Hi there, I’m Dr Thomas Martin from the University of California, San Francisco and I’m providing an update at ASH 2022. One of the presentations that I was able to do was from a study called the IKEMA study and this study was a randomised phase III multinational, multicentre study using isatuximab plus carfilzomib and dexamethasone, a triplet, and comparing it to just carfilzomib and dexamethasone in patients with relapsed and refractory multiple myeloma.
Now, at ASH 2022 we did a subgroup analysis and we compared patients who had early versus late relapse and we compared their outcomes with the triplet versus the doublet and between each other. Early relapse was defined as patients who had relapsed less than 12 months from the initiation of the most recent line of therapy and that was for patients with greater than or equal to two prior lines of therapy, patients who had relapsed less than 18 months if they had had one prior line of therapy and patients who had relapsed within 12 months of stem cell transplant. We considered late relapse were patients who had relapsed more than 12 months from the initiation of their most recent line of therapy for two or more prior lines of therapy and greater than 18 months for patients who had received just one prior line of therapy.
The two groups actually were fairly balanced in terms of patient demographics when we broke it all up. There were perhaps a little more high risk patients, based on cytogenetics, in the early relapse patients versus the late relapse, as you would expect. That included it was more likely for patients to have two or more cytogenetic abnormalities.
We looked at the duration and the relative dose intensity of therapy in these patients and, in fact, they were all able to receive what I consider dose intensive therapy. They all had received essentially more than 90% of all the drugs, including isatuximab and carfilzomib; the only one that was more in the 70-80% range was dexamethasone, so potentially the most toxic regimen.
The most important result was to look at the median progression free survival in the early versus late relapse patients. If we look at just the early relapse patients the median progression free survival was 24.7 months on isa-Kd versus 17 months in Kd. Now, if you think about it, that 24.7 months potentially is 6-12 months longer than the PFS they had in their prior line of therapy so that’s pretty amazing actually. If we take the patients who had late relapse the median progression free survival was 42.7 months versus 21.9 months in the Kd. Again, the isa-Kd triplet had a PFS of 43 months, that’s one of the longest PFS values seen in a relapsed and refractory multiple myeloma trial. So this was actually a very impressive result.
We also looked at the depth of response and no matter if patients had early relapse or late relapse, there was an improved depth of response in those that received the triplet versus the doublet. The depth of response was perhaps better in the late relapse patients, so the MRD negative complete responses were 31% for patients who had late relapse in isa-Kd versus 14% in those patients who had Kd. In the early relapse patients still 18% of patients got into a MRD CR which is pretty amazing also, and that was about 11% in the Kd arm.
We also looked at MRD status whether they had one prior line of therapy, two or more prior lines of therapy or whether they had prior transplant. In every subgroup that we looked at, whether it was early relapse or late relapse, the triplet of isa-Kd performed better than Kd with very respectable rates of MRD negativity in all those subgroups.
So overall there were no worsening side effects or any worsening discontinuations in patients that received the triplet therapy versus doublet therapy and the regimen was very well tolerated.
So, in summary, we found that the addition of isatuximab to Kd resulted in meaningful improvements in PFS and depth of response, and that included MRD negativity and MRD negativity CR rates, with a manageable safety profile in both early and late relapse patients. This should lead to isa-Kd being one of our preferred regimens for patients who have relapsed and refractory myeloma and whether they either have early or late relapse it’s a great regimen to use in that population.
MonumenTAL-1 trial
I’m going to move on, we have some other abstracts that were really important and potentially are going to be practice changing in patients who have relapsed and refractory multiple myeloma. The first one I’ll talk about is the bi-specific T-cell engager called talquetamab. Talquetamab is a G-protein coupled receptor family C group 5 member D bispecific antibody that targets GPRC5D and CD3. This was presented by Ajai Chari, it was called the MonumenTAL-1 study and this was in patients who had relapsed/refractory myeloma who had received three or more prior lines of therapy.
Two of the important components of this are these data were actually presented at ASH and at the same time it was published in The New England Journal of Medicine, so published in the New England Journal in concert with the ASH meeting. In addition the company, Janssen, actually has submitted their application for licensing of this drug in the US to the FDA. So this drug is, in my mind, very important and it has actually been used in patients who had relapsed and refractory, again three or more prior lines of therapy, it was a heavily pre-treated population. These patients had received more than five prior lines of therapy, a number of the patients had extramedullary disease as well as high risk cytogenetics.
I’ll cut to the chase, in this study they actually tested two doses of talquetamab. It was given at 0.4mg/kg subcutaneous by weekly administration, there were two step up doses prior to getting to the full dose, or it was tested at 0.8mg/kg by subcutaneous injection every two weeks. They tested those over time and what they got for overall response rates in both groups was 74% for 0.4mg/kg and 73% for 0.8mg/kg every two weeks. That’s an amazing overall response rate.
They looked at the subfraction of patients who had triple class refractory disease and it was 73% in the 0.4mg/kg q. week, and it was 71% in the 0.8mg/kg q. two weeks. Even in penta-refractory disease the response rates in each group was greater than 70%. So really a very active drug. If we look at the duration of response those patients that had achieved a response, PR or better, the median duration of response was 9.3 months which is also a very good response. That was in patients who had been treated at the 0.4mg/kg and in those that were treated at the 0.8mg/kg the median duration of response was about 13 months. The PFS in the 0.4mg/kg was 7.5 months and in the 0.8mg/kg group every two weeks was 11.9 months, so a very active agent in these late line patients and an agent that, in fact, was tolerable.
If we look at the safety, the safety of targeting GPRC5D is a little bit different than the safety of BCMA targeted bispecifics. Here there are antigens for GPRC5D in the mouth and specifically in the tongue and also in the skin and in the nail beds. So about 50-60% of patients had some skin related changes, some rashes, dry skin, some peeling of the skin; it was all grade 1/2. There were also nail bed changes in patients, that happened again in about 50% of patients and there was dysgeusia, altered taste and decreased appetite. In general there was mild weight loss in some of these patients and this happened in anywhere between 30-50% of patients.
Now, there are management strategies, some are dose reductions and some had dose delays from this therapy, but patients were able to stay on therapy and were able to receive this and actually get a pretty amazing response and a durable response. In this study there were also patients that were treated with prior BCMA and in those patients that were treated with prior BCMA if they had a prior CAR T-cell the overall response rate was 72%; if they had a prior bispecific antibody therapy the overall response rate was about 44%. So still active even in prior BCMA based therapy. A very important agent, hopefully it will be approved soon and we will have access to it in the US and throughout the world.
Pretreatment with tocilizumab prior to the CD3 bispecific cevostamab in patients with RRMM
The next abstract that I really enjoyed was an abstract that was presented by Suzanne Trudel. This was using another novel bispecific T-cell engager, this one is called cevostamab. This bispecific targets FCRH5 and also CD3, so it activates T-cells in the local environment. What they did with this was they actually gave patients tocilizumab prior to using the T-cell engaging therapy. So, on day 1 they got a dose of tocilizumab and they got a step-up dose of cevostamab, that was 3.6mg, and then a week later they got the full dose of cevostamab at 90mg and then two weeks later they started cevostamab again at 90mg and then thereafter did it every three weeks. Patients received 17 cycles, so it was a fixed duration therapy.
The goal of using tocilizumab prior to administration of cevostamab was to try to decrease the incidence of CRS. Lo and behold, they did find that they decreased the incidence of CRS, in fact the CRS compared to a cohort that did not get pre-therapy with tocilizumab, the CRS was 91% and it was mostly grade 1 and 2, it was very small, 2.3%, grade 3. In the group that received tocilizumab prior to cevostamab the CRS was about 39%, again mostly grade 1 and grade 2. So that’s a big difference in the CRS. If you look at when the patients developed the CRS, in the group that did not have prior tocilizumab they could have CRS with the first step-up dose, the first cycle 1 target dose, or for the dose in cycle 2 and the dose in cycle 3. Whereas in the group that received prior tocilizumab before cevostamab, they had their CRS in the step up dose and then in the cycle 1 target dose but they did not see CRS in cycle 2 or after cycle 2, cycle 3 etc. So it really limited the CRS to the first two doses which is a very important finding. This is a way that we’re going to probably administer some of these drugs using tocilizumab, or other drugs, as a prophylaxis to prevent CRS.
Lastly what they showed is that it didn’t affect the overall response rate. In those patients that received prior tocilizumab the overall response rate was 55%, so a really strong overall response rate. That included some patients that had received prior BCMA therapy.
Clinical activity of BMS-986393 (CC-95266) with RRMM
I do want to mention one of my favourite CAR T-cell abstracts from the ASH meeting. This was a study that was presented by Jesus Berdeja; this was an abstract entitled ‘Clinical activity of BMS-986393’, which was a GPRC5D targeted CAR T-cell therapy. This was tested in patients with relapsed and refractory multiple myeloma and what they presented were the first results from a phase I multicentre open label study.
This is a standard CAR T-cell therapy where patients with relapsed/refractory myeloma having received three or more prior lines of therapy, including the standard of a PI, an IMiD and an anti-CD38 antibody. These patients had to progress within 12 months of their last treatment regimen. Prior BCMA-directed therapies were allowed, including prior CAR T-cell therapies.
Patients underwent a screening, they then had leukapheresis. Their CAR T-cells were manufactured; they received bridging therapy as needed and then they started lymphodepleting chemotherapy. It was standard lymphodepletion with fludarabine at 30mg/m2 and cyclophosphamide 300mg/m2 daily for three days. This was a dose escalation in part A and part B of the study will be a dose expansion; so we’re going to talk mostly about part A. They started at 25 million cells, tested 75 million cells, 150 million cells and 300 million cells infused. They got lymphodepletion chemotherapy day -5, -4, -3; they then received their GPRC5D CAR T-cells on day 1 and the primary objective of the study was actually to determine the MTD or the recommended phase II dose.
One of the big important things was CRS – was there a dose response to CRS? In fact, there was – the lower doses had lower incidence of CRS. Overall CRS occurred essentially in about 64% of patients. At the 300 million cells CRS was over 80%, most of it actually was grade 1 and grade 2, there was very little grade 3 CRS. So this was manageable CRS; about half the patients received tocilizumab and another 24% of the patients received steroids for the treatment of their CRS.
When we looked at the best overall response or efficacy, there was a dose response like we’ve seen with prior CAR T-cells. At 25 million CARs the overall response rate was 80%; at 150 and 300 million CARs the overall response rate was 100% and there were more patients that achieved complete response. With CAR T-cell therapy to get prolonged remission duration patients have to achieve a stringent complete response or a complete response, so this actually showed that this CAR was extremely potent.
Again, many of the patients had received prior BCMA therapy. If we look at the non-prior BCMA therapy and we look at overall response rate in that group of patients it actually was 100% and 50% of patients achieved a complete response. If we looked at 9 patients who had had prior BCMA exposure the overall response rate was 78% and about 44% of those patients achieved a complete response. Now, these responses may deepen over time; we’ve seen that with CAR T-cell therapies that these responses deepen over time. They showed a swimlane plot and the swimlane plot did show, again, responses deepening over time and some patients having a durable response. At this point in time the median duration of response and the median PFS has not been reached and we look to see further data in that CAR T-cell dataset.
So, in summary, this GPRC5D CAR T-cell therapy is a very active CAR T-cell therapy and it is active even in patients who received prior BCMA therapy, whether it’s prior autologous CAR T-cell therapy, BCMA targeted, whether it’s belantamab mafodotin, or whether it’s a BCMA CD3 T-cell engager, there was a good overall response rate.
Ultra-sensitive assessment of measurable residual disease (MRD) in peripheral blood (PB) of multiple myeloma (MM) patients using bloodflow
I do want to switch gears a little bit to just tell you about a novel ultra-sensitive MRD test that was presented from the Spanish group, this is from Bruno Pavia’s laboratory. They used an ultra-sensitive tool to look at MRD in the peripheral blood of multiple myeloma patients and they did it, again, using this special tool that’s going to look at binding circulating peripheral blood myeloma cells and trying to see if they can enhance the detection of these myeloma cells in the peripheral blood and to have increased sensitivity and to be able to get to an MRD level of 10-6 or potentially lower.
So this test, which we’ll hear more about over time, actually uses a magnetic labelling of cell surface proteins on plasma cells. It then uses a magnetic separation and then elution of the labelled cells and then next generation flow of these cells to determine how many of those plasma cells that they have isolated are malignant plasma cells.
We’ve heard of other things too, of next generation sequencing of cell-free DNA, and we’ve heard of mass spec of proteins in the blood, but this new blood flow test is going to be the best test. What they’ve seen if they did this next generation flow, and those that were negative in the peripheral blood by this next generation flow had a marked improvement of progression free survival versus those that were positive in this next generation peripheral blood flow assay. They think they can actually detect MRD down to the 10-7 or 10-8 in peripheral blood using this blood flow novel technique from Bruno Pavia’s lab.
That is amazing. If we’re really able to do this with peripheral blood, that test will actually make it so much easier for all of us to assess MRD in our patients who are receiving frontline and relapsed and refractory therapies and including many of these novel therapies as we are able to get deeper and more durable responses in these patients. We can use MRD negativity and specifically sustained MRD negativity as one of our major responses, potentially a response to actually be able to do fixed duration of therapy and be able to take people off therapy.
Phase 3 IFM2017-03 trial
One other study that I was really interested in and I thought was a nice study at ASH was presented by the IFM group. This was the phase III IFM2017-03 trial and it was a dexamethasone sparing regimen with daratumumab and lenalidomide in frail patients with newly diagnosed multiple myeloma. This study was a randomised study; it took patients with newly diagnosed myeloma, they were greater than 65 years of age. They used the IFM frailty score and they had to have a frailty score of ≥2. They were randomised between two arms and one arm was standard lenalidomide 25mg days 1-21 of a 28 day cycle and low dose dexamethasone, it was 20mg weekly, versus lenalidomide and daratumumab by subcutaneous injection – lenalidomide same dose, 25mg, the daratumumab was weekly for 8 weeks, every other week for an additional 8 doses or 16 weeks and then to q. 4-week dosing thereafter like we standard do at this point in time.
They randomised 1:2, two patients to the len-dex arm. Patients were stratified by ISS stage 1 versus 2 versus 3 and age less than 80 versus greater than 80. The primary endpoint of this study was PFS. What they presented in this study was they presented the overall response rate – it was 96% for lenalidomide and daratumumab, the experimental arm, it was 85% for lenalidomide and dexamethasone, the control arm.
They looked at how responses deepened over time, achievement of VGPR or better and that these elderly, frail patients were able to stay on therapy and they were able to get better and better therapy over time. Month 4 the VGPR rate in the daratumumab-lenalidomide arm was 41% but at month 12 if they were still on therapy the VGPR or better rate was 71% and a fair number of those patients had achieved CR. They also showed that the MRD negativity rate was higher in the D arm versus the lenalidomide and dexamethasone arm. So a very tolerable regimen in frail patients getting doublet-based therapy as induction therapy.
Now, this is really one of the first randomised trials that was dedicated to frail patients, that was one of the biggest things, the biggest conclusions for this study. We need more studies that are actually dedicated specifically to frail patients to see if they can stay on therapy etc. And that daratumumab and lenalidomide was superior to lenalidomide and dexamethasone for overall response rates, for VGPR or better and for MRD negativity.
Now, I didn’t tell you much but the safety profile was more favourable without an increased infection or pneumonia rate in the daratumumab and lenalidomide arm versus the lenalidomide and dexamethasone arm. They had very similar rates of treatment discontinuation in this frail population.
So we all have aspired to have a dexamethasone free regimen; these are the first data that actually truly evaluated a dexamethasone free regimen, again in a frail population.
Overall at ASH we had many important abstracts presented: we had abstracts presented on bispecific T-cell engagers, that probably had the most data surrounding a certain therapeutic; many presentations on bispecifics and some were targeting BCMA and CD3, others targeted GPRC5D and BCMA and then one targeted, as we talked about, FCRH5 and CD3. Now these ones are all showing response rates in the 50% to almost 75% range in really relapsed and refractory patients and the goal over the next 3-5 years that we’re all going to see more of, we saw a little bit at ASH, is moving these bispecific engagers into earlier lines of therapy, into the 1-3 prior lines of therapy and also moving it as frontline therapy and potentially even into smouldering multiple myeloma.
We also saw data on CAR T-cells. We have now a novel GPRC5D targeted CAR that’s entering an expansion phase or phase II portion of a study which is showing very high response rates in relapsed and refractory patients, even patients that have had prior BCMA exposure. We hope to see more data from that study over the next 1-2 years. I suspect that potentially would be our first CAR T-cell therapeutic that could be approved for use in multiple myeloma that’s non-BCMA targeted. So we’re very excited about that one.
Then, as I talked about with the IKEMA study, we have some very good regimens, including isatuximab carfilzomib and dexamethasone, in patients who have relapsed/refractory disease in the 1-3 prior lines of therapy. We’re now focussing some effort at identifying good regimens for the frail elderly patients and we’re also advancing our science on ways that we can evaluate peripheral blood MRD. We have mass spec going on, we have cell-free DNA and I showed you data from Bruno Pavia’s lab looking at this special peripheral blood capture technique in peripheral blood, next generation flow cytometry of myeloma cells that might be able to get the sensitivity of MRD down to 10-7 or 10-8.
So it’s a very exciting ASH and I hope you had a chance to see some of the abstracts. If not hopefully you can go online and see some of the presentations. Thank you for your attention
