ASCO Michigan 2024: Take Home Messages in Multiple Myeloma with Dr. Hashmi
Presenter:
Dr Hamza Hashmi, Memorial Sloan Kettering Cancer Center
Conference:
ASCO Direct™ Michigan
The Bottom Line:
Five key clinical trials presented at this year’s American Society for Clinical Oncology (ASCO) Meeting focused on existing and emerging treatments for multiple myeloma (MM). Overall, the trials examined the efficacy of several new treatment regimens that led to deep treatment responses for MM patients, but some of which also lead to significant side effects, most notably neuropathy and ocular toxicities. The results of these trials, as assessed by oncologist Dr Hazma Hashmi, highlight the importance of balancing treatment benefits and patient safety for patients with MM.
Background:
Multiple myeloma (MM) is a cancer of blood (plasma) cells, and while it remains incurable, new treatments continue to emerge that can lead to durable, “deep” responses for patients, as evidenced by the endpoint of “minimal residual disease (MRD) negative” status, which, in turn can lead to improved survival and quality of life for patients with MM. At the ASCO 2024 Annual Meeting, clinical research was presented examining the efficacy of some of the existing and emerging therapies for MM. In his presentation at the ASCO Direct™ Michigan conference, Dr. Hamza Hashmi, MD, an Assistant Professor in the Myeloma and Cell Therapy Service at Memorial Sloan Kettering Cancer Center summarized findings from 5 abstracts on MM, highlighting take-home messages for clinicians and the potential implications of the research for current clinical practice. The five clinical trials discussed by Dr. Hashmi were all phase III, randomized, controlled trials which enrolled patients with either newly diagnosed (ND) MM who were ineligible for a stem cell transplant (transplant-ineligible) or MM that was relapsed or refractory to treatment (R/R).
IMROZ: Quadruplet Therapy Versus Triplet Therapy in Newly Diagnosed MM Patients Ineligible for a Transplant
The IMROZ trial compared a 4-drug (quadruplet) regimen of Isatuximab, Bortezomib (Velcade) with Lenalidomide and Dexamethasone (Isa-VRd) with the standard of care 3 drug (triple) regimen of bortezomib, lenalidomide and dexamethasone (VRd). Patients in the trial were ND, transplant ineligible, 30% were above age 75, most had good performance status and kidney function, and 20% of patients had high risk disease, which Dr Hashmi thought was overall very reflective the kind of patients seen in clinical practice. The addition of Isatuximab to VRd therapy significantly improved progression-free survival (PFS) over VRd (63.2% vs. 45.2%) and doubled MRD negativity rates (46.8% versus 24.3%). This benefit came, however, at the cost of more side effects such as neutropenia and infections, and peripheral sensory neuropathy, which Dr Hashmi thought was likely related to the dosing of bortezomib, noting, “We rarely give bortezomib [Velcade] twice weekly for this long in practice.” He also noted the trial was conducted in Europe, where stem cell transplant is not covered by insurance for patients over 65 years. By comparison, many patients over 65 would be considered fit for transplant in the US population with MM.
BENEFIT: Isatuximab With or Without Bortezomib For Newly Diagnosed Transplant-Ineligible MM Patients
The BENEFIT trial examined the impact of adding bortezomib, once weekly, to the Isa-Rd regimen, as part of the “induction phase” of treatment for ND, transplant-ineligible MM patients. Again, about 30% of patients in the trial were 75 or older, most were fit, and had good kidney function, and about 10% had high risk features. Results showed that MRD negativity rates at 18 months were significantly higher with Isa-VRd than VRd (53% vs. 23%; P<0.0001). While there was no significant difference yet in PFS or overall survival, Dr Hashmi expects this will likely be observed with longer follow up. In addition, because MRD negativity rates after 12 months (51% vs. 21%; P<0.0001) were essentially the same as at 18 months when comparing the 2 regimens, he questioned the need for continuing bortezomib beyond one year, noting: “I really question if there is any role of bortezomib beyond 12 months of therapy.”
DREAMM-7: Belantamab Mafodotin (Blenrep) for R/R MM
The DREAMM-7 trial examined the use of Belantamab Mafodotin (Blenrep), an antibody drug conjugate type therapy, in combination with bortezomib/dexamethasone (BVd) as compared with daratumumab-Vd (DVd) in patients with R/R MM, and Dr Hashmi noted that about 30% of patients in the trial were refractory to prior lenalidomide treatment. At 3-year follow up, there was a significant benefit in PFS for patients in the BVd group as compared with the DVd group (36.6% vs. 13.4%; P<0.00001), and there was a trend toward OS benefit as well with BVd. The principal toxicity associated with Blenrep was ocular toxicity, with approximately 30% of patients experiencing keratopathy, or vision impairment. Ocular toxicity was also a significant cause for dose reduction or discontinuation, with 70% requiring a dose delay, 50% requiring a dose reduction, and about 20% discontinuing the drug due to side effects. Notably, however, the ocular toxicity was reversible upon discontinuation of the drug. Commenting on the toxicity of Blenrep, Dr Hashmi noted: “This drug’s visual side effects may impact quality of life, making it less appealing, despite its efficacy.”
DREAMM-8: Blenrep with Pomolidamide Versus Bortezomib for Relapsed MM
In the DREAMM-8 study, Blenrep was used in combination with pomolidamide and dexamethasone (BPd) and compared to pomolidamide bortezomib, and dexamethasone (PVd) in patients with R/R MM. Trial design was similar to DREAMM-7 but lower doses of Blenrep, given less frequently, were used in an effort to reduce ocular toxicity. About 80% of the patient population were refractory to prior lenalidomide, and notably, about 20% were resistant to prior daratumumab. The 12 month PFS rate was significantly better with BPd versus PVd (71% vs. 51%; P<0.001) which Dr Hashmi thought was impressive for patients who were refractory to daratumumab. MRD negativity was also seen in 23.9% of patients in the BPd group versus 4.8% in the PVd group, and there was a trend toward OS benefit with BPd versus PVd. Dr Hashmi emphasized, “Even with a lower dose, Blenrep carries a risk of ocular toxicity…” and noted the safety findings from the trial, which showed that despite the reduced dosing schedule, about one-third of patients still experienced disabling (grade 3) vision problems.
CARTITUDE-4: CAR T-Cell Therapy for High-Risk MM
In the CARTITUDE-4 trial, CAR T-cell therapy with Ciltacabtagene autoleucel (Cilta-cel), a type of immune-directed therapy, significantly improved PFS (88%) and resulted in higher MRD negativity rates (>70%) when compared with standard of care treatment in a sub-analysis of patients with 1 prior line of therapy and functionally high risk MM, a subtype of MM patients which Dr Hashmi described as having “bad disease biology” features. Key adverse events such as cytokine release syndrome (CRS) in the trial were consistent with the known safety profile of Cilta-cel and were not enhanced in patients with functionally high risk MM, such as those relapsing within 18 months of a transplant or a frontline induction chemotherapy. Dr Hashmi thought that Cilta-cel should be a strong consideration for patients with functionally high risk R/R MM, as “CAR T-cell therapy can overcome the adverse biology of functionally high-risk myeloma”, although he noted that not every patient with first relapse needs Cilta-cel.
Conclusions and Faculty Insights:
Dr. Hashmi emphasized that while these new treatments show great promise for improving survival outcomes for patients with MM, it is essential to balance efficacy with patient safety. Adjustments to treatment regimens, such as limiting bortezomib dosing and extending treatment intervals for Blenrep may help to mitigate severe side effects. He also recommended using CAR T-cell therapy earlier in high-risk patients to control MM patients with aggressive disease and high risk biology.
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Speaker Disclosure:
Dr. Hashmi reported the following disclosures for this presentation: Advisory Board/Consultancy: Janssen, BMS, Karyopharm; Speaker Bureau: Karyopharm, Amgen.