(Guest Lecture): Myeloma Treatment | MCRT Webcast: Experts Discuss Newly Diagnosed Multiple Myeloma Issues

And with that, I'd like to introduce Dr. Luciano Costa, who is going to discuss treatment. So thank you very much for this terrific opportunity to address the myeloma community. I'm going to follow up on Dr. Callender's talk and discuss the initial treatment of patients with multiple myeloma. As you very well show a few minutes ago, the outcomes of patients with multiple myeloma keep getting better. This is going on for, fortunately now, for a couple of decades. But what we really only recently saw is that the outcomes are getting better, not only for patients who are younger and more fit and can tolerate more aggressive therapy, but they're also getting better for the older and more frail patients. As you can see here, however, there's still a big gap to conquer, and the gap is even greater among older patients. And I'll pause here to, you're going to see a lot of curves, a lot of graphs that look like this throughout the day today. I just want to take two minutes to explain those if you haven't seen those graphs before. So we in the medical field are very familiar with those. Those are survival curves, and they tell us at a given time, here for example, two years, what proportion of patients are alive or are alive without progression of the cancer, something that we call progression free survival. So if you look here, for example, at four years, 70% of the patients with myeloma younger than 65 diagnosed in 2008, 2012 are still alive. So the bottom line is the curve on the top, the trace on the top always win. So let's use that principle to guide us to the remainder of the presentation, and the rest of the presentation you're going to see today. So while treatment myeloma has gotten better, and we see patients now going through multiple lines of therapy, there's some very big eye-opener are some studies that come from a broader group of patients than the ones representing clinical trials. So those are patients who are in the community. And Dr. Fonseca and colleagues, there's a similar study also in Europe. Look at how often patients make the second or third line of therapy. And the findings are very concerning, that only about 40 to 50% of the patients make to a second line therapy or to a third line therapy and so on. So it's like almost every step of the way we leave behind about 40% of the patients. And that speaks for how aggressive myeloma can be. That speaks for the fact that not every patient can handle all the therapies we have to offer in second and third line. But also it speaks for the importance to get it right first time around. We know for the majority of patients, the best and the longest lasting response is going to be the first response. That's why we pay so much attention and we care so much about the impact of the initial therapy that a patient receives. So this is the landscape of therapies that we have in 2020. We have the two, I think we'll say the two backbones of myeloma therapy, which are the immunomodulatory drugs like thalidomide or thalamid, pomellidomide, thalidomide, or ravlimid and pomellidomide or pomelis. Those are oral agents. The main side effects tend to be neuropathy in the case of thalidomide, low blood counts and the risk of blood clots with thalidomide, pomellidomide and the blood clots for all those agents. And then we have the proteasome inhibitors. The one mostly used and more well known is proteasomeib or Velcade. The main side effect being neuropathy that unfortunately many of our patients are familiar with. We also have carfusomeib and with the main toxicity signal seems to be some slight increase in risk of cardiovascular events. And icsasomeib, which is biochemically very similar to Velcade. This is ninlaro but has the convenience of being available as a pill as opposed to an injection. And the main side effect of that is gastrointestinal problems. Then we have the kind of the, I think what I consider the greatest novelty in myeloma in the past five years, which is the availability of monoclonal antibodies. So this is kind of the irony of myeloma, which is the cancer that produces antibodies. Other cancers have been able to engineer antibodies to treat breast cancer or treat lymphoma, but took us a while to get antibodies that are engineered to treat myeloma cells. We now fortunately have three and more down the pipeline. We have elotuzumab, we have daratumumab or darzalex, and more recently we have icsatuximab. An old friend are the alkylators like cyclophosphobite or Cytoxor, a bit of mustang, was really the, along with steroids, the first class of agents to have an impact in multiple myeloma. And while more recently we, the regimens that contain alkylators have kind of fallen out of favor a little bit, we still rely heavily on Malfala as the therapy embedded into autologous transplants. So in the United States, we use alkylators almost exclusively as a high dose therapy in terms of transplant. And then we have other agents, of course, the corticosteroids, punabinostat, and more recently selenaxor. So it's a very crowded field and it's very confusing for patients, it's very confusing for physicians. And I'll try to show you some general principles of how we select and recommend therapies. So we use some guiding principles, and I borrowed this figure here that I think very much represents how we make recommendations to the patients. Of course, we have to be well informed as myeloma physicians and know the latest and the greatest in terms of the data. We also take to the table our clinical experience, that goes a long way, but is also very important. And I think, and that's particularly true in myeloma where we deal with patients with sometimes of advanced age with several comorbidities, that the patient's preference and the patient characteristics play an important role in that decision making. Response matters, that's very important. And as highlighted before, that is your best chance to get a durable disease control. But it also matters the functional status, the side effects of therapy, what are the medical problems that patient has, what quality of life the patient has, and how is the therapy going to affect the quality of life, and of course the cost and the distance to treatment center. So we have grown used to first separate patients among patients who are amenable to transplant and patients who are not. And Dr. DeCalle is going to spend quite a bit of time later today discussing specifics about how we make that decision and how much the transplant can contribute to one's outcome. But for patients who do not receive transplant, we deploy the best available regimen up front and then transition to oftentimes an abbreviated form or a single agent that tends to continue until the patient has progression or no longer can tolerate the therapy. For patients who are transplant eligible, those steps are more clearly defined. We usually talk about a brief initial therapy from three to six cycles, pending on the regimen, followed by transplant, which we consider a form of consolidation. At that point, the patient had already had a response, so we're consolidating that response. And then we go into maintenance therapy, which is the agents who have the best data are Revlimid or Linalidomide or Velcade or Bortezomib. Now with some early data about Nilaro or Ixazomib also being useful in maintenance. Which agent to choose depends on a lot of characteristics, including some of the patient's disease features, also how the patient tolerates the therapy during initial therapy, and ultimately factors like cost, convenience, and reimbursement. And at least in the US, we tend to use maintenance until progression or intolerance as opposed to Europe, where oftentimes maintenance is used for a limited duration of time. Once we treat the patient, the first thing we want to know and the patient's going to know is how am I responding? Response to therapy is very complicated, and even we, my love of physicians, I at least every week or every few days are running to a case where I struggle to properly assign response because it's not straightforward. It takes in consideration the measurement of the M-spike, the Dr. Callender explained to you, in the blood and in the urine. I take in consideration sometimes the free light chain assay and takes in consideration a bone marrow test, particularly to assign complete response. The important thing for patients to understand is there are essentially four levels of response. Partial response, a very good partial response, something we call complete response, and a subcategory of complete response, we call it stringent complete response, which is the very best. So it's always a good practice to ask your doctor, what kind of response do I have? And leave for us to figure out all the numbers and the calculations that can be very tricky. Of course, having a complete response is better than not having a complete response, but I want to introduce here, and you can see on those curves, I want to introduce here the notion of minimal residual disease. So complete response sounds very good. It gives the impression that I got rid of the cancer. We know, however, that that's unfortunately not the case. How the complete response means is your disease has gone down to a level that is not detected by the usual bone marrow test, the usual blood test, and the usual urine test. We have now technology that can enable us to assess the bone marrow and look for cancer cells that become detectable even down to one cell in a million. And we call that minimal residual disease. And as you can see on this graph, and this is not a test for one in a million. This is even a test that looked for one in 10,000. And you can see here that the patients who are MRD negative have less than one cell in 10,000. They do far better than everybody else. And the patients who have complete response but still have that disease detectable at the level one to 10,000, they do just as well as patients who had a partial response in terms of long-term survival. So really the beauty of having a complete response resides on those patients who are you know, MRD negative. And I'm showing this, and this is a meta-analysis, so this is a pool of several different studies. All those patients here are incomplete, had a complete response, but you see the patients who are MRD negative do far better than patients who are MRD positive. And the reason why this becomes important is as therapies become better and more effective, we're having fortunately more and more patients reaching a complete response. So the only way we're going to be able to understand the risk of relapse and sort out what patients are candidates for additional therapy or what patients are candidates to de-escalation therapy is by understanding disease at a deeper level. You're also going to see some of this MRD data on some of the slides I'm going to show. So let's talk about, you know, how we now in this day and age, we treat patients with myeloma in the United States. So one of these studies that's possibly the most important study that laid the foundation for how patients are managed in the United States nowadays is the study run by the SWOG, which is one of the federal sponsor cooperative groups that was designed 13 years ago that randomized patients, half the patients received Revlimid index of metastone and half the patients received Velcade Revlimid index of metastone for a number of cycles. And after that, they went on Revlimid index of metastone maintenance into progression. At that point, if you go back in time 10 years, it was a huge debate whether everybody should receive Velcade or if two drugs is sufficient to treat most patients. This trial was not designed as a transplant eligible or non-transplant eligible. Most patients do not receive transplants, but some patients did. And the answer is very clear. The combination of Velcade, Revlimid, and dexamethasone is superior to Revlimid and dexamethasone in terms of time the patients go on alive without cancer coming back. We call progression free survive and the time the patients are alive, we call overall survival. So this really provide the best data to justify that three drugs are superior to two for most patients with multiple myeloma. And proto-some inhibitors along with immunomodulatory agents and steroids really became the foundation of modern myeloma therapy. As I mentioned before, one of the greatest innovation has been the availability of monoclonal antibodies, which are antibodies that are engineered to bind to the cancer cell and recruit the immune system to assist on the destruction of that myeloma cell. And one of the monoclonal antibodies we have the most data in the newly diagnosed setting is daratumumab, which is bound to CD38, which is a protein present on the surface of not only every myeloma cell, but every plasma cell. So this is a study done mostly outside the United States that took a regimen that we don't use much in this country called VMP, which is Velcade, Malfolin, and Prednisone, which is used for patients who are not transplant eligible, mostly in Europe. So all patients here were older than 65 or had medical problems that prevented from getting transplant. But the message is by adding the monoclonal antibodies, patients did much better. Higher level of response, higher proportion of patients getting a complete response, and higher level of patients getting disease below one cell in 100,000. And this later translated into also better survival. More aligned with our practice in the United States, the MYA trial also among patients who are not transplant eligible compare Revlimid dexamethasone versus daratumumab, Revlimid and dexamethasone. And again, we see the same signal. The patients who received the monoclonal antibody have a much better progression-free survival. Higher levels of response, better response, more patients become MRD negative. We also have tried to improve upon the existing classes of agents that we have. And along those lines, we have pursued carfusomib as a better agent than Velcade, as we have seen in the relapse setting where carfusomib or carpolis outperforms Velcade. This is one trial that was performed mostly in Europe where they took Velcade melphalanoprednisone versus carfusomib melphalanoprednisone. And that we're all a little bit disappointed that did not show an improvement with a newer and perceived as better protozoan inhibitor. There is, however, a US-based trial called the Endurance Trial that compare Velcade, Revlimid, and dexamethasone with carpolis, Revlimid, and dexamethasone. The trial is completed and we should learn its results next month at ASCO. For the patients who are newly diagnosed, who are transplant eligible, the de facto regimen used in the United States is Velcade, Revlimid, and dexamethasone. But in most of Europe, the standard regimen is Velcade, Thalidomide, and dexamethasone. So this is the Casio-Pea trial was the first large trial in transplant eligible patients that tested the combination of a protozoan inhibitor, an immunomodulatory agent, and dexamethasone versus the same combination plus daratumumab in patients who go on to receive an autologous transplant. And that, just like we saw for Maya and Alcyon in the non-transplant eligible patients, there was better response, better lab, more patients achieving a CR, and more patients become MRD negative. That is not quite the standard in the US where most patients still receive VRD. There's a smaller study called the Griffin study that was done in the US and has been completed and resulted showing that DARA VRD is superior to VRD in terms of responses, in terms of complete responses, in terms of MRD negative patients. So I believe that in the near future, we're going to see more and more patients receiving quadruple therapy. This is a busy slide, but really summarize the most common or the most recent evidence for regimens used for patients who are transplant eligible. We know the RVD produces about 59% of response after transplant. The KRD from a European study with chirolis instead of Velcade, about 60% of complete response with 58% of the patients become MRD negative. The Cassiopeia study that I showed you, the Griffin study with DARA RVD, and there are some combinations using, for example, chirolis, Revlimid, Dartmoor-Mabb, where the response rate is approaching 90%. So it's really amazing to see how quick and how much the efficacy of those regimens have improved. For non-transplant eligible patients, we see here the efficacy of VMP, which is Velcade, melphalan prednisone, not very much used in this country. But we see that level and quality of response improved as we combine an IMID and a proteosome inhibitor and more so when you combine a monoclonal antibody. So as Dr. Kalender showed to you, the National Comprehensive Cancer Network guideline for multimimiloma endorses those followed regimens as preferred for patients who are non-transplant candidate. The Velcade, Revlimid, and dexamethasone from the SWOG 0777 trial. The DARA-Tumor-Mabb in combination with the Revlimid and dexamethasone. It endorses Revlimid and low-dose dexamethasone, which might be particularly helpful for patients who, for some reason, including age or frailty, are not a candidate for a treat drug combination. And even a combination of Velcade, cyclophosphamide, dexamethasone, which I find particularly helpful in patients who need to start therapy promptly and partitions who are presented with renal failure because all those drugs can be given a full dose immediately without any adjustment for renal dysfunction. For transplant eligible patients, the MCCN recognizes Velcade, Revlimid, and dexamethasone and Velcade, Cytoxel, and dexamethasone as the preferred regimen. Endorses other combinations replacing Velcade, for example, with carfusomib or hexasomib, isomisubstance of patients. And I think over time, we were likely to see the monoclonal antibody-containing combinations make to the list of preferred regimens. So if I were to summarize what we discussed in terms of initial therapy, I think the summary is three drugs is better than two. The backbone being an e-MIDS and a PI and steroids, with the possibility now of an e-MID, monoclonal antibody and steroids, or even a protosome inhibitor monoclonal antibody and steroids. Doublets might be appropriate for failure in elderly patients. We're seeing the emergence of quadruple, including in transplant eligible patients, with an e-MID, a PI, and a monoclonal antibody plus steroids. There's the whole discussion of transplant versus non-transplant that Dr. Decau is going to take. But for us, of course, it's important to recognize that early on so we can properly plan patient's treatment. And then in this country, we use maintenance until progression or intolerance, usually with a single agent. But there might be patients, particularly high-risk patients, defined by cytogenetics or by some other features, where we choose to use a combination of regimens, typically of agents, typically Velcade and Revlimid, as long as tolerated until progression. I'm going to switch gears a little bit and talk about supportive care. Just as important as picking the most effective and safe regimen for our patients and educating the patients on how to take that treatment and how to tolerate the treatment is to address all the other problems and risks that come with the diagnosis of multiple myeloma. One that is very evident is myeloma bone disease. And this complicated cartoon, what you can see is multiple myeloma is a bone-destroying disease by definition. And the way it does that is by really recruiting or energizing the osteoclasts, which are the cells in our bones that are occupied with taking out bone, with bone destruction. And inhibiting the osteoblasts, which are the cells in our bone that are occupied with building bone. The analogy that I make to the patient is like our bones are in constant renovation. And we have the demolition crew, which is the osteoclasts, and the building crew that are the osteoblasts. And the myeloma shows up and essentially stops the construction crew and expedites the demolition crew. So your house looks like a wreck. Our goals with therapy is to stop that signal the myeloma has to increase bone destruction and give medications that will on themselves inhibit or demolition crew and allow new bone formation, strand or bones to prevent fracture. Bone disease is present in the majority of patients at some point in the national history of the disease. It's a major morbidity factor. It is one of the reasons patients suffer the most and really contribute to the mortality. And while we talk a lot about bone modifying agents, by far the most important factor is to control the underlying disease. I like to say that if you treat the myeloma, you probably don't need a whole lot more. Conversely, if you neglect to treat the myeloma and occupy yourself with surgeries, radiation, procedures at the expense of systemic therapy, you'll probably be dealing with another fracture by the time one is healed. So how do we manage myeloma bone disease? So there are a few things that are options. One is surgery. We of course try to avoid. There are circumstances where we can get around. For example, when patients present with a broken leg and a broken arm. For many patients, that's how they learn to have myeloma in first place. There are circumstances where you have enough involvement of the spine that the spine becomes unstable, needs to be operated on. Or we have a compression of the nerves inside the spinal cord that also is a reason for emergent surgery. And sometimes patients present with back pain. There's a lesion there. The surgeon who is seen or their topedic surgeon who is seen does not put things together to know it's myeloma and go in, do a procedure, and then get a biopsy and find out that it's myeloma. In some cases, when you have a compression fracture, which is this collapse of the bones in the back, the patients might derive some benefit and pain relief from balloon kyphoplasty, which is essentially putting a balloon inside the bone in the back and creating a space and injecting some cement. Radiation is very effective for pain control, helpful when the disease is mostly localized. And sometimes we use when the disease is very advanced, we're running out of therapies, we don't think the disease can be controlled systemically, but we want to provide some pain relief. Other things we do for bone disease, we give medications like Zomera or X-Giva, who essentially slow down bone loss and enables bone build. The main complication of those agents, something called osteonecrosis of the jaw, which is a chronic bone destroying infection that happened on the jaw that has been associated with those agents. So it's very important that patients with myeloma who are on those agents or are candidates for those agents have excellent dental care and be evaluated by a dentist before or during those therapies. In the early days of myeloma, we used those therapies in a way forever. As we learn more of the complications, we limit its use mostly to two years. And now there's some evidence that less frequent use may be just as good as monthly use. So discuss that with your doctor. And most important, sometimes we do the more complicated things and forget the basics. All patients with multiple myeloma, unless their disease is uncontrolled and they have high calcium in their blood, they should be on calcium and vitamin D as an assistance to building a new bone tissue. Infection is a big deal in myeloma. Patients with myeloma are sevenfold increase in risk of bacterial infection and tenfold increased risk of viral infection, which of course the theme of the day. Predisposition factors are low immunoglobulins, which many of our patients have because of the myeloma or because of the therapy, being on the use of steroids, have low white blood cell count, or being just functional impaired. The second thing to do, immunize and make sure your family members are immunized. Seasonal flu, pneumococcal hemophilus, and other appropriate vaccines. A big risk is the risk of zoster, which is essentially the chickenpox virus coming back. Chickenpox is an infection that once we have it as children, it never goes away. It stays dormant in our body forever. When our immune system is weakened by treatments or by cancer, it comes back in the form of zoster, which is very painful and can be debilitating. What we do is universal prophylaxis. If you have myeloma, if you are on treatment, you are taking an antiviral, which is near 100% effective and very safe. There are some circumstances where we are going to also use an antibiotic to prevent bacterial infection, particularly a bacteria called pneumococcal, which is the main cause of pneumonia. There is a recent randomized trial that actually showed the levofloxacin, or levoquin, taking for a few weeks after the diagnosis of myeloma can reduce the risk of death due to infection. There is some controversy around that study. Not everybody adopts that. But it is clear that patients are at increased risk of pneumonia. In my practice, at least patients who are on monoclonal antibodies, I tend to use low dose penicillin or low dose doxycycline. Another big threat to patients with myeloma is the risk of blood clot. Myeloma itself increases the risk of blood clots. So does myeloma treatments, particularly the immunomodulatory agents like the lidomide, Revlimid, or pumilis. This risk is super high with the lidomide and high dose dexamethasone. It is less so with things like Revlimid and with the lower dose of dexamethasone that we tend to use nowadays. What physicians should do and what you should discuss with your doctor is use a risk-based approach that takes into consideration what treatment you are taking and what other medical factors you have that would make you more predisposed to develop a blood clot. Based on that, if you are on those drugs, you take something that helps reduce the risk of blood clots, which in the best case scenario is just an aspirin a day, but there will be some combinations of patients and therapies where more intense anti-clot medications are needed. So, if I were to summarize the supportive care, bone disease, we use bone modifying agents for two years. We cannot overemphasize the importance of controlling disease. Control infection with immunization, prevention of shingles, and in some cases, antibacterials. Prevent a blood clot with a risk assessment and a choice of appropriate agent. It goes without saying, pain control is crucial, as many patients present with painful bone lesions or prior fractures. It is very important. There are very few of our patients where the myeloma is the only problem. There's diabetes, there's high blood pressure, sometimes other cancers, sometimes autoimmune diseases and so on, asthma, and our therapy is going to interfere in one way or the other with just about all of those conditions. So, it's very important as we give, for example, high dose steroids, that we are prepared to manage the possible derail of the control of the diabetes or the blood pressure, for example. And last but not least are the non-physical suffering and the non-easily measurable manifestations of having a cancer diagnosis and going to cancer treatment, which is depression and anxiety. It's hard to cover that on a talk, but it's very common, I would say more common than not, particularly early on after the diagnosis. Talk to your doctor. That is just as important as for your well-being as it is preventing infections or treating your bone disease. And with that, I'd like to close and thank you very much for the opportunity and I look forward to the Q&A at the end of the morning session. Thank you. Thank you.