with either acyclovir (Sitavig, Zovirax ) or valacyclovir (Valtrex ). And patients usually continue on one of these agents indefinitely. Patients receiving high dose steroids should also receive PCP, or pneumocystis pneumonia prophylaxis, with Bactrim (Sulfamethoxazole and trimethoprim). For patients that do not tolerate Bactrim, dapsone or pentamidine (Nebupent ) are other options. For patients undergoing stem cell transplant, there are additional infection prophylactic recommendations that would also include bacterial and fungal prophylactics in addition to the viral and PCP prophylaxis they may already be on. SLIDE 54: Infections Patients undergoing transplant or that have severe neutropenia due to any other myeloma therapy should be initiated on levofloxacin (Levaquin ), fluconazole (Diflucan ), acyclovir, and Bactrim. When we take patients through transplant, we do not start Bactrim until 30 days post-transplant, and generally, continue until 6 months unless they have been started on another therapy that requires PCP prophylaxis. SLIDE 55: Renal Dysfunction Renal dysfunction is also a major concern with myeloma patients and have a place for pharmacy intervention to make sure medications are appropriately dose-adjusted based on the patient s renal function percent of patients present with renal dysfunction and causes may include precipitation of monoclonal light chains and renal tubules or hypercalcemia. Supportive care medications throat tightness, vomiting, runny or stuffy nose, chills), fatigue, nausea, back pain, fever, cough, cold-like symptoms (upper respiratory infection). Source Elotuzamab side effects needing medical attention: Infusion reactions (such as fever, trouble breathing, chills, dizziness, rash, light-headedness); infections; risk of new cancers (malignancies); liver problems; fatigue; numbness, weakness, tingling, or burning pain in your arms or legs; diarrhea; sore throat or runny nose; fever; upper respiratory tract infection; constipation; decreased appetite; cough; pneumonia. Source Page 16 of 28

17 requiring dose adjustment based on renal function include things like acyclovir, levofloxacin, and bisphosphonate therapy that I ll talk about more in a minute. Myeloma therapies such as lenalidomide does require renal dose adjustment. Ixazomib has a lower starting dose for patients that are on dialysis or have a creatinine clearance less than 30. So, it s always important to check any renal dose adjustments when initiating new therapy in a patient that has renal dysfunction. SLIDE 56: Myelosuppression 6 Many patients experience myelosuppression, whether from the disease or treatment related to myeloma. Patients then receive supportive care with either blood transfusions or platelet transfusions as necessary, and again, infectious disease prophylaxis for any prolonged neutropenia. Some patients may even require growth factor support. In these cases, considering dose reductions or interruptions may be necessary to get the patient through therapy safely. SLIDE 57: Peripheral Neuropathy Peripheral neuropathy is an adverse effect that affects many myeloma patients and is usually treatment related. The proteasome inhibitors, as a class, can cause peripheral neuropathy in many patients with bortezomib having the highest incidence compared to carfilzomib and ixazomib. Thalidomide is also known to cause peripheral neuropathy whereas the other IMiDs do not have as high an incidence. Prevention can be key, but it s not always possible. Dose reductions may be necessary for bortezomib and thalidomide-based on the severity of peripheral neuropathy a patient is experiencing. Bortezomib was originally given intravenously; however, now the subcutaneous route of administration is preferred. And this is based on a study that evaluated the efficacy of subcutaneous versus intravenous bortezomib. And they found that subcutaneous administration was not inferior to intravenous. However, patients did experience a significant reduction in peripheral neuropathy with the subcutaneous route. So, now, when initiating patients on bortezomib therapy, we often recommend the subcutaneous route to lessen the incidence and severity of peripheral neuropathy. SLIDE 58: Peripheral Neuropathy Dose reductions for bortezomib are based on the grade of peripheral neuropathy a patient is experiencing. For grade 1 or 2 with no pain, patients will be dose reduced by one level or, if receiving twice-weekly bortezomib, will be changed to once weekly. However, patients that have painful neuropathy or grade 3 or 4 peripheral neuropathy, it is recommended to discontinue bortezomib. SLIDE 59: Treatment of Peripheral Neuropathy There s very few treatment options out there for peripheral neuropathy; although, ASCO (American Society of Clinical Oncology) has published peripheral neuropathy treatment guidelines. Their main recommendation or really only medical recommendation is duloxetine (Cymbalta ) as this was the only 6 PRBC - packed red blood cells Page 17 of 28

18 medication studied for painful neuropathy in a large, randomized, placebo-controlled clinical trial. However, it is also noted that gabapentin (Neurontin ) or pregabalin (Lyrica ), as well as compound and topical gels, may also provide patients relief for their neuropathy. Tricyclic antidepressants have been used. However, these should generally be avoided, especially in patients receiving many other medications for their myeloma or supportive care due to the many drug drug, drug-food interactions, and adverse effects you see with these drugs. SLIDE 60: Thrombosis Cancer and myeloma itself put patients at an increased risk for thrombosis. All cancers carry greater than 7 percent risk of thrombosis, and myeloma has a 3-10 percent risk. This can also be increased based on the treatment a patient is receiving for their myeloma with the immunomodulatory agents, specifically thalidomide and lenalidomide with dexamethasone having very high rates of thrombosis. Pomalidomide also carries a risk of thrombosis. SLIDE 61: Thrombosis Other risk factors besides the disease and treatment include obesity, if a patient has had a previous VTE (venous thromboembolism), the patient has a central venous catheter, looking at their comorbid conditions, immobility, and surgery. Prevention is key when it comes to patients receiving immunomodulatory agents and high-dose dexamethasone. All patients receiving these medications should be on VTE prophylaxis. Those with no or only one risk factor may be on an aspirin daily. And patients with two or more risk factors should probably be on enoxaparin (Lovenox ), at the prophylactic dose of 40 milligrams subcutaneous daily or dose adjusted for creatinine clearance. This is the preferred option. Warfarin (Coumadin ) is also an option; however, this is usually not preferred in our patients. Patients that do experience a thrombosis should be treated with treatment dose enoxaparin at 1 milligram per kilogram. Warfarin is also an option here, but again, enoxaparin is preferred. It s also important to continue prophylactic anticoagulation while they re on the duration of the IMiD therapy. SLIDE 62: Bone Health Bisphosphonates should be considered for all patients receiving anti-myeloma therapy because patients with myeloma may have lytic bone lesions or increased bone destruction and invasion. Pamidronate (Aredia ), at 90 milligrams or zoledronic acid (Reclast ) at 4 milligrams may be used. Both agents do need to be renally dose adjusted if used for this setting. However, myeloma patients may present with hypercalcemia, and you would use one of these agents to help treat that. In those cases, you would not want to dose adjust based on their renal impairment. However, prolonging the infusion times to avoid adverse effects would be appropriate. The duration of bisphosphonate therapy is usually given monthly for two years, then, every three months versus stopping therapy. Patients are at increased risk of osteonecrosis of the jaw when receiving bisphosphonate therapy, so it s important to hold for any invasive dental procedures. Page 18 of 28

19 SLIDE 63: Conclusions Dr. Sagar Lonial: So, I think, as we begin to wrap all of this up together, it s important to realize that there are a few standards in terms of how we approach things. Again, as I mentioned earlier, the IMiD proteasome inhibitor combination is a standard now for newly diagnosed myeloma with the addition of monoclonal antibodies that you heard so nicely about already likely coming into that as well. There is a continued role for high-dose therapy and transplants. Maintenance is important, and I would argue needs to be tailored based on the genetics of the patient at the time of presentation. And then, you saw a whole host of new potential targets for the management of patients in the context of relapse disease. And what we don t have at this time point are clear cut biomarkers that suggest you should choose one therapy over another in the context of relapse. I would suggest that you make sure you understand a lot of the potential adverse events or even potential contraindications for giving one of these agents over another so that you can maximize the benefit for any given individual patient at any given time. And, finally, supportive care is critically important in terms of prophylaxis, whether it s infectious, DVT (deep vein thrombosis) prophylaxis, or bone prophylaxis in order to minimize long-term complications of therapy as well as complications of the disease to improve overall quality of life for patients going forward. SLIDE 64: Patient Case So, let s briefly touch on a little bit of a case here, and I can tell you a little bit about how we managed this case. And then, we can talk a little bit about sort of what the moment-to-moment issues in the treatment were that arose. So, this is a 52-year-old healthy man who s asymptomatic and presented because of knee pain. And the knee pain subsequently led to an MRI that showed an abnormal bone marrow signal. This is a patient who had normal renal function and chemistry, hemoglobin of 11, free light chain ratio of greater than 100, and no urine protein. He did have a PET in an MRI that demonstrated no lytic bone disease, and a bone marrow that showed 40 percent plasma cells with normal cytogenetics, and a negative FISH panel. SLIDE 65: Patient Case So, as we begin to think through how to manage this individual patient, would you treat this patient? And so, by the original CRAB criteria that I mentioned earlier on, the answer, historically, would have been no. But, with the revised Myeloma Working Group definition including the three new biomarkers such as free light chain ratio greater than 100, abnormal, more than one bone abnormality by MRI, or greater than 60 percent plasma cells, this is a patient who one would argue does meet the criteria and should be initiated on therapy. And that s what we ended up doing for this gentleman. He did end up receiving bortezomib in combination with lenalidomide and dexamethasone, or the RVD regimen, and we can talk a little bit about management and prophylaxis to minimize sort of symptoms and side effects associated with initial RVD therapy. Dr. Elyse Hall Panjic: So, when I have a patient that is being newly initiated on bortezomib, lenalidomide, and dexamethasone, there are several things I want to discuss with them. This includes appropriate Page 19 of 28

20 prophylaxis with acyclovir they should be taking; in the case of renal dose adjustment is not necessary, twice daily, and also, starting DVT prophylaxis. If this patient had no other risk factors for DVT, we would start him on aspirin daily when he started his lenalidomide. Educating the patient on the risk of rash that may happen with lenalidomide is also important as well as peripheral neuropathy that may be seen with bortezomib. I usually discuss with patients what peripheral neuropathy is, the numbness and tingling that can happen in the hands and feet, and that we want to monitor it closely because we do not want it to impair any of their activities of daily living. Once we ensure the patient is started on therapy and tolerating well, we do want to initiate PCP prophylaxis, generally, with Bactrim. And we usually start that around cycle two, as patients who don t tolerate Bactrim may sometimes experience a rash, and we don t want to be guessing if they re having a rash to the lenalidomide or the Bactrim therapy. So, we stagger the start of those agents. Dr. Sagar Lonial: So, as the patient did well with initial induction therapy, achieved a very good partial response, went on and had stem cells collected, opted for an early transplant, which would be our recommendation for somebody in this clinical situation. And then, we get to the discussion on maintenance therapy. And our approach in terms of maintaining this patient, because he had standard risk disease, would be to offer him single agent lenalidomide, 10 milligrams days 1 through 21 every 28 days on a monthly cycle and treat him until progression. And, again, that was substantiated by data from the CALGB and the IFM trial, and more recently, the maintenance meta-analysis that demonstrated survival benefit for the use of lenalidomide maintenance. As with lenalidomide in the induction therapy setting, some sort of prophylaxis is probably needed, and this patient received an aspirin. When it comes to management of this patient in the context of first relapse that is a very challenging question to really answer in a definitive way. And many of the decisions in this situation would depend on what kind of relapse. Was it a slow, indolent relapse? Was it an aggressive, high-risk relapse? What were the patient s requests in terms of frequency for visits to the office? Did he want all oral therapy? Would he want an antibody-based therapy? Would he want to go back to IV infusions? Those are all things that fit into the algorithm. And I can tell you, programmatically, at our center, patients who are not able to escalate the dose of lenalidomide and add in either an antibody or a proteasome inhibitor, our choice in this situation would be go to salvage therapy with a combination of pomalidomide and daratumumab together based on some of the data you saw. But this is a very open discussion because there are many, many right choices to make for each given patient. So, in summary, I think we ve given you a good overview of how we approach treatment for patients with myeloma and have given you some of the things to watch out for in terms of pitfalls or challenges of therapy as well as ways to try and minimize potential complications of therapy through appropriate education and through appropriate prophylaxis for patients, again, to maximize benefit and minimize impact on quality of life. Page 20 of 28

21 SLIDE 66: Nursing Considerations in Multiple Myeloma Lauren Berger: Thank you Dr. Lonial and Dr. Hall Panjic, I am now pleased to turn the program over to Miss Charise Gleason Charise Gleason: I'm now going to talk to you about nursing considerations in multiple myeloma. SLIDE 67: Initial Diagnosis So when we think of the initial diagnosis, our patient can be very overwhelmed. For the nursing or the advanced practice role comes in from the very start. We want to make sure that we re providing detailed information about treatment, those potential side effects to not only the patient but also the caregiver or family member who's there with them. Remember, your patient isn't always going to absorb everything that you're telling them, so it s really important to provide handouts whenever possible so they can go home, read about the side effects as well and those potential problems that they might have. We also want to talk to our patients about reporting symptoms early and promptly. Sometimes patients don't always want to call us or let us know. And so we want to make sure that they're not waiting until that next visit. It s not unusual for the care team to see them at day one of that treatment cycle. For instance, if they are on an induction regimen with RVD lenalidomide bortezomib and dexamethasone, the care team might see them at day one of the cycle and then those infusion nurses are following them up throughout treatment. We want to make sure all of our nurses on the team are educated but also that we re asking those important questions about having any side effects throughout their treatment. This is also a really good time to bring in the social worker if you have access to a social worker at your institution. Our patients can have a lot of financial issues and questions at that time; they might need assistance with co-pays or transportation. So it s good to bring in that multidisciplinary team and know that they have this available to them from the start. When we see a new patient, we like to give them information about local and national support groups from the start. So we have a packet that we give our patients that has all this information but you can provide this to your patient as well, so some of the national groups that we have are The Leukemia & Lymphoma Society, we have the International Myeloma Foundation, the Multiple Myeloma Research Foundation, the American Cancer Society, so all these resources that a patient can go to and also many of our institutions have information on our websites as well. And we want to think about bringing our patient in to talk about treatment and that shared decision model. We are giving them information and letting them make an informed decision based on that information that we re giving them. SLIDE 68: Managing Steroid Related Side Effects So as we move on to talking about possible side effects, as hard as we try to manage these things, we know there's still the potential to have side effects and with almost all myeloma therapy comes steroids and typically it s dexamethasone for some older frail patients we might use prednisone. But some of those potential side effects that we see related to steroids are things like flushing and sweating. Insomnia is a big problem in this patient population, fluid retention, mood changes. And remember your patient Page 21 of 28

22 might not always realize that they're having some of these symptoms. Again, talking to that caregiver and reminding them that these are the steroid side effects. They might have dyspepsia when we start them on this regimen and did we remember to put them on something for reflux. Vision changes, we think of blurry eyes. These are things you want to tell your patient upfront, the fact that long-term steroid use can cause cataracts. It s not unusual. If they're having some of these symptoms get them in to see ophthalmology. Steroid induced diabetes, some of these patients already have other comorbidities. They might have diabetes from the start, so it is important for them to know those things that they need to monitor with blood glucose changes. Difficulty concentrating, again some of these patients go from no medication to multiple drugs and that s how all these side effects are a potential. Myopathy, they have that muscle weakness, you have an older frail patient who already isn t very mobile and now you put them on steroids where they can have muscle weakness so reinforcing the importance of exercise. These patients are at more risk for infection when they're on these multidrug regimens and also sexual dysfunction. We re not always good about talking about this with our patients so you want to open the door to these conversations so they have that comfort level with you to come to you when they're having these side effects. Hiccups, it might be one of those things that you don't even think to mention, patient starts on this new therapy and suddenly develop hiccups. So some of those treatment strategies that we want to teach our patients is taking steroids with food, can it help and that's what's recommended. Typically, we ask them to take steroids in early a.m. because we know they re going to cause insomnia, but for some patients that actually works better if they take them late at night and that first night they can actually sleep. It's really finding what works best for your patient, knowing those highs and lows - they might have a burst of energy when they start on steroids and crash a bit afterwards. So letting them know this is normal and if it is more than what we would expect, we want them to let us know those things. Also thinking about signs and symptoms of infection, that fever, shaking, chills on steroids. They might not always have a fever but they could have some of these other symptoms that would indicate that they're having an infection issue. Hypotension is another one. With steroids we worry about dyspepsia. So, we Recommend that they take either an over-the-counter or prescription of proton pump inhibitor or an H2 blocker. We put these patients on antiviral and antibacterial when indicated. But we really want them to keep exercising and moving. You ll ask your patient, are you getting exercise? And you will see they say yes I am and then sometimes you look at the caregiver and they re shaking their head no. You want these patients to keep active and then you will also want to educate on the signs and symptoms of diabetes. Are they having high blood sugar or low blood sugar? So some of those things that come with diabetes, confusion, may be increased thirst, frequent urination, aggressiveness, those are all things that you want reported to you. Slide 69: Peripheral Neuropathy The next side effect that we are going to talk about is peripheral neuropathy. Again, this is one of those things that is very challenging in our practices. Patients can come with neuropathy because of other comorbidities, they can have neuropathy from the disease itself, or our treatment can cause that. And you want to be careful when you're talking to your patients that you just don't say neuropathy. You want to Page 22 of 28

23 educate them on one of those things that we re looking for because we know what neuropathy means, but what is it to the patient and you don't want them to think its only numbness and tingling. It can be far more than that. So some of those things that we think of with sensory neuropathy, numbness, tingling, pain in the hands or feet, difficulty hearing - are they having a ringing or buzzing in their ears, are they becoming more week. Do they just feel different? Different sensations? Cold? Patients will refer to this, sometimes with their feet. Like I feel like I'm walking on blocks or I'm always in sand or I m just trying to rub my feet. You want them to know that anything that just feels out of the ordinary those are the things you want them to let you know about. When you think about the motor neuropathy, those are more, am I having trouble fastening buttons and sometimes you actually have to have your patient demonstrate this for you. Patients don't always want to let you know they're having these issues because they are afraid that you're going to stop their treatment, so it s working with them and knowing that we can make dose adjustments and help them through this with other medication. So, again having them fasten buttons for you. Can they pick up a coin? Can they distinguish if you put something in the palm of their hand? Can they tell what that is? Are they having any problems opening things like jars or again unable to feel small objects? Are they having difficulty ambulating? These are all things that you really want to monitor closely for. And what are some of the treatment strategies that we have. It is recommended that they can use cocoa butter on those extremities, B-complex vitamins we recommend those all the time. Folic acid supplements, physical therapy that can be very beneficial. Again, you want the patient to keep moving through this, but one of the biggest things is just that education for them to know to look out for this, but also to let us know. Sometimes we have to start medication. Pain medication, some of the things that we use specific to neuropathy are duloxetine, gabapentin or pregabalin, but these come with side effects as well as everything else. You really want to look at your patient talk to them about some of the side effects they might experience from the medicines that were given them to try to help with the neuropathy such as sedation. We at our center prescribe a lot of topicals. We compound different agents together that we send out that can be helpful to the patient but again insurance doesn't always want to pay for those things. So these are just some of those strategies that you can think of but the most important is you want your patient to let you know and you want to ask them about the symptoms frequently. SLIDE 70: GI Side Effects GI side effects can be a big issue, nausea, vomiting, diarrhea, constipation and diarrhea alternating with constipation, so different drugs cause different GI toxicities. And patients worry a lot about nausea and some of our medications we don't see that as much, but we do always want to prescribe an anti- emetic so the patient can have that at home just in case and with nausea and vomiting you want to think about how frequent is it? Are they're having an episode once in 24 hours? That's far different than are they having six or more episodes in 24 hours. So these are the questions that you want to ask and again you want them to know when to call us so we do prescribe anti-emetics. Page 23 of 28

24 Recommendations for eating are smaller, more frequent meals, avoiding fatty or fried foods can be helpful and avoiding strong odors. If you go to the cancer center you you're not going to see people having popcorn or fish. Those are the kind of things that can really bother patients. You want to think about anticipatory nausea. Can they tell you this happens every time I take the drug? So you can premedicate them and try to avoid that. You want to keep these patients well hydrated. Again it goes back to how many episodes are you having and dose adjustments as indicated. Sometimes it's the medication and again letting the team know that you're having issues with nausea. You don't want the patient suffering with nausea for three weeks waiting to tell you. SLIDE 71: GI Side Effects Diarrhea can be very challenging. We have certain medications that cause quite a bit of diarrhea. Again it's quantifying that amount. Are they having one loose stool in 24 hours or are they having six watery stools every day. So you want to differentiate that. When they are on clinical trials, we are very good about monitoring these and keeping diaries, but how are we doing that on a patient who's on standard therapy. Things that you want to do with diarrhea. Think about those anti-diarrheals, but also instruct your patient to be careful because they can also get very constipated from those drugs too, so it s finding that balance. Think about increasing fluids. These patients can get very dehydrated. You want to avoid caffeinated beverages, carbonated and heavily sugared beverages can make diarrhea worse, and you want to discontinue any medication that you can that might contribute, so maybe there on an oral magnesium that can cause diarrhea or they came to you already on the stool softener. Now they have diarrhea, so you will really want to look at be reviewing that medication list as well. SLIDE 72: GI Side Effects With constipation you think about stool softeners and laxatives. You can recommend that they increase fluid or fiber intake, but you do want to do a close assessment because you can also have an issue that's more serious, so you want to assess for abdominal pain. Do you hear bowel sounds, are they nauseated or vomiting with their constipation. Do they have an inability to urinate? We think of a lot of our myeloma patients with chronic pain have constipation issues, but you can also have a more serious side effect of a core compression. So it's really important to know what that bowel and bladder function is doing. Through any of these you want to think about contacting your nutritionist, if you have access to a nutritionist. Patients also will have anorexia from some of this nausea, vomiting. They just don't feel like eating and again your nutritionist can really help you through many of these issues. We might check additional vitamin levels and recommend other vitamins support as well. We re very fortunate that at our center that we do have access to a nutritionist so we like to bring our nutritionist in early. You don't want to wait until your patient had a 30 pound weight loss so you really want to be looking at that as well, so it s monitoring all these aspects of your patient. Page 24 of 28

25 SLIDE 73: Thromboembolic Events DVT/PE The next side effect that I'd like to talk about our thromboembolic events so those are DVTs and PEs that our patients are at risk for. Many of our therapies increase this risk, such as treatment with immunomodulatory agents. Those risk factors for a patient, when you're assessing your patient, is are they immobile, are they obese or do they smoke, do they have a history of blood clots because we are going to treat those patients a little bit different. Are they on an estrogen supplement? Again, that puts them at a higher risk for developing a blood clot. Erythropoietin, are they on growth factor to stimulate their red cells? Need to look at that because that increases that risk for blood clot. Have they had recent surgery, have they traveled long distance so you want to educate your patient on when they re riding in the car or are on an airplane, how often they need to get up and move around. Do they have a central venous catheter? We see more clots related to catheters. Do they have other comorbid conditions? So these are all things that we take into consideration when we re starting them on therapy and starting them on prophylaxis. Those signs and symptoms that you want to educate your patient on is do they have new swelling, pain, aching in the area, tightness do they feel a knot, and this usually comes on sudden not symmetric. It's usually in one area. Typically we think of the leg, but certainly can happen if you have a catheter up around the neck, upper arm and typically they have a faster heart rate, that tachycardia, they might have veins that are distended, they might have some redness, not always, but these are things that you want to be suspicious of that they've developed the clot and get an ultrasound. Doppler ultrasound is the standard of care for that and these should be considered emergencies and it s a little bit different between a DVT and a PE. Somebody who has had a pulmonary embolism has a sudden shortness of breath. With tachycardia, they might feel like a sense of doom about them and that's not I ve been getting more short of breath over the last two weeks that s I got up today and I'm suddenly very short of breath and they re very anxious with that. These are medical emergencies that you want to get them assessed quickly. So we prophylax patients who are at risk. If they re on treatment with an IMiD and we follow the international myeloma working group guidelines, so if they have no other comorbidities and no history of prior blood clot, than most times were going to put that patient on an aspirin. If they do have a risk factor, we are going to be more aggressive with their anticoagulation with a low molecular weight heparin or one of the oral agents. And you want to continue that anticoagulation for the duration of therapy. It is really important to instruct your patient not to stop that even on their off week so again, if they re on induction with that RVD regimen. They have a week off of treatment they need to understand that they need to continue on that aspirin or that other anticoagulation because the risk of developing a clot continues to be there. At our center even if they stop an IMiD we continue that anticoagulation for about two months afterwards because that risk of developing a blood clot is still there. So you just want to make sure your patients understand what are those signs and symptoms they're looking for. SLIDE 74: Myelosuppression So one of the other things that we spend a lot of time dealing with our patients is that myelosuppression. So we see a lot of anemia in myeloma patients. We see it from the disease and then we see it from treatment. We know that once we get the disease under control these things get better. But what are those things your Page 25 of 28

26 patient going to experience with anemia? Increased fatigue, so you ve got to educate them on the treatment can make you more tired. The disease can do this and if you're anemic they might have more shortness of breath. Are they having difficulty with their activities of daily living? Can they not perform that routine care? Are they having any chest pain with activity? These are patients when they hit a certain level and that is going to vary from your institution that you do tend to transfuse with red blood cells. You can consider erythropoietin but again, that risk of a blood clot is there, so you really have to weigh the pros and cons on whether or not you want to do that, especially if they re on an IMED. Patients can become neutropenic on our regimens. You want to monitor them for infection. You want to teach your patient, what are those signs and symptoms of infection that they need to look out for. It is not unusual to start growth factor support like filgrastim for the patient. Thrombocytopenia, again these are all things we re very familiar with, but how do you teach your patient about this. Are they having increased bruising? Petechiae, we know what that is, but you have to explain to them about the red spots that they might experience. Are they having epistaxis? Are they having any hematuria? These are all things that you want your patient to let you know about. If they have thrombocytopenia they want to avoid activities that can cause bleeding so obviously no contact sports. Things like that that you want to instruct your patient. If your patient s platelets are really low, you may want to think about more restrictions, such as should they be driving themselves. And again this is going to be a care team call but you want your patients to be aware that that can become an issue. And again, you're going to provide transfusion support and typically we have guidelines in the clinics so that can be automatic. You want to reduce the risk of bruising or bleeding. We want our patients to avoid taking ibuprofen. Patients shouldn't take NSAIDs at all to preserve their renal function, but those are the things that can cause a little bit more bruising or bleeding. SLIDE 75: Infection Precautions for Myeloma Patients So just to talk a little bit more about, infection precautions are very important for myeloma patients. We want to instruct on good personal hygiene. One of the best things patients or caregivers, family members, anybody patient going to be around can do for themselves is hand washing. We just can't stress that enough. Avoiding crowds and avoiding sick people. We are more restrictive during flu season, but at those times, if we know we have a patient who s immunocompromised, we might recommend that they wear a mask and have tighter restrictions than on patients who are not immunocompromised. But again hand washing is probably the best thing any of us can do. We want our patients to recognize when to call for infection. We talked about that a little bit, but those fevers, chills, remembering when they're on steroids that they might not actually have a fever. It may be that the family member notices that they're just acting a little different. Or maybe they're confused. An elderly patient who is suddenly confused, you might think about a urinary tract infection. So again, recognizing those signs and symptoms and calling the team right away. We put patients on antibacterials and antivirals at our myeloma center. We pretty much put people on antivirals and leave them on it. We see a lot of shingles in our patients and that risk is Page 26 of 28

27 there if they are on a proteasome inhibitor but the antibacterial, especially when they re on a multidrug regimen is important as well. So we use to think about pneumocystis carinii, which was PCP you see more PJP which is pneumocystis jirovecii pneumonia that we prophylax for. We still use the same medications but you're going to start seeing that different terminology than many of us are accustomed to. One of the other things that we do quite a bit for people who are having chronic infections is consider IV IG for hypogammaglobulinenemia, and so this is something that your patient would come in and get once a month to boost their immune system. You want to remember that they don't get live vaccines. We do recommend the influenza every year, and also the Pneumovax. Again that's going to be recommended with what your myeloma center is doing. SLIDE 76: Adherence to Therapy We have so many new therapies to offer patients now and many of them are oral. Adherence to therapy can be an issue when your patient is coming to the cancer center to get treatment you're giving it to them, but when you're having them take an oral agent you're counting on them to take it and to take it appropriately. So again, what are those things that from the nursing perspective we can do to help keep our patients on treatment? You want to inform them again and the caregiver about the possible side effects and the symptoms to expect. And also discuss the importance of continuing on therapy. You don't want your patient picking and choosing when to take their medicine, you don't want them stopping and starting and essentially sprinkling themselves with their myeloma medication. So, giving them those tools to help them stay on, controlling side effects and giving them those calendars. Having that good communication so they are open and honest with you and that they're having difficulty with this medication, because we can make adjustments or lower doses. You would rather lower a dose and keep your patients on therapy than to have them not taking it appropriately. It can be a very challenging issue with our patients right now. It's wonderful that we have all these options, but you want your patient to get the benefit of it. SLIDE 77: Conclusion So we know that nurses contribute to all aspects of care. Our nursing staff, in advanced practice, we see patients in the clinic in the infusion center and the phone triage we have navigators, so nursing plays such an important role in the management of our patient. We know that side effect management is essential to keep patients on treatment and improve their quality of life. You don't want your patient miserable. You want them to stay on treatment, stay on the highest dose that they can tolerate, so we can get disease control. You want to encourage your patient to be an active participant in their care. You want to give them those resources to help themselves. You want to use the resources that you have available. Getting the social worker in, getting nutrition support, do you have pain management, if you need that. Supportive oncology - you want your patient to be part of that decision-making process. With so many options now in the relapse refractory setting, sometimes we give a patient maybe three options and with a recommendation, so giving them the tools to help them make the appropriate decision with their care team. Page 27 of 28

28 We know that patients are living longer and they re going to be exposed to many therapies over the course of their disease. So if we control these side effects and these issues from the start, they re not going to be limited later on in treatment choices. SLIDE 78: Conclusion Lauren Berger: Thank you, Dr. Lonial, Dr. Hall Panjic and Miss. Gleason for your very clear and informative presentations on diagnosis, treatment and side effects management. The Leukemia and Lymphoma Society is pleased to offer additional resources for healthcare professionals, patients and caregivers. You can access this information from the Resources Tab. Page 28 of 28