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Jun 10, 2020

Dr. Mitul Gandhi, a medical oncologist specializing in hematologic malignancies at Virginia Cancer Specialists, which is part of the US Oncology Network, highlights key abstracts from the #ASCO20 Virtual Scientific Program that aim to improve outcomes for patients with multiple myeloma.


ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. I'm delighted to welcome Dr. Mitul Gandhi, a medical oncologist with Virginia Cancer Specialists, which is part of the US Oncology Network. Dr. Gandhi's clinical and research focus is in malignant hematology.


Today he will highlight key abstracts featured at the ASCO20 Virtual Scientific Program and discuss the potential of new agents and treatment approaches to improve outcomes for patients with multiple myeloma. Dr. Gandhi reports no financial conflicts of interest relating to the issues discussed in this podcast. Full disclosures relating to all Daily News podcasts can be found on our episode pages.


Dr. Gandhi, welcome to the ASCO Daily News Podcast.


Dr. Mitul Gandhi: Thank you for having me. I really appreciate the opportunity to review the abstracts from this year's meeting.


ASCO Daily News: Can you tell us about the abstracts that will likely support new standards of care?


Dr. Mitul Gandhi: So within the world of multiple myeloma, there were several exciting studies that were conducted with investigational agents that are new, and then repurposing existing agents in different lines of therapy. When reviewing this, while it may not change how we practice tomorrow, it certainly informs what may be in the very near future.


I think a representative abstract is 8500, presented by Dr. Richardson and his colleagues, and involved a novel compound CC-92480 in relapsed refractory myeloma. And this is an interesting compound, which is a Cereblon ligase modulator and a next iteration of agent based on the Revlimid and, rather, lenalidomide and pomalidomide mechanism acting on Cereblon and degrading Ikaros and Aiolos.


And this was a phase I study with a phase II expansion based on the maximally tolerated dose. And what they found were that this agent studied in heavily pretreated myeloma patients, all refractory lenalidomide, pomalidomide in the majority refractory to anti-CD38 antibodies. This drug was still able to achieve a response across several dosing cohorts.


They had a complex study design involving twice daily along with once daily dosing, and a 1.0 milligram-per-day dose was identified as a MTD. And at that dose, they found 48% of patients achieved a response, with correlative studies demonstrating degradation in Ikaros and Aiolos consistent with the mechanism of action. 


And so what it tells us is that this mechanism still remains a potent avenue for exploitation in spite of progression on first- and second-rate generation compounds like lenalidomide and pomalidomide. So this informs possible changes in the future, where we would continue to use a compound like CC-92480 in spite of progression on the existing agents.


And we can see itself working in earlier lines of study and complexing with other compounds to the increased response rate. So this is something that we think will be relevant in the future if not relevant tomorrow in terms of standard of care.


ASCO Daily News: There have been substantial improvements in survival for patients with multiple myeloma in recent years, thanks to the introduction and widespread use of multiple novel agents and regimens. Are there new treatment approaches or agents in development that people should be aware of?


Dr. Mitul Gandhi: Absolutely. I think this can be viewed in a few ways. As all the listeners are well aware of and have experience with, the monoclonal antibodies on top of the existing backbone of treatment that has led to significant improvement and outcomes with relapsed refractory patients, both with daratumumab and elotuzumab.


Daratumumab, of course, being in an anti-CD38 antibody and elotuzumab targeting SLAMF7. There are next-generation antibodies on the anti-CD38 backbone, such as isatuximab. And that was studied in abstract 8508 in high-risk multiple myeloma by Dr. Weisel and colleagues from Germany.


So this particular study kind of captures what the goal is, which are moving these monoclonal antibodies higher up in the lines of therapy. So this particular trial looked at higher risk multiple myeloma, defined by chromosomal aberrations, such as deletion 17p, translocation (4;14) or (14;16), or excess copies of 1q21.


These patients received isatuximab on top of the KRd backbone, with an option for pursuing stem cell transplantation. There were 50 patients in the initially presented data -- 46 in the transplant eligible; 4 in the transplant ineligible. And one of the striking things that was identified was a 46% complete response rate in a otherwise high-risk cohort.


So this is emblematic of what the field is moving towards, which is incorporating these novel antibodies on top of an established backbone and seeing better response rate that were initially met. And as an increasing amount of data identifies achieving lower and lower myeloma burden and hopefully MRD negativity, minimal residual disease negativity, earlier on, pretending long-term, better outcomes, incorporation of these novel antibodies is one - exciting, and two - it will hopefully help inform the next generation of therapy.


Notably, these results are still preliminary phase II studies. And longer term follow up will be needed to identify if they are better than the existing outcome. Another study in that same vein is abstract 8507, presented by Dr. Zafar and his colleagues from SWOG, incorporating elotuzumab with the RVd backbone for, again, newly diagnosed, high-risk multiple myeloma.


They define high risk in a similar vein as a German group with translocation (14;16), (14;20), 17 p or gain of 1q21. And they took 103 patients, randomized them to RVd or RVd plus elotuzumab. They found at 53 months median follow up, a relative similarity in the progression-free survival. 31 months for RVd and 34 months for elo RVd with a P value of 0.449.


And there was no overall survival observed, albeit that truncated follow up. Notably, there were higher rates of response with the incorporation of elotuzumab. And so what this study validated is it's certainly using the proteasome inhibitor backbone. But maybe switching the antibody to increase response rates has, at least at this first analysis, there was no improvement in PFS.


Nonetheless, I think it's an important study, as the goal seems to be incorporating novel compounds on top of an existing backbone to improve depth of response. So these are two representative abstracts, which shows where the field is moving. And the patients that are relapsed and refractory, a slew of other studies targeting anti-BCMA are particularly exciting and relevant.


The DREAMM-6 study, abstract 8502, presented by Dr. Nooka,  used belantamab, which is an antibody drug conjugate targeting the BCMA B-cell maturation antigen conjugated to a cytotoxic payload. And in heavily pre-treated penta-refractory patients, they achieved an impressive response rate, with a clinical benefit rate of almost 80%, which is exciting, as these are patients with limited treatment options.


This is a novel mechanism of action with evidence of excellent responses, many that seem to be durable. It did have a unique toxicity profile, which is increasingly being recognized with cutaneous toxicity. So incorporation of opthalmology and identification of mitigation strategies are going to be important as more familiarity is gained.


But there are a number of further studies that are being pursued with belantamab. In context of this, there were three cellular therapy protocols also presented -- abstract 8503 by Dr. Munshi and colleagues, and abstract 8504 by Dr. Mailankody and colleagues, and abstract 8505 by Dr. Berdeja and colleagues. All three were abstracts around cellular therapy using a CAR T construct targeting BCMA with three different compounds.


And all three looked at similar patient populations with heavily pretreated patients. Abstract 8503 by Dr. Munshi looked at 140 patients penta-refractory and triple-class refractory that were treated with this compound in escalating doses. They found at the highest dose cohort at 450 times 10 to the 6 cells, an overall response rate of almost 82%, many of them durable with durability at median of 11 months.


This was associated with cytokine release storm along with some neurotoxicity, both at night, rather, at 96% and 20%, respectively-- but well managed. Similar findings were found on the other cellular products. Orvacabtagene presented by Dr. Mailankody on abstract 8504 and a Juno product in abstract 8505 by Dr. Berdeja.

There was evidence of cytokine release and neurotoxicity in both. But again, with significant response rates in heavily treated patients, many of them durable. So altogether, it shows that an  extension beyond what we discussed initially, where there is next generation of compounds on existing mechanism of actions, these series of abstracts are looking at incorporation of monoclonal antibodies, improving on outcomes in first-line therapy, along with targeting BCMA through either an antibody drug conjugate or through cellular therapy, eliciting responses in very heavily pre-treated patients. Many of them are durable. But with a unique set of toxicities ranging from cutaneous to cytokine release storm.


ASCO Daily News: Dr. Gandhi, are there any other clinical trials that really stood out for you this year?


Dr. Mitul Gandhi: So a few other abstracts I think that are worth noting, with respect to the clinical trials question, I think with the data that's been presented in the abstracts we've talked about, they inform the next generation of studies as we build upon the outcomes that were presented for more mature data, longer term data, and novel combinations.


A few other studies that I think were informative -- abstract 8509, presented by Dr. Kumar and colleagues, involving venetoclax plus bortezomib and dexamethasone in relapsed refractory myeloma. This was interesting because we know that venetoclax seems to have preferential sensitivity and rearranged (11;14) patients for BCL-2 high.


And what the study found in a randomized fashion of 291 patients-- 194 to the venetoclax arm and 97 of the placebo-- in the patients that had a rearranged (11;14) translocation were felt to have BCL-2 high, median duration of PFS was not reached compared to 9.9 months in the placebo arm.


So this is an impressive targeted therapy in a subset of patients. It seems to enjoy very long-term responses in spite of being heavily pretreated with venetoclax, which is a drug that's increasingly gaining experience across a wide swath of hematologic malignancies. And so it speaks to the heterogeneity of this disease and perhaps targeting on a more genomically stratified approach with these targeted compounds.


There are a few other studies I think might be relevant for practical matters on a day-to-day basis in the clinic. One of them was 8518, presented by Dr. Ailawadhi and colleagues, regarding the use of RVd in newly diagnosed myeloma with renal impairment. As we know, many of our patients can present with myeloma-associated kidney dysfunction, whether through light-chain deposition disease or a cast nephropathy with high light-chain levels.


And there sometimes is a bit of a trepidation in administering Revlimid in this setting out of concern for toxicity in the setting of depressed GFR. They performed a retrospective analysis and found that even in patients with baseline depressed GFR ranging from less than 30 or between 30 and 60, the incorporation of lenalidomide helped achieve almost equivalent outcomes in patients compared to patients who had a preserved GFR greater than 60.


So in their transplant-ineligible patients, for example, they found a median PFS of 36 months compared to 30 months in people with and without creatinine clearance less than 60. In their transplant-eligible patients, interestingly, they found a PFS of 48 months versus 43 months in the same cohort. So this speaks to the ability to safely administer this drug in achieving nearly equivalent outcomes compared to the people who have baseline intact kidney function.


So with appropriate monitoring, modification of dosing, and attention to myelosuppression, it seems as though we should be using lenalidomide-based induction therapy, which we would otherwise would if the patient's GFR was preserved and still able to achieve long-term durable responses.


A couple of other smaller studies that I think are worth mentioning include abstract 8515, presented by Dr. Cornell and colleagues, regarding bortezomib induction in light-chain amyloidosis prior to autologous stem cell transplant. There has been some question regarding what the best induction strategy is in patients who presented with light-chain amyloid.


And so this was a retrospective analysis of the CIBMTR database. We're looking at patients who had received a bortezomib-based induction versus no induction prior to proceeding with a stem cell transplant using high-dose melphalan. And it was fairly clear in their followup that a bortezomib-based induction was associated with decreased risk of relapse within two years -- 13% in the bortezomib arm versus 22% in the patients that presented directly to transplant -- and translated into overall longer PFS as well.


So this validates the use of bortezomib in patients prior to stem cell transplantation in a niche population with amyloid. Similarly, abstract 8516, presented by Dr. Zhang and colleagues, questioned whether the incorporation of an alkyqlating agent on top of this proteasome inhibitor backbone would help in these patients with light-chain amyloid.


There has been an increased use of cyclophosphamide, bortezomib, dexamethasone induction based on smaller phase II studies. So this group looked at retrospectively a bortezomib plus an alkylating backbone versus one with bortezomib alone. And found that the overall hematologic response rate was fairly similar -- 73% in the patients that received bortezomib plus an alkylator versus 85% that did not, which was not statistically significant.


So it seems as though while there is a temptation to use the alkylator, it may not be necessary. And bortezomib alone may be sufficient. But of course, it would be on a case-by-case basis. But it adds to the body of literature regarding how to treat these patients with amyloid. So I thought those were helpful analyses in a smaller population but which may be relevant tomorrow in clinic.


ASCO Daily News: Well, thank you, Dr. Gandhi, for sharing your valuable insights on these promising developments in this field.


Dr. Mitul Gandhi: Thank you for the opportunity. I appreciate it.


ASCO Daily News: And thank you to our listeners for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us on Apple Podcast.

Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.


COI Disclosure:

Dr. Mitul Gandhi - No Relationships to Disclose