Welcome to the second day of our recap of the latest findings on myeloma treatments reported at the American Society of Clinical Oncology (ASCO) meeting. Monday featured updates on treatment options for newly diagnosed multiple myeloma (NDMM) patients, including quadruplet therapies, CAR T-cell therapy, and bispecific antibody therapy. Let us break down the key findings for you…
While three-drug induction regimens (that is, those containing a proteasome inhibitor such as Velcade or Kyprolis, an immunomodulatory agent – typically Revlimid, and dexamethasone) were once standard for NDMM, recent clinical trials have shown a clear benefit to adding an anti-CD38 monoclonal antibody such as Darzalex (daratumumab) as first-line therapy for myeloma patients, particularly prior to stem cell transplant.
In the first abstract (Abstract: 7500), researchers from France reported that Sarclisa (isatuximab) is the first anti-CD38 monoclonal antibody to significantly improve progression-free survival (PFS)—that is, the length of time during and after treatment in which a patient is living with a disease that does not get worse— in combination with VRd for newly diagnosed patients who were ineligible for a stem cell transplant.
Findings from the phase 3 IMROZ trial showed Sarclisa in combination with Velcade (bortezomib), Revlimid (lenalidomide), and dexamethasone (Isa-VRd) followed by Sarclisa-Rd reduced the risk of recurrence or death by 40% versus VRd followed by Rd. The safety profile was consistent with previous studies of the combination of Isa-VRd. Further details of the study of 446 patients were simultaneously published in the New England Journal of Medicine (Facon T, NEJM 2024).
The second abstract (Abstract: 7501) that reported updates from the phase 3 BENEFIT study of Isa-VRd versus IsaRd in patients aged 65-79 years with NDMM who were determined to be ineligible for a stem cell transplant. Researchers from France evaluated the prolonged use of bortezomib for 18 months with reduced intensity weekly schedule versus IsaRd.
Results showed that Isa-VRd significantly increased the minimal residual disease (MRD) negativity—that is no disease was detected after treatment—to 53% compared to 26% of patients who were treated with IsaRd. This benefit was observed as early as 12 months and was consistent across various subgroups, including those with high-risk cytogenetics or stage III disease. These trial findings were simultaneously published in Nature Medicine (Leleu X, Nat Med 2024).
Findings from both of these studies further support the use of Isa-VRd as a new standard of care for patients with NDMM.
In the next abstract (Abstract: 7502), researchers from Spain reported updated results from the Phase 3 PERSEUS study that showed the anti-CD38 monoclonal antibody Darzalex (daratumumab) in combination with Velcade (bortezomib), Revlimid (lenalidomide), and dexamethasone (D-VRd), followed by a maintenance regimen of subcutaneous Darzalex plus Revlimid (D-R) demonstrated superior PFS and increased depth of response compared to VRd induction and R maintenance in newly diagnosed patients.
The recent analysis showed deeper responses and higher rates of MRD over time in 355 patients treated with D-VRd + D-R compared to 354 patients treated with VRd + R.
The researchers reported that the rates of deep and sustained MRD negativity were associated with improved progression-free survival (PFS)—that is, the length of time during and after treatment in which a patient is living with a disease that does not get worse— with Darzalex-based quadruplet regimen in these patients.
Results from the primary analysis of the PERSEUS study were published earlier this year in The New England Journal of Medicine (Sonneveld P, 2024).
The authors concluded that these data further support D-VRd and D-R maintenance as a new standard of care for newly diagnosed patients.
The first abstract (Abstract: 7505) highlighted findings from an analysis of the CARTITUDE-2 study that evaluated Carvykti with or without Revlimid maintenance in patients who achieved less than CR after transplant ASCT and frontline therapy.
Researchers from France noted that a single infusion of Carvykti with or without Revlimid maintenance demonstrated deep and durable responses. Of the 17 patients treated with Carvykti 94% achieved an ORR, with 94% also achieving a CR or better. The safety profile was similar to prior trials of Carvykti with or without Revlimid maintenance. After 22 months median follow up, most common side effects were low white blood cell counts, cytokine release syndrome (CRS) or flu-like symptoms, neurotoxicity, and infections.
Further studies, with a median follow up greater than 2 years, will continue to examine the potential role of CAR T-cell therapy in frontline treatment of patients.
In the next abstract, Dr Luciano Costa and colleagues reported Abstract: 7504 that Carvykti as second-line therapy significantly improved PFS and deepened responses versus two standard therapies for patients with functional high-risk multiple myeloma—that is patients whose disease progressed either after the start of frontline treatment or 18 months following a transplant. This patient population is known to have poor prognosis, and yet has not been well represented in prior clinical trials.
Patients treated with Carvykti compared to the standard of care [that is, either Pomalyst (P) + Vd or Dara-Pd until disease progression] had higher overall response rates (90% vs 79%), complete response or better (71% vs 35%), and MRD negativity (63% vs 19%). Researchers noted that similar results were observed in functional high-risk patients.
CRS and neurotoxicity with Carvykti was comparable among other clinical trials of patients who received Carvykti versus standard therapies as second-line treatment. The researchers conclude that Carvykti could benefit patients with functional high-risk multiple myeloma.
Tecvayli is the first “off-the shelf” BCMA-targeted bispecific antibody approved for patients with heavily pretreated RRMM. In this abstract (Abstract: 7506), French researchers presented the first results of a single-arm (that is, no treatment comparison group) from the phase 3 MajesTEC-7 study that evaluated Tecvayli in combination with Darzalex and Revlimid (Tec-DR) in NDMM patients who were deemed ineligible for stem cell transplant. The authors reported an overall response rate for Tec-DR was 92%, with 73% achieving a very good partial response or better. Infections (96%) and CRS (62%) or flu-like symptoms, were the most common side effects reported—all of which resolved, according to the authors.
We look forward to additional data from this and other clinical trials investigating Tecvayli-containing regimens in the upfront treatment setting.
Currently, DRd or VRd are considered standard treatment options for NDMM patients who were deemed ineligible for stem cell transplant. However, many elderly (that is, adults 70 years or more) or frail patients do not respond to upfront therapy and new treatment options with improved activity are needed.
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. In prior trials, iberdomide has demonstrated promising activity in MM patients refractory to Revlimid or Pomalyst.
In the final abstract (Abstract 7507), researchers from France presented their findings on an all-oral triplet iberdomide, Ninlaro (ixazomib), a proteasome inhibitor, and dexamethasone in elderly patients with myeloma after 1 prior line of therapy.
The researchers found that overall response rate was 65% and 52% did not experience disease progression one year after treatment with the all-oral regimen. Response rates and PFS were maintained in frail patients and those who were refractory to DRd or VRd. Most common side effects were low white blood cell counts, infections, and numbness or tingling in hands, arms, or feet.
Additional studies will continue to examine the potential role of an all-oral triplet regimen of iberdomide, Ninlaro, and dexamethasone in elderly or frail patients with myeloma after 1 prior line of therapy.
Be sure to tune in tomorrow for our final recap of clinical trial data presented at the annual ASCO meeting.
