Bispecific Antibodies Represent Appealing Option for Heavily Pretreated Patients With Relapsed/Refractory Multiple Myeloma

Amrita Krishnan, MD

Bispecific antibodies have shown promising efficacy in clinical trials for patients with relapsed/refractory multiple myeloma, potentially creating another treatment option for this population, according to Amrita Krishnan, MD, who added these agents have elicited responses in patients with triple-class refractory and penta-drug refractory multiple myeloma.

“[There is] durability in those responses, suggesting that [bispecific antibodies] are an active class of drugs. It’s exciting that we have BCMA- and non-BCMA–directed targets, and [bispecific antibodies are] an off-the-shelf therapy that will be easily available to patients,” Krishnan said in an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on multiple myeloma.

In the interview, Krishnan, who was the chair of the IPC event, discussed emerging data on bispecific antibodies, the exploration of the antibody-drug conjugate belantamab mafodotin-blmf (Blenrep), and the challenges of delivering CAR T-cell therapy in the right setting to the appropriate patients with multiple myeloma. Krishnan is a director of the Judy and Bernard Briskin Center for Multiple Myeloma, a professor in the Department of Hematology and Hematopoietic Cell Transplantation, and chief of the Division of Multiple Myeloma in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope.

OncLive^®: Could you expand on the efficacy displayed by bispecific antibodies being investigated in multiple myeloma?

Krishnan: My presentation was on relapsed/refractory multiple myeloma and new treatment options, specifically in regard to bispecific antibodies. I spoke about non-BCMA–directed targets, such as GPRC5D, which is a receptor expressed on keratinized tissue and hair follicles, and it is highly expressed in plasma cells. There is a drug called talquetamab that targets CD3 and GPRC5D.

I presented data from the phase 1 [MonumenTAL-1 trial (NCT03399799)], suggesting [GPRC5D] is an active target and [talquetamab is an active] drug, with response rates of [more than] 60% in patients with advanced refractory multiple myeloma with a median of 6 prior regimens. There were some unique toxicities to this drug, namely due to this target [of GPRC5D], such as nail dystrophy and dysgeusia in about 60% of patients. As expected with this class of drug, [we saw [cytokine release syndrome (CRS) of any grade in 75% of patients, though] the majority of the CRS was grade 1/2.

The other target I spoke about was FcRH5, which is expressed on B cells, and a bispecific antibody targeting FcRH5 is called cevostamab. I presented some of the phase 1 trial [NCT03275103] data with this drug, also suggesting high response rates of 50%-60% in advanced refractory multiple myeloma. CRS [was reported] in the majority of patients, but [it was] mild, grade 1/2 CRS.

Could you expand on toxicities in the MonumenTAL-1 trial?

The unique toxicity we saw was the dysgeusia in 60% of patients. It’s still unclear why that happened, because a GPRC5D is not expressed on the tastebuds. Nonetheless, we’ve all had the experience of patients not being able to taste sweet or salty foods. Some of that can improve with dose reductions or dose delays. The nail dystrophy is very common and expected. Patients can get pitting of the nail, while some patients can lose their fingernails because of the on-target effects with [talquetamab on] GPRC5D.

We also saw a skin rash in about 60% of patients, generally grade 1/2, and plantar palmar desquamation [was observed]. There was some peeling of the skin on the hands and feet that usually was mild, and we were able to manage it with some topical creams.

Could you expand on the response rates that were seen in the MonumenTAL-1 trial?

The exciting thing about talquetamab was a response rate of [more than] 60% in patients who had advanced refractory multiple myeloma, including responses seen in triple-class refractory and penta-drug refractory [multiple myeloma], which we know are particularly challenging groups of patients to treat.

Looking at cevostamab, how may dosage correlate with response rates based on the phase 1 study?

It was a phase 1 dose-escalation trial, so investigators needed to get to a certain target dose. The majority of the responses were seen [at the 20 mg target dose and above in this study]. It’s not particularly surprising that most bispecific antibodies start at extremely low doses that are usually not the clinically therapeutic dose before you get to a target dose.

What could these bispecific antibodies mean for the treatment paradigm in relapsed/refractory multiple myeloma?

Bispecific antibodies are incredibly exciting for us in the multiple myeloma field because we can see responses in [patients who are] penta-drug refractory and patients who are heavily pretreated.

CRS is a challenge and needs to be managed appropriately. As we roll [bispecific antibodies] out into wider use, there will be a learning curve for physicians. Another thing that we do need to be watchful for is infection. We are starting to see infections in these patients that are more reminiscent of what we saw in patients undergoing [allogeneic stem cell] transplants. This means more T-cell mediated infections, including cytomegalovirus, pneumocystis jiroveci pneumonia, and, given the pandemic, we have seen many COVID-19 infections and deaths.

Moving to the presentation from Maung Myo Htut, MD, of City of Hope, could you expand on what was observed in the phase DREAMM-2 trial (NCT03525678) with the treatment of belantamab mafodotin in patients with relapsed/refractory multiple myeloma?

The DREAMM-2 trial was an open-label, dose-escalation trial in advanced refractory multiple myeloma. Patients had a median of 6 or 7 prior lines of therapy, so these were very heavily pretreated patients. Moreover, we saw an overall response rate [ORR] of 32%, which was notable [for a single agent], suggesting that [belantamab mafodotin] is a very active drug.

The challenge with the drug was the keratopathy, which was seen in about 70% of patients i[in DREAMM-2]. This is due to the monomethyl auristatin F, the [cytotoxic] warhead [of belantamab mafodotin], which can cause ocular toxicity. There have been many strategies in terms of mitigating that ocular toxicity. The drug is delivered through a Risk Evaluation and Mitigation Strategy program. Patients need to have a baseline eye exam and an eye exam before each dose of the drug. Eyedrops are used with the start of the drug, and in subsequent studies, different dosing schedules are going to be explored to try to further mitigate this ocular toxicity.

How did phase 1/2 DREAMM-5 trial (NCT04126200) expand on the knowledge of belantamab mafodotin when investigating it in combination with other agents?

DREAMM-5 was a phase 1/2 trial looking at belantamab mafodotin in combination [with various agents]. One of the notable combinations was with a T-cell costimulatory molecule, [feladilimab (GSK3359609)]. [In] 23 patients administered belantamab mafodotin and [feladilimab], the response rate was 48%, which is encouraging, and 26% of those patients had a very good partial response or better. Ocular toxicity [did occur] in about 70% of patients. This study suggested that [belantamab mafodotin plus feladilimab] showed an increase in clinical activity, though the toxicity profile remained unchanged.

Could you explain the importance of the phase 1 MagnetisMM-1 trial (NCT03269136), which investigated elranatamab (PF-06863135) in patients with relapsed/refractory multiple myeloma?

MagnetisMM-1 was a phase 1 study of the BCMA-directed bispecific antibody, elranatamab, which showed strong efficacy in this heavily pretreated group of patients who had a median of 6 prior lines of therapy, and 98% [of patients were] triple-class refractory. Adverse effects [AEs] were similar to [AEs seen with] other BCMA-directed bispecific antibodies, with [any-grade] CRS [occurring in 87.3% of patients], though these were mostly grade 1/2 events. There was also hematologic toxicity, which is not unexpected in this heavily pretreated group of patients, and an ORR of 64%.

Looking at [patients] that had prior BCMA-targeted therapy, the ORR was 54%, suggesting that prior BCMA-directed therapy is not necessarily an exclusion to subsequent BCMA-directed therapy of a different class.

Your colleague, Murali Janakiram, MD, MS, of City of Hope, discussed CAR T-cell therapy in multiple myeloma. How can shifting these therapies into earlier settings potentially help patients with relapsed/refractory multiple myeloma?

Both the idecabtagene vicleucel [ide-cel; Abecma] and ciltacabtagene autoleucel [cilta-cel; Carvykti] data that were presented [during the IPC] showed that CAR T cells directed against BCMA in multiple myeloma have extremely high response rates of about 95%. Durability of response appears longer with cilta-cel than with ide-cel, but there are certain strategies that are being explored to try to optimize the progression-free survival [PFS], especially with ide-cel, such as maintenance strategies. Toxicity profiles across the CAR T-cell therapies include CRS, acute and delayed neurologic toxicity, infections, and cytopenia.

The biggest challenge is not the efficacy of CAR T-cell therapies, which remains without a doubt, Rather, it is access to CAR T-cell therapies in terms of manufacturing slots at centers that offer CAR T-cell therapy. For patients who have advanced refractory disease, it is very difficult for them to wait for such therapies, and, unfortunately, we lose patients before they are able to gain access to CAR T-cell therapy. Part of this presentation was to educate patients and physicians in regard to being referred early for CAR T-cell evaluation if patients have relapsed disease. Some of the CAR T-cell therapy trials are starting to look at earlier relapses of multiple myeloma, affording the opportunity for CAR T-cell therapy [to be administered] earlier in the course of disease.

How is cilta-cel being evaluated further in the phase 2 CARTITUDE-2 trial (NCT04133636)? What data have been read out from this study?

CARTITUDE-2 is a trial looking at cilta-cel in earlier lines of therapy in [patients refractory to] lenalidomide [Revlimid]. At a follow up of 17.1 months, [20 patients in cohort A] showed a response rate of 95%, which is not surprising, though we still need a bit of data in terms of durability of responses, but these data suggest this approach has validity in earlier lines of therapy.

Your colleague Nitya Nathwani, MD, of City of Hope, discussed the use of autologous stem cell transplantation (ASCT) in multiple myeloma. How did the phase 3 DETERMINATION study (NCT01208662) help determine when ASCT is an appropriate treatment?

The DETERMINATION study looked at induction [with lenalidomide, bortezomib (Velcade), and dexamethasone (RVD), followed by either further RVD or ASCT as consolidation. Both arms received lenalidomide maintenance until disease progression.

What this trial showed was that its primary end point of PFS was met, and there was a highly significant increase in PFS in patients who received early, up-front, ASCT. But, with a median follow up of about 76 months, the overall survival [OS] was similar between both arms.

To many in the transplant world, [these findings] cemented the role of ASCT, given that there was a significant PFS advantage. As I said earlier, that was the primary end point of the study. Given the improved OS in multiple myeloma in our current era, we may need to wait longer before we will see any OS differences [between the 2 arms].

Notably in patients with high-risk multiple myeloma, the median PFS for RVD alone was only 17.1 months compared with 55.5 months in patients who received ASCT. Even more so for patients with high-risk myeloma, this trial really showed a significant benefit to early, up-front ASCT.

What have all these developments meant for the treatment of patients with multiple myeloma?

Multiple myeloma therapy continues to evolve in an incredibly exciting way. The fact that we have a new class of drugs in patients who are so heavily pretreated that can show high response rates and durability of responses represents new hope for our patients with multiple myeloma.

The DETERMINATION study still confirms the role of ASCT as part of the initial treatment for patients with multiple myeloma, and CAR T cells remain an important part of our therapy for multiple myeloma that likely will be moved into earlier [lines of treatment] as we work through the challenges of logistics and access to CAR T-cell therapy.

Is there any ongoing research at your institution that you would like to highlight?

We have a lot of exciting clinical trials. We have some trials with different CD38-directed therapies, specifically radioimmunotherapy and some other CD38-directed antibodies that may be able to overcome some degree of CD38 resistance. We have a CAR T-cell therapy with a different target other than BCMA, which is being evaluated in a phase 1 study [NCT04674813]. We have novel agents, such as small molecules, also under study.