Small Molecule Drugs Remain Vital in Addressing Refractory Multiple Myeloma

Immunotherapies have become the cornerstone of treatment for patients with multiple myeloma (MM) and continue to be the primary focus of evolving therapeutic approaches. However, not all patients respond to these treatments, and many ultimately relapse. Alternative options, such as proteasome inhibitors (PIs) and other targeted therapies, including BCL2 and BRAF/MEK inhibitors, offer hope in these challenging cases. At the International Myeloma Society's 21st Annual Meeting in Rio de Janeiro, Brazil, experts presented innovative treatment solutions for relapsed patients who need novel approaches.¹

Targeted inhibitors, such as BCL2, BRAF/MEK, and NSD2 inhibitors, have shown notable benefits in refractory patients. Image Credit: © Nihad - stock.adobe.com

The relapsed/refractory (R/R) setting is characterized by an increasing mutational burden and complex clonal dynamics. Both persistent driver mutations and the emergence of new subclones contribute to disease progression. A full genome sequencing study of over 400 R/R patients exposed to either PIs or immunomodulatory agents found that the mutational landscape across R/R stages was not significantly different from that of newly diagnosed patients. This was also observed between patients in early and late stages of relapse. While most driver mutations persist as the disease progresses, some mutations, like NRAS and KRAS, may disappear or decrease in prevalence.

New mutations often accumulate at the subclonal level, leading to increased clonal complexity and diverse myeloma cell populations. Mehmet Samur, PhD, senior research scientist at Dana-Farber Cancer Institute, described three main patterns of clonal evolution: the emergence of new subclones that were not detected at diagnosis and later became dominant, the expansion of existing subclones present at diagnosis, and static evolution, where clonal patterns do not change significantly.

“When we look at the clonal mutations, there was no increase; the clonal mutation load was the same across treatment protocols,” Samur noted. “But when you look at the subclones, there was significant change. So, if you look at the clonal patterns, [you can see] how the disease progressed from early stages to later stages.”

Samur also discussed the impact of melphalan (Evomela; Spectrum Pharmaceuticals), used in combination therapies such as daratumumab (Darzalex; Janssen Biotech, Inc) with lenalidomide (Revlimid; Bristol Myers Squibb) and dexamethasone (VRd). This combination appeared to increase the overall mutational load compared with VRd alone. Melphalan-containing regimens may drive the acquisition of more subclonal mutations, which can increase clonal complexity over time, leading to therapy resistance and disease progression.

Rising resistance to major drug classes, including lenalidomide refractoriness and early anti-CD38 antibody resistance, presents a significant challenge in the R/R setting. Approximately 30% to 80% of patients with MM become refractory to lenalidomide. Studies have shown that combining anti-CD38 antibodies with PIs can significantly improve progression-free survival (PFS). In the phase 3 CANDOR trial (NCT03158688), researchers evaluated the combination of carfilzomib (Kyprolis; Onyx Pharmaceuticals), daratumumab, and dexamethasone, demonstrating improved PFS in lenalidomide-refractory patients.²

As anti-CD38 antibodies become more widely used, patients previously exposed to them will require new approaches to overcome refractoriness. Results from the DREAMM7 (NCT04246047) and DREAMM8 (NCT04484623) trials show that the BCMA-targeted antibody-drug conjugate (ADC) belantamab mafodotin (Blenrep; GlaxoSmithKline) combined with bortezomib (Velcade; Millennium/Takeda) and dexamethasone demonstrated a PFS of 25 months in the lenalidomide-refractory group, indicating the potential of ADCs when used with other standard therapies.^3,4

“With no standard of care for relapse from T-cell redirection therapies, non-T-cell therapies can achieve substantial responses, but the durations are very short,” said P. Joy Ho, MBBS DPhil, FRACP, FRCPA, director at the Institute of Haematology, Royal Prince Alfred Hospital. “Ongoing trials on non-T-cell agents remain crucial, especially given concerns about T-cell exhaustion and the mutational spectrum of their targets.”

Targeted inhibitors, such as BCL2, BRAF/MEK, and NSD2 inhibitors, have shown notable benefits in refractory patients. Research has also identified new transcription factor targets, such as MYC, RAS, and STAT3, which were previously considered untreatable. Advances in protein degradation techniques now allow for the development of inhibitors targeting these difficult targets. Gene and CRISPR screens have identified other potential targets, such as Pik5 kinase, and drugs like apixaban 201, originally developed for autoimmune diseases, are showing efficacy in MM.

In an unpublished study, Marc Raab, MD, PhD, professor of medicine at University Hospital Heidelberg, and his team found that apixaban 201 had a 92% response rate in primary myeloma cells. Further research showed that treating myeloma cells with apixaban 201 led to lysosomal disruption and the induction of autophagy. This suggests that Pik5 inhibition could enhance the effectiveness of checkpoint inhibitors.

Raab also discussed other targeted inhibitors, such as venetoclax (Venclexta; AbbVie, Inc), which demonstrated a 60% response rate in combination with dexamethasone in the CANOVA phase 3 trial (NCT03539744); the BRAF inhibitor dabrafenib (Tafinlar; Novartis) and the MEK inhibitor trametinib (Mekinist; Novartis), which showed an 80% overall response rate in trials; and the investigational NSD2 inhibitor KTX-0201 (Kuria Therapeutics). Although these treatments are not yet widely approved, they present opportunities for personalized therapies in MM.⁵

Despite promising clinical trial results, most patients do not have access to these therapies.

“This graph shows countries with universal healthcare, but that doesn’t guarantee access to high-cost medicines,” said Hang Quach, MD, director of hematology at St. Vincent’s Hospital Melbourne. “Only a third of the world’s countries spend over $4,000 per person on healthcare, while many spend as little as $750.”

Even in countries with universal healthcare, barriers to accessing novel treatments persist. Quach emphasized the importance of prioritizing accurate diagnosis and cost-effective treatments, such as PIs and cyclophosphamide-based regimens, over more complex assessments like molecular risk stratification.

In conclusion, as more patients relapse, the complexity of the disease demands innovative approaches beyond existing treatments. Small molecule drugs, including PIs and targeted inhibitors, remain highly relevant, offering interventions that address the underlying biology of RRMM. Additionally, the repurposing of agents underscores the potential of existing drugs to provide new therapeutic avenues. Though challenges remain, the future of MM treatment holds significant promise, with continued innovation paving the way toward improved patient outcomes.

REFERENCES

1. Quach H, Ho P, Stewart K, et al. Relapsed: treatments outside of immunotherapy. International Myeloma Society 21 Annual Meeting. September 28, 2024. Rio de Janeiro, Brazil.

2. Study of carfilzomib, daratumumab and dexamethasone for patients with relapsed and/​or refractory multiple myeloma. (candor). ClinicalTrials.gov Identifier: NCT03158688. Updated April 14, 2024. Accessed September 28, 2024. https://clinicaltrials.gov/study/NCT03158688?tab=history

3. Evaluation of efficacy and safety of belantamab mafodotin, bortezomib and dexamethasone versus daratumumab, bortezomib and dexamethasone in participants with relapsed/​refractory multiple myeloma (dreamm 7). ClinicalTrials.gov Identifier: NCT04246047. Updated December 13, 2023. Accessed September 28, 2024. https://www.clinicaltrials.gov/study/NCT04246047

4. Belantamab mafodotin plus pomalidomide and dexamethasone (pd) versus bortezomib plus pd in relapsed/​refractory multiple myeloma (dreamm 8). ClinicalTrials.gov Identifier: NCT04484623. Updated May 28, 2024. Accessed September 28, 2024. https://clinicaltrials.gov/study/NCT04484623

5. A study designed to evaluate the safety and efficacy of venetoclax plus dexamethasone (vendex) compared with pomalidomide plus dexamethasone (pomdex) in participants with t(11;14)-positive relapsed or refractory multiple myeloma. ClinicalTrials.gov Identifier: NCT03539744. Updated July 19, 2024. Accessed September 28, 2024. https://clinicaltrials.gov/study/NCT03539744