Velcade

Effect of Velcade combined with Dexamethasone on multiple myeloma.

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Abstract

Objective: To compare the effect and safety between Velcade-Dexamethasone (VD)and revised Vinorebine+Pirarubicin+ Dexamethasone (VAD) regiment for multiple myeloma (MM).

Methods: Thirty-six patients with MM were reviewed, 16 of whom were treated with VD (VD Group) and the others with VAD. European Group for Blood and Marrow Transplant (EBMT) criteria and National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) were chosen to analyze the efficacy and side effects.

Results: In the VD group and the revised VAD group, the rates of complete response, partial response, minimal response, no change and progress disease were 50% vs. 5%, 25% vs. 25%, 18.8% vs. 15%, 6.2% vs. 35% and 0 vs. 20%, respectively. The total response rates were 93.8% vs 45%. There was significant difference in the overall response rate between the 2 groups (P<0.05). The side effects were less serious, and the endurance was better in the VD group than those in the revised VAD group. No serious effects of hematology and cardiology were seen, and good endurance was showed in the renal dysfunction in the VD group.

Conclusion: Velcade combined with dexamethasone is a safe and effective regiment for multiple myeloma with good safety and endurance.

Transplant Remains King for New Myeloma

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Significant improvement in PFS versus systemic treatment.

Upfront autologous stem cell transplantation after high-dose induction chemotherapy resulted in a significant survival advantage for patients with newly diagnosed myeloma, as compared with induction plus additional chemotherapy, a randomized trial showed.

Overall, bortezomib (Velcade)-containing induction therapy followed by melphalan and stem-cell transplantation resulted in a 24% reduction in the hazard for disease progression or death at 36 months as compared with induction therapy plus four additional cycles of bortezomib-containing chemotherapy. The magnitude of the hazard reduction approached 50% for certain subgroups.

A second phase of the trial, involving randomization to consolidation therapy, has yet to be completed, Michele Cavo, MD, said during a press briefing prior to the American Society of Clinical Oncology meeting.
“We performed a multivariate analysis … and we found that randomization to upfront auto-transplant was an independent variable positively affecting patient outcomes,” said Cavo, of Bologna University in Italy. “In comparison to those patients who did not have an auto-transplant, those randomized to high-dose chemotherapy and upfront autologous stem cell transplantation had a significantly higher probability of achieving at least a 90% reduction in tumor burden.”
High-risk patients — including International Staging System (ISS) III and high-risk cytogenetics — appeared to derive the greatest benefit from auto-transplantation, he added.
During the discussion the followed Cavo’s presentation, the combination of drugs used for induction — bortezomib, cyclophosphamide, and dexamethasone (VCD) — came into question, as lenalidomide (Revlimid) is used more often than cyclophosphamide in the United States. Cavo responded that the different induction regimens have not been compared in randomized trials, so superiority of one versus the other remains uncertain. The primary message of the study relates to the superiority of upfront transplantation, he added.
Use of the VRD (sometimes called RVD) induction regimen — bortezomib, lenalidomide, and dexamethasone — might have led to different results, Noopur S. Raje, MD, of Massachusetts General Hospital Cancer Center in Boston, acknowledged in an email. Another European study reported at the 2015 American Society of Hematology meeting demonstrated superiority for upfront auto-transplantation when VRD induction therapy was used, she added.

Historically, autologous hematopoietic stem cell transplantation has represented the preferred treatment strategy for transplant-eligible patients with newly diagnosed myeloma. However, the introduction of immumodulatory agents (imids) and proteasome inhibitors has dramatically improved the rate of complete response in myeloma and significantly increased PFS and overall survival in previously untreated patients.
“In the current era, prospective comparisons of novel agent-based therapies versus auto-transplant, single versus double auto-transplant, and consolidation therapy versus no consolidation therapy are needed in patients with newly diagnosed multiple myeloma,” said Cavo. “These objectives were addressed in a large prospective, multicenter, intergroup, randomized phase III study, conducted by the European Myeloma Network.”
All patients started treatment with three to four cycles of VCD followed by randomization to four cycles of bortezomib-melphalan-prednisone (BMP) therapy or to melphalan plus auto-transplant. All patients received maintenance therapy with lenalidomide, and investigators randomized them a second time to VRD consolidation therapy or no consolidation. At centers that normally perform dual auto-transplants, patients were further randomized to one or two transplant procedures.
The trial had a primary endpoint of PFS. Cavo reported findings from the first randomized stage of the trial. Data analysis included 512 patients treated with chemotherapy and 754 randomized to auto-transplant. The report occurred after a median follow-up of 23.9 months.
The results showed a hazard ratio for progression or death of 0.76 in favor of the transplant group (95% CI 0.61-0.94, P=0.01). Subgroup analysis showed a consistent trend in favor of upfront transplantation. Significant differences emerged from analyses of patients with revised ISS III disease status (N=167, HR 0.52, 95% CI 0.32-0.85, P=0.01) and patients with high-risk cytogenetics (N=412, HR 0.72, 95% CI 0.54-0.97, P=0.03).
The multivariate analysis identified four independent predictors of PFS:
ISS 1 – HR 0.44, 95% CI 0.28-0.67, P<0.0001
Standard-risk cytogenetics – HR 0.57, 95% CI 0.41-0.78, P<0.0001
Randomization to auto-transplant – HR 0.61, 95% CI 0.45-0.82, P=0.001
<60% bone marrow plasma cells – HR 0.67, 95% CI 0.48-0.99, P=0.014
The complete response rate (stringent plus conventional) was similar for the chemotherapy (43.7%) and auto-transplant (41.6%) arms. However, significantly more patients in the transplant group achieved very good partial response or complete response (84.4% versus 74.0%, P<0.0001).

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

New Therapies Bring Progress Against Multiple Myeloma.

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The 21st century has seen great strides in treatment for multiple myeloma, a cancer of the bone marrow once considered a death sentence. In fact, thanks to research by Dana-Farber scientists, this blood cancer that took the lives ofGeraldine Ferraro and Leonard P. Zakim has become a chronic disease for many patients.

Ken Anderson, MD, and his colleagues have helped transform multiple myeloma into a more manageable illness by shepherding many novel drugs from the laboratory to the patient bedside.

Over a decade ago, median survival in multiple myeloma was just 2 to 3 years. Today, James (Jim) Bond of Cleveland, Ohio, who bicycles across his home state every year to raise money for cancer research, has been living with multiple myeloma for 20 years. Bond credits Dana-Farber’s clinical trials for his longevity.

Multiple myeloma is estimated to strike 22,350 people in the U.S. in 2013. Although there is still no cure, Dana-Farber researchers have contributed to the following advances.

  • Velcade. In 2003, the FDA approved a drug called bortezomib (Velcade), which today is standard treatment for newly diagnosed myeloma, thanks to research conducted by Anderson,Paul Richardson, MD, and their colleagues at Harvard Medical School and elsewhere.
  • Studying the tumor’s “neighborhood.” Around the time that Velcade was approved, Anderson and his team were also investigating the drug thalidomide (Thalomid) as a treatment for myeloma. They explored the effect of medications not just on the tumor cells but also on those surrounding the tumor, including non-cancerous immune and other cells.
  • Thalidomide, Revlimid and Pomalidomide. Anderson and his team discovered that thalidomide and its close cousin lenalidomide (Revlimid) actively recruit immune cells to fight cancer. Clinical trials led by Richardson and colleagues set the stage for the approval of lenalidomide to treat advanced myeloma in 2006. The most potent immunomodulator studied by both the laboratory and clinical team to date, called pomalidomide (Pomalyst), was approved in February 2013.
  • Combination drugs. Because many genetic mutations drive a single tumor, cancer is often best treated with combinations of therapies. Dana-Farber researchers hope to personalize multiple myeloma treatment by categorizing patients based on the molecular pathways that drive their cancer, and prescribe the appropriate combinations of drugs.
  • Stem cell transplant. This procedure is still a key component of treatment for multiple myeloma.  DF/BWCC is a leading provider of stem cell transplantation, which involves giving the patient healthy bone marrow harvested from his or her own stem cells, or sometimes those of a donor.

Source: dana-farber.org