The State of Myeloma in 2024 

Two new FDA approvals and promising clinical trials bode well for the future 

By Dr. Joseph Mikhael, IMF Chief Medical Officer 

The pace of change in the field of myeloma is incredible! New approvals are expanding treatment options, research data is showing great promise, and more healthcare professionals are being trained in myeloma. Most importantly, myeloma patients are living longer and more fulsome lives. 

There has not yet been a time of such activity in myeloma until now. We seek to do everything possible to tackle this terrible disease, and I would like to briefly reflect on the state of myeloma – past, present, and future. 

When I started my work in myeloma more than 20 years ago, we had very few drugs available to treat our patients. Today, we have nearly 20, and the rate of development of new drugs continues to accelerate! Most recently, several very important clinical trials reported data that will be sure to influence treatment in myeloma. 

Drugs and quadruplets in clinical trials 

As reported in the Winter 2024 edition of Myeloma Today (https://www.myeloma.org/resource-library/myeloma-today-winter-2024), based on data from the ISKIA phase III clinical trial and PERSEUS clinical trials, using quadruplet (4-drug) combinations will soon become the new standard of care in the treatment of patients with newly diagnosed multiple myeloma (NDMM) who are eligible for an autologous stem cell transplant (ASCT). 

The ISKIA study demonstrated that the addition of Sarclisa® (isatuximab-irfc) to the combination of Kyprolis® (carfilzomib) + Revlimid® (lenalidomide) + dexamethasone [Isa-KRd] as pre-ASCT induction therapy and post-ASCT consolidation therapy significantly increased the rates of minimal residual disease (MRD)-negativity in every treatment phase, including in patients with high-risk disease, when compared to KRd alone. 

The primary results of the PERSEUS phase III clinical trial of Darzalex® (daratumumab) + Velcade® (bortezomib) + Revlimid + dexamethasone [D-VRd] in ASCT-eligible patients with NDMM demonstrated significantly improved progression-free survival (PFS) and increased depth of response across relevant subgroups when compared to VRd alone. These data support the use of D-VRd followed by maintenance therapy with Darzalex + Revlimid [D-R] as a new standard-of-care for ASCT-eligible patients with NDMM when compared to VRd alone followed by maintenance with Revlimid. 

Data from the IMROZ clinical trial of Sarclisa in combination with VRd [Isa-VRd] in patients not intending to proceed to transplant will be released soon and we anxiously await positive results. 

See below for an update on two studies with Blenrep® (belan tamab mafodotin-blmf), a drug that we hope to have for our patients in the near future. 

Two new FDA approvals 

The most newsworthy items in myeloma right now are the two approvals by the U.S. Food and Drug Administration (FDA) of the earlier-line use of chimeric antigen receptor (CAR) T-cell therapies. 

On April 4, the FDA approved Abecma® (idecabtagene vicleucel or “ide-cel” for short) for the treatment of relapsed or refractory multiple myeloma (RRMM) after 2 or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. This approval is based on data from the KarMMa-3 phase III clinical trial, which demonstrated a PFS of roughly 13 months in the Abecma arm of the study vs. 4 months in the control arm with standard regimens. 

Abecma was previously FDA-approved for use in myeloma after at least 4 prior lines of therapy. On April 5, the FDA approved Carvykti® (ciltacabtagene autoleucel or “cilta-cel” for short) for the treatment of patients with RRMM who have received at least 1 prior line of therapy, including an immunomodulatory agent and a proteasome inhibitor, and are refractory to Revlimid. Carvykti is the first and only B-cell maturation antigen (BCMA)-targeted therapy approved for the treatment of patients with myeloma as early as first relapse. 

The new FDA approval is based on data from the CARTITUDE-4 phase III clinical trial. In the Carvykti arm of the study, PFS was not reached at 24 months vs. PFS of 12 months with Pomalyst® (pomalidomide) + Velcade + dexamethasone [PVd] or Darzalex + Pomalyst + dexamethasone [DPd] in patients with relapsed and Revlimid-refractory myeloma who received 1 to 3 prior lines of therapy. Carvykti was previously FDA-approved to be used in myeloma after at least 4 prior lines of therapy. 

The two new approvals expand previous indications, making these important CAR T-cell therapies available to patients earlier in their treatment journey. This development closely followed the recent assessment by the Oncologic Drug Advisory Committee (ODAC). The ODAC meeting brought together experts, hematologists, pharmaceutical companies, and patients with myeloma. The IMF was well represented by our leadership and the myeloma patients who spoke at the proceedings. 

New data coming soon 

If you are already impressed by what is happening in the present, be ready to be amazed by the future! In the coming months, we anticipate new data from dozens of clinical trials in CAR T-cell therapies, bispecific antibodies, novel drug combinations, and even newer ways to target and treat myeloma. Certainly, there are many challenges for patients and their loved ones in the fight against myeloma, but I stand on solid ground when I say that the state of the union in myeloma is indeed great. 

Blenrep® Demonstrates Positive Results 

Promising data reported from DREAMM-7 and DREAMM-8 clinical trials of belantamab mafodotin-blmf combinations 

Multiple myeloma is a cancer of the bone marrow plasma cells, white blood cells that make antibodies. Cancerous plasma cells are called myeloma cells. All patients with myeloma express B-cell maturation antigen (BCMA), a protein involved in myeloma cell growth and survival, on the surface of their myeloma cells. 

Blenrep® (belantamab mafodotin-blmf) is an antibody-drug conjugate (ADC), a new class of drugs for myeloma. It is the combination of a monoclonal antibody and monomethyl auristatin F (MMAF), a drug that can kill myeloma cells. The monoclonal antibody portion of Blenrep is designed to find and attach to BCMA, enabling Blenrep to enter the myeloma cell. Then Blenrep releases MMAF, which leads to cell death. 

The DREAMM Clinical Trial Program yielded an interim analysis of the DREAMM-7 study in February 2024, followed by an interim analysis of the DREAMM-8 study in March 2024. Both studies demonstrated positive results. 

DREAMM-7 

Blenrep combination vs. DVd 

Data from an interim analysis of the DREAMM-7 phase III clinical trial of Blenrep in combination with Velcade® (bortezomib) and the steroid dexamethasone [Vd] in second-line and later treatment of relapsed or refractory multiple myeloma (RRMM) were presented at the American Society of Clinical Oncology (ASCO) Plenary Series on February 6, 2024. 

The Blenrep combination demonstrated a statistically significant and clinically meaningful improvement, nearly tripling median progression-free survival (PFS) versus the combination therapy of Darzalex® (daratumumab) + Vd [DVd] in patients with RRMM. 

The Blenrep combination showed a 59% reduction in the risk of disease progression or death when compared to DVd. With a median follow-up of 28.2 months, the median PFS was 36.6 months with the Blenrep combination vs. 13.4 months with DVd. The PFS effect was observed across all patient subgroups, including those who were refractory to Revlimid® (lenalidomide) and those with high-risk cytogenetics. The safety and tolerability profile of the Blenrep combination was consistent with the known profile of the individual agents. 

As noted by DREAMM-7 principal investigator Dr. María-Victoria Mateos, (IMWG member and the Head of Myeloma and Clinical Trials Unit, Haematology Department, and Professor of Medicine at the University of Salamanca, Spain): “Anti-BCMA therapies are helping to improve outcomes for patients with multiple myeloma, and having an off-the-shelf option, like belantamab mafodotin, that can be administered in a community oncology treatment center where the majority of patients are treated has the potential to transform the way we treat myeloma at or after first relapse.” 

DREAMM-8 

Blenrep combination vs. VPd 

On March 7, 2024, positive results were reported from an interim analysis of the DREAMM-8 phase III clinical trial of Blenrep in combination with Pomalyst® (pomalidomide) + dexamethasone [Pd], vs. Velcade + Pd [VPd] as second-line and later treatment for patients with RRMM. This clinical trial met its primary endpoint of PFS at a pre-specified interim analysis and was unblinded early based on the recommendation by an Independent Data Monitoring Committee (IDMC). 

The Blenrep combination significantly extended the time to progression (TTP) or death vs. VPd. A positive overall survival (OS) trend was also observed with the Blenrep combination at the time of this analysis. The trial continues to follow up for OS. The safety and tolerability profile of the Blenrep combination was consistent with the known profile of the individual agents. 

To stay in the know about the key developments in the field of myeloma, sign up at subscribe.myeloma.org (https://www.myeloma.org/subscribe.myeloma.org) for our quarterly journal Myeloma Today (https://www.myeloma.org/multiple-myeloma-journals) and weekly e-newsletter Myeloma Minute (https://www.myeloma.org/resource-library/myeloma-minute?utm_source=print&utm_medium=pdf&utm_campaign=myeloma-minute-webpage&utm_id=mt.234), and contact the IMF InfoLine with your myeloma-related questions and concerns. Phone lines are open 9 a.m. to 4 p.m. (Pacific) Monday through Friday at 1.800.452.CURE in the U.S. and Canada and 1.818.487.7455 worldwide. To submit your query electronically, email [email protected] (mailto:[email protected]). 

(This article was published in the 2024 Spring Edition of the IMF's quarterly publication, Myeloma Today. Read the full publication here (https://www.myeloma.org/resource-library/myeloma-today-spring-2024).)