Triple-class refractory multiple myeloma a ‘launching pad’ for groundbreaking therapies
The last few years have seen major therapeutic advancements in the field of triple-class refractory multiple myeloma.
“Already, we are seeing patients, who would otherwise likely have untreatable and end-stage disease, entering deep remissions and staying there while living quality lives for months to sometimes years,” said Clifton Mo, MD, hematologic oncologist and associate director of clinical research for multiple myeloma at Dana-Farber Cancer Institute.
Mo spoke with Healio about recent treatment advances, the potential for chimeric antigen receptor T cell therapies and other treatment options, and the greatest challenge in triple-class refractory multiple myeloma.
Healio: What are some recent developments in the treatment of triple-class refractory multiple myeloma?
Mo: Over the past few years, multiple new drugs have been approved for the treatment of triple-class refractory myeloma in the U.S.
The first was selinexor, which was granted accelerated approval in combination with dexamethasone in July 2019. Selinexor [Xpovio, Karyopharm Therapeutics] is a first in class inhibitor of nuclear export that works by inducing nuclear retention of both tumor suppressor proteins and oncogenic mRNA. It was granted full approval in combination with [bortezomib (Velcade, Millennium/Takeda)] and dexamethasone in 2020, based on the BOSTON trial.
Then we had the approval of belantamab mafodotin [GSK2857916, GlaxoSmithKline] in August 2020 for patients who had seen at least four prior lines of therapy. This drug is a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate that does not require it to be given in combination with weekly dexamethasone. Although the response rate of single-agent belantamab mafodotin was only 30% approximately, the median duration of response was about a year, suggesting that this form of therapy can give patients very meaningful amounts of clinical benefit when a response is achieved.
This drug is overall very gentle with the one notable exception of its propensity to cause corneal keratopathy, which can cause clinically significant blurry vision in a minority of patients. Unfortunately, this potential for ocular toxicity has made some patients somewhat fearful of the treatment option, although ongoing studies are looking at different ways of hopefully mitigating the toxicity of this drug through methods such as less frequent dosing and using the drug in combination with other myeloma agents.
Then, last, but of course, not least, would be the FDA approvals of our first two BCMA-directed CAR T-cell therapies in multiple myeloma, the first being [idecabtagene vicleucel (Abecma; Bristol Myers Squibb, 2seventy bio)]in March 2021, and the second being [ciltacabtagene autoleucel (Carvykti; Janssen, Legend Biotech)] earlier this year. Both of these CAR T-cell products boast response rates that are well in excess of 50%, with Abecma demonstrating a 73% response rate in the KarMMa study and Carvykti demonstrating a whopping 98% overall response rate in the CARTITUDE-1 trial.
Access to these therapies is currently somewhat of an issue in terms of manufacturing slots, and at most academic centers currently, getting to commercial CAR T-cell therapy involves first being on a wait list. However, I remain hopeful that over the coming months to years this will become less and less of an issue.
Finally, although this is not yet an advancement as it's not yet FDA approved, the clinical development of teclistamab and the possible approval of this drug by the end of the year will hopefully be another major therapeutic advancement in the triple-class refractory myeloma space. Teclistamab (JNJ-64007957, Janssen) is a bispecific antibody with binding sites for both BCMA on the myeloma cell and CD3 on the T cell. It works very similarly to CAR T-cell therapy but has the obvious advantage of being "off the shelf" and immediately available to a patient in need, as opposed to the patient having to wait weeks for cell manufacturing.
The past few years have seen a number of major victories in the relapsed refractory multiple myeloma treatment space, which is not to say that we still don't have a long way to go to turn this into a highly survivable, if not curable, disease; but certainly, the past few years have been an excellent and very promising start of a new era in myeloma therapeutics.
Healio: What factors are taken into consideration when developing a treatment plan for these patients?
Mo: In terms of the most recent approvals, the immediate availability of CAR T-cell therapy or lack thereof needs to be considered a major factor.
Both Abecma and Carvykti are undeniably efficacious and generally well tolerated and so are very attractive treatment options. However, neither one is guaranteed to be immediately available to an individual patient in need of a new line of therapy, both by way of limited availability of manufacturing slots as well as the turnaround time necessary for cell manufacturing and eventual infusion of the product. So that's a major consideration that somewhat tempers, but by no means should eliminate, the current excitement around commercially available CAR T-cell therapy.
Another important consideration would be a patient's appropriateness for CAR T-cell therapy vs. “off the shelf” therapy. In order for a patient to benefit from CAR T-cell therapy, their disease needs to be effectively kept in check for a period of weeks while the manufacturing process is occurring, and not every patient can be safely and effectively bridged in this regard. So, although CAR T-cell therapy is arguably the most potent of treatment options for patients with triple-class refractory disease, it's not necessarily the best option for patients with very aggressive and rapid relapse of their disease.
There are also risks and toxicities fairly specific to CAR T-cell therapy — most notably cytokine release syndrome and neurotoxicity. Although both are generally low grade, there is a risk for more severe manifestations of both CRS and neurotoxicity, and there are some patients for whom the possibility of these higher-grade events does pose some degree of safety concern.
Also, a patient's personal preference and level of comfort regarding the differing side-effect profile of currently available treatment options should always be considered and respected. For example, I have had patients who have very strong reservations about the possibility of any degree of blurry vision, which is a well-known side effect of belantamab mafodotin, while I've had other patients who have little concern, if any. The right answer for one patient may be the completely wrong answer for another patient based on what risks and side effects they're most and least comfortable dealing with.
Healio: What is the potential for CAR T-cell therapy in triple-class refractory multiple myeloma?
Mo: CAR T-cell therapy has already been a "game changer". With further improvement in cell persistence, manufacturing time and possibly post CAR T-cell therapy maintenance treatment, the degree of clinical benefit could significantly exceed the already considerable benefit that exists today.
We are also exploring the potential benefits of CAR T cells directed against cellular antigens other than BCMA. For example, GPRC5D-directed T-cell therapies are being evaluated in multiple clinical trials, so there's a lot of room for further improvement in long-term outcomes for patients beyond what we are already seeing with BCMA-directed therapy.
Lastly, immune effector cells other than CAR T cells are currently being evaluated in clinical trials here and in other centers, which are attempting to harness the power of both the adaptive and innate arms of the immune system in ways that are somewhat different from single-antigen-directed CAR T-cell therapy. It's my personal hope that the prognosis of patients with triple-class refractory disease is going to be further improved by a more thorough and multipronged channeling of the immune system's power to fight cancer.
Healio: How has COVID-19 impacted delivering treatment to these patients?
Mo: Certainly, there is some degree of concern regarding T-cell depletion and exhaustion that comes along with some of our newest and most exciting therapies, and we need to be careful and do everything we can to try to mitigate the risk of severe infection, obviously including COVID-19, in our patients.
That being said, it is important to note that maintaining good disease control is also of paramount importance. In terms of protecting patients from severe COVID-19, we saw this clearly in the 650 patients International Myeloma Society dataset analysis that was conducted back in 2020 in the “pre-vaccine era," in which one of the major risk factors for severe COVID-19 in patients with multiple myeloma was inadequately controlled disease.
In this dataset, patients who were in a good remission had an approximately 50% lower risk of dying from COVID than patients with uncontrolled disease. Now, of course, this was in the pre-vaccine era, and now we have not only vaccines, but effective therapeutics such as Paxlovid, and, personally, I'm seeing overall better outcomes and less clinically severe COVID than I did a couple of years ago. But the principle of protecting a patient from COVID by adequately treating their myeloma remains relevant and important.
Healio: What is the greatest challenge in the management of triple-class refractory disease?
Mo: I don't know that there's one particular greatest challenge, but maybe it's avoiding the temptation to think of triple-class refractory disease as a static entity or a feared eventuality beyond which only limited benefit is possible for the patient, as opposed to thinking of it as a launching pad for groundbreaking new therapies that have the ability to significantly shift the paradigm.
Much has been said over recent years about the poor prognostic implications of triple-class refractory disease, and certainly the data from before a few years ago support that negative implication; but at the same time, there is no shortage of promising therapies that will hopefully over the next 4 to 5 years cause the moniker of triple-class refractory disease to lose at least some of its intimidating and negative implications.
Healio: What can be done to address these challenges?
Mo: Keep working, keep enrolling your patients into well-designed clinical trials and stay positive.
References :
- Berdeja JG, et al. Lancet. 2021;doi:10.1016/S0140-6736(21)00933-8.
- Chari A, et al. Blood. 2020;doi: 10.1182/blood.2020008150.
- Grosicki S, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)32292-3.
- Munshi NC, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2024850.
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