Andrew J. Cowan, MD, an assistant professor of medicine at University of Washington School of Medicine, and hematologist/oncologist at Seattle Cancer Care Alliance, discusses efficacy and safety of BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma.

A phase I study has treated a total of 7 patients thus far; these patients have been heavily pretreated with a median of 10 prior regimens. Approximately 75% of patients had a high-risk feature at the time of study entry. One patient died at day 33 post-CAR T-cell therapy due to cytokine release syndrome (CRS) and concurrent fungal infection, says Cowman. After that incident, the protocol was modified and no additional dose-limiting toxicities have been observed since then. The most common grade ≥3 adverse events observed with the treatment were neutropenic fever (70%), CRS (100%), and neurotoxicity (70%).

An 100% overall response rate was observed with the therapy with no relapses. The median follow-up is 20 weeks, but the patient currently with the longest- follow-up has shown no evidence of disease for ≥1 year, concludes Cowan. However, longer follow-up and of more patients are needed to determine if the durability of response is improved in patients treated with BCMA CAR T-cell therapy.

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Andrew J. Cowan, MD, discusses efficacy and safety of BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma.
 

Dr. Cowan on Efficacy and Safety of BCMA CAR T-Cells in Multiple Myeloma

Andrew J. Cowan, MD, an assistant professor of medicine at University of Washington School of Medicine, and hematologist/oncologist at Seattle Cancer Care Alliance, discusses the future of selinexor (Xpovio) in multiple myeloma.

In February 2018, the FDA Oncologic Drugs Advisory Committee (ODAC) voted 8 to 5 against the accelerated approval of the new drug application (NDA) for selinexor. The committee decided to delay the decision which would have been based on data from the phase II STORM trial in anticipation of data from the phase III BOSTON trial. Initially, the agent had shown an objective response rate of 26% in heavily pretreated patients, many of whom were refractory, says Cowan.

On July 3 2019, the FDA granted an accelerated approval to selinexor for use in combination with dexamethasone for adult patients with relapsed/refractory multiple myeloma who have received ≥4 prior therapies and whose disease is refractory to ≥2 proteasome inhibitors, ≥2 immunomodulatory agents, and a CD38-targeted monoclonal antibody. Its full approval is contingent on results of the BOSTON trial, which is evaluating the addition of selinexor to bortezomib (Velcade) and low-dose dexamethasone versus bortezomib/low-dose dexamethasone alone in patients with relapsed/refractory disease who have received 1 to 3 prior regimens.

Although the agent appears to have limited activity as a single agent, it has shown signals of activity when used in combination with dexamethasone, explains Cowan. The results of the phase III trial will help to further establish its role in the disease.

Dr. Cowan on the Future of Selinexor in Multiple Myeloma

Andrew J. Cowan, MD, an assistant professor of medicine at University of Washington and hematologist/oncologist at Seattle Cancer Care Alliance, discusses the role of venetoclax (Venclexta) in multiple myeloma.

The oral BCL-2 inhibitor has shown a lot of promise in the treatment of patients with multiple myeloma. Data from the 2017 ASH Annual Meeting showed a 40% overall response rate (ORR) for patients who harbored t(11;14) by fluorescence in situ hybridization. This led to further studies such as the phase III BELLINI trial, in which patients with relapsed multiple myeloma were randomized to receive venetoclax with bortezomib/dexamethasone or bortezomib/dexamethasone alone. Notably, t(11;14) did not serve as an exclusion criteria in the trial. In early 2019, the study was halted due to an increased risk of death observed in patients who received venetoclax.

Despite these safety concerns, venetoclax has the potential to play an important role for patients with relapsed multiple myeloma, especially in those with t(11;14), says Cowan. Given the fact that these patients did not have a substantial increase of death, the use of venetoclax in myeloma may be contingent on a biomarker-driven approach with t(11;14).

Cowan has treated several patients with venetoclax. Most recently, a patient with t(11;14) and plasma cell leukemia who hadn't responded to anything, responded well to venetoclax. Moving forward, it will be important to understand the cause of the increased toxicity in the overall population receiving venetoclax before it can be definitively said that venetoclax doesn't have a role in myeloma.

Dr. Cowan on the Role of Venetoclax in Multiple Myeloma

Andrew J. Cowan, MD, an assistant professor of medicine at University of Washington School of Medicine and hematologist/oncologist at Seattle Cancer Care Alliance, discusses patient eligibility criteria for transplant in multiple myeloma.

There is no reason to be dogmatic about who is transplant-eligible and -ineligible, says Cowan; there are many factors that must be considered. For example, frailty and comorbidities are important. Age is another potential factor to consider, but older patients may be able to tolerate transplant just as well as younger patients. Although age should not be the sole determinant for transplant eligibility, most patients do develop comorbidities as they age that would, in general, limit their ability to undergo transplant, explains Cowan.

Patient preference is also important to consider. Some patients may not be interested in a transplant. Thorough discussions should be had before a decision is reached as several data sets have shown an improvement in progression-free survival with the use of a transplant by about 14 months. Although it is not a cure for multiple myeloma, transplant does confer a survival benefit.

Dr. Cowan on Patient Eligibility Criteria for Transplant in Multiple Myeloma

Andrew J. Cowan, MD, an assistant professor of medicine at University of Washington School of Medicine and hematologist/oncologist at Seattle Cancer Care Alliance, discusses treatment strategies for patients with transplant-eligible and -ineligible multiple myeloma.

Apart from whether or not a patient is transplant-eligible or not, treatment strategies do not differ dramatically, says Cowan. Three-drug regimens are increasingly becoming the mainstay of treatment for patients, whether they are eligible for transplant or not. However, frailer patients or those who have advanced-stage disease may be better suited to receive doublets such as lenalidomide (Revlimid) and dexamethasone or bortezomib (Velcade) and dexamethasone, says Cowan.

Clinicians do not have to be dogmatic about approaches, adds Cowan. Now, clinicians have data from the phase III MAIA trial. The results were presented at the 2018 ASH Annual Meeting and subsequently published. In the trial, patients with transplant-ineligible disease were randomized to receive daratumumab (Darzalex), a CD38-directed monoclonal antibody, lenalidomide and dexamethasone, or lenalidomide and dexamethasone alone. The results demonstrated that patients who received the triplet were 45% less likely to progress versus those who received the doublet. Notably, daratumumab does not cause a lot of neuropathy, making it a good option for patients who are frailer.

Andrew J. Cowan, MD

Articles

Dr. Cowan on Efficacy and Safety of BCMA CAR T-Cells in Multiple Myeloma

Dr. Cowan on the Future of Selinexor in Multiple Myeloma

Dr. Cowan on the Role of Venetoclax in Multiple Myeloma

Dr. Cowan on Patient Eligibility Criteria for Transplant in Multiple Myeloma

Dr. Cowan on Treatment Strategies in Transplant Eligible- and -Ineligible Myeloma