Day 2 of ASH myeloma presentations brought us some updates on the use of FDA-approved treatments, including a closer look on the length of Revlimid maintenance therapy, and the clinical potential of a few investigational therapies for heavily pre-treated patients with myeloma.
There were two presentations that reported findings on patients’ quality of life following Darzalex-containing treatment regimens. Dr. Aurore Perrot and colleagues analyzed quality of life data collected from older (median age: 77 years) patients in the phase 3 MAIA trial, which showed the combination Darzalex-Revlimid-dexamethasone (D-Rd) improved progression-free survival (PFS) in older patients with newly diagnosed multiple myeloma (NDMM) who were not planning to have high-dose chemotherapy and a stem cell transplant vs Rd alone (Abstract 472).
Dr. Perrot reported that older patients treated with D-Rd showed sustained improvements in global health (overall health-related quality of life) and physical functioning, with notable reduction in pain through the duration of therapy. Additionally, a higher percentage of older patients continued on D-Rd longer compared to Rd.
In the next presentation, Dr. Silbermann and colleagues reviewed quality of life data obtained from transplant-eligible NDMM patients in the phase 2 GRIFFIN study which compared Darzalex-Revlimid-Velcade-dexamethasone (D-RVd) with RVd (Abstract 473). The authors found that the addition of Darzalex to RVd resulted in greater improvements in health-related quality of life for patients who continued on Revlimid maintenance treatment following induction and consolidation therapy versus RVd alone, again with a notable reduction in pain symptoms. Overall, these findings further support the addition of Darzalex to RVd in transplant-eligible patients with NDMM without compromise of health-related quality of life.
Pretreatment with Tocilizumab
Tocilizumab has proven to be an effective treatment to lessen the impact of cytokine release syndrome, a common side effect experienced by patients who receive either CAR-T or bispecific monoclonal antibody treatment. Preclinical trials suggest that tocilizumab could prevent the development of cytokine release syndrome without limiting the anti-myeloma activity of treatment. In this presentation, Dr. Suzanne Trudel and researchers shared their findings from a phase 1 study that examined whether a single dose of tocilizumab could reduce cytokine release syndrome in myeloma patients who receive the next-generation bispecific antibody, cevostamab (Abstract 567). The results showed that pretreatment with tocilizumab significantly lowered the percentage of patients who experienced cytokine release syndrome (39% with tocilizumab pretreatment versus 91% without pretreatment) without any impact on anti-myeloma activity. The researchers conclude that the data support additional investigation of the use of tocilizumab pretreatment with the goal of substantially reducing the severity of cytokine release syndrome and potentially enabling the outpatient administration of cevostamab and other bispecific antibodies, compared to current protocols, which call for administration in the hospital setting only.
Optimal Duration of Revlimid Maintenance
Revlimid maintenance after stem cell transplant is standard of care for myeloma patients; however, the optimal length of time of maintenance therapy remains uncertain and may differ in subgroups of patients. Dr. Charlotte Pawlyn and colleagues presented their analysis of data from the Myeloma XI trial which included NDMM patients who were intending to receive high-dose chemotherapy and those who were not (Abstract 570). Their analysis reported clear evidence that continuing Revlimid maintenance beyond 3 years is associated with improved progression free survival, or the time before the disease came back, supporting recent findings from the DETERMINATION and STAMINA studies. There does, however, appear to be a time after stem cell transplant at which continuing maintenance may no longer have ongoing benefit over observation. The current analysis suggests that between 4 and 5 years, the benefit diminished in all patients, and this may occur earlier in the subgroup of patients who were minimal residual disease negative after stem cell transplant. Ongoing long term follow up of this and other studies is needed to define the optimal time point of stopping or continuing maintenance.
Emerging Treatment for RRMM
Dr. Dan Vogl and colleagues reported the final safety and efficacy findings from a phase 1 study of Modakafusp alfa, a first-in-class antibody–cytokine fusion protein (immunocytokine), allowing specific delivery of IFN to myeloma cells and immune cells involved in destruction of myeloma cells (Abstract 565). This trial was composed of heavily pre-treated myeloma patients, as participants had received at least 3 prior lines of treatment (including a proteasome inhibitor and one immunomodulatory drug), with 7 median lines of therapy. The results obtained from 30 myeloma patients showed:
- 43% of all patients responded to 1.5 mg/kg modakafusp alfa
- 60% of patients who did not receive prior BCMA-directed therapy responded to 1.5 mg/kg modakafusp alfa
- Most common side effects were low platelet, red cell, and white blood cell counts
The authors conclude that modakafusp alfa has a novel mechanism of action, a manageable safety profile, and encouraging efficacy at 1.5 mg/kg with once-a-week dosing. A phase 2 study to better define the best dosing with the optimal benefit/risk profile is currently enrolling.
CELMoDs are a new class of myeloma drugs that work like immunomodulators such as Revlimid and Pomalyst. They also stimulate the immune system and kill myeloma cells directly, even for myeloma that has become resistant to certain treatment. Dr. Paul Richardson and colleagues presented their findings from a phase 1/2 trial evaluating mezigdomide (Abstract 568), an oral CELMoD, alone or in combination with dexamethasone in myeloma patients who had previously received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. The median number of previous treatment regimens was 6. The results showed:
- 41% of patients responded to treatment
- 50% of patients who received prior anti-BCMA therapy responded
- Most common side effects included low blood cell and platelet counts
The researchers concluded that mezigdomide + dexamethasone had a manageable safety profile and demonstrated promising efficacy in patients with RRMM, including those with prior BCMA-targeted treatment. Mezigdomide is currently being evaluated in combination with standard treatment regimens in MM as part of a large, ongoing phase 1/2 trial and phase 3 trials in combination with proteasome inhibitors are planned.
BMS-986354 is a next-generation CAR T-cell treatment that is made with a faster manufacturing process (about 5 or 6 days as opposed to several weeks with currently approved products). Dr. Luciano Costa and researchers reported their findings from the phase 1 CC-98633-MM-001 trial in patients who previously had received an autologous stem cell transplant, proteasome inhibitor, immunomodulatory drug, and an anti-CD38 monoclonal antibody – Darzalex or Sarclisa (Abstract 566). The results showed:
- 95% of patients responded to treatment
- 80% 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 CAR T-cell therapy)
- Other side effects included low white and red blood cell counts and low platelet counts
The study continues to enroll patients in the dose-expansion phase.
Stay tuned for more highlights from ASH!