Combination bortezomib and doxorubicin in relapsed/refractory multiple myeloma

Shah JJ, Orlowski RZ, Thomas SK

The first in class proteasome inhibitor bortezomib (B) received its initial regulatory approval for therapy of patients with multiple myeloma (MM) in the relapsed/refractory setting. Modulation of proteasome function, however, is also a rational strategy for chemosensitization, and a variety of agents have shown synergistic activity with bortezomib pre-clinically, including anthracyclines. This formed the basis for evaluation of a regimen of bortezomib with pegylated liposomal doxorubicin (PLD).

PLD+B, in a phase I study, induced a predictable and manageable toxicity profile, and showed encouraging anti-MM activity. In a recent international, randomized phase III trial, PLD+B demonstrated a superior overall response rate and response quality compared to bortezomib alone, as well as a longer time to progression, duration of response, progression-free survival, and overall survival.

Sub-analyses revealed benefits in almost all clinically relevant subgroups, including several which would be considered to have high-risk disease. These findings have led to the establishment of the PLD+B regimen as one of the standards of care for patients with relapsed and/or refractory myeloma. Efforts are now underway to build on this combination further by adding other active anti-myeloma agents.

Down syndrome reveals key to fighting cancer

People with Down syndrome rarely get most kinds of cancer, and U.S. researchers have nailed down one reason why — they have extra copies of a gene that helps keep tumours from feeding themselves.

The findings could lead to new treatments for cancer, the researchers reported in the journal Nature on Wednesday, and further study of Down patients might reveal more ways to fight tumours.

The researchers at Harvard University and elsewhere made use of a new kind of embryonic-like stem cell called an induced pluripotent stem cell or iPS cell. These cells, made from ordinary skin, can be transformed to act like powerful stem cells, the body’s master cells.

Using iPS cells from a volunteer with Down syndrome and mice genetically engineered to have a version of the condition, the researchers pinpointed one gene that protects against tumours.

“It is, perhaps, inspiring that the Down syndrome population provides us with new insight into mechanisms that regulate cancer growth,” they wrote. Down syndrome is the most common genetic cause of mental retardation, occurring in one out of 700 live births. The Down syndrome theory had long been explored by Harvard’s Dr. Judah Folkman, who died last year. Folkman, whose name is on the study, developed theories about how tumour cells grow blood vessels to nourish themselves in a process called angiogenesis.

Folkman also noticed how rare cancer is among Down patients, except for leukemia, and he wondered whether the genes explain why. A study of nearly 18,000 Down’s patients showed they had 10 per cent the expected rate of cancer.

People with Down syndrome have a third copy of chromosome 21, where most people have two copies.
The extra copy gives them extra versions of 231 different genes.

“One such gene is Down syndrome candidate region-1 (DSCR1, also known as RCAN1),” Harvard’s Sandra Ryeom and colleagues wrote.

This gene codes for a protein that suppresses vascular endothelial growth factor or VEGF — one of the compounds necessary for angiogenesis.

Genome sequencing of multiple myeloma

The Multiple Myeloma Research Foundation (MMRF) announced a collaboration with the Broad Institute of MIT and Harvard to systematically uncover the molecular changes underlying multiple myeloma by whole genome sequencing of individual patient tumors. The MMRF will provide both patient samples for analysis as well as funding for the project. All data from this collaboration will be put in the public domain.

"We are delighted to work with the MMRF, which has been a visionary organization in accelerating cancer research for the sake of patients and their families," said Eric S. Lander, PhD, Director of the Broad Institute. "Through our work together on this critical pilot project in whole cancer genome sequencing, we hope not only to advance clinical progress for multiple myeloma, but to build knowledge and technical capabilities that can be applied to many other human cancers."

"Three years ago, the MMRF launched a partnership with the Broad Institute and the Translational Genomics Research Institute — the Multiple Myeloma Genomics Initiative — a comprehensive genome mapping program to identity new targets and eventually new therapies for this incurable disease," said Kathy Giusti, Founder and CEO of the MMRF, and a multiple myeloma patient. "As part of that larger effort, we are confident that this groundbreaking research will accelerate the development of next-generation treatments to extend the lives of multiple myeloma patients. Additionally, we believe that this work will not only ultimately pave the way to a cure for patients with multiple myeloma, but will benefit patients with other types of cancer."

The creation of comprehensive catalogs of all commonly occurring cancer mutations is a current approach of several national and international consortia, including The Cancer Genome Atlas (TCGA) led by the US National Institutes of Health and the International Cancer Genome Consortium (ICGC), to understand major tumor types such as leukemia, lung cancer, glioblastoma and others. To date, only a handful of whole cancer genomes have been sequenced and only one has been published.

"The few cancer genomes sequenced to date have been informative, but we need many more to transform cancer research and ultimately cancer therapy," said Stacey Gabriel, PhD, Co-Director of the Broad Institute's Genome Sequencing and Analysis Program. "This exciting collaboration with the MMRF will advance these goals by contributing public domain data."

Importance of Oral Hygiene

Good oral hygiene and proper dental care apply to all age groups but the needs of the elderly population can be slightly different than the needs of younger people.

I will try to list several areas of concern and how they pertain to this age group.

Why save your teeth?

A missing tooth affects many things including your oral health, your bite, your speech, your general health and your appearance.

When a tooth is lost, the remaining teeth may drift into the empty space, causing changes in biting and chewing and possibly causing pain in your jaw from the bite being misaligned. Remaining teeth may be more prone to decay if they are misaligned.

Many speech sounds that we make are made because of the position of the tongue against your teeth or the roof of your mouth. Having missing teeth can cause changes in a person's speech.

People with missing teeth often cannot chew their food properly to be digested and subsequently may end up with digestive problems and/or nutritional deficiencies.

Missing tooth will affect your appearance and may have a negative effect on one's self-esteem.

Oral health and your heart
Recent research shows that there is a link between periodontal (gum) disease and heart disease. People who have gum disease may be at a higher risk for heart attacks, although no one is certain how this happens. The current theory is that bacteria present in infected gums can become loose and move throughout the body. The same bacteria that cause gum disease and irritates our gums might travel to your arteries.

What can you do? Proper home care, including brushing and flossing regularly, is essential as well as regular visits to your dentist for periodontal maintenance.

Oral health and bisphosphonates
Patients who have been receiving intravenous bisphosphonates should avoid having teeth pulled at all costs. Many people are being treated with bisphosphonates for a variety of medical problems including osteoporosis, multiple myeloma, breast, lung and other cancers and Paget's disease. While those medications are terrific in treating a number of medical conditions, there is a risk of developing an osteonecrosis (breakdown) of the jaw bone as a result of an invasive dental procedure while taking these medications.

The most important step to prevent these problems is to have a dental consultation before beginning the bisphosphonate therapy and having all invasive procedures done before therapy is initiated.

Oral health and diabetes
It is estimated that one-third of the population in the U.S. has diabetes, yet only one-half of these patients are diagnosed.
The biggest problems for diabetics from a dental point of view are infections, periodontal disease and salivary problems.
Infections can result in improper healing following extractions and other surgical procedures.

Diabetics are very susceptible to periodontal disease and in their case it may be more severe and more difficult to maintain than in a person without diabetes.

Finally, salivary flow can be diminished in diabetics, which will result in a higher rate of caries (cavities).

Proper diet, good oral hygiene and regular dental visits can help keep the oral problems of diabetes in check.

Oral health and tobacco use
While the usage of tobacco has been declining in the last decade, it is still very high in the population and its consequence in the mouth is oral cancer. While the rate of oral cancer isn't as high as with other cancers, it is often devastating and fatal.

A word to the wise is sufficient with tobacco use, both smoking tobacco and chewing tobacco.

If you currently use tobacco, quit immediately. If you don't use it, don't start.

Older patients' dental needs
In tough economic times such as these, there is concern about the cost of maintaining one's oral health.

One doesn't need to do high-cost elective dental procedures if there are monetary constraints. But there is a need for all patients of all ages to maintain proper oral hygiene and seek regular professional care to prevent the consequences of neglect.

Keep periodontal disease under control with proper brushing and flossing techniques and regular cleanings.

Have broken teeth fixed or extracted before they result in infections.

Have ill-fitting dentures fixed or replaced so they don't cause irritations.

Have an oral cancer screening regularly.

Prevention is more prudent and less costly than repair.

Dr. Francis X. Barra, Doctor of Dental Surgery, is the director of dentistry at FoxCare Dental Associates and is a member of the medical staff at A.O. Fox Memorial Hospital in Oneonta.

Thalidomide sourcing from offshore

Owing to costs, Canadian myeloma patients are acquiring lower-cost Thalidomide from countries like Mexico, Brazil and India.

Canadians buy the drug over the Internet, in person in Mexico, or friends and relatives bring it back.

The cost is a fraction of that in Canada, athough self-importing Thalidomide is illegal in Canada.

Thalidomide costs in Canada can reach $40,000/year. Provincial drug plans and private insurers do not usually reimburse the expense.

Apparently Health Canada may permit a patient to bring up to a 90-day supply of Thalidomide into Canada.

Although Revlimid and Velcade are approved by Health Canada most provinces refuse to fund them.

A Mexican company, Laboritorios Serral, produces Thalidomide under the brand name Talizer. Apparently the drug can be imported or family members can pick up the drug from an authorized pharmacy in Mexico, if they have the patient's prescription and identification.

However, Canadian doctors are concerned about taking drugs without Health Canada oversight.

New Drug ACE-011 Acceleron Pharma

Acceleron Pharma eports that it will expand its workforce and build new offices and facilities this year. The company signed a lease in Cambridge, MA, further expanding its research laboratory and office space by 19,700 sq. ft. In conjunction with this, Acceleron will increase its workforce by more than 50% to support growth in R&D and manufacturing.

Acceleron’s lead program, ACE-011, is currently in Phase II studies in multiple myeloma patients with osteolytic bone disease. ACE-011 has been shown to increase bone mineral density and red blood cells and is being jointly developed by Acceleron and Celgene.