Speakers Suggest Moving Newer Agents Into Earlier Lines in MM

Speakers sought to demystify cellular therapies in multiple myeloma (MM) at the European Hematology Association 2021 Virtual Congress.

Despite treatment advances, there is significant need for more effective agents in MM for patients who experience relapse on immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies, said Paula Rodriguez Otero, MD, a professor and clinician at the University of Navarra in Spain, who spoke about cellular therapies at the congress.

She discussed the promise of belantamab mafodotin, an antibody drug conjugate (ADC), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell infusions. 

Belantamab mafodotin has FDA and European Medicines Agency approval. In the pivotal DREAMM-2 phase 2 study (N = 97), among patients with 3 previous lines of treatment and refractory to PIs and IMiDs, the drug achieved an overall response rate (ORR) of 32% and a median duration of response of 11 months. Patients were treated with the approved 2.5 mg/kg dose.

With belantamab mafodotin, as with other ADC agents, “ocular toxicity is one of the major concerns,” Rodriguez Otero said. In DREAMM-2, keratopathy was observed in 72% of patients (n = 68) receiving the 2.5 mg/kg dose, median time to onset was 37 days, and median duration of the first event was 86.5 days, although “the good news” was that all patients recovered from keratopathy.

“We need to understand and manage it well to get the best from this drug," Rodriguez Otero said, emphasizing the need for medical education on managing keratopathy with ADCs.

BiTEs have demonstrated encouraging efficacy and are poised to challenge the growing use of CAR T-cell therapies, although both BiTEs and CAR T-cell therapies share common toxicities, including cytokine release syndrome (CRS), neurotoxicity, and cytopenias. However, with BiTEs “this is less frequent, less severe, and confined to the first cycle of treatment,” she said.

BiTEs target the antigen BCMA on the myeloma cell and cause T-cell binding, leading to release of cytokines and cell destruction. For different BCMA-BiTEs under evaluation, efficacy rates have been “outstanding,” with ORRs from 26% to 80%, Rodriguez Otero said. “Responses are quick, generally by the first month, tend to deepen over time, and stay durable, so this platform of drugs is very interesting for the treatment of relapsed, refractory MM.”

All-grade CRS is present in 40% to 76% of patients across multiple BCMA-BiTEs currently under evaluation in clinical trials, including teclistamab, PF-3136, AMG701, and cevostamab. “Importantly, no or few patients developed grade 3 or higher CRS in these studies,” she said. Median onset is 1 to 2 days and median duration is also 1 to 2 days.

Compared with CAR T-cell therapy, neurotoxicity with BiTEs is mostly uncommon and mostly grade 1/2. Cytopenias are more common but short-lasting and manageable with growth factors, she said.

CAR T-cell therapy does show “outstanding efficacy” with a manageable adverse event profile, but toxicities are a concern, and further understanding is needed of macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH), both potentially fatal; however, patient and physician education can improve use of these therapies, Rodriquez Otero said.

She said 80% to 90% of patients treated with CAR T-cell therapy will develop CRS, although “the good news is that grade 3 or higher CRS is very uncommon.” As regards MAS/HLH, “it is clear that we need a better definition for these conditions and probably more guidance.”

Move Newer Agents to Earlier Lines

Many treatments may be available for MM, but opinions differ on how these should be sequenced and in what combinations, said Joseph Mikhael, MD, a professor in the Translational Genomics Research Institute at City of Hope Cancer Center and chief medical officer for the International Myeloma Foundation.

There are 2 schools of thought, he said. One is that MM should be treated aggressively early on to achieve deep, long-lasting remission; the other is that MM should be modulated by treating it much as you would hypertension. Neither is optimal, Mikhael said, although choosing the right course of treatment early on is critical because the survival curve angles downward as progressive lines of therapy add up. “Save the best for last is great for a movie, but it really doesn’t work in MM,” he said. “We want to bring our better therapies earlier and earlier in the disease course.”

He advised careful reflection and a strategy-based approach when initiating new treatment, given the large number of options. For early relapse in MM, he advised selection of therapies with mechanisms of action not previously used. At City of Hope, “If patients are progressing on lenalidomide maintenance, which is very common, it’s typical to not add another drug to it. We change classes.” He also advised use of triplets over doublets, citing growing trial evidence supporting this preference. 

The current choice for induction therapy tends to be a triplet combination, such as bortezomib-lenalidomide-dexamethasone, or carfilzomib-lenalidomide-dexamethasone (for transplant eligible patients), with lenalidomide maintenance. After first relapse, a monoclonal antibody is added to these agents if it’s not been used before. By third relapse, newer agents such as selinexor-dexamethasone, belantamab mafodotin, melphalan flufenamide, and CAR T-cell therapies are employed.

“We are going to see the greater introduction of quadruplets in front lines. We may even bring CAR T-cell therapy earlier [induction], and many of the things that are used in the third relapse plus lines are going to be brought earlier [first relapse],” he said.

BiTEs vs CAR Ts

Philippe Moreau, MD, of Chu Nantes-Hotel Dieu, France, said the value of combinations becomes clear when looking at the progression-free survival (PFS) times of older vs newer agents.

Daratumumab is an option for patients refractory to IMiDs and PIs, such as pomalidomide/dexamethasone and carfilzomib, but PFS times approximate 4 months, and for triple-class refractory patients, some of the newer agents don’t do much better: selinexor/dexamethasone, 3.7 months PFS; belantamab mafodotin, 2.9 months; and melfulfen, 4.2 months, Moreau said. “We have definitely better outcomes with the combination of these agents.”

However, recent studies of CAR T-cell therapies and BiTEs have demonstrated impressive outcomes and bear consideration, he said.

The pivotal KarMMa phase 2 study of FDA-approved CAR T-cell therapy idecabtagene vicleucel (ide-cel) enrolled patients refractory to 3 classes of agents (immunomodulatory, PIs, and anti-CD38 antibodies) including the last line of treatment.

At the target dose of 450 x 10⁶, the ORR was 82% (n = 70). “That’s outstanding as compared to belantamab mafodotin in the same setting, as compared with selinexor, as compared with melflufen,” Moreau said. The PFS at the target dose was 12 months, but with a sharp drop-off.

In 2022, there is potential for another CAR-T cell therapy approval: ciltacabtagene autoleucel (cilta-cel). In the LEGEND-2 study (N = 57), the median PFS was 20 months and the median overall survival was 36 months at a 25-month follow-up. CRS events were mostly grade 1 to 2.

In CARTITUDE-1, the ORR was 97.9% (N = 97) at the optimal cilta-cel dose, including an 80.4% complete response. “The median time to response was very quick. You can see a response in 1 month, in fact,” Moreau said. Median PFS was 18 months. “Potentially we should try to use CAR T-cell therapies earlier in the course of the disease, in less-advanced patients with a lower tumor burden as well."

Among BiTEs, teclistamab is promising with a manageable safety profile and subcutaneous administration. Also, the response rate according to recent findings was 65% (n = 40) at the optimal dose at a follow-up of 6.1 months, and this was in a triple refractory cohort.

Similarly, talquetamab has demonstrated a tolerable safety profile with subcutaneous administration, and an overall response rate was 70% (n = 30) in a recent study.

Comparing CAR T-cell therapies with BiTEs, Moreau noted the “off-the-shelf” value of BiTEs vs up to 2 months required for CAR T-cell development, as well as BiTEs’ subcutaneous administration vs CAR T cells’ intravenous administration, higher incidence of CRS with CAR T cells, and superior ORR with CAR T cells vs BiTEs (82%-98% vs 65%-70%).