New drugs show remarkable improvements over standard care for multiple myeloma and chronic lymphocytic leukemia according to research presented during a late breaking clinical trial session at the 59^th American Society of Hematology (ASH) Annual Meeting and Exposition.

The first randomized trial to evaluate the use of a monoclonal antibody drug for treating newly diagnosed multiple myeloma [LBA-4] shows that adding the drug, daratumumab, to one of the standard treatment regimens reduced the likelihood of disease progression or death by 50 percent. The regimen also induced significantly deeper response and higher rates of negative minimal residual disease (MRD). The Phase III trial, conducted in patients who were not eligible for a stem cell transplant, suggests daratumumab is a beneficial addition to one of the current first-line therapies for these patients.  

Maria-Victoria Mateos, MD, PhD, of the University Hospital of Salamanca–Instituto deInvestigación Biomédica de Salamanca, Salamanca, Spain presented the results of this research.

Stem cell transplantation is used as intensification therapy in young patients with multiple myeloma. For people who cannot receive a stem cell transplant, one standard treatment involves two chemotherapy drugs, bortezomib and melphalan, together with the steroid prednisone. Daratumumab is a newer drug designed to directly target tumors while also equipping a patient's own immune cells to attack the cancer cells. It is approved for patients whose myeloma has relapsed after an initial course of treatment.

"Our results support that daratumumab in combination with bortezomib, melphalan, and prednisone should become a new standard of care in transplant-ineligible multiple myeloma patients," said senior study author Jesus F. San-Miguel, MD, Medical Director of the Clínica Universidad de Navarra in Pamplona, Spain. "Monoclonal antibodies like daratumumab have already been approved for use in relapsed patients; here, we are showing that the benefits extend to newly diagnosed patients, as well."

The trial enrolled 706 patients. All received nine 6-week cycles of the standard treatment regimen. Half were randomly assigned to receive daratumumab along with the standard treatment and continued taking daratumumab once a month after the first nine treatment cycles. To date, patients have been tracked for a median of 16 months.

In terms of the study's primary endpoint, progression-free survival, patients receiving daratumumab showed a significantly (50%) lower rate of disease progression or death compared to those receiving standard treatment alone, a benefit that was consistent across all demographic and biologic subgroups. This improvement appeared to be largely driven by a significantly better responsiveness to therapy, a higher rate of complete remission, and a tripling of the proportion of patients reporting MRD negativity.

Both study groups showed similar rates of adverse events with the exception of upper respiratory tract infections and pneumonia, which occurred somewhat more frequently in those taking daratumumab, but the majority of these resolved.
The trial is the first of several ongoing studies to evaluate daratumumab as a front-line treatment for newly diagnosed multiple myeloma to report results.

This study was supported by Janssen Research & Development, LLC.

In the Phase III Murano Study [LBA-2], treatment with the targeted cancer drug venetoclax in combination with rituximab more than doubled the likelihood that patients with chronic lymphocytic leukemia (CLL) would survive for two years without cancer progression compared to treatment with the standard chemo-immunotherapy drug bendamustine with rituximab The study is the first randomized trial to show venetoclax is superior to a standard chemo-immunotherapy regimen and the first randomized study to evaluate the survival benefit of venetoclax in combination with rituximab, according to researchers. 

The trial was presented by John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre and Royal Melbourne Hospital.  It focused on patients who experienced continuing or recurrent CLL after initial cancer treatment. CLL accounts for about a quarter of new cases of leukemia each year.

Leukemia cells survive an abnormally long time by producing proteins that interfere with the normal process of cell death. Venetoclax is designed to hasten the death of leukemia cells by binding to and blocking the activity of one such protein, known as BCL-2. By contrast, bendamustine works by interfering with cancer cells' DNA. Rituximab is a monoclonal antibody designed to help the body's immune system recognize and attack leukemia cells.

Venetoclax is approved for use against CLL in the United States and several other countries, but approvals are limited to small subgroups of patients, such as those with a specific genetic abnormality. The present trial, carried out at 109 sites globally, sought to assess the safety and efficacy of venetoclax in a broad patient population.

The trial enrolled 389 patients whose CLL had persisted or recurred after at least one previous course of treatment including chemotherapy. Half of the patients were randomly assigned to a regimen of six monthly doses of venetoclax plus rituximab and half received six cycles of bendamustine plus rituximab. Patients assigned to the venetoclax arm continued to use venetoclax alone for two years or until leukemia returned. To date, researchers have tracked patients for a median of about two years. 

The vast majority (84.9%) of patients receiving venetoclax survived for two years without showing evidence of disease progression, compared to just 36.3 percent of those who received bendamustine. Venetoclax also outperformed bendamustine for the trial's secondary endpoints, which included overall survival and markers of cancer remission. In particular, those on venetoclax were far more likely to achieve MRD clearance, which was achieved in 83.5 percent of those taking venetoclax and 23.1 percent of those taking bendamustine. These results suggest venetoclax could be discontinued after two years with a low risk of recurrence in those patients with a deep remission, researchers said. 

"This is the first randomized trial comparing any of the new agents targeted to treat CLL against a standard chemoimmunotherapy program, and it has proved the superiority of the chemotherapy-free approach," said lead study author John Seymour, MBBS, PhD, director of the Haematology Department at the Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia. "It suggests that venetoclax should replace chemotherapy for relapsed/refractory CLL and is suggestive that the combination with rituximab is the preferred manner to use the drug. There is also evidence of eradication of detectable disease that opens the prospect of time-limited therapy in this setting." While venetoclax was associated with a greater risk of abnormally low white blood cell counts, there was no increase in severe infections or deaths related to this side effect, said Seymour.
The researchers continue to monitor participants to assess long-term survival and disease progression.

This study was supported by Genentech, a member of the Roche Group, and AbbVie.