Jun 24, 2021
Dr. Mitul Gandhi, medical oncologist-hematologist at Virginia Cancer Specialists of the US Oncology Network, highlights therapeutic advances in multiple myeloma featured at the 2021 ASCO Annual Meeting.
ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Mitul Gandhi, a medical oncologist specializing in hematologic malignancies at Virginia Cancer Specialists, which is part of the US Oncology Network. Dr. Gandhi will discuss therapeutic advances in multiple myeloma featured at the 2021 ASCO Annual Meeting. He reports no conflicts of interest relating to our discussion today, and full disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/podcasts.
Dr. Gandhi, welcome to the ASCO Daily News podcast.
Dr. Mitul Gandhi: Thank you for having me.
ASCO Daily News: Let's first look at the OPTIMUM MUKnine trial. It's Abstract 8001. And it reported high overall response rates in patients with ultra high-risk multiple myeloma with Dara-CVRd induction therapy. What are your takeaways from this study, Dr. Gandhi?
Dr. Mitul Gandhi: Sure. So, the OPTIMUM study was conducted by the UK group, and it's noteworthy for several reasons. The way they had constructed the trial, they designed and developed a platform primarily to enrich for a predefined subset of very high-risk individuals, whether it was through a set of genetic assessment or with central gene expression profiling.
And the way the trial was conducted, while patients were waiting to ascertain the results of the gene expression profiling (GEP) they could receive two cycles of bridging therapy. Once those results were furnished or they met the cytogenetic risk criteria, patients who subsequently consented to the intervention protocol which was a dose intensified regimen, five drug regimen, incorporating daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone.
So, patients would receive induction for up to six cycles, and that would include the two cycles of potential bridging therapy as GEP was being evaluated on an every 21 day basis. And then this was followed by a modified conditioning regimen consisting of high-dose melphalan at 200 milligrams per meter squared along with weekly bortezomib which was continued even following autologous stem cell rescue, really until count recovery. Subsequently, patients received an additional six cycles of daratumumab, bortezomib, revlimid, or lenalidomide followed by 12 cycles of daratumumab and rituximab until progression.
This was a complex study design with an intensified induction consolidation and maintenance phase, but it did yield a impressively high OR rate, or overall response rate, at 94% with very good partial response or greater seen in 77% after assessment following autologous transplantation, including 46% complete response (CR). And of those with CR, they had identified 63% achieving MRD negativity as well.
And I think the authors should be commended for one, enriching a high-risk subset of patients both on conventional cytogenetics and/or GDP, and then two, utilizing the most active agents that we currently have to elicit high responses and then to consolidate on those following transplant. I think some of the take homes from the study are the ability to demonstrate feasibility of central genomic risk stratification related to more precisely identify and select high-risk patients as this is kind of an area of unmet need of where to augment therapy appropriately. I think it's still a question whether or not this is the exact dose intensified regimen that's going to elicit the best long-term outcomes in these highest risk patients and whether or not the conventional surrogates for a long-term progression-free survival (PFS) benefits such as MRD really apply to this as there is some controversy regarding that.
Nonetheless, I think this offers a kind of a reproducible platform that can be emulated to identify the highest risk patients. You can do that prospectively, and then to selectively incorporate the most active agents and potentially the next generation of novel agents, including immunomodulators, cellular therapy, bi-specific antibodies earlier in the treatment course, and really try to elicit the deepest initial response and hopefully see that translate into longer term durable control. So, this was a complex study design that was impressively executed, and again with an ability to enrich for the highest risk subsets.
ASCO Daily News: Excellent. Thanks for sharing your takeaways from the OPTIMUM trial. Well let's focus on the phase II CARTITUDE-2 study. That's Abstract 8013. This study reported that deep and early responses were yielded with a single infusion of cilta-cel in patients who had received one to three prior lines of therapy for multiple myeloma. What are your thoughts on this trial?
Dr. Mitul Gandhi: So, Dr. Usmani presented the CARTITUDE-2 update on behalf of his co-collaborators. And the listeners probably are aware of some of the preliminary data that was presented at ASH as well in 2020, but this is a phase I/II protocol. Currently the phase II data are being presented with a proprietary CAR T platform which has two BCMA single domain antibodies on the CAR T construct along with a co-stimulator domain. And as kind of summarized in the title, the single dose was infused.
So, amongst 113 patients who were initially recruited, 97 ultimately were treated with some fallout attributed to progressive disease. Like many of the other CAR T studies, this was a uniformly high-risk and heavily pretreated population. Median age was 61. High-risk cytogenetics were in 23% of patients. And there was about 20% of patients who had harbored plasma cytomas as well.
Response rates were impressively high at almost 98%, and 67% obtaining a stringent complete response (CR). Much like the other CAR T experience, response continued to deepen over time. And encouragingly, duration of response was actually not reached time of presentation. Kind of amplifying the depth of response, of the patients assessable for MRD, 93% had achieved an MRD negative state at a sensitivity of 10 to the minus fifth cells, leading to a 12-month PFS of 77% and an OS of 89%. So, these are all welcome numbers and response data, again, in a heavily pretreated population who have been exposed to what we believe all the more active agents in the disease. In parallel with kind of response, with particularly with CAR T is the toxicity data.
And encouragingly, while CRS, or cytokine release syndrome, which is typified in CAR T therapy was seen in about 95% of patients, only 4% had grade 3 to 4 CRS. So, on the whole, quite manageable. Median time to onset was 7 days with duration of 4 days and resolved with appropriate medical therapy, including tocilizumab. They did report one patient who had grade 5 CRS with hemophagocytic lymphohistiocytosis (HLH) with the remainder, I was summarizing kind of the low level of grade 3, 4 experience. There was additionally neurotoxicity and 21%, with 10% having grade 3 or higher. Again, resolved with supportive care measures.
So, in totality this builds on the CAR T experience with high response rates, deep response, rates including achievement of stringent CR and high rates of MRD negativity with only a single dose of CAR T cells infused, again amplifying the efficacy of this platform on a heavily pretreated population and potentially allowing for extended treatment-free intervals as well or options for retreating in people who don't achieve MRD with a manageable toxicity profile at experienced centers. Certainly there's still work that's going to be done to better delineate the extent of CRS and how to appropriately treat that along with the neurotoxicity, but along with several other abstracts presented at this meeting and meetings prior, builds on the CAR T experience, knowledge rapidly coming to the forefront in myeloma therapy.
ASCO Daily News: Great. So, some good developments for previously treated patients. Well, now I'd like to focus on newly diagnosed multiple myeloma. Let's look at the CARDAMON trial, Abstract 8000, and the FORTE trial, Abstract 8002. These studies explored novel therapies that are emerging for newly diagnosed multiple myeloma. So in their presentations, these trial investigators seem to question the value of standard of care autologous stem cell transplant (ASCT). So do you think these new data call into question the advantages of the up front ASCT approach in newly diagnosed multiple myeloma?
Dr. Mitul Gandhi: That's a great question. And as providers in the myeloma community know, there's still an ongoing debate whether or not to ubiquitously apply a high dose melphalan conditioning and stem cell rescue across the spectrum of all patients with myeloma who are transplant eligible or reserving it for certain patients or not. Some of this is borne out of saving unnecessarily aggressive therapy, who would otherwise achieve an excellent response of induction. Along with some concern for secondary genotoxic effects imparted by the melphalan itself and perhaps propagating more biologically aggressive subclones. And to that end, these two abstracts explored whether or not transplant-free approaches would be feasible.
So, the CARDAMON study enrolled 281 patients where all patients received kyprolis, cyclophosphamide, and dexamethasone for four cycles, and of those patients achieving at least a partial response (PR), they were subsequently randomly assigned to continuous KCd or autologous stem cell transplant. And what the authors concluded, KCd induction followed by KCd maintenance was not inferior to autologous stem cell transplant with PFS at 2 years measured at 70% versus 76%, and that difference meeting the criteria that was prespecified in terms of their confidence interval for noninferiority.
So, on the surface you could argue based on the results that were presented that there was equivalence. But a few caveats that are important to bring up, the first was that follow-up was short. It was only two years, and so it's very plausible that with longer follow up, the noninferiority that was seen may not be borne out with extended follow up. The other point the author's note was that MRD negativity was higher in the autologous stem cell group at 53% compared to 35.8% of the non-transplant group. And various studies have reported this to be a reasonable surrogate for long-term PFS, not always. And so again highlights the fact that with longer follow up, we may see a separation of the curves.
Their subset analyses did not demonstrate any obvious areas, rather a subset of patients that would have derived preferential benefit, although the numbers were quite small. So, while an initial conclusion may be that there was a relative equivalence for a transplant-free approach, I'd argue that it's probably still a bit premature to make that conclusion and noninferiority may not be identical with longer follow up. And additionally, this probably is an induction regimen that is not as commonly employed in the U.S. But it does again help to the body of literature regarding this question of transplant for all versus not, although there may be hopefully more discriminatory power to see where it would be beneficial.
The FORTE study presented by Dr. Gay and her colleagues was a bit larger at 464 patients and slightly different. Patients were randomly assigned to one of three arms, carfilzomib plus cyclophosphamide plus dexamethasone for four cycles induction followed by autologous stem cell rescue, carfilzomib, lenalidomide, dexamethasone induction for four cell cycles followed by autologous stem cell rescue, or carfilzomib, lenalidomide, dexamethasone without autologous stem cell for 12 cycles.
So, those were the three arms, and then there was a second randomization to lenalidomide versus lenalidomide plus carfilzomib maintenance. Patients were prespecified in terms of their cohorts of high-risk, standard risk, or the so-called double hit which was people, patients rather, harboring two high-risk cytogenetic features. And so what the authors concluded that across the board, the arm containing carfilzomib, lenalidomide, dexamethasone with autologous stem cell rescue demonstrated superior PFS compared to all of the other, rather, the other two arms. And similarly intensification of maintenance incorporating kyprolis plus revlimid resulted in superior 3 year PFS compared to revlimid alone in 90% versus 73%.
So what do we take away from this? Well, it's not a conventional induction approach in the U.S., with RVd still predominantly being used, particularly after the endurance data was presented at last year's ASCO showing equivalence of a bortezomib induction strategy versus carfilzomib strategy. It does support and lend credence to the use of high dose melphalan autologous stem cell rescue as patients who are in this arm seem to enjoy a more longer and durable progression-free survival across all subsets, including standard risk, high-risk, and the double hit strategy. So there wasn't any particular subset that could be identified that would have performed equally well with KRd alone without autologous stem cell rescue.
Putting these two abstracts together, I would still argue that there remains a very important role for our high dose melphalan and autologous stem cell rescue currently an induction, rather following induction, in appropriately selected patients. And while we may not have identified patients on preselected criteria based on their cytogenetic risk, it's conceivable that we might identify response based criteria, whether it's MRD or otherwise, to perhaps see who may be able to abstain from transplantation. And there are several protocols that are actively accruing, some that have been preliminarily presented, and some that will be presented in subsequent meetings that might lend evidence to this. But for now based on the data sets that were presented at this year's meeting at ASCO, there still seems to be support for use of high dose melphalan and autologous stem cell rescue.
ASCO Daily News: Right. Well staying with the issue of transplantation, for over a decade investigators have been exploring the curative ability of alloHCT in select patients with high-risk multiple myeloma. Fast forward to 2021 and the phase II double blind, placebo controlled, blood and marrow transplant clinical trials network 1302 trial. That's Abstract 7003. This study found that when performed with a reduced intensity conditioning regimen of bortezomib, fludarabine, and melphalan, alloHCT was safe in patients with high-risk multiple myeloma. What are your thoughts on this, and do you anticipate further research on the role of alloHCT in patients with multiple myeloma and high-risk features?
Dr. Mitul Gandhi: So, this is an interesting abstract presented by Dr. Nishihori and her colleagues specifically looking at the role of ixazomib maintenance following a reduced intensity conditioning regimen of fludarabine, melphalan, and bortezomib in patients with high-risk myeloma. So this study was a phase II study enrolling patients under the age of 70 with high-risk myeloma defined by cytogenetics, or presence of plasma cell leukemia, or relapse within 24 months of an autologous stem cell transplant, which has been identified as a prognostic factor independent of baseline risk of poor outcomes, with the goal of administering the reduced intensity conditioning followed by HLA matched donor unmanipulated graft with methotrexate and tacrolimus GVHD prophylaxis, and starting at day 60, randomization ixazomib versus placebo maintenance.
It should be noted that the goal initially was to enroll 110 patients, but ultimately only 57 patients were accrued over the course of 4 years from 2015 to 2018, 52 ultimately receiving an allogeneic HCT and 43 proceeding to maintenance. And so this in and of itself highlights the challenges of running an alginate transplant trial in myeloma mainly because sick patients may be by the point where allogeneic transplant is being entertained or inability to achieve sufficient disease control in order to pursue the transplant.
But with respect to the study itself, they reported a PFS and overall survival (OS) outcome at 24 months, of 52% and 85% respectively, with transplant-related mortality at a respectable 11%. So in context of the small studies that had previously been reported in this space of allo SCT and myeloma, this was improved treatment-related mortality related to the procedure itself. With respect to the question at hand regarding the role of ixazomib maintenance, interestingly they showed no difference in PFS, with ixazomib versus placebo at 55% and 59% and OS at 95% and 87%. In terms of the toxicity, it was not trivial. Grade 3 to 4 acute GVHD at day 100 was 9.5% in the ixazomib arm, 0% in the placebo arm. And chronic GVHD was 69% versus 64%.
So, where do we take all of this data in context? I think there is a signal of lower transplant-related mortality compared to historical controls, and so it probably speaks to the improved ability to identify patients and also get them through transplant with this modified conditioning. The follow up, however, was abbreviated, and so there may be increased relapse over time as well. In terms of where does this fit in the armamentarium of therapy with refractory myeloma, I think that's still to be determined. And perhaps it's going to be occupying more of a niche role given the blossoming repertoire of highly efficacious immune-based agents, whether it's modified cellular therapy with CAR T a upcoming NK cell products that are being explored, and of course by specifically antibodies that have been robustly presented at this meeting demonstrating impressive responses.
So, it's very conceivable that patients who were previously would be entertained for allogeneic SCT will now be in are treated with this kind of repertoire of novel immune agents. And so it may become a more of a niche role in patients who have exhausted all conventional or investigational approaches, but it does suggest that with this modified reduced intensity conditioning, treatment-related mortality can be lowered. With respect to the question at hand, it does not appear as though maintenance ixazomib helps these patients. And so observation alone following transplant versus an alternative maintenance strategy would be indicated.
ASCO Daily News: OK. Well I'd like to ask you about the Apollo trial. That's Abstract 8046. This study looked at health-related quality of life of previously treated patients with multiple myeloma on a regimen of pomalidomide and dexamethasone plus subcutaneous daratumumab. Any surprises here, Dr. Gandhi?
Dr. Mitul Gandhi: So, the Apollo study is a phase III trial primarily evaluating the efficacy of pomalidomide plus dexamethasone versus pomalidomide dexamethasone plus the incorporation of subcutaneous daratumumab in patients with myeloma who had received one prior line of therapy. And primary outcomes data had already been presented with improved rates of disease control with incorporation of daratumumab. With respect to this abstract, Dr. Terpos presented quality of life and patient-reported outcomes that was collected in parallel with the intervention arm of this study, and so they utilized the EORTC 30 item questionnaire to assess quality of life and subjective data from patients.
And what they found was in the patients who had been on the DPD arm, or the daratumumab arm, there was a greater reduction in pain and no real augmentation or introduction of increased adverse events related to the additional agent. Moreover, there was no decline in physical or emotional functioning with DPD, but there was worsening decline in those elements compared to baseline for patients receiving pomalidomide and dexamethasone alone. There were higher rates of improvement with respect to control of disease symptoms, physical functioning, emotional functioning on the DPD arm.
So, what does this tell us? Well in general, I think we've seen a plethora of agents that have improved outcomes with our patients with myeloma who are now living for years on therapy, increasingly and often even into a second decade. And so gaging the impact of therapy on quality of life, subjective sense of well-being is critical as these patients are going to be on therapy for quite a while. And so independent of serologic and laboratory response, we certainly want the interventions to improve functional capacity. And this data would suggest that you can achieve that in parallel with achieving better and deeper responses, which intuitively makes some sense, and they are often congruous.
Involving the incorporation of an additional agent didn't worsen the sense of adverse events, but in fact improved the general sense of well-being. So this adds to the body of work of daratumumab on a MM dexamethasone backbone parting benefit without toxicity and also lending credence to the notion that by improving myeloma parameters, we're going to be in parallel improving quality of life. And so with the advent of all the other agents and novel compounds that are being developed after the acute toxicity period, we'd also expect to see improvement in quality of life as well. And so I think this was an important contributor to telling us this.
ASCO Daily News: Excellent. Well thank you so much, Dr. Gandhi. I really appreciate your time today. Before we wrap up, any final thoughts from you on advances in multiple myeloma? There's certainly some really impactful work being done in the field.
Dr. Mitul Gandhi: Yeah. I think I would encourage all the listeners to review the abstracts presented, particularly the oral abstracts as they get into some of the granularity on detail regarding the individual CAR T and bispecific antibody products, and very nicely demonstrate the durable responses that are being achieved in heavily pre-treated patients. Obviously kind of the next sort of hurdle in the field is to democratize these agents and make sure they're readily available for all patients. And there's a lot of work being done to ensure that management of the acute toxicity can be managed more broadly. So I think I'd pay particular attention to the oral abstract sessions which really demonstrate the novel agents that are being investigated.
ASCO Daily News: Dr. Gandhi, thanks again for being on the podcast today to highlight some great new therapies in multiple myeloma.
Dr. Mitul Gandhi: Thank you for having me.
ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts.
Dr. Mitul Gandhi: None disclosed.
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