Darlene Dobkowski, MA

Treatment with Venclexta (venetoclax), in addition to Velcade (bortezomib) and dexamethasone, significantly improved progression-free survival (PFS) in patients with 

 (MM) compared with placebo, according to results of the BELLINI trial published in 

Despite this significant improvement, researchers observed an higher mortality rate in patients treated with Venclexta compared with placebo, which may be due to an increased rate of infections.

“Multiple myeloma remains an incurable malignancy despite new therapies that have become available,” said Dr. Shaji Kumar, Mark and Judy Mullins Professor of Hematological Malignancies, consultant in the division of hematology and professor of medicine at Mayo Clinic, in an interview with 

“Given this, newer therapies that work through different mechanisms can make a significant impact on the outcomes of patients with this cancer. From that standpoint, venetoclax offers a new therapeutic approach for these patients.”

Kumar added that findings from this trial may also lead to new types of therapies and limiting them to patients with the most benefit. “The fact that we observed the activity primarily in the context of translocation t(11;14) (a genetic abnormality) also opens up the opportunity to develop a biomarker-guided therapy for this cancer,” said Kumar. “The increased risk of death observed in patients who did not have this translocation also enables us to limit the therapy to those patients who (have) the maximum benefit.”

Venclexta is an oral BCL-2 inhibitor that induces apoptosis, or programmed cell death, the study authors wrote. Results from a phase 1 trial previously showed that Venclexta with Velcade and dexamethasone was safe and tolerated in patients with relapsed or refractory MM.

In this current phase 3 trial, researchers assessed the efficacy and safety of this treatment in 291 patients (median age, 66 years; median time from diagnosis, 3.5 years) with relapsed or refractory MM. These patients previously received one to three lines of therapy and were either naïve or sensitive to proteasome inhibitors (ie, Velcade). In addition, patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, which indicates that a patient can at least walk and perform selfcare tasks, although work activities may be limited.

Patients were randomly assigned 800 mg of Venclexta orally once per day (194 patients; median age, 66 years; 50% men) or placebo (97 patients; median age, 65 years; 57% men). Both groups also received 1.3 mg/m2 of Velcade subcutaneously or intravenously and 20 mg of dexamethasone orally. The first eight cycles of the assigned treatment were given in 21-day cycles, which increased to 35-day cycles from the ninth cycle until unacceptable toxicity, disease progression or when a patient withdrew from the trial.

The primary endpoint for this trial was PFS based on assessment by an independent review committee, or a team not associated with the trial to potentially minimize bias. Study authors defined PFS as the time from randomization (when patients received their treatment assignment) to the first instance of disease progression or all-cause death. Researchers also analyzed safety in patients who received at least one dose of a drug assessed in this trial. Follow-up was conducted for a median of 18.7 months.

Disease progression or death occurred in 39% of patients in the Venclexta group vs. 56% of those in the placebo group during follow-up. The median PFS for patients assigned Venclexta was 22.4 months compared with 11.5 months in those assigned placebo.

The most common treatment-related adverse events, including severe events, observed in the Venclexta and placebo groups included pneumonia (16% vs. 9%, respectively); neutropenia, or a low number of white blood cells called neutrophils (18% vs. 7%, respectively); anemia, or a lack of healthy red blood cells (15% for both groups); thrombocytopenia, or a low level of platelets called thrombocytes (15% vs. 30%, respectively) and diarrhea (15% vs. 11%, respectively).

Serious adverse events related to the treatment occurred in 48% of 

 compared with 50% of those assigned placebo. This included 4% of patients in the Venclexta group with fatal infections compared with no fatal infections in the placebo group.

Three deaths in patients assigned Venclexta were related to the treatment, with two deaths related to pneumonia and one related to septic shock, or an infection that leads to dangerously low blood pressure levels and organ failure. In contrast, no deaths in patients assigned placebo were related to the treatment.

“Ongoing clinical trials are examining venetoclax and combination of this drug with other standard of care myeloma therapies in patients with translocation t(11;14),” said Kumar. “A better assessment of the efficacy and toxicity of this drug, especially when used in different combinations, will be critical to guide us in terms of its use in this patient population. We also need to understand the mechanisms of resistance that have been observed in other patients and in patients who initially responded, but subsequently had disease progression. These biological studies, in turn, will allow us to develop rational combinations in order to extend the benefits from this drug.”

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The phase 3 trial found that this treatment improves progression-free survival (PFS) during 18.7 months of follow-up, although patients treated with Venclexta (venetoclax) a had increased mortality rates compared with those treated with placebo.

Venclexta With Velcade and Dexamethasone May Improve Progression-Free Survival in Relapsed or Refractory Multiple Myeloma

Vitamin D supplements correlated with a reduced incidence of advanced cancer, especially in patients with normal weight, according to study results published in 

“These findings suggest that vitamin D may reduce the risk of developing advanced cancers,” said Dr. Paulette Chandler, assistant professor of medicine at Harvard Medical School and associate epidemiologist in the division of preventive medicine at Brigham and Women’s Hospital, in an interview with 

. “No other treatment or supplement has been identified that is associated with an over 15% reduction in advanced total cancer risk. Vitamin D is a supplement that’s readily available, cheap and has been used and studied for decades, and has a great safety profile.”

The VITAL trial compared the benefits and risks of vitamin D and marine omega-3 fatty acids — or fish oil — with placebo to prevent cancer and cardiovascular disease in 25,871 patients (mean age, 67.1 years; 51% women), which included men 50 years and older, and women 55 years and older. All patients did not have a history of cancer or cardiovascular disease upon enrolling in the trial. Given that this was a randomized-controlled trial, patients were randomly assigned vitamin D supplementation, omega-3 fatty acids, both agents or placebo.

The primary end point for this analysis was the rate of a composite, or combined, end point of metastatic and/or fatal cancer and the time from when a patient enrolled in the trial to a diagnosis of metastatic or fatal cancer. Researchers also monitored how body mass index (BMI) potentially modified the effect of vitamin D supplementation on developing metastatic or fatal cancer.

During a median intervention, or treatment, period of 5.3 years, 1,617 patients developed invasive cancer. A previous report from this trial noted that cancer incidence did not differ by treatment groups. Researchers found that patients assigned vitamin D had a significantly greater reduction in advanced cancers compared with those assigned placebo (1.7% vs. 2.1%).

Patients with normal BMI, defined as less than 25, who were assigned vitamin D had a significant reduction in incident metastatic or fatal cancer. This was not observed for overweight (BMI between 25 and 30) and obesity (BMI ≥ 30).

“A dynamic interplay between obesity, inflammation and immune system activation may contribute to the differential response to vitamin D3,” Chandler explained. “Vitamin D and immunity share an important connection because vitamin D receptors are on the surfaces of many cells in the immune system. Vitamin D may help bolster and regulate the immune system. Receptors are like a lock in a door that is opened with the right key. Opening the lock may start a cascade of actions that changes how a cell behaves.”

Chandler added that findings from this study may support further research into this specific area.

“Our findings, along with results from previous studies, support the ongoing evaluation of vitamin D supplementation for preventing metastatic cancer — a connection that is biologically plausible,” Chandler said. “Additional studies focusing on cancer patients and investigating the role of BMI are warranted. Vitamin D deficiency is common among cancer patients, with one study reporting rates of vitamin D deficiency as high as 72% among cancer patients. There is also evidence that higher amounts of body fat are associated with increased risk for several cancers.”

The reduced incidence in developing advanced cancer in patients at least 50 years and older was more prominent in those with normal weight vs. overweight or obesity.

Vitamin D May Reduce Risk for Developing Advanced Cancer

CAR-T cell therapy with Kymriah (tisagenlecleucel) safely and effectively treated children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL), in addition to adults with non-Hodgkin lymphoma (NHL), according to study findings published in 

“Although median follow-up is shorter in the [post-market requirement] study compared with the pivotal trials, there now exists substantial experience in the short-term follow-up 

safety and efficacy outcomes of tisagenlecleucel

Study authors assessed data from 511 patients from 73 centers from the post-market requirement study, of whom 410 had available follow-up data. Patients were either children or young adults with relapsed or refractory ALL (255 patients; median age at infusion, 13.2 years; 58.8% men) or adults with NHL (155 patients; median age at infusion, 65.4 years; 53.5% men), all of whom were treated with Kymriah.

Several outcomes were included in this study such as the incidence and severity of cytokine release syndrome, or the release of small proteins from immune cells into the blood which may result from 

. Duration of response was defined as the period between the date of first complete or partial remission to relapse, progression or death. Event-free survival in patients with ALL was the time between Kymriah infusion to all-cause death, treatment failure or relapse. Progression-free survival (PFS) in patients with NHL was defined as the time from Kymriah infusion to all-cause death or disease progression. Overall survival (OS) was considered the time between the Kymriah infusion and all-cause death. Follow-up was conducted for a median of 13.4 months in patients with ALL and 11.9 months in those with NHL.

The complete remission rate for patients with ALL was 85.5%. For 12 months, patients with ALL had a duration of response of 60.9%, event-free survival of 52.4% and OS of 77.2%.

In patients with NHL, the best overall response rate was 61.8%, which included an initial complete remission rate of 39.5%. Duration of response during a six-month period was 55.3%. In addition, patients with NHL had a PFS rate of 38.7% and an OS rate of 70.7%.

Cytokine release syndrome of grade 3 or more, which requires supportive care and Actemra (tocilizumab) either with or without corticosteroids, occurred in 11.6% of all patients. Neurotoxicity, or damage to the peripheral nervous system or the brain, was reported in 7.5% of all patients.

Safety and efficacy observed in this real-world study for patients with non-Hodgkin lymphoma similarly reflect findings from previous pivotal trials.

Kymriah Safely Treats ALL and NHL in Real-World Setting

Treatment with Poteligeo (mogamulizumab) resulted in clinically meaningful antitumor activity in patients with adult T-cell leukemia/lymphoma, according to results from the MIMOGA study published in 

The study also found that a patient’s immune system status before initiating Poteligeo, a targeted drug known as a monoclonal antibody, was significantly associated with treatment outcome.

In this prospective observational study, study authors enrolled 101 patients (mean age, 69 years; 42% women) with adult T-cell 

 who were not previously treated with Poteligeo. All patients were treated with Poteligeo and underwent immune monitoring before, during and after treatment.

The primary goal of this study was to clarify the immune dynamics of lymphocyte subsets in blood after treatment with Poteligeo. This included regulatory T cells, which regulate or suppress foreign cells within the immune system, contributing to immune response. A secondary goal included identifying molecular and immunological mechanisms that determine the efficacy of treatment or the occurrence of side effects.

Upon enrollment, study authors observed a significant inverse correlation, or a negative relationship, between serum soluble interleukin-2 receptor levels, which are associated with immune system activation, and the percentage of Tax-specific cytotoxic T lymphocytes, or cells within the immune system that can potentially kill other cells. This was not observed with cytomegalovirus pp65-specific cytotoxic T lymphocytes, which can protect the body from infection.

Treatment with Poteligeo resulted in an overall response rate, meaning all partial and complete responses, of 65%. In addition, patients had a median progression-free survival, meaning the time from the start of treatment until disease worsened, of 7.4 months and an overall survival (OS), meaning the time from the start of treatment until death, of 16 months. Patients with a higher percentage of Tax-specific cytotoxic T lymphocytes were more likely to have longer survival. This was not seen with cytomegalovirus pp65-specific cytotoxic T lymphocytes.

Several factors were considered significant independent unfavorable prognostic factors for OS, including higher soluble interleukin-2 receptor levels, clinical subtype (either acute or lymphoma type) and a lower percentage of particular B cells — CD2-CD19+ — within peripheral blood mononuclear cells, or cells that deliver responses to the 

. This may signify that patients with more B cells have somewhat of a favorable immune status, which may lead to better outcomes with this particular treatment.

“On the basis of the present study focusing on the patients’ immunological status before mogamulizumab and its influence on outcome, further time series analysis, in addition to comprehensive genomic analysis, is warranted to establish predictive markers for treatment success and to better understand the mechanisms of action of mogamulizumab,” the study authors wrote.

Study results also determined that immune system status before treatment may predict outcomes post-treatment.

Darlene Dobkowski, MA | Contributors

Venclexta With Velcade and Dexamethasone May Improve Progression-Free Survival in Relapsed or Refractory Multiple Myeloma

Vitamin D May Reduce Risk for Developing Advanced Cancer

Kymriah Safely Treats ALL and NHL in Real-World Setting

Poteligeo May Result in Antitumor Activity in Adult T-Cell Leukemia/Lymphoma

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