Dr Baz on AE Management Discussions in Multiple Myeloma

Rachid Baz, MD, section head, Myeloma, Department of Malignant Hematology, Moffitt Cancer Center; co-director, Pentecost Family Myeloma Research Center, discusses the importance of educating patients with multiple myeloma about potential adverse effects (AEs) they may experience during treatment and highlights potential future directions for research and treatment in this disease.

When discussing treatment options with patients with multiple myeloma, oncologists should consider both the short-term and long-term AEs that patients may experience, and educate patients about each of these anticipated toxicities, Baz says. If patients and their care teams are better prepared to anticipate, recognize, and manage treatment-related toxicities, the management of their disease will be improved, Baz emphasizes.

The multiple myeloma treatment paradigm is at a point of potential expansion, Baz notes. Several novel therapies have become standard treatment options for patients with relapsed/refractory disease, Baz explains. For instance, the CAR T-cell therapy 

idecabtagene vicleucel (Abecma) was FDA approved

 in 2021 for patients with relapsed/refractory multiple myeloma who have received at least 4 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. Ciltacabtagene autoleucel (Carvykti), another CAR T-cell therapy, 

 in 2022. Bispecific antibodies have also entered the scene for patients with this disease. 

Teclistamab-cqyv (Tecvayli) received FDA approval

 in 2022 for patients with disease that is relapsed/refractory to 4 or more prior lines of therapy. Additionally, 

 were both FDA approved in August 2023 for this indication.

Between CAR T-cell therapies and bispecific antibodies, oncologists need to better define treatment sequencing and decision-making strategies so patients can experience the best outcomes from each of these therapies, according to Baz. Over the next few years, further research may elucidate the optimal use of therapies already in use today for patients with multiple myeloma, Baz concludes.

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Rachid Baz, MD, discusses the importance of educating patients about potential adverse effects associated with multiple myeloma treatments.

Dr Baz on the Incidence of AEs With Ide-Cel in Triple-Class–Exposed Multiple Myeloma

Rachid Baz, MD, section head, Myeloma, Department of Malignant Hematology, Moffitt Cancer Center; co-director, Pentecost Family Myeloma Research Center, discusses the incidence of cytopenias and infections in patients with multiple myeloma enrolled in the phase 3 KarMMa-3 trial (NCT03651128).

The KarMMa-3 trial evaluated the BCMA-directed CAR T-cell therapy idecabtagene vicleucel (ide-cel; Abecma) vs standard of care (SOC) in patients with triple-class–exposed relapsed/refractory multiple myeloma.

This adverse effect (AE) analysis found that the rate of grade 3/4 cytopenias was higher among patients who received ide-cel than those who received a SOC regimen, Baz says. However, the incidence of cytopenias in this population was time-limited and largely restricted to the first 3 months of treatment. After this time point, the rates of cytopenia decreased and this AE became more manageable, Baz emphasizes. Compared with findings from earlier studies investigating standard treatment regimens in multiple myeloma, KarMMa-3 did not demonstrate higher rates of cytopenias with ide-cel in this population, Baz highlights. For instance, patients with relapsed/refractory multiple myeloma who received ide-cel in the phase 2 KarMMa-1 trial (NCT03361748) experienced rates of cytopenias that were comparable to those observed in the ide-cel arm of KarMMa-3, Baz explains.

Hematologists are typically comfortable with managing cytopenias in patients with multiple myeloma who receive CAR T-cell therapy, and often use growth factor support or transfusion support when necessary, according to Baz. Rarely will patients require additional support measures, such as a stem cell boost, after receiving CAR T-cell therapy, Baz emphasizes.

Additionally, the overall incidence of grade 3/4 infections was high in both arms and remained consistent over time. Any-gradebacterial infections in the KarMMa-3 AE analysis were more common in the first 3 months after infusion, Baz explains. However, beyond the first 3 months, the infection rates were comparable to those observed in multiple myeloma populations receiving other therapies, Baz concludes.

Rachid Baz, MD, discusses findings from an analysis of cytopenias and infections in patients with multiple myeloma enrolled in the KarMMa-3 trial.

Dr Baz on the Background of the KarMMa-3 Trial in Relapsed/Refractory Multiple Myeloma

Rachid Baz, MD, hematologist, medical oncologist, head, Myeloma Section, the Department of Malignant Hematology, codirector, the Pentecost Family Myeloma Research Center, Moffitt Cancer Center, discusses the use of idecabtagene vicleucel (ide-cel; Abecma) vs standard regimens in patients with triple-class–exposed, relapsed/refractory multiple myeloma, highlighting an analysis of cytopenias and infections in patients from the phase 3 KarMMa-3 trial (NCT03651128).

The KarMMa-3 trial assessed ide-cel, a CAR T-cell product, in patients with advanced multiple myeloma, for which limited treatment options exist, Baz begins. The preceding phase 2 KarMMa study (NCT03361748) indicated a high response rate and significant progression-free survival benefits for patients with relapsed/refractory multiple myeloma who received ide-cel, particularly those who had received a median of 5 or 6 prior lines of treatment, Baz explains.

Within patients enrolled in the KarMMa-3 trial, most severe cytopenias linked to ide-cel manifested early, and there was minimal occurrence of prolonged cytopenias, most of which were manageable. The prevalence of bacterial infections decreased over time, although the incidence of viral infections exhibited a stable pattern. Notably, no novel safety concerns arose with the use of ide-cel in this trial, and its safety profile remained consistent with earlier reports.

With response rates reaching 81% in patients in KarMMa who received ide-cel at the target dose of 450×106 CAR+ T cells, the question arose whether this treatment could be administered earlier in the disease course, he expands. This prompted KarMMa-3, which randomly assigned patients who had received 2 to 4 prior lines of treatment 2:1 to receive ide-cel or 1 of 5 commonly used chemotherapy regimens, Baz states. There was no crossover option for patients progressing on standard chemotherapy regimens, he elucidates.

Eligible patients needed to have triple-class-exposed disease, meaning prior exposure to lenalidomide or an immunomodulatory drug; prior exposure to carfilzomib (Kyprolis), bortezomib (Velcade), or a proteasome inhibitor; and prior exposure to CD-38 antibodies, Bazcontinues. The primary adverse effect observed with ide-cel was cytokine release syndrome, accompanied by cytopenias and infection risks. To provide a comprehensive understanding, investigators compared these safety findings with those in patients receiving other myeloma therapies after 2 to 4 prior lines of therapy, he concludes.

Rachid Baz, MD, discusses the use of idecabtagene vicleucel vs standard regimens in triple-class–exposed, relapsed/refractory multiple myeloma.

Rachid Baz, MD, hematologist and medical oncologist, myeloma section head in the Department of Malignant Hematology at Moffitt Cancer Center, director of clinical research in the Malignant Hematology Department, discusses the role of alkylating agents in relapsed/refractory multiple myeloma.

Alkylating agents have been available for use in patients with relapsed/refractory multiple myeloma for some time, Baz explains. Many patients who require fourth- or later-line treatment have not been exposed to these agents, so alkylating agents, such as cyclophosphamide, melphalan (Evomela), and melphalan flufenamide (melflufen; Pepaxto) have a role in the heavily pretreated population.

Melflufen was granted FDA approval in February 2021 for use in combination with dexamethasone in patients with relapsed/refractory multiple who have received at least 4 prior lines of therapy, including at least a proteasome inhibitor, an immunomodulatory agent, and a CD38-directed monoclonal antibody. The agent is delivered by leveraging aminopeptidases, which are highly expressed in myeloma cells. In turn, melflufen is more targeted compared with conventional alkylating agents, Baz adds. 

However, it is critical to mitigate the cytopenia and myelosuppression that often arises with melflufen, Baz says. Although melflufen can be considered in patients who are refractory to 1 alkylating agent, it should be avoided in patients who have progressed on 2 or more alkylating agents because data suggest these patients have a very low response rate with the agent, Baz concludes. 

Rachid Baz, MD, discusses the role of alkylating agents in relapsed/refractory multiple myeloma. 



Dr. Baz on the Role of Alkylating Agents in Relapsed/Refractory Multiple Myeloma 

Rachid Baz, MD, hematologist and medical oncologist, myeloma section head in the Department of Malignant Hematology at Moffitt Cancer Center, director of clinical research in the Malignant Hematology Department, discusses the utility of venetoclax (Venclexta) in patients with heavily pretreated multiple myeloma.

Venetoclax is often utilized in those with t(11;14) disease, which accounts for approximately 15% of all patients with multiple myeloma, according to Baz. Additionally, venetoclax is starting to be utilized in earlier treatment settings for this patient population, given the immense benefit that has been observed, Baz says. 

Data presented on the use of venetoclax plus daratumumab (Darzalex) earlier on in the disease showed that the doublet resulted in response rates that were over 90%. Moreover, many patients achieved minimal residual disease negativity, Baz adds. If a patient with t(11;14) disease has a late relapse, venetoclax would be recommended, as long as they had not been previously treated with the drug, Baz explains. However, many patients in the United States may have already received venetoclax and are unlikely to have gotten to the third-or fourth line of treatment without having received the agent, Baz concludes. 

Rachid Baz, MD, discusses the utility of venetoclax in patients with heavily pretreated multiple myeloma.

Dr. Baz on the Utility of Venetoclax in Heavily Pretreated Multiple Myeloma

Rachid Baz, MD, associate member, head of the Myeloma Section at Moffitt Cancer Center, discusses the potential use of selinexor (KPT-330) in patients with multiple myeloma.

Physicians at Moffitt Cancer Center have had selinexor in the clinical trial setting for the past 4 to 5 years—since the first phase I trial in hematologic malignancies, says Baz. The agent has demonstrated activity in patients who have penta-refractory disease, though it may be worthwhile to study in combination, explains Baz.

If it was used in combination, it could be given on a once-weekly schedule. Investigational combinations include those with bortezomib (Velcade), carfilzomib (Kyprolis), and lenalidomide (Revlimid), all of which have demonstrated high response rates so far, states Baz. Teasing out where those combinations will fall will be important, explains Baz. It is unlikely that selinexor will be used in combination with dexamethasone.

In July 2018, Karyopharm Therapeutics, the manufacturer of the XPO1 inhibitor, submitted a new drug application to the FDA for the treatment of patients with penta-refractory multiple myeloma.

Dr. Baz on Selinexor in Multiple Myeloma

Rachid Baz, MD, hematologist and medical oncologist, Moffitt Cancer Center, discusses how treatment approaches vary for patients with multiple myeloma.

Historically, physicians tried to avoid alkylating agents for patients who were eligible for transplant, Baz explains. Now, when considering treatments for elderly patients, the determinant outcome of these patients turns out to be based on fitness or frailty. For patients considered to be frail, a doublet regimen of lenalidomide (Revlimid)/dexamethasone that is dose-adjusted, or a subcutaneous injection of weekly bortezomib (Velcade) and dexamethasone could be choices.

For patients of intermediate fitness, a reasonable treatment would be bortezomib, lenalidomide, and dexamethasone. Emerging, ongoing clinical trials are challenging that data for the future.

Rachid Baz, MD

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