Friday marked the second day of the 19th International Myeloma Society Annual Meeting in Los Angeles, California. Some of the studies presented today provided updates to data previously presented at meetings earlier this year and late last year. Updates from trials such as these give a sense of the durability of these treatments with longer follow-up. Let’s dig into a big day of updates in myeloma treatment.
Newly Diagnosed Multiple Myeloma
Maintenance treatment following autologous stem cell transplant (ASCT) for multiple myeloma remains a topic of active investigation. A prior study showed that extended post-ASCT maintenance treatment with Kyprolis, Revlimid, and dexamethasone (KRd) after KRd as first-line therapy improved the depth and duration of response. In this study,, Dr. Andrzej Jakubowiak from the University of Chicago and colleagues evaluated the difference between KRd and standard Revlimid (R) maintenance. Results showed:
- More patients treated with KRd achieved MRD negativity than patients who received R (47% vs 29%)
- Median PFS (the time before disease progression) was greater for patients treated with KRd than R (59 months vs 41 months)
The authors note that this is the first randomized phase 3 trial demonstrating superior PFS with extended post-transplant KRd therapy compared to R maintenance and may represent a new standard of care for some patients.
In the next presentation, French researchers evaluated the impact of treatment duration with Darzalex plus Revlimid and dexamethasone (D-Rd) and response on survival time and the time before disease progression in newly diagnosed multiple myeloma patients who were not eligible for stem cell transplantation. In this analysis, patients received D-Rd or Rd treatment for 18 months or longer.
Researchers found that D-Rd significantly prolonged survival and time until disease progression compared to Rd.. No new safety concerns were identified, and side effects with D-Rd generally decreased over time. Based on these results the authors recommend D-Rd treatment should be continued for at least 18 months to improve prolonged survival and time before disease progression. In Europe, maintenance therapy is often given for a fixed duration in contrast to the U.S where maintenance therapy is typically given until the myeloma returns.
Earlier this year at ASCO 2022, Dr. Paul Richardson at the Dana-Farber Cancer Institute presented findings from one of the most important studies to investigate the optimal timing of ASCT in newly diagnosed myeloma patients.
In this analysis, Dr. Paul Richardson and colleagues evaluated data from the study to assess the best timing of ASCT based on the presence of high-risk cytogenetics. Cytogenetic abnormalities are widely accepted markers for high risk of poor prognosis in patients with multiple myeloma, such as the presence of deletion of chromosome 17p (del[17p]), translocation of chromosomes 4 and 14 (t[4;14]), and translocation of chromosomes 14 and 16 (t[14;16]). To learn more about chromosomal abnormality terminology please see our recent FAQ blog here.
The results showed:
- In high-risk patients, PFS was significantly longer for patients who received RVd+ASCT compared to RVd alone (55.5 months vs 17.1 months)
- In standard-risk patients, PFS was significantly longer for patients who received RVd+ASCT compared to RVd alone (82.3 months vs 53.2 months)
These findings suggest that early transplant may be critical for patients with high-risk cytogenetics.
Relapsed/Refractory Multiple Myeloma
In this presentation, Dr. Paul Richardson and colleagues report the final overall survival analysis of the Phase 3 ICARIA-MM study which compared Sarclisa-Pomalyst-dexamethasone with Pomalyst-dexamethasone in patients with relapsed/refractory myeloma. The initial results from this trial were the basis for the approval of Sarclisa in combination with Pomalyst-dexamethasone. Sarclisa is in the same class of treatments as Darzalex.
The results of the final analysis showed an improvement in survival by 6.9 months and significantly improved the duration of clinical benefit (that is, time before another treatment is required). These findings support the use of Sarclisa-Pd as a standard-of-care therapy for patients with relapsed/refractory myeloma.
The next presentation European researchers reported updated, longer-term results from the phase 3 IKEMA, which investigated Sarclisa-Kd compared to Kd in relapsed myeloma patients who received 1-3 prior lines of therapy. The results showed:
- 44.1% of patents achieved a complete response with Sarclisa-Kd compared to 28.5% with Kd
- 33.5% of patents achieved MRD negativity with Sarclisa-Kd compared to 15.4% with Kd
Achieving MRD negativity led to better outcomes in both treatment arms, with Isa-Kd patients having a more than 2-fold higher likelihood of achieving MRD negativity. These results demonstrate the benefit of adding Sarclisa to Kd for the treatment of relapsed myeloma patients who received 1-3 prior lines of therapy.
CELMoDs are new class of drugs being developed in multiple myeloma that are related to, but functionally different from the immunomodulators like Revlimid and Pomalyst. For example, they stimulate the immune system and kill myeloma cells directly, even for myeloma that has become resistant to certain therapies.
In this presentation, Dr Paul Richardson presented results from a phase 1/2 study that assessed the safety, tolerability, and preliminary efficacy of mezigdomide plus standard treatments in patients with relapsed or refractory myeloma. Patients were randomized to receive either mezigdomide, Velacade, and dexamethasone (MeziVd) or mezigdomide, Kyprolis, and dexamethasone (MeziKd). Enrolled patients had previously received between 2 and 4 treatment regimens.
The results showed:
- The most common serious side effect experienced by patients who received mezigdomide, Velacade, and dexamethasone was low neutrophil counts
- Over 70% of patients responded to therapy with either MeziVd or MeziKd, suggesting synergy with proteasome inhibitors
The researchers concluded that that MeziVd and MeziKd demonstrated a manageable safety profile and promising efficacy in patients with RRMM. These results support further evaluation of these mezigdomide combinations in phase 3 studies.
B-Cell Maturation Antigen (BCMA)-Targeted Therapies
Blenrep (belantamab mafodotin)
Blenrep is a BCMA-targeting antibody–drug conjugate approved for patients with relapsed/refractory myeloma as monotherapy at 2.5 mg/kg once every three weeks. Preclinical data has shown there is an added benefit when Blenrep is combined with standard of care treatments. Researchers reported early results from a phase 1/2 study evaluating the safety, tolerability, and preliminary efficacy of Blenrep in combination with Kd in patients with relapsed/refractory myeloma after 1-3 prior lines of treatment.
The results from 19 patients showed that low platelet counts (30%) and blurred vision (20%) were the most frequent side effects. Of the 10 patients evaluated for efficacy, 9 achieved a response to therapy. The researchers conclude thatBlenrep combined with Kd has a safety profile that is in keeping with that expected for each individual drug, adding that recruitment is ongoing in an expansion phase based on the preliminary safety and efficacy results.
Dr. Naresh Bumma from The Ohio State University reported updated findings from a first-in-human, open-label phase 1/2 trial assessing the safety, tolerability, and preliminary efficacy of REGN5458, a BCMA- and CD3-directed bispecific antibody, in patients with relapsed/refractory multiple myeloma who were refractory, or intolerant to, two or more prior lines of systemic therapy, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody. The results showed:
- 75% of patients who received REGN5458 monotherapy (200 mg to 800 mg) achieved a response to therapy
- Fatigue was the most frequent side effect (45.2%)
- 38.4% of patients experienced cytokine release syndrome (which is a flu–like syndrome in which a patient experiences fevers, chills, and low blood pressure after administration of a bispecific antibody)
The researchers conclude that REGN5458 monotherapy shows a manageable safety and tolerability profile. The phase 2 portion of the study is currently recruiting.
Myeloma experts Dr. Ajay Nooka and Dr. Ravi Vij review they day’s highlights here.