Venetoclax

What is Venetoclax? So Venetoclax is a Bcl2 antagonist and a Bcl2 inhibitor. And Bcl2 is a very important protein in most cancers, right, because it's an anti-apoptotic mechanism in the sense that it keeps the cell from dying, right? This is the programmed cell death that every cell should go through. And Bcl2 has a big role to play. Venetoclax targets specifically Bcl2. That Bcl2 inhibition is important because it basically opens the door for those cells to finally die in that mechanism, right? We have other pathways that lead to apoptosis, but we have several clinical trials that have demonstrated that the inhibition of Bcl2 leads ultimately to those myeloma cells dying, which is ultimately the goal that we want. How is Venetoclax administered? Venetoclax has been extensively studied, possibly in the past 10 years. And all that research came from especially B-cell malignancies like lymphomas, because we're very familiar with Venetoclax in that domain. Most recently we have seen a lot of clinical trials that focus on Venetoclax as a single agent as well as in combination. It all started with a phase one clinical trial that was a dose escalation study for this drug and it was monotherapy and then they added, they did a cohort expansion to add dexamethasone to it. The schedule for these doses, this medication is a week daily oral medication, okay? So initially they started at 400 milligrams, 800 milligrams in another group, and ultimately those that have been established in other clinical trials has been 800 milligrams daily. Typically we do this on a 28-day cycle when it's in a combination. So the phase one trial that led to further studies of Venetoclax in combination demonstrated responses of an overall response rate around 40% on its own. When they added dexamethasone it was about 65% and obviously that created a lot of interest. Then they started looking at the alternative of Venetoclax in combination with dexamethasone and another agent such as proteasome inhibitors because in oncology we have a very common concept of adding drugs to see if they have synergy but more importantly if they don't have cumulative toxicity. That way we can tackle different pathways at the same time and try to kill as many bad guys as we can in the process. Proteasome inhibitors that have been studied in myeloma in combination with Venetoclax, we have vortezomib which is probably one of the most commonly used proteasome inhibitors and this was on the Bellini trial. The Bellini trial was a phase three clinical trial that compared vortezomib, venetoclax, and dexamethasone versus just venetoclax and dexamethasone. Interestingly enough this trial initially had to be stopped by the FDA because they initially presented with an increased number of deaths in the trial. There were about five deaths on that trial if I remember correctly and ultimately they realized that it came down from complications that arise from the treatment, mainly infections. At the same time, because this trial originally was designed for all comers, they did the subgroup analysis and realized that the patient that clearly benefited from the addition of venetoclax to Velcid was the subgroup of patients that had a translocation 11-14. A translocation 11-14 is basically a piece of chromosome 11 and a piece of chromosome 14 swapped in places. Those patients benefited from the addition of venetoclax tremendously and they did not have the complications that led to dying in the other patients. That's why we currently use as an off-label use venetoclax for patients with translocation 11-14 only. Patients that do not have translocation 11-14 or do not have BCL2 expressions should not be starting with venetoclax. Right now it's not FDA approved. We only use it as off-label. Venetoclax has also been studied in combination with other very common drugs like carfilzomib, another chromosome inhibitor, and daratumumab, which is an anti-CD38. They both led to tremendous responses. You look at the overall response rates for the Bellini trial in combination with Fortezumib. We're talking about overall response rates in the 90 percent. Obviously for those patients with translocation 11-14, that's a group of patients. And a progression for survival that is the stability of the disease of almost 36 months compared to barely nine months in the comparator arm. Daratumumab resulted in similar numbers. The addition of daratumumab to venetoclax led to overall response rates over 90 percent. So those are very impressive and encouraging numbers for a population that is so heavily pretreated. In all these trials, these patients received a median line of therapy around five. So that's a hefty number of previous lines of therapy for them. Most recently there's another study that is evaluating the patients with translocation 11-14 to receive venetoclax in combination with pomalidomide, which is another oral agent. It's still accruing, it's still ongoing, so we don't have obviously any data for that. But it's a very appealing option for a patient because it would be an oral alternative, right? Just pills, pills, and pills. And that simplifies the life for the patients without having to go to the infusion center to get dosed. Is ramp up dosing needed when using venetoclax in the myeloma setting? The dosing for venetoclax is very different to B-cell malignancies. Does not require a step up dose, right? A ramp up as we call it. In B-cell malignancies like lymphomas, the main driver of that ramp up is the fact that we can encounter TLS or tumor license syndrome. And tumor license syndrome is a life-threatening complication that can put the patient in grave danger if it's not managed appropriately. As a result, we do this ramp up in which we escalate the dose on a weekly basis. Myeloma, that's not the case. In all the studies that we've seen with venetoclax, there has not been clear evidence of TLS. As a result, we start the patients on the standard dose of either 400 or 800 milligrams daily. If you look at all the trials, both doses have been studied. Ultimately, it's a matter of tolerance because venetoclax can have a very notorious toxicity, mainly gastrointestinal. Nausea, vomiting, diarrhea can happen. But most importantly, hematological, like decreasing their blood counts, mainly platelets and white blood cells. So higher risk of infections can occur. That's actually what happened on the Bellini trial with all these deaths, right? That patients were in trouble from infections, not so much TLS. TLS is not something that we encounter typically in myeloma. So the main side effects that we encounter with venetoclax are gastrointestinal and hematological. The way that we manage those side effects, obviously, if the problem is nausea, vomiting, diarrhea, we can use medications to help with this to mitigate the side effects. But we could also consider reducing the doses, right? So if we started the patient on an 800 dose, going down to the 400 milliliter dose makes sense, right? Because at the end, the rule of thumb is that we cannot become worse than the disease. We cannot provide more side effects than the benefit that the drug is actually given. If the problem is hematological, and it's, again, mainly platelets and white blood cells. So if the patient has very low white blood cell count, there are higher risk of infection. We want to mitigate those. If the patient's developed severe neutropenia, which is quantified by less than 500 neutrophils, then we start the patient on prophylactic antibiotics, all right? We consider always an antibiotic, an antiviral, and if need be, an antifungal as well. But that's for the patient that really get very low on their numbers. When the platelets go down, then risk for bleeding can increase, of course. And again, we want to make sure that the patient is at a safe level in terms of their blood counts. So once again, if we need to dose reduce and go from 800 and go to 400 milligrams, that's perfectly fine. As a matter of fact, there are a lot of myeloma doctors that would simply start the patient at 400, and if tolerated, we can escalate to 800. That would be another very reasonable approach to mitigate the side effects. The most important thing is that all these side effects, when venetoclax is used in combination with other agents such as bortezomib, such as carfilzomib, such as daratumumab, those side effects are not necessarily cumulative, okay? So they kind of preserve the original toxicity that we can encounter with those agents, right? But the cytopenias are not necessarily going to be worse. The GI toxicity is not necessarily going to be worse. We just need to be aware of them. I always say we have to be aware of the side effects, but not necessarily be afraid of them. If the white blood cell count is too low, sometimes we can also provide the patients with growth factors like nupurgen and ulasta, and that will help them increase the neutrophil count to keep them out of trouble. And that is something that we can consider in myeloma because it will not have a negative impact on the disease. I will not have a negative impact on the efficacy of the drug as well. So that is a consideration, especially to keep the patient at a safe level. Should prophylactic IVIG be considered to prevent possible infections? Myeloma is a disease that comes from plasma cells, right? And the job that plasma cells do is to produce those proteins, those antibodies. The disease on its own can put the patient on a, what we call, on a hypogammaglobulinamic state. That will put them at risk for infection on its own. Every drug that we use currently in myeloma can also increase the risk of low levels of IgG. And this IgG, when it hits 500, the patients start having a higher risk of infections and recurrent infections, especially operative respiratory tract infections can occur. Whenever the patient are below 500 and have recurrent infections, IVIG should be considered. Also, if the patient is having an ongoing infection that has not resolved, we can boost the patient with IVIG to help them increase their immune system that way. Is vanetoclax therapy a fixed duration or is it taken until progression? Whenever we start a patient on treatment, we know that the treatment for the most part is going to be until this is progression or intolerable side effects. And that applies to any line of therapy. At some point, we can talk about maintenance, right? Like, for instance, right after transplant, we talk about revelant maintenance, Velcade revelant maintenance, whatever the case may be based on the biology of the disease. Once we have relapse of these diseases at some point and we start vanetoclax in combination with something, then we continue this treatment for as long as we can, meaning until this is progression or intolerable side effects. And we continue with the same doses. It's not necessarily the dose of vanetoclax based on a maintenance quote unquote. We could, however, and we should adjust the dose of the other agent. For example, Bortezomib can be given days one and 15 rather than days one, eight, and 15. Carfilzomib can be given also days one and 15. And that's especially if the patient is having issues with toxicity, right? Because again, we want to minimize the risk of them having toxicity. When we use daratumumab, we know that the schedule for daratumumab is going to be weekly for eight doses, then every other week for eight doses, then monthly until this is progression or intolerable side effects. So the monthly daratumumab kind of becomes the maintenance, but you keep going with the vanetoclax on a daily basis. The target population for a vanetoclax trial is very simple. Anybody who has a translocation, 11, 14. In myeloma, we have a really good problem to have, and it's that nowadays we have extended the life expectancy of our patients by a big margin. But we did that through clinical trials, through research. So analyzing that subgroup of population that has a translocation, 11, 14, is very important because it will ultimately lead to potentially an FDA approval for this medication, which means another drug that we can use for them. Anybody who has a translocation, 11, 14, and there is any clinical trial that is available should definitely consider it because ultimately it's going to benefit everybody, including themselves.