Emerging Drug Classes in Myeloma

Over the past decade, multiple myeloma treatment has rapidly evolved. This has been driven by many factors, including a deeper understanding of how myeloma cells grow and survive. Researchers are now developing therapies that target new biological pathways, offering hope for people whose disease has stopped responding to existing options.

This article highlights four investigational drug classes that use distinct mechanisms of action to treat relapsed or refractory multiple myeloma and related conditions like AL amyloidosis.

1. BCL-2 inhibitors
2. Bromodomain inhibitors
3. Cereblon E3 ligase modulators
4. Immunocytokines

Understanding how these emerging treatments work can help you explore potential clinical trial opportunities with your care teams. 

Lisaftoclax for relapsed or refractory myeloma and AL amyloidosis

Lisaftoclax (APG-2575) is an oral BCL-2 inhibitor that is currently approved for use in China. It is currently being studied in combination with standard therapies for relapsed or refractory multiple myeloma and immunoglobulin light-chain (AL) amyloidosis. 

In the ongoing Phase I/II trial (NCT04942067), 52 patients have received lisaftoclax with pomalidomide and dexamethasone (Pd), daratumumab, lenalidomide, and dexamethasone (DRd), or Pd for AL amyloidosis. Participants had a median age of 69 and had received multiple previous treatments. 

Across the study arms, the overall response rates ranged from 61% to 86%. Several patients have achieved a complete or very good partial remission, including those with heart function improvement in the AL amyloidosis group. Lisaftoclax was generally well tolerated. Common side effects included neutropenia and mild gastrointestinal symptoms.

No major drug-drug interactions were identified. 

Inobrodib in combination with pomalidomide and dexamethasone for relapsed/refractory myeloma

Inobrodib (CCS1477) is a first-in-class oral therapy that targets the proteins involved in cancer cell growth. 

In an ongoing Phase I/IIa study (NCT04068597), inobrodib was evaluated in combination with pomalidomide and dexamethasone in 48 patients with relapsed or refractory multiple myeloma who had received a median of six prior therapies. 

Most participants were refractory to at least three lines of therapy. One in three participants had prior BCMA therapy. The combination was generally tolerable. Common side effects include neutropenia, thrombocytopenia, and infections. No new safety concerns were observed. Responses were observed across all dose levels. There was a 75% response rate in the highest dose group. and also seen in patients who were refractory to pomalidomide and had been exposed to anti-BCMA. 

Two pomalidomide-naïve participants achieved complete responses and minimal residual disease (MRD) negativity. These findings suggest that inobrodib may enhance the efficacy of existing oral regimens and support continued evaluation toward a pivotal trial.

We had the privilege of interviewing lead researcher of this study, Dr. Emma Searle 

Phase 1 cemsidomide with dexamethasone for relapsed or refractory myeloma

Cemsidomide (CFT7455) is a new oral therapy that selectively targets and degrades proteins IKZF1 and IKZF3, which are important for myeloma cells’ survival. 

In an early-phase clinical trial (NCT04756726), 32 patients with relapsed or refractory myeloma, most of whom had already received CAR-T or bispecific antibody treatments, received cemsidomide with dexamethasone. 

The study found that cemsidomide was generally tolerable, and the expected side effects, like low blood counts, were manageable. The treatment showed early signs of activity, with 22% of patients achieving partial or better responses and a total clinical benefit rate of 38%. Because it is taken orally and may work well with other therapies, cemsidomide represents an emerging option that could simplify treatment for some patients in the future. Individuals with relapsed or refractory myeloma may wish to discuss participation in early-phase clinical trials like this one with their specialist to stay informed about evolving treatment approaches.

Phase 2 dose optimization of modakafusp alfa in relapsed or refractory myeloma

Modakafusp alfa is a new type of treatment called an immunocytokine that delivers interferon-α directly to CD38-positive cells, a key marker found on myeloma cells. In a Phase 2 trial (NCT03215030), 146 patients with relapsed or refractory multiple myeloma received either 120 mg or 240 mg of modakafusp alfa every four weeks.

The overall response rate was 32% in the 120 mg group and 41% in the 240 mg group, with responses lasting up to 9 months in some patients. The most common side effects were low blood counts and infections, which were more frequent at the higher dose. Despite these side effects, the study confirmed that modakafusp alfa is an active single-agent therapy, even in patients who had already been treated with several other regimens, including BCMA-directed therapies. 

This research represents a growing area of study focused on targeting CD38 in new ways. People with myeloma who have tried more than three therapies without success may benefit from talking with their care team about ongoing immunocytokine trials or other emerging treatments that use similar mechanisms.

Looking forward for the approval of these growing therapies for relapsed and refractory myeloma

These four early-stage studies represent a wave of innovation in multiple myeloma therapy. Each drug class, BCL-2 inhibitors, bromodomain inhibitors, CELMoDs, and immunocytokines, targets a different biological pathway, offering new hope for people whose myeloma has relapsed after many treatments.

While these results are preliminary, they highlight how the mechanisms of action behind these therapies could reshape future treatment strategies. Staying informed about ongoing clinical trials and discussing them with your specialist can help you explore the full range of available and emerging options.

Stay tuned for new treatment updates and FDA approval announcements with HealthTree News. 

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Sources: 

• Randomized Phase 2 Dose Optimization Trial of Modakafusp Alfa in Relapsed/Refractory Multiple Myeloma (RRMM)
• Initial Results of a Phase 1 First-in-Human Study of Cemsidomide (CFT7455), a Novel MonoDACTM Degrader, with Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma
• Lisaftoclax (APG-2575) Combined with Novel Therapeutic Regimens in Patients (pts) with Relapsed or Refractory Multiple Myeloma (R/R MM) or Immunoglobulin Light‑Chain (AL) Amyloidosis
• Tolerability and Clinical Activity of Novel First-in-Class Oral Agent, Inobrodib (CCS1477), in Combination with Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma