An Expanding Armamentarium Calls for Tailored Therapy in Relapsed/Refractory Myeloma

The treatment paradigm for relapsed/refractory multiple myeloma has expanded rapidly with the recent integration of selinexor (Xpovio) and BCMA-directed therapies, such as belantamab mafodotin-blmf (Blenrep) and idecabtagene vicleucel (ide-cel; Abecma), said Ravi Vij, MD, MBA, who added that the field is now pushing beyond BCMA as a target and evaluating novel therapies, such as oral cereblon E3 ligase modulators (CELMoDs), which could become the next generation of immunomodulatory drugs (IMiDs).

However, the wealth of options in this space has led to sequencing challenges that ongoing research efforts are attempting to overcome, Vij explained. Notably, it seems clear that a “one-size-fits-all” approach is not optimal for this patient population.

“We have an abundance of riches [in multiple myeloma], but with that comes an abundance of questions on how to best sequence these treatments and which treatments are best for a given patient [population],” Vij said.

“There has been a lack of uniformity in the treatment of patients with relapsed/refractory multiple myeloma, [but] evidence [suggests treatment should] be tailored to patient and disease demographics. That will continue to play a major role in our decisions on how to treat patients, which drugs to give, and in which sequence because there is probably no algorithm that will fit all of our patients,” Vij added.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on multiple myeloma, Vij, a professor of medicine in the Section of Bone Marrow Transplantation and Leukemia at Washington University School of Medicine in St. Louis, and medical director of the Siteman Cancer Center at Barnes West County Hospital, discussed how he is navigating the growing armamentarium in relapsed/refractory multiple myeloma.

OncLive®: What has the field learned about dosing and toxicity management with selinexor since its approval?

Vij:Selinexor is certainly an agent that has shown activity in triple-class refractory disease. It’s an agent with a unique mechanism of action and will be increasingly used in the months and years to come.

[Selinexor] in combination with bortezomib [Velcade] and dexamethasone given once-weekly seems to be better tolerated compared with the twice-weekly dosing regimen. When bortezomib was given once weekly, the regimen showed much lower rates of neuropathy [vs] what we expect with twice-weekly bortezomib, which was used as the comparator in the BOSTON study [NCT03110562].

With time, we have also learned how to manage the toxicities [associated with] selinexor. We do have to give patients antiemetics and, in some cases, an appetite stimulant and an anti-diarrheal. [Patients require] close monitoring. Intravenous fluids and growth factor support may be necessary in heavily pretreated patients.

Do you anticipate selinexor-based combination strategies could enhance the drug’s utility?

Selinexor is being tried in several other combination regimens. In addition to the bortezomib combination, combinations with pomalidomide [Pomalyst], lenalidomide [Revlimid], daratumumab [Darzalex], and carfilzomib [Kyprolis] are being tried in the STOMP study [NCT02343042]. In these different arms of the study, varying dose levels of selinexor have been established as being the best tolerated. Even these other combinations are likely to have a role in the treatment [of patients with multiple myeloma] going forward.

Shifting to BCMA-directed therapies, could alternative dosing strategies minimize the toxicities associated with belantamab mafodotin?

Belantamab mafodotin was the first BCMA-directed therapy that was approved by the FDA. [This agent] allows for patients with triple-class refractory [multiple myeloma] to get an effective treatment.

The regimen studied in the DREAMM-2 trial [NCT03525678] required [belantamab mafodotin] to be administered once every 3 weeks. We saw that patients had approximately a 30% response rate, with a durability of response around 3 months.

However, patients did have ocular toxicity with this regimen and keratitis was the major adverse effect on this trial. Despite the fact that patients often had to dose-hold [belantamab mafodotin] for extended periods of time, few patients progressed. That has allowed for less frequent dosing [with belantamab mafodotin] to be explored in ongoing trials.

In the future, perhaps giving [belantamab mafodotin] anywhere from every 4 to 6 weeks or up to every 8 weeks [will be optimal and those approaches are] being tested. [Those alternative dosing regimens] may help to reduce the ocular toxicity of the drug. It is important to be proactive [in preventing] the ocular toxicity from developing in the first place.

How have BCMA-directed therapies affected the treatment paradigm? What is your hope for the bispecific antibodies coming down the pike?

Among the BCMA-directed therapies, we have antibody-drug conjugates, CAR T-cell therapies, and bispecific antibodies.

In 2020, we certainly saw the bispecifics come to the floor. More than half a dozen bispecifics are involved in phase 1/2 studies and all have shown very encouraging response rates in up to two-thirds of patients. Several patients have [obtained] complete remissions as well [with bispecifics].

At this time, we lack any data [regarding] the durability of these responses, although in several of these studies, some patients are up to 2 years without progression.

Cytokine release syndrome [CRS] has been more manageable [with bispecifics] compared with what we’ve seen with CAR T-cell therapy. [CRS with bispecifics] is usually grade 1 or 2, although several patients have required tocilizumab [Actemra]. Neurological toxicity is also minimal with this group of drugs.

[Bispecifics] are given subcutaneously or intravenously and the dosing schedules vary from once weekly to once every 3 or 4 weeks. Ultimately, the schedule of administration may play a role in the future as to which of these drugs are adopted [into clinical practice].

Additional targets beyond BCMA have been explored. GPRC5D and FcRH5 are targets that were presented at the [2020 ASH Annual Meeting and Exposition]. We saw once again that over half of the patients with heavily pretreated disease responded and there were anecdotal reports of responses in patients who progressed on BCMA-based treatments.

How does the unique mechanism of action used by CELMoDs make it a promising modality for the treatment of patients with relapsed/refractory multiple myeloma?

CELMoDs are going to be the next generation of IMiDs. We are used to lenalidomide and pomalidomide as treatment backbones in multiple lines of therapy. CELMoDs are designer molecules that attach to the cereblon molecule, which was ultimately found to be the main target of IMiDs. We are seeing up to a third of heavily pretreated patients responding to CELMoDs with little in the way of hematologic toxicities in some of these trials. We have 2 CELMoDs in development: iberdomide and CC-92480. Both of [these CELMoDs] look promising and, hopefully, these agents will be the IMiDs of the future.

What activity has venetoclax (Venclexta) demonstrated for the specific subset of patients with t(11;14)?

Venetoclax was studied in the BELLINI trial [NCT02755597], a randomized study where venetoclax was combined with bortezomib and dexamethasone and compared with bortezomib and dexamethasone alone. Although the progression-free survival of the entire cohort was improved [with the addition of venetoclax], there was actually a detriment in overall survival [with the triplet vs the doublet].

However, the patients who had t(11;14) and overexpressed BCL-2 did seem to benefit from [venetoclax, bortezomib, and dexamethasone]. This has led to the narrowing of the development program [of venetoclax in multiple myeloma] for the time being to the specific subset of patients with t(11;14). [Venetoclax] will be a welcome addition to the [multiple myeloma] armamentarium because the response rate and durability of response is very encouraging, even in heavily pretreated patients.

What challenges remain with CAR T-cell therapy in relapsed/refractory myeloma? How do you anticipate selecting between ide-cel and ciltacabtagene autoleucel (cilta-cel) if cilta-cel is approved?

CAR T-cell therapy is certainly a very promising development, so we are looking forward to being able to use these [therapies] now that [one] has been commercialized. Both [ide-cel and cilta-cel have shown] encouraging results. We have more mature results with ide-cel, and we’ve seen over 70% of patients respond with more than one-third of patients achieving a complete remission. The median duration of remission is approximately 1 year [with ide-cel]. This is certainly much better than any of the other drugs available for this patient population, and the one-time administration of the product is an advantage.

There are logistical challenges with CAR T-cell therapy because the treatment does take several weeks to be able to administer to patients, [who have to] jump through hoops of insurance approvals, apheresis, and [product] manufacturing. [During that time], a patient’s disease needs to be kept in control, possibly with bridging therapy.

CAR T-cell therapy will offer an important additional line of treatment to many of our patients; however, this treatment does have some issues with CRS and neurologic toxicity in that an elderly population may not be amenable to benefit from this modality of treatment.

[An FDA approval for] cilta-cel will follow in the months to come. Although we have no head-to-head comparison [between ide-cel and cilta-cel], the data with cilta-cel are also encouraging, with a nearly 100% response rate and about two-thirds of patients responding. The other advantage that cilta-cel seems to have is that the median time to CRS onset is 7 days, which makes it more amenable for outpatient administration. One issue that was recently raised had to do with delayed neurologic toxicity. That is something that we are still awaiting more information on because it may be [a factor we use] to determine in which situations we should use cilta-cel [vs] ide-cel.

How do you anticipate the field will navigate the abundance of riches poised to enter the treatment arena for relapsed/refractory disease?

The availability of BCMA-based treatments and selinexor for patients with triple-class refractory [multiple myeloma] is a major development. We have [melphalan flufenamide (melflufen; Pepaxto)], which is approved for a similar demographic of patients. These [therapies] are going to be employed increasingly in the months to come, often in combination regimens that are yet to be developed.

[Ultimately, incorporating these therapies] will lead to better outcomes for our patients. Time will tell us how we are able to incorporate all of these treatments into the paradigm.