Click Here to watch Just the PI3K Delta Inhibitor Phase 3 Trial Video from EHA 2022
Presented at EHA 2022 the ADPS or Activated PI3K Delta Syndrome is a relatively new disease that was only fully characterized in 2013. It is a primary immune dysregulatory disorder, which means it is a rare genetic disorder that involves both immune deficiency, which shows up as frequent infections and immune dysregulation, which can involve things like autoimmunity lymphoproliferation symptoms can vary widely from person to person and in general it a progressive disease and can lead to end organ damage as well as malignancies, including lymphomas in multiple family members. Before we get to challenge of treating a disease rare orphan disease like this, I would like to also point out that a challenge in primary immunoregulatory dysregulatory disorders.
Or what we in the vernacular call in bone marrow of immunity is a diagnosis. So more of these genetic diseases are being discovered and genetic testing is becoming more accessible, at least in Europe and north America. These patients experience a protracted diagnostic Odyssey for patients with ADPS and most of immunity.
The median time to diagnosis. From the onset of symptoms in infancy or early childhood can be seven to eight years. As we have seen in the natural history studies problems with treating any disease of this nature, is that in order to treat the dysregulation, we usually use immunosuppressive agents, but because this patient population is already susceptible to infections, we have to be very careful about suppressing the immune system.
In other words, they often need several types of medications, including immuno global in supplementation and immuno modulators, like rapamycin and mycophenolate morph, or some other agent or rituximab. Some of which have opposing actions. This is further complicated. If the patient has lymphoma. And there are no approved therapies for treatment of ADPS, as yet with the exception of hematopoietic stem cell transplantation, the existing therapies do not treat the root cause of the disease, which is a hyperactive enzyme found in the immune cell, known as P110 Delta, even with hematopoietic stem cell transplant.
There appears to be non-immune media. Problems, including kidney disease, which do not get better. And there are problems related to graft acceptance by the host and the rational for using Leniolisib in the treatment of people with ADPS is directly as is because it directly targets the hyperactive enzyme.
P110 delta and inhibits it. That is why it is called PI3K kinase inhibitor. And there are a class of these drugs, which are in clinical use in oncology, hematology, and but Leniolisib is a medication that has been developed by the sponsor for specifically for this rare inherited genetic disorder.
What we are seeing to date so far is that this affects the immune cells and allows them to develop correctly. This particular medication, which may have implications both for the deficiency and dysregulation aspects of the disease. For example, we have recently presented. Data in that in 12 weeks, the Leniolisib reduces the size of patients, swollen lymph nodes and spleens, which becomes, they usually become swollen because of chronic inflammation infection, as well as B and TCE dysregulation.
And we are excited to present the long term outcome on, in fall at European society of immunodeficiency, which is another meeting coming up in October. So the aims and design of this phase 3 study that was presented at European Hematology Association or EHA 2022 is to, it was a randomized placebo controlled trial to further investigate what we observed in the phase two dose escalation trial that we already published in 2017 using the same medication.
The co-primary endpoints were interesting because they address two large components of the disease. The live B cell replenishment lets us know that eventually we may see better antibody production and infection fighting in these patients. As we use this medication longer term and early indication that was seen in the published phase 2 long term study was where three of the original 6 patients were able to stop the immuno global replacement therapy was presented at ASH meeting in 2018. The design was typical for a randomized control trial, where in 31 patients were randomized two each to one in a placebo controlled design. 21 of them received Leniolisib. Let's say about a dose of 70 milligram overly twice a day.
And what is unusual though, is that the length of time we have been follow following these patients who rolled over to a long term extension study and. These patients have been followed. Some of these patients have been followed for the long term in the sense about 3 to 4 years for now.
And eligibility was interesting in the sense that included patients from ages of 12 to 75, but the weight criteria of greater than equal to 45 kilograms made recruitment of younger patients, rather challenging. And. We presented safety as well as reduction in lympho neuropathy reduction in splenomegaly as well as swollen or what is not as swollen spleens, increasing the IB cells and improvement in cytopenias at the European hematology association (EHA 2022) meeting.
And at ESCI, another colleague of mine, Dr. Virgil dam has presented results related to lymphocyte, subsets, and further illustrate the reconstitution of the immune system. The finding of this study data. And what are the implication for clinical practice? The answer to this is complex.
We, I'm not sure we can make too much kind of implication because we haven't published data though. We have it, and we are going to be discussing it in various meetings coming for in the near future. Remember what I presented at European hematology association (EHA 2022) is only 85 days or 12 week data of this use of this medication.
So the findings from recently completed studies have been presented. Scientific congresses, as and the product is still investigational and sponsor of the product is working closely with the regulatory authorities around the world, seeking app its approval. The full implications will be realized when approved product is available for APDS patient populations worldwide.
And the questions that remain unanswered. Are the pediatric population under the age of 12 years, because this particular data I'm showing you here, I have shown you in as well as we will be showing in future is limited to patients that are 12 years and older. There are currently two studies planned in younger pediatric population at multiple centers in United States, north America, as well as in Europe.
And the first study is scheduled to start sometime this. And the, in the field of inborn errors of immunity, our IEI is growing and APDS is no exception. We do not have a complete understanding of the genetic penetrance, why symptoms vary so widely, even sometimes within the same family, we also hope to learn more about the natural history of this disease and non-immune mediated parts of the disease, which may impact kidney central nervous system and other body organs.
Are there other users of this kind of approach in for medical oncology and hematology healthcare professionals? I will say the hematologists should consider using PI3K K and a is modulation in other hematology conditions. And oncology and hematology healthcare professionals are already using this class of drugs with some serious side effect concern in lymphoma patients.
And what are the most common questions our colleagues have asked so far is any adverse side effects. And we have not seen any serious adverse side effects that required stoppage of medication in any of the 31 patients that are being reported in this clinical trial and all 6 patients that we have published continue to be on this medication for more than 5 years.
So people have asked us about improvement in infection rates and other comorbidities, and that data will be presented with the long term follow up of these patients in future research. So we are very excited to present the long term outcome in the fall, as well as in winter in various scientific meetings, as we so stay tuned, I would say.
Timothy J. Brown, MD, Fellow, Hematology and Oncology, Perelman School of Medicine. He has published research in JAMA Oncology, JCO Oncology Practice, Blood, JCO Precision Oncology, and Supportive Care in Cancer.
Click Here to Watch the BRCA1, BRCA2 or PALB2 in pancreatic cancer EHA 2022 Interview
Presented at EHA 2022 the this study that we presented at ASCO 2022 is titled a descriptive study on the treatment and outcomes of patients with platinum-sensitive advanced BRCA or PALB2-related pancreatic cancers who have progressed on rucaparib. This reseaerch study was is a follow-up study to a phase 2 clinical trial of patients with platinum-sensitive, advanced pancreatic cancer who had a germline or somatic pathogenic variant in BRCA 1, BRCA 2, or PALB2 patients who had the platinum-sensitive disease were placed on a maintenance rucaparib treatment, which is a PARP inhibitor.
The clinical question we had was how do we treat these patients after their cancer has progressed on rucaparib in pancreas cancer. In particular, is very limited data to guide our management. So broadly, what we were interested in is looking at what patients were treated with after they've come off of the protocol study, and broadly we were interested in particular in the use of platinum-based versus non-platinum-based chemotherapies.
We looked at outcomes such as overall survival progression-free survival objective response rates by 1.1 and an endpoint called PFS two, which we defined as the time from enrollment on the initial clinical trial until progression on the second line chemotherapy. The original clinical trial had 42 patients that had enrolled of these 42, 18 had progressed and were treated with platinum-based chemotherapy, 5 progressed and were treated with non-platinum-based chemotherapy.
11 patients at the time of data cutoff remained on the initial clinical trial research. 6 patients did not receive any further therapies after progression, and 2 patients received other therapies such as targeted therapies or radiation broadly. What we found was that of the 18 patients who received platinum-based chemotherapy after progression rucaparib the median overall survival was 14.8 months.
Of those five patients who received non-platinum-based chemotherapies, the median overall survival was 28.9 months. Although there's a numerical difference here, the limited sample size prevent us from drawing any definitive conclusions about superiority, the objective response rates for those who receive platinum-based chemotherapies was 22.2%.
Whereas those who received non-platinum-based chemotherapies was 40%. We also looked at the type of platinum that patients received. If they received further platinum-based chemotherapy, there were nine patients who received a Cisplatin-based regimen and nine patients who received an Ozil platinum-based regimen.
The patients who received Cisplatin had a median overall survival of 13.8 months. And those who received oxaliplatin-based therapies had a median overall survival of 19 months. the objective response rates. For those who received cisplatin was 11.1% compared to 33.3%. For those who received oxaliplatin, we could not identify any particular patterns with regard to times that patients spent on recap, AIB, and outcomes following progression on chemotherapy.
And so the conclusion from this study was that this is a small observational study where we looked at how to treat patients following progression on chemotherapy. And although the sample size is too small to make any definitive comparisons, it does appear that chemotherapies still remain an option in select patients.
I think the most common clinical question that clinicians have after treating patients with pancreas cancer on PARP inhibitor is can you still use platinum-based chemotherapies? Because we believe that if patients have progressive disease on platinum-based chemotherapies, PARP inhibitors won't work, we don't necessarily know that the alternative is true.
If patients who progress on PARP inhibitors, if we can still use platinum-based chemotherapies, it does appear based off the results of this study. That platinum-based chemotherapy still have some activity in this patient population.
We are still hoping to better define how to identify which patients should be treated with a platinum-based versus non-platinum-based chemotherapy as the subject of ongoing work, I would say today and in the future. Clinicians can feel comfortable tailoring post-progression chemotherapy decisions based off of patients individual comorbidities.
Currently, we are attempting to better understand the genotype-phenotype connection between BRCA and PFS2 mutations, as well as their response to both PARP inhibitor therapies and post-progression chemotherapy. This is work that is ongoing that we're hoping to finish in the next year or so.
Again, I want to emphasize that patients who have progressive disease on PARP inhibitor they can still be treated with chemotherapy if they are still treatment candidates. I think that we still have too small of a sample size to derive any definitive conclusions between which.
Robert M. Rifkin, MD, is a board-certified medical oncologist and hematologist specializing in malignant and benign hematology, treating cancer and blood disorders. He has an advanced sub-specialty expertise in coagulation disorders, multiple myeloma, and biosimilars. Dr. Rifkin practices evidence-based medicine and follows National Comprehensive Cancer Network (NCCN) guidelines for cancer treatment.
Click Here to watch the MM-6 Trial EHA 2022 Interview
Median age was 73 years (range, 48-90 years), with 81% aged >65 years; 97% had ≥1 comorbidity at the start of IRd therapy.
Efficacy data after an additional 11 months of follow-up (data cut-off: May 4, 2021) showed that iCT to IRd improved responses.
Overall response rate (ORR) had improved from 65% (CR 9%, VGPR 25%, PR 32%), at the end of 3 cycles of V-based induction, to 78% (molecular CR [mCR] 1%, stringent CR [sCR] 3%, CR 32%, VGPR 25%, PR 17%) following iCT to IRd.
At a median follow-up of 18.5 months, the 18-month PFS rate was 84%. The safety profile of IRd was consistent with previous clinical studies.
Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 64% of patients and treatment-related serious TEAEs in 12% (including 4 on-study deaths), while 16% of TEAEs led to study drug discontinuation.
Here we have analyzed the latest updates on the data for this patient subset with an additional 11 months of follow-up to further evaluate efficacy and safety, and to determine reasons for premature (within 4 cycles of IRd) discontinuation.
Sixty-eight patients (67%) had completed or discontinued the study since first patient enrolment on November 15, 2017.
Among these patients, 14 (21%) discontinued within 2 cycles of IRd and 27 (40%) discontinued within 4 cycles.
With longer follow-up, use of iCT from V-based induction to IRd to achieve long-term PI-based therapy in NDMM patients demonstrates efficacy via improved response rates and acceptable PFS in this real-world setting.
Over 80% of US MM-6 patients were aged >65 years and most had ≥1 comorbidity prior to study entry.
The rate of patients discontinuing within 4 cycles of iCT (7 cycles of PI-based therapies in total) is concerning because these patients may not receive the full benefit of long-term PI-based treatment.
To date, the majority of premature discontinuations were reported as being due to patient request (44%) followed by TEAEs (30%).
Dosing - 4 mg ixazomib + 25 mg lenalidomide + 40 mg dexamethasone.
For up to 3 years, all participants are requested to take ixazomib 4 mg on Days 1, 8, and 15, lenalidomide 25 mg on Days 1 through 21, and dexamethasone 40 mg on Days 1, 8, 15, and 22 in 28-day cycles until progression or intolerable toxicity.
The treatment phase of this trial is expected to last up to 78 months, including a 42-month enrolment period and a 36-month IRD treatment term (39 cycles) with ixazomib and/or lenalidomide and/or dexamethasone for the final subject recruited.
This is a review featured at EHA 2022 of the latest updates on a combination clinical trial including Dexamethasone, Ixazomib, and Lenalidomide from the European Hematology Association (EHA). The abstract of interest is a little bit unusual in its design. A previous trial has been conducted called "MM-6." And that was a little bit unique in that we studied newly diagnosed multiple myeloma patients, and they could have received any Velcade based induction, whether it was a double or a triplet.
After three cycles, if they had stable responding disease, they were then switched to an all-oral triplet combination, which consisted of Ixazomib, Lenalidomide, and Dexamethasone, otherwise known as IRD. And we've previously published on this group showing the feasibility and potential benefits of an in-class transition.
We studied around 100 patients in that single-arm study. However, this abstract is a little bit different in that what we did was we took the 6 databases and then we also started to do matched para-analysis with a large myeloma registry known as INSIGHT MM: a large, global, prospective, non-interventional, real-world study of patients with multiple myeloma.
We matched patients with those who were in treatment phase in the United States, and they were treated with a slightly different regimen where there was parental Velcade given as a subcutaneous injection. So, this was not an all-oral dosing schedule. One of our aims was to see if with all oral regimens we could improve compliance, adherence, and keep people on clinical trial therapies longer.
Myeloma has become a maintenance treatment disease, so what we did was match pair analysis with some of the increased risk I've alluded to. Using the six data points with the in-class transition, we showed, when compared to the INSIGHT MM registry, a higher overall response rate and a longer duration of therapy.
This was somewhat nice and added some validity to the in-class transition approach and, more importantly, the ability to stay on a prolonged all-oral maintenance treatment with Ixazomib, lenalidomide, and dexamethasone. And while this is preliminary data, I think it's encouraging and may pave the way for future class transitions in multiple myeloma treatment.
There's a tremendous number of multiple myeloma drugs being developed into a lot of new treatments, some of which are CAR-T cell specific antibodies, antibody drug conjugate molecules with novel mechanisms of action, some of which are oral, some of which are not. I think this approach provides some good evidence that in class transition, and even using all oral regimens like Ixazomib, lenalidomide, and dexamethasone will really help people stay on maintenance treatment longer and hopefully improve our overall outcome in multiple myeloma and decrease missed dose.
So, although the study design is a bit unusual, it really demonstrates the value of an all-oral regimen, especially in the COVID era. Interestingly, when we designed 6, INSIGHT MM was already up and running. COVID changed a lot of things. A lot of them are now very difficult to analyze. but in the MM-6 trial, COVID was something that played very well with the study because it was an all-oral regimen and patients didn't really have to go to the physician's office frequently. They could stay at home, practice isolation, and monitor themselves for adverse reactions while staying away from COVID. The data research is still in progress. So, I think overall, this showed that using the in-class transition and avoiding parental medication increased our response rates and duration of maintenance treatment.
The next step for the MM-6 Trial research would be to design a successor study with some in-class transitions. I know we're looking at the feasibility of doing that, but certainly the concept of in-class transition will be here to stay. And it's how we exploit that in myeloma. And then, obviously, with the insight database and that registry, now closed for a little bit. All that data and insight will start to mature and will be the foundation for a lot of future analyses. I don't know that we'll be able to quite do this same comparison between a registry and a retrospective study, while it has some shortcomings as an eye opener in terms of response rates and duration of therapy.
I think that the clinical trials data overall speaks for itself. As providers become more comfortable with all oral regimens and doing final dose reduction and dose adjustments, toxicities, and then importantly, really measuring patients’ quality of life while watching for new or worsening symptoms. Multiple myeloma patients are on therapies for a very long time, hopefully using Ixazomib, lenalidomide, and dexamethasone, and all the therapies get to minimal residual disease negativity, which is really our goal.
If you remain minimal residual disease negative for a long period of time, at some point you may be able to stop therapy for multiple myeloma, following symptoms, of course. So, this database can, in part, serve as a small part of the foundation for achieving minimal residual disease negativity in newly diagnosed patients. Although that wasn't really our primary endpoint, I think that's everybody's goal at the end of the day.
Long-term PI based treatment duration can enhance results in multiple myeloma across treatment settings. However, there are a variety of physical, geographical, and/or socioeconomic challenges to long-term parenteral PI therapies in community practice. The US MM-6 research (NCT03173092) is looking at in-class transition (iCT) from parenteral bortezomib (V)-based induction to all-oral ixazomib-based therapy with ixazomib, lenalidomide, and dexamethasone (IRd) in a heterogeneous community population in the United States. The study's goal is to extend the length of PI-based treatment while maintaining quality of life and enhancing outcomes. We previously presented promising efficacy and safety data for the first 101 MM-6 patients in the United States (Girnius Blood 2020). We reviewed the latest updates data for this patient subset with an additional 11 months of follow-up to assess effectiveness and safety, as well as causes for premature (within 4 cycles of IRd) discontinuation.
Transplant-ineligible/transplant-delayed (24 months) Patients with Newly Diagnosed Multiple Myeloma at community sites in the United States who had achieved stable disease or better after three cycles of Velcade based induction were given xazomib, Lenalidomide, and Dexamethasone (ixazomib 4 mg, days 1, 8, 15; lenalidomide 25 mg, days 1-21; dexamethasone 40 mg, days 1, 8, 15, 22) for up to 39 28-day cycles, or until progressive disease or unacceptable toxicity. The primary goal is to achieve 2-year diesease progression-free survival (PFS). The rates of partial response (PR), very good partial response (VGPR), and complete response (CR), as well as the length of therapies are important secondary endpoints. For the current study, sites with patients who had stopped using US MM-6 trial were contacted for extra information.
As of June 1, 2020, 101 individuals had been registered and treated at 21 sites. The median age was 73 years (range, 48-90 years), with 81% older than 65 years and 97% having at least one comorbidity at the commencement of ixazomib, lenalidomide, and dexamethasone therapy. After a further 11 months of follow-up (data cut-off: May 4, 2021), efficacy data showed that iCT to Ixazomib Lenalidomide Dexamethasone improved response and disease progression. Following iCT to IRd, the overall response rate (ORR) increased from 65% (CR 9%, very good partial response 25%, PR 32%) at the end of three cycles of V-based induction to 78% (molecular CR [mCR] 1%, stringent CR [sCR] 3%, CR 32%, VGPR 25%, PR 17%). At the most recent data cut-off, 33 patients (33%) were still on therapy; the median duration of ixazomib, lenalidomide, and dexamethasone was 11.7 months, and the overall median duration of therapy (for all PI-based therapy, including Velcade based induction) was 14.6 months. The 18-month PFS rate was 84% at a median follow-up of 18.5 months. Ixazomib Lenalidomide Dexamethasone safety profile was similar to earlier clinical trials. Treatment-emergent adverse events (TEAEs) of grade 3 were documented in 64% of patients, and treatment-related significant TEAEs in 12% of patients (including 4 on-study deaths), with 16% of TEAEs leading to study drug cessation. Since the first patient's enrolment on November 15, 2017, 68 patients (67%) either completed or discontinued the trial. 14 (21%) of these patients ceased ixazomib, lenalidomide, and dexamethasone within two cycles, and 27 (40%) discontinued within four cycles.
In this real-world situation, the use of iCT from Velcade based induction to Ixazomib Lenalidomide Dexamethasone to achieve long-term PI-based therapy in Newly Diagnosed Multiple Myeloma patients reveals efficacy via enhanced response rates and acceptable progression-free survival with longer follow-up. Over 80% of MM-6 patients in the United States were over the age of 65, and the majority had at least one comorbidity prior to study entry. The rate of patients discontinuing iCT after four cycles (seven cycles of PI-based therapies total) is problematic since these patients may not benefit fully from long-term PI-based treatment. To date, the bulk of early discontinuations (44%) have been attributed to patient requests, followed by TEAEs (30%). The planned US MM7 iCT oncology research in relapsed or refractory MM will address expanded site education and improved patient follow-up to reduce premature discontinuations.
Aaron T. Gerds, MD, MS, Associate Professor of Medicine, Deputy Director for Clinical Research at the Cleveland Clinic Taussig Cancer Institute and Medical Director of the Case Comprehensive Cancer Center Clinical Research Office at Cleveland Clinic.
Click Here to watch the Reveal Study EHA 2022 Interview
At the EHA 2022 (European Hematology Association) meeting, we presented an abstract from the REVEAL study. Really focusing in on thrombosis risk in patients with polycythemia vera, with respect to their blood counts outside of the adequate the REVEAL study is a very large prospective observational study of patients with polycythemia vera treated in both.
Community practices as well as academic practices. And it is a cross-sectional study where we enrolled 2,500 patients, again, four observations. So, there was no therapeutic intervention there. And they were followed for a minimum of 36 months after enrollment. So, we got a pretty good broad swipe of data before they enrolled on this observational study, as well as afterward.
And again, the focus of this abstract was looking at thrombotic event. The reason we focus on thrombotic events is we have a really old way of looking to identifying patients who have high risk for thrombosis and low risk for thrombosis. Basically, anybody who is older, or who has had a history of a blood clot is considered to be high risk for thrombosis.
And then everybody else is considered to be low risk. So very antiquated. And the thought is that perhaps we can look at other parameters to refine our ability to identify clot risk in these folks. Cause thrombosis is the major complication of PV and there have been prior studies that have been published that show that yeah, perhaps an elevated white count or elevated platelet counts might be associated with thrombosis risk, but it's not a certainty.
And moreover, when you control the hematocrit, do these factors still hold. So, we took the REVEAL database and we looked for patients who had at least enough blood counts in order to make a judgment on things. And from the 2,500 patients that were enrolled wet things down to about 2100 patients but still a very large database.
In fact, the largest database of polycythemia vera ever made, we looked at a couple of different cutoffs, white counts that were above normal, above 11, or below 11, as well as platelet counts with a cutoff of four, 400 to see if these markers had any prediction for thrombosis in these populations.
And what we saw is yes, as the white count increases, we do see increased risk of thrombosis. Additionally, we see. Platelet counts above 400 were associated with thrombosis risk. But oddly enough, when we looked at platelet counts above 600, it wasn't associated with thrombosis risk, and we're not in quite sure why we saw that.
Probably a couple of different reasons. One is the interaction between thrombosis risk, and platelet count may not be that strong. And secondarily, there were a few patients with platelet counts above 600 enrolled in the study. So, the numbers may not be big enough really to appreciate that increased risk of thrombosis.
Secondly, we took all the patients who had controlled hematocrits, so hematocrits less than 45, and look to see in those patients to see. Increasing white blood cell count or platelet counts was associated with thrombosis risk. And it looked like there was a trend when the white count was over 11 for increased thrombosis risk.
But certainly, when the white count became over 12, there was an association between that elevated white blood cell count or leukocytosis and future blood clot risk. We also confirmed in this study that classic markers of thrombosis risks such as age and history of blood clots were also predictors.
So, in the end. The important take-home points from this study were that we should really be starting to think more broadly about risk stratifying patients for thrombosis who have PV and moving beyond the classic thrombo hemorrhagic model and including things like white count and potentially platelet count during discussions it was also brought up that JAK2 allele burden can predict thrombosis and perhaps that could be included as well.
And in fact, these are analyses that we are undertaking with this database.
Hang Quach, MBBS(Hons), SpecCertOC, FRACP, FRCPA, MD, Haematologist with clinical and research interests in multiple myeloma, in particular myeloma, lymphoma and myeloid disorders at St Vincent’s Health Melbourne and University of Melbourne Australia.
Click Here to watch the CANDOR Study EHA 2022 Interview
The study that I will be discussing today is the frailty subgroup research of the CANDOR study, which is a phase 3 study comparing Daratumumab, Carfilzomib and Dexamethasone.
That's Dara KD with KD that's Carfilzomib and Dexamethasone in patients with relapse refractory, multiple myeloma. Now in the treatment of multiple myeloma sometimes efficacious treatment can result in poor outcome. If patients are FRA and cannot tolerate treatment now we know from the phase three can or study that the triplet combination of Dara KD is effective and result in a 41% relative risk reduction in progression or death compared to a Carfilzomib and Dexamethasone.
So, in this research, what we wanted to know was whether frail patients can stand to benefit as much from Dara KD as a fit patient. So, all patients in the candle study were categorized into a fit, intermediate fit or frail, according to the IMWG frailty index that incorporates age performance status and comorbid.
And so, what we found was that Dara KD resulted in a better progression, free survival compared to a KD across all subgroups of fit and FRA patients. And so, in fit patients, the median over the median progression free survival was not reached compared to approximately 18 months with KD.
And in the frail subgroup of patients, the median progression-free survival was approximately 19 months with Dara KD compared to only 9 months with KD. With respect to overall response rate there was an increase in complete response rate with Dara KD across all subgroups of a fit frail patients and with respect to side effects all treatment, emergent, adverse events, all grade were seen in over 95% of patients in all subgroup of fail and fit.
But what was important was that there was no increase in toxicity in the FRA subgroup of patients compared to the fit subgroup of patients. And in fact, the rate and profile of toxicity was very similar across the fit and frailty subgroup of patient. And so, what we can conclude from this study is that Dara KD resulted in a better progression, free survival compared to KD across or fit and frail subgroup of patients.
And there is not an increase. In toxicity in frail patients necessarily compared to their fit patients and that the frail patients can stand to benefit from Dara KD with respect to overall response rate and depth of response that did translate it to a better progression, free survival compared to KD.
The most common question I get asked about this study is that what dose of Carfilzomib would I use in combination with daratumumab and Dara zone in the real-world setting? And in the candle study, indeed. The dose of Carfilzomib that was used was the traditional twice weekly 56 milligram per meter squared on days 1, 2, 8, 9, 15, 16, every 28 days.
Now we know from the arrow study subsequently that a weekly schedule of car was N of 17 milligram per meter squared weekly. That stays 1, 8, 15, every 28 days resulted in a better progression, free survival, and was better tolerated compared to the twice weekly schedule. So many of us are now moving towards a weekly schedule of.
Carfilzomib when used in combination with daratumumab and dexamethasone. And I would personally use from 56 milligram per squared, weekly or 70 milligrams per squared, weekly.
This data will affect the way we treat patients today and highly relevant only because Dara KD has been approved and is now commonly used as a regimen in patients with relapse refractory in multiple myeloma in many jurisdictions in the world. And what's important is that patients with relapse refractory multiple myeloma are commonly elderly if not frail.
So, at least based on this data clinicians can rest assured that Dara KD can be effective as well, tolerated in their elderly and frail patients with relapse refractory, multiple myeloma.
I think the one major thing that I would like oncology and hematology healthcare professionals to be aware of and this more practical rather than to do with the clinical study is that Carfilzomib ought to be used with caution in patients with uncontrolled hypertension, with pulmonary hypertension or with cardiovascular comorbidities particularly if they are frail and elderly patients.
And in these patients, it's important that they be monitored very closely and that the underlying comorbidities are well controlled and that the dose of Carfilzomib may need to be reduced at the outset, if not at the at the treatment emerging adverse event.
Professor Peter Hillmen, MD, leads the Experimental Hematology section in LICAP and the Translational Hematology Research group. He is a Professor of Experimental Hematology and Honorary Consultant Hematologist at Leeds Teaching Hospitals NHS Trust at the University of Leeds.
Click Here to watch the FLAIR Trial EHA 2022 Interview
At EHA 2022 I presented the interim research of the second part of the FLARE trial, which is a randomized phase 3 trial in previous stances, CLL patients which the total trial we recruit just under 1500 patient. What we presented here was the first interim analysis of comparison of Ibrutinib (I) and venetoclax (V) compared to Ibrutinib (I) monotherapy where half the patients had reached 2 years.
That was 2,274 patients randomized. So, we analyze over five total that comparison and setting MRD. First of all, we showed that the treatment well tolerated, there were no. Significant tissues with adding the venetoclax (V) to Ibrutinib (I). We saw slightly more neutropenia, slightly more diarrhea but nothing that was dose limiting or treatment limiting and tumor syndrome was only a very small portion and unmanageable.
The primary endpoint of this past the trial was MRD eradication using in blood and marrow, but maybe marrow 10 minus 10,000. And what we showed was that in the Ibrutinib (I) no patients achieved MRD eradication and in the hyper at 2 years, 71 total, 1% just over a patients achieve node to the blood.
And 65% in the marrow, about 43% had stopped treatment in two years and others will stop at later on we, we guide therapy by MRD early patient. In addition, the complete remission rate was higher for the with just under 60% of patients achieving negativity with I compared to only 8% with alone.
We don't have survival that we expect that to be next year, we're seeing continuing increasing depth of remission with subsequent continuous therapy in flare. We can continue the therapy for up to six years to go and respond. And we also showed similar to some of the phase 2 trials that patients.
For features with chemotherapy IGHG only mutated for example, were more likely to have an MRD negative emission than those who were mutated. So almost 80% of patients with unmutated disease were MRD negative by 2 years. And likewise, 11 deletions more patients achieved naivety with 11 to disease.
Without percent negativity in 2 years, so really by encouraging results, indicating that we can use this combination. Safely and that we will stop the majority of patients where under negativity and we anticipate we to prolonged survivals, progression free survivals without all that data won't be out until next year.
So, I think the most common questions asked, include whether the combination of I plus that is safe. Which we demonstrated earlier say, were also asked about the use of MRD to define duration of therapy. And this is one of the trials which uniquely does that. And I think it's clear that if we use MRD to guide therapy, then we're going to get the most out of the accommodations of who won some patients.
If we use a fixation treatment will still be MRD positive who would be negative with further treatment.
The further question that's often asked is about the poorest features. So, the I unmutated and why we would see a higher response rate and allocation rate would the unmutated rather than mutated, which is for chemotherapy, the wrong way around. And the reason I think is because IGHV unmutated disease is very dependent on BSO receptor signaling and, the targets the BSO receptor pathways.
So, I think specifically like, such as ibrutinib (I) is likely to see a better response rate, the combination of has been studied in a number of other trials, one other phase three trial, which will probably lead to the approval of the combination in re in, in certain bodies. And so, I think the combination of will be available and our data from FLAIR, especially when we have the additional data, which we see next year, which will be.
A large dataset will reinforce the use of this combination for the poorest patients. And so, I think, will it impact routine practice, but probably not just yet. So, in our population, I think we need approval of the combination first and I'm not sure where that's planned for.
But probably in the next 12 months, we'll see approvals coming through, and I think this data becomes important.
So, this is the only the second in FLAIR. We have we expect next year to see the definitive comparison with progression survival as employed for I+V compared to FCR which is a key endpoint of the trial. And also, a building on this combination. I, in terms of MRD and progression through survival. So, I think in the next 12 to 18 months, we should see data emerging from this trial, which include survival outcomes.
And if they show an advantage in favor of the combination and then it'll. It will be treatment changing and we'll change the way we treat patients globally.
This is an early readout of a combination of a large phase trial. And we will show further data in future, but it's important. We get long term data cause the outcomes are so good. For CLL, I think we'll lead it. We're moving towards using IGHD mutations data on (inaudible) to define the type of we're using CLL.
As things stand at the moment, the evidence suggests that we should be using and mutated patients. I mutated. Whereas, for the other patients, unmutated probably 17 (inaudible). If we want to stop therapy, a combination of Ibrutinib (I) is more logical. And so I think we're waiting for obviously more mature data.
But I think it's encouraging that we will be using a biological map cause to define a clear choice.
Aaron T. Gerds, MD, MS, Associate Professor of Medicine, Deputy Director for Clinical Research at the Cleveland Clinic Taussig Cancer Institute and Medical Director of the Case Comprehensive Cancer Center Clinical Research Office at Cleveland Clinic.
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It's my pleasure today to discuss with you the results of the MOMENTUM study as presented at EHA 2022. So, the MOMENTUM study is an incredibly important study in the development of a drug called Momelotinib, a JAK inhibitor that differentiates itself from other inhibitors that are already approved for the treatment of patients with myelofibrosis.
A key off-target effect on a molecule called ACVR1, also known as ALK2, It does have the kind of canonical JAK inhibition of JAK2 that we see with other JAK inhibitors. But again, the standout feature is this off-target effect on ACVR1/ALK2 CVR. What that does is it's a master regulator of iron metabolism in our body and actually affects hepcidin levels.
It can lower hepcidin levels, thus treating the inflammatory component of anemia. Anemia is an incredibly important problem in patients with myelofibrosis. It is a diagnostic criterion as well as a prognostic criterion for patients with this disease. And there is some retrospective research suggesting that if we could impact disease-related anemia and improve it, patients could have better overall survival in addition to better quality of life and potentially better resource utilization.
So, in this trial, the MOMENTUM study, momelotinib as a JAK inhibitor slash ACVR1 inhibitor was pitted against Danazol in anemic patients with myelofibrosis previously treated with JAK inhibitors. These patients also had to be symptomatic and have enlarged spleens. The top line results were previously released in a press release from the company.
But in these abstracts, we have much more detail on the outcomes for the primary endpoint of this study. The primary endpoint of the study was an improvement in symptom burden at week 24. Additional key secondary endpoints included spleen vine responses at week 24, as well as transfusion independence at week 24. So, taking that last point is key because Danazol was selected as a comparator arm because it is used to treat anemia in myelofibrosis patients as recommended by the NCCN and ESMO guidelines.
So, in those results, the Momelotinib arm outperformed the Danazol arm in terms of transfusion independence at week 24. Moreover, Momelotinib was able to shrink spleens as well as improve symptoms in patients to a much greater degree as compared to Danazol. I think that is really the key take-home point from this study. The top-line total study results were presented by Dr. Verstovsek, and the special subset of patients with thrombocytopenia were presented by Dr. Verstovsek at the EHA 2022 meeting in two separate abstracts. And the reason that we focused on patients with lower platelet counts is that Earlier Momelotinib trials, as well as this trial, did include patients with thrombocytopenia.
In fact, we included patients with a platelet count as low as 25,000. Therefore, severe thrombocytopenia was included in this study, and a fair number of patients did have severe thrombocytopenia. And I think that's really important to note because Currently available Ruxolitinib and Fedratinib have limits on how much we can use them in clinical oncology and hematology and what doses because of thrombocytopenia.
Of course, there is the approved Pacritinib that can be safely given to patients with platelet counts of less than 50,000. So as more and more JAK inhibitors come into clinical use every day in the clinic, I think it's going to be really important how we try to separate these things out and which patient populations have data that supports the use of these drugs as well.
And again, these were a lot of the top-line results from this momelotinib study, but the work going forward would really be on identifying the best populations for each of these JAK inhibitors. Now that we have almost an embarrassment of riches in the number of JAK inhibitors approved, the next step for this particular drug is really regulatory approval.
This was a registration and the data is being further cleaned up and correlated and is being put together for regulatory submission to the FDA for hopefully regulatory approval sometime in the year 2023. The quicker we can get momelotinib to our patients, the better.