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MMRF ASH 2023 Blog: ASH Day 1!

Welcome to our 2023 recap of the latest findings on myeloma treatments reported at the American Society of Hematology (ASH) meeting that kicked off Saturday in San Diego. Highlights from today included real-world data on the use of the bispecific antibody Tecvayli, health-related quality of life findings with the CAR T-cell therapy Abecma, the use of minimum residual disease negativity, iberdomide maintenance therapy, and updates on the treatment of high-risk newly diagnosed disease and smoldering myeloma.

Relapsed/Refractory Multiple Myeloma

Tecvayli (Teclistamab)

Tecvayli (Teclistamab) was the first “off-the shelf” BCMA-targeted bispecific antibody approved for patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM; that is patients who have received 4 or more lines of therapy), including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody. In this Abstract 91, Dr. Danai Dima and colleagues from the Cleveland Clinic reported that treatment with Tecvayli in a real-world setting showed similar responses to the previously reported data from the MajesTEC-1 clinical trial without any new side effects.

Of the 102 patients with RRMM included in Dr. Dima’s analysis, 25% were non-Hispanic Black, 44% had extramedullary disease (EMD; that is, myeloma cells that are growing outside of the bone marrow) and more than 80% (83/102) would not have met the MajesTEC-1 eligibility criteria.  Their findings showed:

The authors note that results from the real-world study of the safety and efficacy of Tecvayli were like previously reported data from the MajesTEC-1 clinical trials; however, complete response (CR) rates were lower.  The lower CR rates may be due to the fact that a majority of patients evaluated did not meet the eligibility criteria MajestTEC-1 trial population; due to stringent eligibility criteria, patients in clinical trials tend to be less sick and/or have fewer comorbidities than real-world patient population, so outcomes are typically better in clinical trials. Low blood cell counts and infections remain a challenge, thus, close monitoring, supportive care and other measures are important to help patients continue with therapy.

Abecma (idecabtagene vicleucel)

Dr. Michel Delforge and colleagues in Belgium reported findings from a preliminary analysis (Abstract 96) that showed the chimeric antigen receptor T cell (CAR T-cell) therapy Abecma (idecabtagene vicleucel) significantly improved health-related quality of life when compared to standard regimens [that is, Darzalex (dara, daratumumab), Pomalyst (pomalidomide), and dexamethasone; Darzalex, Velcade (bortezomib), and dexamethasone; Ninlaro (ixazomib), Revlimid, and dexamethasone; Kyprolis (carfilzomib) and dexamethasone; or Empliciti (elotuzuamb), Pomalyst, and dexamethasone].

Researchers evaluated data from patient-reported outcomes that were collected as part of the KarMMa-3 trial.  In the phase 3 trial, Abecma significantly improved progression-free survival (PFS) and treatment response rates as compared with standard regimens, in patients with triple-class exposed (TCE) RRMM who had received 2–4 prior regimens (Rodriguez-Otero P, et al. N Engl J Med 2023).

Health-related quality of life captures information on the physical and mental health status of individuals, and on the impact of disease and treatment on a patient’s quality of life. The results from the patient-reported outcomes showed statistically significant and clinically meaningful improvements in health-related quality of life including cognitive functioning, fatigue, and pain reduction for patients with RRMM who received Abecma compared with standard treatment regimens. The authors noted that health-related quality of life improvements occurred earlier with Abecma therapy than with standard regimens, starting at approximately 2-3 months following infusion and were sustained for more than 2 years.

Minimum Residual Disease

A couple of abstracts evaluated the role of minimal residual disease (MRD) as a tool to measure the success of therapy.  MRD is an important topic in the field of multiple myeloma, in large part because we have very active treatment regimens that can bring deep and sustained responses to patients, something that was not possible just several years ago. Measuring MRD refers to counting the number of multiple myeloma cells that remain in a patient after a course of therapy is completed. For some patients, achieving MRD negativity (that is, no disease was detected after treatment) is associated with a significantly longer time before disease progression (progression-free survival [PFS]) and overall survival; however, to date, there has been limited information about its clinical meaning in patients treated with CAR T-cell therapy.

In the first presentation, (Abstract 94), Dr. Aintzane Zabaleta and colleagues from Spain found that achieving sustained MRD negativity resulted in significantly prolonged survival of RRMM patients treated with newer immunotherapies such as CAR T-cell therapy and bispecific antibodies (also known as T-cell engagers). The researchers reported that MRD negativity was associated with 88% reduction in the risk of progression and/or death. MRD negative rates were significantly higher in patients treated with CAR T-cell therapy (78%) than bispecific antibody therapy (35%).

In the next abstract, Nizar Bahlis, MD and colleagues from Canada reported (Abstract 338) that Venetoclax (Ven) combined with daratumumab (D) and dexamethasone (d) [VenDd] showed higher rates of MRD-negativity and sustained MRD-negativity compared to bortezomib plus Dd (DVd) in patients with t(11;14)-positive RRMM.

Venetoclax is a potent and selective oral BCL-2 inhibitor with demonstrated anti-myeloma activity in patients with t(11;14)-positive RRMM. The combination of VenDd has shown a high overall response rate and tolerable safety profile in the early phase study. The results in 81 patients showed:

The authors concluded that VenDd treatment showed higher rates of MRD-negativity and sustained MRD-negativity compared to DVd in patients with t(11;14)-positive RRMM.

Iberdomide Maintenance Therapy

Maintenance therapy with Revlimid (lenalidomide) is the standard of care following induction therapy and ASCT; however, all patients are at risk of relapse following transplantation, and up to 30% stop Revlimid maintenance therapy due to intolerable side effects. Thus, new treatment options with improved activity and tolerability are needed for maintenance therapy.

Iberdomide is a novel, potent oral cereblon E3 ligase modulator (CELMoD™), which is similar to but more potent than Revlimid, with a dual function: activate the immune system and directly kill myeloma cells by inducing the destruction of proteins that drive cancer growth.  Researchers from the Netherlands reported (Abstract 208) that iberdomide maintenance therapy following ASCT showed an improvement in response over time in patients who received IMiD/PI-based induction with or without anti-CD38 antibody therapy and ASCT.  Researchers noted that:

The most common serious side effects observed with iberdomide were low blood cell counts, infections, and fatigue.

The researchers conclude that iberdomide represents a novel effective post-ASCT maintenance strategy with a favorable safety profile and superior response improvement at 6 months than what has been observed with Revlimid maintenance. Iberdomide is currently being studied (versus Revlimid) as maintenance therapy following ASCT in a phase 3 trial.

Smoldering Multiple Myeloma

While observation is considered standard of care for smoldering multiple myeloma (SMM) patients who have been identified as having a high risk of progressing to active myeloma, therapeutic intervention at the SMM stage may help delay the progression to MM.

Dr. Ola Landgren, and colleagues from the University of Miami presented the final analysis of the phase 2 CENTAURUS study that showed Darzalex monotherapy demonstrated clinical activity in 123 patients with Intermediate-Risk or High-Risk SMM after a median follow-up of approximately 7 years (Abstract 210).

The researchers examined 3 different dosing schedules (that is, long intense; intermediate; short intense) to determine the optimal schedule of treatment administration for the phase 3 AQUILA study.  At a median follow up of 85 months, the study found:

The researchers conclude that this final analysis of CENTAURUS continue to demonstrate the clinical activity of DARA monotherapy in patients with intermediate- or high-risk SMM after a median follow-up of about 7 years, which supports the ongoing phase 3 AQUILA study and future SMM trials.