Transforming Multiple Myeloma Treatment: The Promise of Novel Drug Classes

Multiple myeloma is the second most prevalent blood cancer diagnosis in the United States, after non-Hodgkin lymphoma. Males are significantly more likely than females to have multiple myeloma. Myeloma incidence is highly tied to age, with older adults having the highest incidence rates and being diagnosed most frequently between the ages of 65 and 74. Approximately 95% of cases are detected at a distant or metastatic stage, with a 5-year relative survival rate of around 53% for this stage. The majority of researchers are unsure of the specific cause of multiple myeloma. They have made progress, however, in understanding how particular alterations in DNA might cause plasma cells to become malignant.

As per the assessment done by DelveInsight, the total incident cases of multiple myeloma in the 7MM comprised more than 70,000 cases in 2022 and are projected to increase during the forecast period. DelveInsight estimates that the total incident multiple myeloma cases were the highest in the United States. Data suggests that roughly half of newly diagnosed multiple myeloma patients are ineligible for transplant, and around a third of eligible patients do not receive the transplant.

Despite the significant advancements in multiple myeloma treatment, including various biological drugs and their combinations like IMiDs (lenalidomide, pomalidomide), anti-CD38 monoclonal antibodies (daratumumab, isatuximab), anti-SLAM7 monoclonal antibody (elotuzumab), and new proteasome inhibitors (carfilzomib, ixazomib), relapse after first-line therapy remains a common challenge for most multiple myeloma patients.

Relapse Refractory Multiple Myeloma Treatment: The Race for CAR-Ts and Bi-specific Antibodies

The relapse refractory multiple myeloma treatment landscape is undergoing a radical transformation with the recent FDA approvals of two CAR-Ts, namely, ABECMA (Bristol-Myers Squibb) and CARVYKTI (Johnson & Johnson), and one bispecific antibody, TECVAYLI (Janssen), opening up new avenues for companies developing therapies for later-line treatment, mainly fourth-line and above (4L+). Several key players are racing to bring their candidates to the multiple myeloma treatment market, and we estimated that about four more bispecific antibodies and CAR-Ts will join the fray by 2025. Some of the frontrunners in this space are Pfizer, Johnson & Johnson (Janssen), Regeneron Pharmaceuticals, Roche (Genentech), Abbvie, TeneoOne, CARsgen Therapeutics, and others, who are harnessing the power of CAR-Ts and bispecific antibodies for relapse refractory multiple myeloma treatment. 

Johnson & Johnson is already a dominant force in multiple myeloma with its blockbuster products DARZALEX/DARZALEX FASPRO. In frontline multiple myeloma clinical studies, DARZALEX was successful and is now considered the standard of therapy. DARZALEX has outperformed rivals’ expectations regarding effectiveness and safety and is expected to rule the multiple myeloma market. The frontline setting is still relatively untapped and can provide lucrative opportunities. For example, DARZALEX, in combination, secured an FDA nod in both frontline transplant-eligible and ineligible patient pools.

With the recent approval of the bispecific antibody TECVAYLI for relapse refractory multiple myeloma, Janssen is ready to grab the market share in the bispecific space. The company is also poised to launch another bispecific antibody, talquetamab, for relapse refractory multiple myeloma treatment, which is on track to receive approval in 2023 for 4L+ relapse refractory multiple myeloma in the US and Europe. Talquetamab’s results were impressive with an ORR of 73% in the Phase I/II trial of RRMM. 

In January 2021, talquetamab was granted PRIority MEdicines (PRIME) designation by the European Commission. In June 2022, Janssen announced that US FDA had granted BTD for talquetamab to treat adult patients with R/R multiple myeloma who have previously received at least four prior lines of therapy. Recently, in June 2023, the company presented the updated results from its Phase I studies investigating talquetamab as a monotherapy and in combination with other drugs in patients with R/R multiple myeloma at the American Society of Clinical Oncology (ASCO) 2023 conference.

Another bispecific antibody that is eyeing approval in 2023 is elranatamab by Pfizer, which delivered an ORR of 61% in the Phase I/II trial. Elranatamab will face stiff competition from Johnson & Johnson’s talquetamab and TECVAYLI, as well as from Regeneron Pharmaceuticals’ linvoseltamab and REGN5459, Roche’s cevostamab, and Abbvie’s ABBV-383 (TNB383B). Regeneron’s linvoseltamab targets BCMA × CD3 in RRMM patients and showed an ORR of 64% in the 200 mg dose group and 50% in the 50 mg dose group in a Phase II trial presented at ASCO 2023. Regeneron plans to file for approval in the second half of 2023. 

Another approach in relapse refractory multiple myeloma treatment involves the use of CAR-T cell therapies. Although CAR-T treatments have demonstrated significant effectiveness, they also come with safety issues such as called Cytokine Release Syndromes (CRS). Cost, convenience, and manufacturing turnaround time initially could prevent CAR-T from being widely adopted, but over time, companies may reduce side effects and speed up manufacturing time. CAR-Ts might not pose a significant threat to DARZALEX due to its better efficacy and safety profile, and its evolving use in earlier lines of setting.

Two CAR-T cell therapies, ABECMA and CARVYKTI, have already received approval and are available in the multiple myeloma market. These therapies were developed by Bristol-Myers Squibb and Johnson & Johnson, respectively. Several companies are developing CAR-Ts, such as Arcellx, Novartis, CARsgen Therapeutics, and others. All of them are targeting later lines of multiple myeloma and are in the early phases of clinical development. In June 2023, Arcellx announced that the FDA has put a hold on its CART-ddBCMA program for RRMM due to a patient death, despite showing a remarkable 100% ORR in 38 patients in Phase I, as reported at ASH 2022. CARsgen Therapeutics plans to file BLA in 2024 for zevorcabtagene autoleucel, which also achieved a stunning 100% ORR in heavily pretreated RRMM patients in Phase II. Whereas, Novartis is developing PHE885, a BCMA-targeted CAR-T for RRMM. 

How BMS is Revolutionizing Multiple Myeloma Treatment with CellMoDs?

Bristol-Myers Squibb, which is a major player in the multiple myeloma treatment space with its IMiDs REVLIMID and POMALYST, is not resting on its laurels. In 2022, the Food and Drug Administration (FDA) approved a generic version of REVLIMID. After the patent expiry of POMALYST in 2024, the company, to maintain its market presence, is coming up with novel cellMoDs for multiple myelomas, such as mezigdomide and iberdomide in different lines and combinations that might bring a change in the treatment paradigm. Mezigdomide will be used as a replacement for POMALYST, and iberdomide for REVLIMID. The company presented results from different cohorts showing that iberdomide + dexamethasone + daratumumab achieved an ORR of 45.9% in Phase I/II and started Phase III of this cohort, while mezigdomide + bortezomib + dexamethasone achieved an ORR of 73.7% in Phase I/II. 

The Battle of Bcl-2 Inhibitors in Multiple Myeloma Treatment: AbbVie’s Venetoclax vs. BeiGene’s BGB-11417

Besides IMiDs, CAR-Ts, and bispecific antibodies, the multiple myeloma pipeline also includes small molecules, ADCs, and interferons. Small molecules include two Bcl-2 inhibitors, venetoclax and BGB-11417, by AbbVie and BeiGene, respectively. VENCLEXTA/VENCLYXTO (venetoclax) is an oral B-cell lymphoma-2 (BCL-2) inhibitor developed by AbbVie and Genentech. In March 2019, the US FDA placed a partial clinical hold on Venetoclax’s multiple myeloma trials after new safety concerns were raised during a review of the BELLINI Phase III trial. This trial was designed to assess the safety and activity of Venetoclax in combination with standard Velcade (bortezomib) and dexamethasone in relapsed or refractory myeloma patients. Overall responses and very good partial responses were also better among those receiving venetoclax, researchers reported. 

In July 2019, the US FDA removed the partial clinical hold based upon agreement on revisions to the CANOVA study protocol (Myeloma Positive for the t(11;14) Genetic Abnormality), including new risk mitigation measures, protocol-specified guidelines, and updated futility criteria. A Phase III (NCT03539744; CANOVA) clinical trial evaluates Venclexta for treating relapsed or refractory (11;14)-positive Multiple Myeloma. This ongoing study was 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. 

The company, in its pipeline update, mentioned the CANOVA study is nearing completion, and the data readout is expected in 2022, with regulatory submissions anticipated in 2023. At ASH 2021, AbbVie also presented final overall survival results from BELLINI; in the final OS analysis, the addition of venetoclax to bortezomib and dexamethasone showed significantly improved PFS but resulted in increased mortality versus placebo in the total population. 

Both companies target a specific subset of t(11;14)-Positive RRMM. AbbVie plans to file for approval in the US in 2023 for venetoclax based on Phase III results. BeiGene is conducting a Phase I/II trial for BGB-11417, which seems more potent than venetoclax and can potentially overcome venetoclax resistance.

ASCO 2023: Key Takeaways for Multiple Myeloma Treatment

At ASCO 2023 annual meeting, several pharma companies presented their data readouts. With 40,000+ attendees, approx 3,500 poster sessions, more than 400 oral abstracts, and 75+ late-breaking abstracts were presented during the ASCO 2023. More than 2,900 abstracts spanning all major disease sites and research areas were presented at this year’s meeting. Breast cancer accounted for the maximum number of sessions presented during the conference, followed by GI and Lung cancer. Our team of analysts has analyzed the important abstracts relevant to multiple myeloma. The team analyzed the launch of the results and assessed the impact on the overall indication domain. Some of the key abstracts presented and analyzed include

Evolving Dynamics of Multiple Myeloma Therapeutics Segment

The multiple myeloma treatment market is expected to grow in the upcoming years, owing to the rise in incident cases of multiple myeloma, high adoption of newer therapies, rich emerging pipelines, and increased investment in R&D activities. Some factors, such as toxicities, the burden of long-term therapy, differences in clinical care, practice patterns between treatment centers, and access to and cost of therapy in real-world settings, may also play a role in the observed gap between trial-based and real-world outcomes.

As per DelveInsight analysis, the total multiple myeloma market size in the 7MM was estimated to be nearly USD 20 billion in 2022, which is expected to show positive growth by 2032. In 2022, the US accounted for the maximum share of the total market in the 7MM, i.e., approximately 70%, followed by EU4 and the UK.

In addition, the multiple myeloma treatment landscape has witnessed remarkable evolution in recent years, offering new hope to patients battling this complex hematologic malignancy. From conventional chemotherapy to targeted therapies and immunomodulatory agents, advancements have paved the way for more personalized and effective interventions. The advent of proteasome inhibitors, monoclonal antibodies, and CAR-T cell therapies has revolutionized the management of multiple myeloma, enhancing response rates and extending survival. Additionally, a deeper understanding of the disease’s genetic and molecular intricacies has enabled the development of precision medicine approaches, tailoring treatments to individual patients’ characteristics. With ongoing research and clinical trials, the future holds promise for even more innovative therapies, potentially transforming multiple myeloma into a chronic condition, allowing patients to lead fuller, longer lives.