Treatments Branch Out in Newly Diagnosed and Relapsed/Refractory Multiple Myeloma

Peter Voorhees, MD

Therapeutic strategies such as defining the optimal timing of autologous stem cell transplant (ASCT), implementing CAR T-cell agents, and introducing BCMA-directed bispecific antibodies are building on current standards of care (SOCs) in multiple myeloma to produce more effective treatments for patients with various stages of disease, according to Peter Voorhees, MD.

“We’ve come a long way in the world of multiple myeloma. The unprecedented progression-free survival [(PFS) data] that we’re seeing in the frontline space is a testimony to that,” Voorhees said following an OncLive^® Institutional Perspectives in Cancer webinar on multiple myeloma, which he chaired.

In an interview with OncLive^®, Voorhees highlighted important topics that his colleagues discussed at the meeting, including the important role of up-front ASCT and distinct adverse effects (AEs) to be aware of when using different CAR T-cell therapies. He also addressed potentially practice-changing data with BCMA-directed therapies and noted the options that exist for patients who have already received BCMA-targeted approaches.

Voorhees is the director of outreach for hematologic malignancies in the Plasma Cells Disorder Program in the Department of Hematologic Oncology and Blood Disorders at Atrium Health Levine Cancer Institute in Charlotte, North Carolina.

OncLive^®: Your colleague, Manisha Bhutani, MD, of Atrium Health Levine Cancer Institute, presented on frontline management of multiple myeloma. What did the phase 3 DETERMINATION trial (NCT01208662)show about the survival benefit with transplant in newly diagnosed multiple myeloma?

Voorhees: DETERMINATION was a randomized trial that looked at up-front vs deferred ASCT for newly diagnosed, fit patients with multiple myeloma. The patients assigned to up-front transplant received 3 cycles of [bortezomib (Velcade) plus lenalidomide (Revlimid) and dexamethasone (RVd)] induction, then underwent transplant. After recovery from transplant, they got 2 cycles of RVd consolidation, and then they went on lenalidomide maintenance. The other arm, the deferred arm, received 8 cycles of RVd and went on to lenalidomide maintenance.

One of the important aspects of this trial is that those patients who went on to lenalidomide maintenance remained on it until disease progression or the emergence of unacceptable AEs. [This trial found] that the likelihood of achieving minimal residual disease negativity was higher for those patients who got up-front transplant.

There was also a significant improvement in median PFS for those patients who got up-front transplant. The median PFS in the non-transplant arm was 46.2 months vs 67.6 months for those who got up-front transplant. That median PFS of 67.6 months in the up-front transplant arm is the longest median PFS that has been reported in a randomized trial in the newly diagnosed multiple myeloma space. That tells us we’re doing well with these patients.

When you look at overall survival [OS], to date, with a median follow-up of 76 months, there is no difference in OS. The question remains: With longer follow-up, will an OS advantage emerge?

This trial certainly tells us that up-front transplants still play an important role in myeloma therapy, particularly for those with high-risk cytogenetics. When [the investigators] looked at standard-risk vs high-risk cytogenetic patients, specifically those with the deletion 17p, or 4;14 or 14;16 translocations, the relative benefit of up-front transplant was even stronger.

Additionally, although not statistically significant, there was a trend toward improved OS for the high-risk patients who got up-front transplant. For now, transplant is here to stay.

Barry Paul, MD, of Atrium Health Levine Cancer Institute, spoke about CAR T-cell therapy for multiple myeloma. What AEs with CAR T-cell therapy should clinicians be aware of?

There’s a number of AEs to be careful with regarding CAR T-cell therapy. The first and the most recognized is cytokine release syndrome [CRS]. Interestingly, when you look at multiple myeloma CAR T-cell products that are FDA approved, specifically idecabtagene vicleucel [Abecma; ide-cel] or ciltacabtagene autoleucel [Carvykti; cilta-cel], the kinetics of CRS are a bit different.

For ide-cel, the median time to the onset of CRS is approximately 2 days after a CAR T-cell infusion, whereas for cilta-cel, it’s approximately 6 to 7 days. There is a delayed onset of CRS with cilta-cel relative to ide-cel.

Most patients who get CAR T-cell therapy for multiple myeloma will get CRS. Thankfully, most of the CRS we see is grade 1 or 2 in severity. Grade 1 would be a fever alone without any other significant findings. Grade 2 would be a fever with a change in blood pressure, or perhaps a change in oxygen saturation.

Grade 3 and higher CRS can be seen, but it is uncommon. As we’ve learned to use these products, we’ve come to treat grades 1 and 2 CRS more aggressively, thereby reducing the likelihood of grade 3 and higher CRS.

The other [AE] is immune effector cell–associated neurotoxicity syndrome [ICANS]. This is typically seen, on average, a couple of days after the onset of CRS. Because of the differences in the times to onset of CRS between the 2 products ide-cel and cilta-cel, there are differences in the time to the onset of ICANS between the 2 products as well. Most of these events are grades 1 and 2 in severity, so the likelihood of grade 3 and higher ICANS is low. However, we are seeing approximately 20% of patients developing some form of neurologic AEs after CAR T-cell therapy.

Some other unusual neurologic syndromes have been described after myeloma CAR T-cell therapy that treating providers need to be aware of. We’ve seen cases of Bell’s palsy, for example, after CAR T-cell infusion, and we’ve seen rare cases of Guillain-Barré syndrome.

There’s also a Parkinsonian effect that was most readily appreciated with the early experience with cilta-cel, although we think it’s a class effect, [an AE] that could occur with any BCMA-targeted CAR T-cell therapy. However, once the Janssen team modified how they look for Parkinson-like features early on after patients have received cilta-cel and treated those proactively, the rates of this Parkinsonian syndrome seem to have decreased, and certainly the higher-grade versions of it have significantly decreased. Nonetheless, it’s something that we need to be careful about.

Hematologic toxicity is common. Specifically, grade 3 and higher thrombocytopenia, anemia, and neutropenia. [Those who receive CAR T-cell therapy] are heavily pretreated, relapsed/refractory patients. They oftentimes have somewhat compromised bone marrow reserves going into CAR T-cell therapy, they get 3 days of fludarabine and cyclophosphamide, and then they have CAR T-cell infiltration into the bone marrow after we infuse these cells, so not surprisingly, we see fairly significant cytopenias in some patients, which will require transfusion support, growth factor support, and prophylactic antibiotics.

Infection risk is another aspect of this that we need to be careful with. There is the infection risk that comes with neutropenia, which is due to the lymphodepleting chemotherapy with fludarabine and cyclophosphamide, as well as the CAR T-cell infusion itself. But there is also an on-target, off-tumor toxicity of plasma cell depletion.

These CAR T-cell therapies are good at killing myeloma cells, but they’re also good at killing normal plasma cells. This typically leads to significant hypogammaglobulinemia. Many of our patients need intravenous immunoglobulin therapy for a good number of months after they’ve been through CAR T-cell therapy, until their normal plasma cell pools repopulate and recover.

Additionally, some T-cell immune deficiency occurs in the short term after CAR T-cell therapy, in part related to the fludarabine-based lymphodepleting chemotherapy that we give. For that reason, we prophylax against [varicella-zoster virus] reactivation, we prophylax against [Pneumocystis jirovecii] pneumonia, and we have to be cognizant of the risk of invasive fungal infections, which have been seen in rare cases. Infection remains a considerable concern, even more so in the COVID-19 pandemic. For those patients who are willing, we try to get them fully vaccinated before they get CAR T-cell therapy.

Regarding the presentation given by Shebli Atrash, MD, of Atrium Health Levine Cancer Institute, on BCMA-directed therapy, what has the phase 2 MagnetisMM-3 study (NCT04649359)shown about the efficacy of elranatamab (PF-06863135)?

Elranatamab is a BCMA-targeted bispecific antibody. Like CAR T-cell therapy, this is another way of redirecting T cells against multiple myeloma. The way that the bispecific antibodies work is that 1 component of the antibody binds to the myeloma cell through BCMA expressed on its cell surface. The other component of the antibody binds to T cells through CD3. In essence, you’re creating an immune synapse between the myeloma cell and the T cell, and forcibly activating the T cell in the presence of the myeloma.

A number of BCMA bispecific antibodies are in development. Elranatamab by Pfizer is 1 of them. The MagnetisMM studies that they’re currently conducting are of strong interest. The first-in-human MagnetisMM-3 trial has clearly demonstrated significant activity with this bispecific antibody in patients with relapsed/refractory multiple myeloma, the overwhelming majority of whom have triple-class refractory disease. These are patients who have disease that’s refractory to CD38 antibodies, proteasome inhibitors [PIs], and immunomodulatory drugs [IMiDs] like lenalidomide and pomalidomide [Pomalyst].

With the MagnetisMM program and the Pfizer bispecific, we are seeing response rates in the 60% to 65% range, the overwhelming majority of which are very good partial responses and complete responses. Follow-up is relatively short, but for those patients who are responding, responses seem to be durable.

There is also some data on the use of elranatamab after prior BCMA therapy. We’re seeing response rates of 50% to 55% in that group of patients, so there may be a role for BCMA bispecific antibody therapy post other BCMA-targeted therapy, so that’s interesting. All the various BCMA bispecifics that are out there [include] elranatamab, teclistamab [Tecvayli], the AbbVie product, the Regeneron product, and the Bristol Myers Squibb product.

The bottom line is that the response rates we’re seeing are anywhere from 60% to 70%, depending on what study you look at. Given that these are off-the-shelf therapeutics, they could completely change the way we treat triple-class refractory and relapsed/refractory myeloma.

The presentation given by Cindy Varga, MD, of Atrium Health Levine Cancer Institute, looked beyond BCMA-directed therapy. What other options are available for patients after they’ve received BCMA-directed therapy?

I alluded to the response rate of elranatamab, the BCMA bispecific antibody, post other BCMA-targeted therapy, with a response rate of approximately 55%. The Janssen team has shown similar findings with teclistamab, where teclistamab post BCMA-targeted therapy had a response rate of approximately 55%. Follow-up is short, so how durable those responses are remains to be seen.

There are data emerging on the role of BCMA-targeted CAR T-cell therapy after previous treatment with a BCMA-directed antibody-drug conjugate or bispecific antibody. There was a small cohort of patients in the [phase 2] CARTITUDE-2 trial [NCT04133636] that received cilta-cel post a BCMA-targeted antibody-drug conjugate or bispecific antibody. The overall response rate [ORR] is not the impressive 97% that we saw in the [phase 1b/2] CARTITUDE-1 program [NCT03548207]. It was more in the order of 60% to 65%. Many of [those responses] were deep, but the complete response rate was not nearly as notable in that cohort of patients relative to what we saw in the BCMA-naïve patients in the CARTITUDE-1 program.

Additionally, Levine Cancer Institute was part of a multi-institutional consortium looking at real-world experience with CAR T-cell therapy in multiple myeloma. We’ve presented data with ide-cel in the real-world experience, and interestingly, the ORR and PFS are virtually superimposable to what was seen in the [phase 2] KarMMA-2 program [NCT03601078] that led to the FDA approval of ide-cel.

However, we found that for the patients who’d had prior BCMA therapy, their PFS was expected to be lower. BCMA-directed therapy post other BCMA-directed therapy is not going to be as strong as it is in BCMA-naïve patients.

Other targets beyond BCMA are of strong interest. A good example is talquetamab, which is a bispecific antibody that targets the protein GPRC5D. This is a cell surface marker on plasma cells. The initial experience from the first-in-human phase 1 study shows an ORR in the order of 70%, which is quite exciting.

Interestingly, the target GPRC5D is expressed on hair follicles as well as other structures in the mouth. We see nail changes and rash, and sometimes early on in treatment, we can see oral ulcerations, dry mouth, and dysgeusia. These are unique on-target, off-tumor toxicities of this specific antibody. The good news is that much of this, perhaps with the exception of the dysgeusia, responds well to topical corticosteroids, and the dysgeusia does seem to improve with repeated administration.

Another bispecific antibody with a novel target is cevostamab [RG 6160], which targets FcRH5, another plasma cell–specific marker. [We’re] seeing impressive response rates in the order of 50% in a heavily pretreated, relapsed/refractory myeloma population, including a sizable minority of patients in that trial who had received previous BCMA-directed therapy.

Both talquetamab and cevostamab may emerge as important SOCs in the future for the treatment of patients who have quad-refractory disease, which is disease refractory to CD38 antibodies, PIs, IMiDs, and BCMA-targeted therapies.

What main message would you like colleagues to take away from the meeting as a whole?

The DETERMINATION trial showed the longest PFS that has ever been seen in the transplant-eligible population.

[It will be interesting to] take these bispecific antibodies and CAR T-cell platforms and apply them to patients with newly diagnosed multiple myeloma, particularly those with high-risk disease, who have not enjoyed the same level of benefit as their standard-risk counterparts with the current SOC.