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. 

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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

Articles

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

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

Dr. Baz on Selinexor in Multiple Myeloma

Dr. Baz on Varying Treatment Approaches for Patients With Multiple Myeloma