Bortezomib

Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

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Abstract

BACKGROUND

Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed.

METHODS

In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)–negative status.

RESULTS

At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P=0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group.

CONCLUSIONS

The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma.

Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

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Abstract

Background

Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed.

Methods

In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)–negative status.

Results

At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P=0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group.

Conclusions

The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma.

Acupuncture Reduces Neuropathy Associated With Bortezomib.

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Acupuncture may be able to reduce neuropathy associated with the use of bortezomib (Velcade, Millennium Pharmaceuticals, Inc.) in multiple myeloma patients, suggest new data. The results are early, but patients treated with acupuncture appeared to experience both subjective and objective improvements in symptoms.

“Acupuncture is feasible and safe for treating multiple myeloma patients with persistent and moderate pain due to bortezomib-induced peripheral neuropathy [BIPN],” said Ting Bao, MD, an assistant professor of medicine at the University of Maryland, in Baltimore. She noted that all patients appeared to have decreased pain and improved function, as evidenced by improved scores on standardized measures.

Dr. Bao presented her results here at the 10th International Conference of the Society for Integrative Oncology (SIO).

Bortezomib is an effective treatment for multiple myeloma, but its use can cause sensory neuropathy, which can limit dose and duration of treatment, she explained. “Peripheral neuropathy is one of the most common and severe toxicities, and treatment is limited to symptom management.”

Symptoms are often difficult to manage, and available treatment options frequently do not provide total relief and can cause adverse effects. Conversely, Dr. Bao pointed out, acupuncture has no side effects, and several studies have demonstrated the efficacy of acupuncture in treating peripheral neuropathy.

“As such, we hypothesized that acupuncture was a safe, feasible, and effective approach to treating BIPN, and that it works through modulating serum cytokines,” Dr. Bao said. “So as a first step in testing this hypothesis, we designed a single-arm, single-institution study.”

Safe and Feasible

For their pilot study, Dr. Bao and colleagues enrolled 27 patients with multiple myeloma who were experiencing persistent bortezomib-induced peripheral neuropathy of grade 2 or greater, despite receiving adequate medical intervention, and who were no longer using the agent.

All patients in the cohort received 10 acupuncture treatments for 10 weeks (2x/week for 2 weeks, 1x/week for 4 weeks, and then biweekly for 4 weeks), and their responses to treatment were evaluated with the Clinical Total Neuropathy Score (TNSc), the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity (FACT/GOG-Ntx) questionnaire, and the Neuropathy Pain Scale (NPS).

The TNSc was evaluated by a trained research nurse using both subjective and objective measurements. The researchers also obtained serial serum levels of proinflammatory and neurotrophic cytokines at baseline and at weeks 1, 2, 4, 8, and 14.

Dr. Bao explained that all of the patients had grade 3 to 4 neuropathy, and the median time after discontinuing bortezomib was 19 months, making spontaneous recovery not very feasible. “Neuropathy was already affecting their daily activity,” she said.

At weeks 10 and 14, TNSc, FACT/GOG-Ntx, and NPS all showed significant reduction, suggesting decreased pain, improved function, and improved objective neuropathy measurement (P-values were 0.02 and 0.03 for TNSc at weeks 10 and 14, respectively, and <.0001 for both FACT/GOG-Ntx and NPS at weeks 10 and 14).

Mechanism Unclear

However, results of nerve conduction studies did not significantly change between baseline assessment and end of study. “Fifteen patients had nerve conduction studies before and after acupuncture,” said Dr. Bao. “The majority did not show change.”

“Disappointingly, there was no correlation between symptom reduction and nerve conduction studies,” she continued. “And more disappointingly, 12 serum biomarkers did not show any significant change over time. So the mechanism remains unclear.”

Dr. Bao concluded that even though the mechanism of action still remains unclear, acupuncture is safe, feasible, and may be able to reduce pain and improve function, and that they are planning a follow-up randomized trial.

“These results were very promising, and the next step will be to look at a randomized controlled trial, and that will ultimately be the next step to see if acupuncture is effective in treating bortezomib-induced neuropathy,” said Richard Lee, MD, assistant professor of general oncology at the University of Texas MD Anderson Cancer Center in Houston.

Acupuncture may also be useful in treating other types of neuropathy, said Dr. Lee, who was approached byMedscape Medical News for an independent comment. “This is a very active area of investigation. Our group at MD Anderson, Dr. Bao’s group, and others are looking at peripheral neuropathy.”

“There are many different types of chemotherapy that can cause neuropathy, such as platinum-based agents and taxanes,” he continued. “Whether or not this type of treatment is universal for all types of chemotherapy, we don’t know. We really need further studies to investigate its use with other agents.

Source: Medscape.com

Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma.

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BACKGROUND

Bruton’s tyrosine kinase (BTK) is a mediator of the B-cell–receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin’s lymphoma, including mantle-cell lymphoma.

METHODS

In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.

RESULTS

The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.

CONCLUSIONS

Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma.

Source: NEJM

 

Therapeutic effect of neural stem cells expressing TRAIL and bortezomib in mice with glioma xenografts

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Treatment of glioblastoma remains a challenge in neuro-oncology. We investigated if treatment with neural stem cells engineered to express membrane-bound TRAIL (NSCs-mTRAIL) alone or in combination with proteasome inhibitors is a feasible therapeutic approach for experimental glioma. Glioma cells showed resistance to soluble TRAIL and proteasome inhibitors alone, but responded well to their combined treatment. In co-culture with NSCs-mTRAIL, glioma cells appeared to be more prone to apoptosis than to treatment with soluble TRAIL, which was enhanced by proteasome inhibitor bortezomib. In vivo, the survival of animals bearing intracranial glial xenografts was significantly improved by NSCs-mTRAIL. The addition of bortezomib further enhanced the efficacy of NSCs-TRAIL treated group in one of examined tumor models. These data demonstrate that therapy with NSCs-mTRAIL is a potent cell based approach for treatment of glioma. Such an approach warrants further search for therapeutics capable of increasing sensitivity of glioma cells to mTRAIL in vivo.

source: cancer letter