 The title of this talk is somewhat deceiving. Drug sequencing is an incredibly important topic. Fortunately, our patients are living decades now, and so to study this the right way would take a very, very long time to do regimen after regimen after regimen and follow the outcomes would be very difficult. Fortunately, we have a large data repository. Many of them, one of them is CODA, and that will eventually give us answers as to how to do this the right way. But for now, the data comes from clinical trials and subset analyses of these clinical trials where we can glean some kind of information as to how to do the sequencing and which drug to do when. And so, disclosures. Myeloma is a chronic illness. In fact, if you look at about 80% of patients blood work 10 years prior to their diagnosis, there was a preceding MGUS or smoldering myeloma. So, they have active myeloma. They're treated with induction and then a consolidation type treatment. They go into remission and then after that remission the disease becomes pretty much chronic and they're on therapy for the rest of their life and each remission is shorter and shorter than the prior, and that's generally speaking. That's changing as well. So, upfront. What do we know about treating upfront myeloma? First of all, we know that three drugs are better than two. That's generally the combination of a proteasome inhibitor and an imid and a steroid. As we heard before, the achievement of minimal residual disease negativity correlates with improved outcome, but we don't know how that changes management, at least right now. And then we know that even patients who achieve a complete remission still benefit from autologous stem cell transplant. So, there's a variety of regimens you can see here. These are phase two trials that show the most commonly used upfront regimens. And they all have a very good rate of achieving a 90% reduction in the paraprotein burden. And so, you know, we have a lot of good options. In fact, the carfilzomib Revlimid dex regimen, 96% are alive at three years. So, that's pretty good. This SWAG S0777 study looked at the addition of bortezomib to linalidomide index in newly diagnosed patients. And it randomized them to...it took about 500 patients randomized to Lendex versus Bortezomib Lendex. And patients were followed...patients went on to Lendex maintenance until progression. And you can see the subgroups were the same. The patient characteristics were the same in both groups in all the different characteristics. The response rate was much higher in the triplet regimen compared to the doublet. And the rate of complete remission was double the rate of...in the triplet regimen compared to the doublet regimen. And there was a benefit in both progression-free survival and overall survival with a triplet VRD compared to RD alone. And there was not any evidence of additive toxicity, you know. And the bortezomib was given IV. And that's why there's some more neurologic toxicity with IV bortezomib. And we know that. Okay, so we know that the addition of bortezomib to Lendex correlates with significantly better progression-free and overall survival. And that's the...that tells us triplet is better than doublet. And so if we have such a great response, why do we still have to do a transplant? And that is because transplant still has an overall survival benefit and transplant deepens our response. And so David Viesel went through this trial, but to go through it again quickly, RVD with transplant versus RVD without transplant, everybody got Lend maintenance. PFS was the primary endpoint, similar characteristics in both arms, high risk, about 20% of patients in both groups. And you have a much higher overall response rate. It was significantly different in the transplant group and a lot more MRD negativity, 80% in the transplant group versus 65% in the non-transplant group. So PFS was significantly better in patients who received autologous stem cell transplant. And in multivariate analysis, the transplant still held up in terms of a prognostic factor for progression-free survival. So we have to encourage our patients to get a consolidative transplant. There was no difference in overall survival, but we need longer-term follow-up. And the toxicity you can see was not significantly better. Obviously you have greater hematologic toxicity in patients undergoing high-dose chemo. So transplant is associated in newly diagnosed patients with a 31% reduction in risk of progression and death, improved time to progression, increased MRD negativity, and the overall survival data in this trial is still to be determined. And we have a confirmatory trial in the U.S. by Dana-Farber that is still enrolling patients. Interim analysis may be showing a benefit toward overall survival. And this trial looked at carfilzomib lentilidomide index with or without autologous transplant for newly diagnosed patients with multiple myeloma. And as we saw earlier, we have a higher overall response rate with the transplant arm. We have a higher stringent complete remission rate in the KRD with transplant compared to KRD without transplant. And we have improvement in achievement of minimal residual disease negativity, 100% after 18 cycles of therapy with KRD plus autologous stem cell transplant. And this is the Mayo Clinic's recommendation. This is all changing very quickly, but everybody with high risk should... It's recommended to get four cycles of carfilzomib lentilidomide index, followed by autologous stem cell transplant. The definition of high risk is changing. We now have data that T11-14 is no longer standard risk. So, all right. Now we'll talk about salvage therapy. So, we know that patients who have become refractory to both bortezomib and lentilidomide have a dismal prognosis. This slide, it's from 2012, which is not incorporating common use of carfilzomib. So, this is all data or other drugs that we now have. But look, nine-month overall survival in patients that have progressed on both lentilidomide and bortezomib. This is not the case right now, I could tell you that. With all the new drugs that we have. And this slide is showing you with each regimen, if somebody is on six-line therapy, look at that. Terrible, terrible survival. So, we have a need for new therapies. And thankfully in the last year, we have four new drugs approved for multiple myeloma. Currently, what do we have in our box of chocolates? We have imids, philidomide, lentilidomide, and pommilidomide. Proteasome inhibitors, we have bortezomib, carfilzomib, and we have the oral proteasome inhibitor. Ixazomib, we have anthracycline. We have alkylating agents. Of course, the steroids have to be part of every regimen. We have histones, the acetylase inhibitors, verinostat, and pentobinostat. And we have monoclonal antibodies. Elotuzumab, which is a monoclonal antibody to CS1 or SLAM F7. And we have diratumumab, which is a CD38 monoclonal antibody. So, we'll go through all of these. So, we have all different cocktails of drugs. And it's unfortunate, as David said before, it's alphabet soup. Here, these trials looked at these regimens' second-line therapy. But if you look at these fifth-line therapy, these regimens, 70% overall response rate in patients that have had five lines of prior therapy and PFS and OS of 20 months, 10 months, and not reached is pretty good. So, we have very potent agents. We can combine them in all different ways. And our patients are really benefiting from these drugs. How do we pick salvage therapy? So, we have to look at two things. The disease. How fast is the M-spike and the paraprotein rising? Is it tripling in a month? Or is it progressing by 0.1 over a year? Do we have plasma cell leukemia? Is there bulky extramedulary disease? So, you have to look at that. And at the same time, look at the host, the age, the comorbidities, the organ function, and the frailty index are all important determinants in what you're going to pick. These are the key phase three clinical trials for the newer agents that we have approved in the last year. And so, we're going to go through all of these trials in brief. So, carfilzomib is a tetrapeptide epoxy ketone proteasome inhibitor. It binds selectively and irreversibly to the proteasome. And this is the ASPIRE trial. It was a randomized open-label phase three study of 792 patients randomized to carfilzomib lendex versus lendex. And it showed a significant progression-free survival benefit 26.3 versus 17.6 months. And that maintained in high-risk patients. So, there was no significant difference in overall survival according to this follow-up analysis. And the adverse events, you have to look for increased dyspnea, hypertension, cardiac events. Most of them were not grade three. These are grade one. These side effects can be managed. And so, the next drug we'll discuss is daratumumab. This is a humanized CD38 IgG Kappa monoclonal antibody. It has both anti-myeloma effects, and it also has effects on the immune cell subsets and the immune microenvironment. There's a decrease in T regulatory cells and an increase in your cytotoxic and helper T cells seen with daratumumab. So, it can change the natural history of the disease depending on when, in the course of illness, you use it. And so, it has a very high response rate when combined with other agents. This is the CASTR study, which showed daratumumab bortezumib dex versus bortezumib dex alone. And you can see a significant improvement in the one-year PFS. These patients had a median of two lines of therapy. So, they're not heavily pretreated. Keep that in mind. And then, this Pollock study looked at daralendex versus lendex, and these patients had only a median of one prior line of therapy. So, this was done early in the disease course, and you have a significant improvement in the progression-free survival. The next drug is elotuzumab. This is a monoclonal antibody against CS1, or the other name for it is SLAMF7. It's found on malignant and healthy plasma cells, and it's also found on NK cells. So, this monoclonal antibody has direct anti-myeloma cell activity, and it also increases the natural killer cell subset. And so, with multiple myeloma, the NK cell number and function decreases as the disease progresses. And so, using this earlier on in the disease course has more of an effect. And this is the eloquent two-study, randomized patients who have had one to three prior lines of therapy, elolendex versus lendex. And the characteristics were the same. You can see about 10% had T414, and 30% had deletion 17p. That's very high. The overall response rate was 80% in elolendex, and 66% in lendex alone. And overall survival was not significantly different. And you can see that as the years go on, there's a larger difference between the two groups. Overall response rate. What's interesting about elotuzumab is that there is a tail on the curve, that scene, and there is a way to determine who are the patients who will benefit and who will have that long-term remission. There's an FC gamma receptor subtype that cannot unfortunately be checked commercially, but we do know certain patients with a low affinity to FC gamma receptor 3A are the long-term remitters with elotuzumab, and those patients can have very, very long-term remission. So toxicity, not additive toxicity. You have some hematologic, not significantly different. This is well tolerated. Now we move to exasamib, which is the oral proteasome inhibitor. The way that it works, it's a capsule. It's hydrolyzed by the body, and then it blocks protein degradation by binding to the 20S subunit of the proteasome, the 26S catalytic site. And so this drug was studied in the tourmaline study. It was a randomized trial looking at exasamib lendex versus placebo lendex. And patients had one to three prior lines of therapy. The characteristics were similar between the both groups. 20% and 17% were high-risk cytogenetics. 69 and 70% had a prior proteasome inhibitor. And so the overall response rate and median PFS were significantly better in the Ninlaro or exasamib lendex arm. And what's interesting is that the high-risk patients had similar median PFS as standard-risk patients. Now this is a very small subset of patients, but it's very unusual for patients that have had that have high-risk cytogenetics, deletion 17p, to have the same median PFS as standard-risk. Now you can argue that patients that have already lived to achieve one to three prior lines of therapy are not truly high-risk. But that said, this warrants further examination. Safety, you have some diarrhea, you have skin changes, and you still have peripheral neuropathy with this drug similar to Bortesimib. Not a lot of grade three, but you still see it. Next is the newly approved H-dac inhibitor, Panabinostat. The way these drugs work is they deacetylate the histone, open up the chromatin, and allow different genes to be expressed. Do we know which genes? No. But we have certain different expressions of genes. And so this study, Panorama, looked at Bortesimib dex versus Panobortesimib dex. It was given IV, the Bortesimib, and then after a certain number of cycles, it was switched from twice weekly to once weekly. And you have a small PFS benefit for months. But what is interesting is that a lot of these patients were already exposed to Bortesimib. And this held up in a subgroup of patients who received Bortesimib and an IMID. So side effects with Panobinostat, cardiac, you have to check in EKG. Patients with a prolonged QTC should not receive the drug because there's a black box warning. GI side effects and hematologic toxicity. So with all this data, what are we going to take home for drug sequencing? So one interesting thing to note, pomalidomide, regardless of what prior therapy the patient had, lenalidomide, Bortesimib refractory, len or Bortesimib refractory, the overall response rate is the same. So pomalidomide can be used after any regimen. It's not going to affect the response rate if a patient is refractory to two drugs. Still the same response rate. Another interesting thing to note, Panobinostat. This study looked at patients, Panobinostat with lenalidomide and DEX. And you can see even in rev refractory patients, you have the same overall response rate, about almost 40%. And so there's a potential that Panobinostat can restore sensitivity to imid. So this is a potential drug to use after len refractory. This is a subset study of one of the carfilzomib trials in which investigators were allowed to add on any FDA approved drug to patients already on carfilzomib as part of the carfilzomib clinical trials. And what's interesting is that even fourth line therapy, even though there was a small amount of patients, you still have an overall response rate of 40%. With the addition of any of these drugs, dexamethasone, lenalidomide, cyclophosphamide, thalidomide, and even doxorubicin. And so the addition of any FDA approved agent, well not any, but these, often restore sensitivity and continues to be, you can continue to see a response on a carfilzomib-based regimen. And then this drug, Dr. Siegel talked about, which is the anti-PD1 inhibitor. You can see it's being, we are using it as compassionate use in a lot of patients with myeloma that are refractory to all FDA approved agents and may not be clinical trial candidates. But you can see that the response rate is still high in len refractory patients. And so the take home points for where to use what drug, response to palm and dex does not depend on prior therapy. HDAC inhibitors can potentially be used late in the disease course. They can restore sensitivity to lenalidomide. When progressing on carfilzomib, response can be recaptured with almost any other FDA approved drug. Pembrolizumab lendex can restore response in refractory patients. Daritumumab, as we said, it changes the immune subset milieu. Maybe there are effects. If you use it earlier on in the disease, we just don't know what it's going to do to the natural history of the disease when used early on because of the changes it makes on the immune cell subsets. And then with elotuzumab, remember it, some, what depends on NK cell functionality and so it may not be effective later in the disease course. So use it early. And this is the NCCN guidelines and recommendations of all the different cocktails from myeloma. Thank you. Okay. Two questions. One, clinical, because we have so many options, patients who really want to live longer, we are starting to see more plasma cell leukemia and CNS involvement. Do we know how to predict those or manage those prevent those or how we manage those? Right. We know that combination therapies are better than using one drug at a time, sequential therapy and that's because even before diagnosis, there are so many clones of disease. And so when we're using one drug maintenance therapy, we're breeding resistance and there's actually a nice trial that was presented at ASH and it showed the number of clones with LEN maintenance and without LEN maintenance and they're just exponentially greater. And I believe that perhaps you're breeding more aggressive, more resistant disease and we are seeing more extra medullary and CNS disease. And I think that's why. And once you have this, how do you manage it? How do you? So, you know, we can do IT chemotherapy. And what are the biological drugs that have an effect on CNS patients? Do the biological therapies have some effect? I'm wondering if immunotherapy can indeed do that because you're not only stimulating what goes into the body but the immune cell subsets that are upregulated may have some effect.