Updates 12/4/08

Multiple Myeloma and farming. A systematic review of 30 years of research. Where next?: http://7thspace.com/headlines/297830/multiple_myeloma_and_farming_a_systematic_review_of_30_years_of_research_where_next.html

Collaboration with Luc Montagnier and Howard Urnovitz: http://www.businesswire.com/portal/site/home/permalink/?ndmViewId=news_view&newsId=20081118005583&newsLang=en

New study backs solvent, leukemia link: http://www.reuters.com/article/healthNews/idUSTRE4AH85R20081118

New Data Will Be Presented at ASH on VELCADE(R) (Bortezomib) for Injection-Based Therapies in Multiple Myeloma and Non-Hodgkin’s Lymphoma: http://www.marketwatch.com/news/story/New-Data-Will-Be-Presented/story.aspx?guid=%7BE97D11F5-5E5D-44A9-9DE8-107A45ED8C6F%7D

Balloon kyphoplasty may be effective in cases of osteolytic vertebral fractures: http://www.orthosupersite.com/view.asp?rID=32844

New Data On Infinity’s Lead Anti-Cancer Candidates to be Presented At AACR: http://biz.yahoo.com/pz/080407/139640.html

Last decade brought progress in treatment of multiple myeloma: http://www.hemonctoday.com/article.aspx?rid=33067

Proteolix to Present Clinical and Preclinical Data at the 50th Annual Meeting of: http://www.earthtimes.org/articles/show/proteolix-to-present-clinical-and,635444.shtml

Avoiding Drug Interactions: http://www.fda.gov/consumer/updates/interactions112808.html

Hana Biosciences to Present Data On Marqibo: http://www.marketwatch.com/news/story/Hana-Biosciences-Present-Data-On/story.aspx?guid=%7B8D819D09-D14C-4A4A-ADA8-5F492C0483E1%7D

Immunomedics to Present At 50th ASH Annual Meeting: http://www.globenewswire.com/newsroom/news.html?d=155623

The International Myeloma Foundation Says Patient Experience — Longer Survival and Improved Quality of Life –: http://www.marketwatch.com/news/story/The-International-Myeloma-Foundation-Says/story.aspx?guid=%7B1875A655-BD2E-4928-9FF4-D4DC8BE31E2F%7D

Xencor to Present New Data from Pre-Clinical Antibody Programs at Upcoming ASH Conference: http://www.marketwatch.com/news/story/Xencor-Present-New-Data-Pre/story.aspx?guid=%7BC6B80729-F42A-4D05-B5B8-8E57696558A8%7D

Astex presents updates on AT7519 and AT9283: http://www.pharmalive.com/News/index.cfm?articleid=588778&categoryid=15

DVT risk increased among patients with multiple myeloma precursor: http://www.hemonctoday.com/articlePrint.aspx?type=print&rID=33199

Veterans form bone marrow cancer support group in Naples: http://www.naplesnews.com/news/2008/nov/22/veterans-form-bone-marrow-cancer-support-group-nap/

Updates 10/29/08

Outpatient Stem Cell Transplant Feasible for Multiple Myeloma: http://www.cancerpage.com/news/article.asp?id=12756

Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT: http://bloodjournal.hematologylibrary.org/cgi/content/abstract/blood-2007-12-129718v1

Celgene Corporation and Acceleron Pharma Initiate Phase 2 Study of ACE-011 in Patients with Multiple Myeloma: http://www.marketwatch.com/news/story/celgene-corporation-acceleron-pharma-initiate/story.aspx?guid=%7b277E3FD5-229F-42F6-AF14-FADC075CAD3F%7d&dist=hppr

RocketBoom Founder Fighting For Father’s Life; Meanwhile, Drug Company Is Committing PR Suicide: http://www.techcrunch.com/2008/10/14/rocketboom-founder-fighting-for-fathers-life-meanwhile-drug-company-committing-pr-suicide/

Biogen, Tysabri & A Dying Democratic Fundraiser: http://www.pharmalot.com/2008/10/biogen-tysabri-a-dying-democratic-fundraiser/

Velcade®, Cytoxan® and Prednisone Highly Effective for Relapsed Myeloma: http://professional.cancerconsultants.com/oncology_main_news.aspx?id=42721

Geron Commences Combination Clinical Trial Of Anti-Cancer Drug GRN163L In Patients With Multiple Myeloma – Update: http://www.rttnews.com/Content/BreakingNews.aspx?Node=B1&Id=746535%20&Category=Breaking%20News

CD56 Immunohistochemistry Identifies Residual Multiple Myeloma in Bone Marrow Specimens: Presented at ASCP: http://www.docguide.com/news/content.nsf/news/852571020057CCF6852574E80062AAF8

Study shows link between gene variations and cancer survival: http://www.hindu.com/thehindu/holnus/099200810231602.htm

Exelixis Reports Positive Phase 1 Data for XL228 at EORTC-NCI-AACR Symposium: http://www.businesswire.com/portal/site/google/?ndmViewId=news_view&newsId=20081023005373&newsLang=en

Support groups give cancer patients empathy, hope: http://www.gmtoday.com/news/local_stories/2008/Oct_08/10252008_07.asp

Judoka Tackles Two Opponents: http://www.westcoaster.ca/modules/AMS/article.php?storyid=5395

Attacking Cancer Stem Cells

Wednesday, October 08, 2008

Attacking Cancer Stem Cells
A screening approach identifies drugs that halt cells that feed tumors.

By Courtney Humphries

All cancer cells were once thought to be equal, but recent research suggests otherwise. A growing body of evidence indicates that only certain cancer cells are capable of generating and maintaining a tumor. Dubbed cancer stem cells, they can divide indefinitely to perpetuate the cancer over time. They may also be the reason why some therapies fail to wipe out a cancer entirely: cancer stem cells seem to be particularly resistant to standard cancer treatments and can remain behind like the roots of a weed.

If this hypothesis holds true, cancer stem cells could be the most promising target for new therapies. A team of researchers at Harvard Medical School has now developed a new way to find drugs that selectively kill cancer stem cells or prevent them from dividing. The team is currently using the method to identify drug candidates for leukemia, a disease for which cancer stem cells have been well characterized. The researchers believe that the approach could eventually extend to other kinds of cancer.

David Scadden, cochair of the Harvard Stem Cell Institute and a collaborator on the project, says that typical high-throughput drug screens, which use cell lines grown in petri dishes, don’t always yield good results because the cells are too removed from their natural context. With stem cells in particular, he says, “the microenvironment seems to be an important contributor for how the cells function.” When grown in the lab, the cells can lose their “stemness,” or ability to generate new cells. Instead, the Harvard drug-screening method uses cells taken directly from diseased animals.

To better mimic the natural environment of cancer stem cells, the team incorporated other cells that support them. “Cancer cells don’t exist in isolation,” says Kimberly Hartwell, a research fellow at Brigham and Women’s Hospital, who helped lead the project. In tissues, she says, these cells “may hijack the support system–what we call the stromal cells.” Stromal cells form connective tissue surrounding an organ; scientists believe that they help provide an environment where stem cells flourish.

To find treatments for leukemia, the team first isolated leukemic stem cells from the bone marrow of diseased mice, then added them to stromal cells from the bone marrow. These two cell types were placed in plates with tiny wells that can be treated with drugs and analyzed using robotic methods. By transplanting the leukemic stem cells into a healthy mouse, the scientists have confirmed that the cells retain their ability to form new cancerous cells for up to four weeks.

To determine how different drugs affect the cells, scientists use an imaging analysis method developed in collaboration with the Broad Institute. The automated system searches for drugs that decrease the number of leukemic stem cells, which are labeled with a fluorescent red marker. The software also analyzes the structure of the cells. Leukemic stem cells tend to group together to form structures called cobblestones, which Hartwell describes as “a biological readout of stemness.” By evaluating the number of cobblestone formations, the team can find drugs that interfere with the activity of cancer stem cells.

The researchers are currently screening libraries of FDA-approved drugs and known bioactive compounds, as well as RNA molecules. They are also using libraries of compounds, developed by Stuart Schreiber at the Broad Institute, known to prevent the type of DNA alterations seen in leukemia. The team has already identified compounds that can kill off cancer stem cells without affecting stromal cells.

Scadden’s team is also performing parallel tests on normal bone-marrow stem cells, in order to identify compounds that specifically target cancer stem cells without killing their normal counterparts. Scadden says that these studies could also provide potential treatments for diseases beyond cancer by identifying drugs that expand normal stem cells.

Robert Weinberg, a professor of biology at MIT, believes that the overall idea of targeting cancer stem cells is an attractive one because it suggests a path to therapies that are truly curative. But he says that it’s not clear whether the Harvard screening approach will be applicable to solid tumors, rather than to cancers of the blood like leukemia. He also cautions that the approach faces some difficulties. “It’s already clear that cancer stem cells are more resistant to most therapies than the bulk of the cancer cells in the tumor,” he says. Furthermore, if it is possible to wipe out cancer stem cells selectively, it still remains unproven whether doing so will truly eradicate the tumor.

Cancer stem cells were first identified in leukemia in 1994, but in the past several years, the cancer stem-cell hypothesis has gained ground as stem cells have been identified in other types of cancer, including those of the breast, prostate, brain, and pancreas. Although most scientists now agree that cancer stem cells exist, they still debate the cells’ exact role in cancer. Other types of cancer pose a greater challenge for screening than do blood cancers such as leukemia because the cancer stem cells are buried within solid tumors, making them more difficult to access and characterize.

Treatment of Myeloma: Cure vs Control

Treatment of Myeloma: Cure vs Control
S. VINCENT RAJKUMAR, MD
From the Division of Hematology, Mayo Clinic, Rochester, MN.

Supported in part by grants CA62242, CA85818, CA93842, and CA100080 from the National Cancer Institute, Bethesda, MD.

Individual reprints of this article are not available. Address correspondence to S. Vincent Rajkumar, MD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (rajkumar.vincent@mayo.edu).

Although not often openly acknowledged, “cure vs control” is the dominant philosophical difference behind many of the strategies, trials, and debates related to the management of myeloma. Should we treat patients with myeloma with multidrug, multitransplant combinations with the goal of potentially curing a subset of patients, recognizing that the risk of adverse events and effect on quality of life will be substantial? Or should we address myeloma as a chronic incurable condition with the goal of disease control, using the least toxic regimens, emphasizing a balance between efficacy and quality of life, and reserving more aggressive therapy for later?

To be sure, if cure were known to be possible (with a reasonable probability) in myeloma, it would undoubtedly be the preferred therapeutic goal of most patients and physicians. But this is not the case. Myeloma is generally not considered a curable disease; however, new definitions of cure have been suggested, including operational cure, which is defined as a sustained complete response (CR) for a prolonged period.1,2 Cure vs control is debated because the strategies currently being tested are not truly curative but rather are intended to maximize response rates in the hope that they will translate into an operational cure for a subset of patients.

For decades, the treatment of myeloma was restricted to conventional chemotherapy with alkylators and corticosteroids, and the question of cure vs control never arose. The response rate with alkylators and corticosteroids was only about 50%, and CR3,4 was rare. Cure was never a goal of therapy because it was assumed to be unattainable. Instead, the goal was to control the disease as much as possible, providing the best quality of life to the patient for the longest duration by judicious, intermittent use of the 2 available classes of active chemotherapeutic agents.

In the 1990s, high-dose therapy with autologous stem cell transplant (ASCT) became part of standard practice when it was found to prolong survival compared with conventional chemotherapy.5-7 Subsequently, bisphosphonates were found to be effective in decreasing the incidence of bone lesions.8,9 In the past decade, thalidomide,10 bortezomib,11-13 and lenalidomide14,15 emerged as effective agents for the treatment of myeloma, producing spectacular results in combination with other known agents in terms of response rate, CR rate, progression-free survival (PFS), and (more recently) overall survival. Numerous combinations have been developed, resulting in a veritable alphabet soup of clinical trials,16 and drug combinations are vying with each other for the highest response rate (and prominence).17,18 The results obtained with new combinations have indeed been remarkable and have prompted a relatively new philosophy of treating myeloma with the goal of potential cure rather than disease control. These philosophical differences underpin the various clinically relevant debates regarding myeloma currently confronting patients and physicians. In fact, it is not uncommon to find that well-meaning investigators interpret the same clinical trial data in opposite ways because they ascribe to different philosophies (cure vs control).19 Although this commentary focuses on myeloma, the cure-vs-control debate may be relevant to other similar chronic malignant and nonmalignant disorders.20-28

Complete Response

If cure is the goal, then CR is the critical first step. High CR rates require greater intensity of therapy. Although overall survival is usually better in patients who achieve CR than in those who do not, this could be more a reflection of underlying disease biology, with CR functioning as a prognostic marker for those with inherently favorable disease biology. It is far from clear whether increasing or intensifying therapy for patients without CR until such status is achieved actually prolongs overall survival. In other words, although the achievement of CR is a favorable prognostic factor, modifying therapeutic strategy with the sole purpose of achieving CR in a patient who is otherwise responding well to therapy is of unproven value.

The following 6 important caveats concerning CR should be kept in mind.29 First, CR is a surrogate marker for improved overall survival and as such is the means to a goal, not the ultimate goal. Second, in clinical trials, CR is often but not consistently associated with better overall survival.30-33 Third, trying to achieve the highest CR rate may cause harm because overall survival is a composite end point based not just on efficacy but on safety as well. High CR rates frequently require more aggressive, more toxic therapy. Fourth, a small monoclonal protein (minimal residual disease) is not in itself clinically important and is commonly present in the general population in the form of monoclonal gammopathy of undetermined significance.34-36 In many patients, reduction of myeloma to a state similar to monoclonal gammopathy of undetermined significance (near-CR or very good partial response) may be all that is required for best long-term survival. Fifth, CR in myeloma, unlike CR in large cell lymphoma, reflects profound tumor reduction but not elimination of the clone and thus is not a true surrogate for cure. Finally, myeloma may not be a single disease cytogenetically37-42; achievement of a CR seems particularly important in the 15% of patients with high-risk myeloma, whereas survival is similar in patients without high-risk features who have and have not achieved CR.

For those who embrace cure as the goal of therapy, these caveats aside, CR is a desirable and important first step. For those who favor treating myeloma as a chronic disease with the goal of disease control, CR remains just as desirable but is not the goal.

Combination vs Sequential Therapy

As the number of active chemotherapeutic agents has increased, so too has the number of studies evaluating the efficacy and safety of various combinations of these agents. Several comparative trials of 2-drug vs 3-drug combinations (eg, lenalidomide-dexamethasone vs bortezomib-lenalidomide-dexamethasone) are being conducted. In these trials, the 3-drug combination in all likelihood will produce a higher CR rate and PFS compared with the 2-drug regimen. However, the effect on overall survival is often not clear. Patients who receive a 2-drug regimen as initial therapy still have the third drug available for relapse, whereas those who receive the 3-drug regimen do not. Those who are treated with the 2-drug regimen will likely endure fewer adverse events. If cure is the goal, then the best chance for eradicating all malignant cells is early in the disease course with the best available multidrug combination. If disease control is the favored approach because cure is not considered to be possible with currently available drugs, then starting with the 2-drug combination makes sense, reserving the third agent for relapse. Clearly, trials testing 2-drug vs 3-drug combinations should have overall survival as the primary end point. However, such is often not the case because the required sample size is too large. As a result, decisions are usually made on the basis of one’s underlying bias in the cure-vs-control debate.

Autologous Stem Cell Transplant

Currently, the most important question for patients with myeloma is whether ASCT as initial therapy is still needed with the availability of several new active antimyeloma drugs. Autologous stem cell transplant is remarkably safe and can be done on an outpatient basis in 40% of patients.43 It improves CR rates and prolongs median overall survival in myeloma by approximately 12 months.5,7,44,45 Given the promising results obtained with a single ASCT, double (tandem) ASCT was investigated. With double ASCT, patients receive a second ASCT shortly after recovery from the first procedure.6,46 A French randomized trial found significantly better survival in recipients of double vs single ASCT.47 Results of ASCT can be further improved by incorporating new active chemotherapeutic agents into the transplant strategy, resulting in extraordinarily high CR rates, PFS, and survival. If cure is the goal, double ASCT incorporating novel chemotherapeutic agents before, during, and after ASCT is the ideal therapeutic regimen.48

In contrast, impressive results can be obtained with a strategy of long-term oral therapy, with consideration to patient preference regarding the timing (early vs at the time of relapse) and number (1 vs 2) of transplants.49 If disease control is the goal, then it is desirable to have a treatment algorithm that takes into account patients’ needs, goals, and attitudes toward overall survival vs quality of life. Physicians who choose this approach look to supporting data from 3 randomized trials showing that survival is similar whether ASCT is done early (immediately after induction therapy) or delayed (at the time of first relapse),32,50,51 as well as to trials that have not shown a clear overall survival advantage with double ASCT.52-54 Physicians who prefer this approach also use as supporting evidence a Spanish randomized trial in which patients who responded to induction therapy had similar overall survival and PFS with either ASCT or continued chemotherapy,55 suggesting that patients with disease refractory to induction therapy benefit the most from ASCT.56,57

Allogeneic Transplant

Only a small percentage of patients with myeloma meet the eligibility requirements for allogeneic transplant: appropriate age, availability of a human leukocyte antigen–matched sibling donor, and adequate organ function.58 The high treatment-related mortality, mainly related to graft-vs-host disease, has made conventional allogeneic transplants unacceptable for most patients with myeloma, even though it is currently the only potentially curative approach. Several recent trials have been conducted using ASCT followed by a reduced-intensity ASCT (nonmyeloablative or mini-allogeneic transplant).59 The main concerns with this approach are relatively high early mortality and morbidity; treatment-related mortality is approximately 15%, and there is a high risk of acute and chronic graft-vs-host disease. Further clinical trials have resulted in conflicting results.60,61 For those who favor a curative approach, the data available and the potential for cure are sufficient to justify this therapy outside of a clinical trial setting in high-risk patients. In contrast, for others this form of therapy cannot be justified outside of a clinical trial until further data are available.

Cure or Control?

The cure-vs-control debate colors the approach to the treatment of smoldering (asymptomatic) disease, duration of therapy, choice of drugs, and many other clinical decisions in myeloma. It also substantially affects the interpretation of study results and the approach to the care of patients with myeloma.

So, should it be cure or control in myeloma? In the setting of designing and conducting clinical trials, both strategies should be explored simultaneously. Some patients desire a potentially curative approach and are not greatly concerned about the risk of adverse events, whereas others think quality of life is more important than overall survival and are unwilling to risk their quality of life for a potential cure. Having clinical trials available to cater to both types of patients is important. For example, the Mayo Clinic myeloma group is currently pursuing an approach with single-agent lenalidomide as initial therapy for myeloma with other drugs added as needed, with an emphasis on quality of life and disease control. At the same time, we are testing a multidrug combination strategy with 4 active agents in the attempt to develop a curative “myeloma CHOP (cyclophosphamide-hydroxydaunomycin [doxorubicin]-vincristine [Oncovin]-prednisone)” regimen; the CHOP regimen has been used successfully to cure large cell lymphoma. Thankfully, many centers have a similar selection of trials targeting both options.

Outside of a clinical trial setting, I prefer disease control as the treatment goal, except in selected high-risk patients in whom an aggressive approach to achieving CR may be the only route to long-term survival.62-65 The disease control approach involves targeting very good partial response (minimal residual disease) rather than CR as a goal; using limited, less intense therapy first and moving to more aggressive approaches as need arises (sequential approach); allowing patients to help determine the timing and number of transplants (patient choice); and avoiding allogeneic transplant. Although cure is the ultimate goal of our long-term research, we need more data from randomized trials before resorting to highly intense therapy that is more toxic and unlikely to lead to a cure outside the setting of a clinical trial. On this one point, proponents of both cure and control can agree.

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Lacy MQ, Gertz MA, Dispenzieri AA, et al. Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc. 2007;82(10):1179-1184.

Facon T, Mary JY, Harousseau JL, et al. Front-line or rescue autologous bone marrow transplantation (ABMT) following a first course of high dose melphalan (HDM) in multiple myeloma (MM): preliminary results of a prospective randomized trial (CIAM protocol) [abstract 2729]. Blood. 1996;88 (suppl 1, pt 1):685a.

Barlogie B, Kyle R, Anderson K, et al. Comparable survival in multiple myeloma (MM) with high dose therapy (HDT) employing MEL 140 mg/m2 + TBI 12 Gy autotransplants versus standard dose therapy with VBMCP and no benefit from interferon (IFN) maintenance: results of Intergroup Trial S9321 [abstract A-135]. Blood. 2003;102(11):42a.

Cavo M, Cellini C, Zamagni E, et al. Superiority of double over single autologous stem cell transplantation as first-line therapy for multiple myeloma [abstract A536]. Blood. 2004;104:155a.

Fermand JP, Alberti C, Marolleau JP. Single versus tandem high dose therapy (HDT) supported with autologous blood stem cell (ABSC) transplantation using unselected or CD34-enriched ABSC: results of a two by two designed randomized trial in 230 young patients with multiple myeloma (MM) [abstract P10.2.2]. Hematol J. 2003;4(suppl 1):S59.

Goldschmidt H. Single vs. tandem autolgous transplantation in multiple myeloma: the GMMG experience [abstract]. Hematol J. 2003;4(suppl 1):S61.

Bladé J, Sureda A, Ribera JM, et al. High-dose therapy autotransplantation/intensification versus continued conventional chemotherapy in multiple myeloma patients responding to initial chemotherapy: definitive results from PETHEMA after a median follow-up of 66 months [abstract 137]. Blood. 2003;102(11, pt 1):42a-43a.

Rajkumar SV, Fonseca R, Lacy MQ, et al. Autologous stem cell transplantation for relapsed and primary refractory myeloma. Bone Marrow Transplant. 1999;23(12):1267-1272.

Bladé J, Esteve J. Treatment approaches for relapsing and refractory multiple myeloma. Acta Oncol. 2000;39(7):843-847.

Bensinger WI. The current status of reduced-intensity allogeneic hematopoietic stem cell transplantation for multiple myeloma. Leukemia. 2006 Oct;20(10):1683-1689. Epub 2006 Aug 3.

Crawley C, Lalancette M, Szydlo R, et al; Chronic Leukaemia Working Party of the EBMT Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT. Blood. 2005 Jun 1;105(11):4532-4539. Epub 2005 Feb 24.

Garban F, Attal M, Michallet M, et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood. 2006 May 1;107(9):3474-3480. Epub 2006 Jan 5.

Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007;356(11):1110-1120.

Haessler J, Shaughnessy JDJr, Zhan F, et al. Benefit of complete response in multiple myeloma limited to high-risk subgroup identified by gene expression profiling. Clin Cancer Res. 2007;13(23):7073-7079.

Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007 Jan;21(1):151-157. Epub 2006 Nov 9.

Sagaster V, Ludwig H, Kaufmann H, et al. Bortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a chromosome 13q-deletion. Leukemia. 2007 Jan;21(1):164-168. Epub 2006 Nov 9.

Moreau P, Attal M, Garban F, et al; SAKK; IFM Group Heterogeneity of t(4;14) in multiple myeloma: long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials. Leukemia. 2007 Sep;21(9):2020-2024. Epub 2007 Jul 12.

Updates from Inside Blood 9/28/08

Blood, 15 September 2008, Vol. 112, No. 6, pp. 2177-2178.

NEOPLASIA

Comment on Oerlemans, page 2489
Many facets of bortezomib resistance/susceptibility
Shaji Kumar, and S. Vincent Rajkumar
MAYO CLINIC
In this issue of Blood, Oerlemans and colleagues present a fascinating report, detailing a mechanism by which cells acquire resistance to therapy with the proteasome inhibitor, bortezomib.
Proteasome inhibition represents one of the most successful anticancer strategies of this decade, improving the outcomes of many patients. The ubiquitin proteasome pathway is critical to normal cellular functioning and is involved in signal transduction, transcriptional regulation, and response to stress, among other pathways. The 26S proteasome consists of a core 20S catalytic complex and a 19S regulatory complex, forming 2 outer and 2 inner rings that are stacked to form a cylindrical structure.1 The 19S complex is responsible for selecting the ubiquitinated proteins for catalytic degradation by the 20S complex, which possesses chymotryptic, tryptic, and peptidylglutamyl-like activities. This critical cellular function has been successfully targeted for cancer therapy, as highlighted by the efficacy of proteasome inhibitor bortezomib in a wide spectrum of hematological and solid tumors.2 In fact, the introduction of bortezomib resulted in a paradigm shift in the treatment of multiple myeloma, and has undoubtedly contributed to the improved survival seen among patients with this incurable malignancy.3 The mechanism of antimyeloma activity of bortezomib is the subject of intense study. Bortezomib is currently believed to exert its effects through multiple pathways that target both the tumor cell and its microenvironment. For example, inhibition of the NFkB pathway leading to decreased cell proliferation and induction of apoptosis is one of the major effects of bortezomib therapy. Treatment with bor-tezomib prolongs survival in relapsed myeloma as well as newly diagnosed disease, leading to its regulatory approval for clinical use in both situations.4 However, resistance to therapy develops inevitably. Furthermore, nearly a third of the patients with multiple myeloma never respond to treatment with bortezomib, depending on the clinical situation. While some resistance mechanisms may be reversible in a small proportion of patients following withdrawal of the drug, as demonstrated by the efficacy of retreatment, the majority need to switch therapy. Understanding the mechanisms of resistance to proteasome inhibition will not only allow better use of proteasome inhibitors such as bortezomib, but should also allow the rational design of synergistic drug combinations.

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Mechanisms of resistance and susceptibility to proteasome inhibition. Signaling through canonical or noncanonical pathways leads to phosphorylation, ubiquitination, and subsequent degradation of the IkB kinases through the proteasome pathway, resulting in NFkB translocation to the nucleus and transcription of target genes. Constitutive NFkB signaling can result from mutations in regulatory genes, such as Traf3, leading to increased sensitivity of the cell to proteasome inhibition. Mechanisms of resistance include: (1) the 26S proteasome acquiring resistance due to mutations or overexpression of the PSMB5 subunit; (2) proteasome inhibitors being antagonized by upregulation of heat shock proteins, such as Hsp27; and (3) increased activity of the aggresome pathway. These resistance mechanisms can be targeted to increase the efficacy of proteasome inhibition.

Malignant cells may develop several mechanisms to escape the effects of proteasome inhibition, including alterations in the proteasome complex itself leading to decreased function, increasing the efficiency of alternate mechanisms of protein degradation (the aggresome pathway), or modulation of cell signaling pathways that are affected by proteasome inhibition. Oerlemans et al, in this issue of Blood, report on a mutation involving the β5 unit of the proteasome catalytic unit (PSMB5) that leads to impaired binding of bortezomib and thus decreased proteosome inhibition. These investigators also noted a significant upregulation of the PSMB5 subunit following exposure to bortezomib and other proteasome inhibitors, an effect that wanes with time off-therapy, but reappears rapidly after re-exposure to the inhibitors. These studies were carried out using human monocytic/macrophage THP1 cells, and whether these findings are applicable to malignant cells in diseases like myeloma is unclear. However, these findings do highlight the susceptibility of proteasome units to genetic modifications under constant selection pressure, as can occur with continued treatment in patients. Mutation and overexpression of PSMB5 can lead to bortezomib resistance in lymphoma cells lines. While mutations such as this may explain development of resistance, baseline differences in susceptibility may be due to polymorphisms involving the PSMB5 locus.5
An alternate mechanism used by the cell for ubiquitinated protein degradation and disposal is the aggresome pathway, which can potentially compensate for proteasome pathway inhibition and contribute to drug resistance. This physiological compensatory mechanism has been targeted for enhancing the efficacy of proteasome inhibitors. Use of HDAC6 specific inhibitors, such as tubacin, can shut down the aggresome pathway and can synergize with and enhance the effect of proteasome inhibition on the tumor cell.6 Upregulation of the heat shock protein Hsp27 is yet another mechanism of proteasome inhibitor resistance and has been targeted as an avenue for enhancing proteasome inhibition as well as reversing resistance to this class of drugs.7
Finally, identification of mechanisms that confer sensitivity to proteasome inhibition is as important as understanding mechanisms of resistance. Recent studies have identified mutations involving genes associated with regulation of NFkB pathways that result in constitutive activation of the NFkB pathway.8 Cells that carry these mutations appear to be particularly sensitive to the effects of proteasome inhibition, a finding that could allow us to tailor the use of this class of drugs in the future.
Footnotes
Conflict-of-interest disclosure: The authors declare no competing financial interests.
REFERENCES
Adams J. The proteasome: structure function, and role in the cell. Cancer Treat Rev. 2003;29(suppl 1):3–9.[Medline] [Order article via Infotrieve]
Rajkumar SV, Richardson PG, Hideshima T, et al. Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol. 2004;23:630–639.[CrossRef]
Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516–2520.[CrossRef][Medline] [Order article via Infotrieve]
Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487–2498.[Abstract/Free Full Text]
Wang L, Kumar S, Fridley BL, et al. Proteasome {beta} subunit pharmacogenomics: gene resequencing and functional genomics. Clin. Cancer Res. 2008;14:3503–3513.[Abstract/Free Full Text]
Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A. 2005;102:8567–8572.[Abstract/Free Full Text]
Chauhan D, Li G, Shringarpure R, et al. Blockade of Hsp27 overcomes bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res. 2003;63:6174–6177.[Abstract/Free Full Text]
Keats JJ, Fonseca R, Chesi M, et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell. 2007;12:131–144.[CrossRef][Medline] [Order article via Infotrieve]
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Blood First Edition Paper, prepublished online September 17, 2008; DOI 10.1182/blood-2008-02-141614.
Submitted February 26, 2008
Accepted July 25, 2008
Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure
Michael Wang*, Meletios A. Dimopoulos, Christine Chen, M. Teresa Cibeira, Michel Attal, Andrew Spencer, S. Vincent Rajkumar, Zhinuan Yu, Marta Olesnyckyj, Jerome B Zeldis, Robert D Knight, and Donna M Weber
Department of Lymphoma and Myeloma, M.D. Anderson Cancer Center, Houston, TX, United States
Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece
Department of Medicine, Princess Margaret Hospital, Toronto, ON, Canada
Hematology Department, Institute of Hematology and Oncology, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain
Division of Hematology, Centre Hospitalier Universite de Purpan, Toulouse, France
Department of Malignant Hematology and Stem Cell Transplantation Service, The Alfred Hospital, Melbourne, Australia
Mayo Clinic Cancer Center, Rochester, MN, United States
Celgene Corporation, Summit, NJ, United States
* Corresponding author; email: miwang@mdanderson.org .
This analysis assessed the efficacy and safety of lenalidomide+dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. Of 704 patients, 39% were thalidomide-exposed. Thalidomide-exposed patients had more prior lines of therapy and longer duration of myeloma than thalidomide-naive patients. Lenalidomide+dexamethasone led to higher overall response rate (ORR), longer time-to-progression (TTP) and progression-free survival (PFS) versus placebo+dexamethasone despite prior thalidomide exposure. Among lenalidomide+dexamethasone-treated patients, ORR was higher in thalidomide-naive versus thalidomide-exposed patients (p=.04), with longer median TTP (p=.04) and PFS (p =.02). Likewise for dexamethasone alone-treated patients (p =.03 for ORR, p =.03 for TTP, p=.06 for PFS). Prior thalidomide did not affect survival in lenalidomide+dexamethasone-treated patients (36.1 vs. 33.3 months, p > .05). Thalidomide-naive and thalidomide-exposed patients had similar toxicities. Lenalidomide+dexamethasone resulted in higher rates of venous thromboembolism, myelosuppression and infections versus placebo+dexamethasone, independent of prior thalidomide exposure. In conclusion, lenalidomide+dexamethasone was superior to placebo+dexamethasone in relapsed or refractory MM, independent of prior thalidomide exposure. Although prior thalidomide may have contributed to inferior TTP and PFS compared with thalidomide-naive patients, these parameters remained superior compared with placebo+dexamethasone; similar benefits compared with placebo+ dexamethasone were not evident for thalidomide-exposed patients in terms of overall survival. Studies were registered at www.clinicaltrials.gov under: NCT00056160 and NCT00424047.
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
Blood First Edition Paper, prepublished online September 19, 2008; DOI 10.1182/blood-2008-02-140434.
Submitted February 22, 2008
Accepted August 24, 2008
Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping
David C Johnson, Sophie Corthals, Christine Ramos, Antje Hoering, Kim Cocks, Nicholas J Dickens, Jeff Haessler, Harmut Goldschmidt, J. Anthony Child, Sue E Bell, Graham Jackson, Dalsu Baris, S. Vincent Rajkumar, Faith E Davies, Brian G.M. Durie, John Crowley, Pieter Sonneveld, Brian Van Ness, and Gareth J Morgan*
Institute of Cancer Research, London, United Kingdom
Erasmus Medical Center, Rotterdam, Netherlands
University of Minnesota, Minneapolis, MN, United States
Cancer Research and Biostatistics (CRAB), Seattle, WA, United States
University of Leeds, Leeds, United Kingdom
University of Heidelberg, Heidelberg, Germany
University of Newcastle, Newcastle, United Kingdom
National Cancer Institute, Bethesda, MD, United States
Mayo Clinic, Rochester, MN, United States
Cedars-Sinai Medical Center, Los Angeles, CA, United States
* Corresponding author; email: gareth.morgan@icr.ac.uk .
A venous thromboembolism (VTE) with the subsequent risk of pulmonary embolism is a major concern in the treatment of multiple myeloma patients with thalidomide. The susceptibility to developing a VTE in response to thalidomide therapy is likely to be influenced by both genetic and environmental factors. To test genetic variation associated with treatment related VTE in patient peripheral blood DNA, we used a custom-built molecular inversion probe (MIP) based single nucleotide polymorphism (SNP) chip containing 3404 SNPs. SNPs on the chip were selected in “functional regions” within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response and side effects associated with myeloma therapy. Cases and controls were taken from three large clinical trials: MRC Myeloma IX, Hovon-50 and ECOG EA100, which compared conventional treatments with thalidomide in myeloma patients. Our analysis showed that the set of SNPs associated with thalidomide-related VTE were enriched in genes and pathways important in drug transport/metabolism, DNA repair and cytokine balance. The effects of the SNPs associated with thalidomide related VTE may be functional at the level of the tumor cell, the tumor-related microenvironment, and the endothelium. The clinical trials described in this paper have been registered as follows: MRC Myeloma IX: ISRCTN68454111, HOVON50: www.clinicaltrials.gov under identifier NCT00028886, and ECOG EA100: www.clinicaltrials.gov under identifier NCT00033332.
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Blood First Edition Paper, prepublished online September 24, 2008; DOI 10.1182/blood-2008-05-155952.

Submitted May 7, 2008
Accepted August 15, 2008
Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator
Yan Jiao, John Wilkinson IV, Xiumin Di, Wei Wang, Heather Hatcher, Nancy D. Kock, Ralph D’Agostino Jr., Mary Ann Knovich, Frank M. Torti, and Suzy V. Torti*
Department of Cancer Biology, Wake Forest University Health Sciences, Winston-Salem, NC, United States
Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC, United States
Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, United States
Section of Hematology/Oncology, Wake Forest University Health Sciences, Winston-Salem, NC, United States
Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, NC, United States
Department of Biochemistry, Wake Forest University Health Sciences, Winston-Salem, NC, United States
* Corresponding author; email: storti@wfubmc.edu .
Curcumin is a natural product currently in human clinical trials for a variety of neoplastic, preneoplastic and inflammatory conditions. We previously observed that in cultured cells, curcumin exhibits properties of an iron chelator. To test whether the chelator activity of curcumin is sufficient to induce iron deficiency in vivo, mice were placed on diets containing graded concentrations of both iron and curcumin for 26 weeks. Mice receiving the lowest level of dietary iron exhibited borderline iron deficiency, with reductions in spleen and liver iron, but little effect on hemoglobin, hematocrit, transferrin saturation or plasma iron. Against this backdrop of subclinical iron deficiency, curcumin exerted profound effects on systemic iron, inducing a dose-dependent decline in hematocrit, hemoglobin, serum iron and transferrin saturation, the appearance of microcytic anisocytotic red blood cells, and decreases in spleen and liver iron content. Curcumin repressed synthesis of hepcidin, a peptide that plays a central role in regulation of systemic iron balance. These results demonstrate that curcumin has the potential to affect systemic iron metabolism, particularly in a settling of subclinical iron deficiency. This may affect the use of curcumin in patients with marginal iron stores or those exhibiting the anemia of cancer and chronic disease.

Combination Therapy Helps to Combat Myeloma 9/28/08

By Steven Reinberg
HealthDay Reporter

WEDNESDAY, Aug. 27 (HealthDay News) — Patients with multiple myeloma who could not tolerate high dose chemotherapy lived longer and better by adding the drug Velcade to standard treatment, a new study found.

The finding could make multiple myeloma, a cancer of the blood’s plasma cells, a chronic rather than a lethal disease. And it would be particularly valuable to older patients and those with medical conditions that preclude them from receiving high doses of the standard drug therapies melphalan and prednisone, or a transplant, experts said.

“The addition of bortezomib (Velcade) resulted in significant prolongation in time to disease progression with a reduction of 52 percent in risk of progression,” said lead researcher Dr. Jesus F. San Miguel, of the Hospital Universitario de Salamanca in Spain. “There was also a significant prolongation of survival, with a 40 percent reduction in the risk of death.

The two-year survival rate among patients taking Velcade with melphalan and prednisone was 82 percent, compared with 69 percent among patients not receiving Velcade, San Miguel said.

The findings are published in the Aug. 28 issue of the New England Journal of Medicine.

San Miguel’s team randomly assigned 682 patients with newly diagnosed myeloma to nine six-week cycles of treatment with melphalan and prednisone, or treatment with the two drugs plus Velcade. They found that the time to disease progression among patients receiving Velcade was 24 months, compared with 16.6 months among those getting melphalan and prednisone alone.

Also, 71 percent of the patients receiving Velcade had a partial response to treatment, compared to 35 percent of those receiving melphalan and prednisone alone. And complete responses to treatment were seen among 30 percent of those receiving Velcade, compared to 4 percent for those given Alkeran and prednisone alone.

Responses to treatment continued for 19.9 months among those given Velcade, compared to 13.1 months for those not given the drug.

“The benefit of Velcade was not only observed in good-risk patients, but also in high-risk patients,” San Miguel said. “We now have a new standard of care for newly diagnosed patients.”

Dr. Bart Kamen, chief medical officer of the Leukemia & Lymphoma Society, thinks this new drug combination could be a real benefit for myeloma patients who aren’t eligible for high-dose chemotherapy or a transplant.

“We are in a new era in the treatment of myeloma,” Kamen said. “We have a new paradigm of relatively easy drugs compared to the usual chemotherapy, which is adding to quality of life and longevity in myeloma. That’s a big deal.”

Kamen believes this new treatment and others being developed may make myeloma a chronic condition that can be controlled. “The future, with repetitive doses of lower doses of medicine to control the myeloma, is clearly surfacing,” he said.

Dr. Len Lichtenfeld, deputy chief medical officer at the American Cancer Society, agreed that this new treatment is a viable option for patients who are ineligible for standard myeloma treatment.

“It’s an exciting time in the treatment of myeloma, and this treatment represents a significant additional option for patients with myeloma who are not candidates for transplant, those who are over 65 or may have other significant illnesses that prevent them from being considered for transplant,” Lichtenfeld said.

Until recently, myeloma was a disease with a very limited life expectancy, Lichtenfeld said. “Now, with all the new treatments we have, be it the bone marrow transplant or whether it be the use of the newer drugs, the outlook for myeloma patients has improved considerably,” he said.

These treatments don’t mean the disease can be cured, Lichtenfeld said. “But we are clearly in a situation where we have made substantial progress,” he said.

EU approves VELCADE for all stages of multiple myeloma 9/9/08

EU approves VELCADE for all stages of multiple myeloma
Source: (cancerfacts.com)
Tuesday, September 09, 2008

HIGH WYCOMBE, England – Sept. 9, 2008 – The European Commission has approved VELCADE® in combination with melphalan and prednisone for the first-line treatment of patients with multiple myeloma who are not eligible for high-dose chemotherapy with bone marrow transplant. The approval was announced today by Janssen-Cilag / Ortho Biotech the biotech partnership that is marketing the drug in Europe.

In 2005, VELCADE was approved in the European Union for multiple myeloma after first relapse. VELCADE as a treatment by itself has already been approved in 87 countries for the treatment of multiple myeloma patients who have relapsed and, or did not respond to other treatments.

This approval for frontline treatment is based on phase III results from the VISTA trial, recently published in the New England Journal of Medicine, which demonstrated statistically superior results across all effectiveness measures compared to melphalan and prednisone. In particular, complete response (CR) rates were similar to those that have been achieved in the transplant setting. VISTA stands for: VELCADE as Initial Standard Therapy in Multiple Myeloma: Assessment with melphalan and prednisone results.

“VELCADE has already made an important contribution for patients with multiple myeloma at first relapse,” said Professor Jesus San Miguel, M.D., University of Salamanca in Spain, the principal investigator for the VISTA trial. “The marketing authorization from the EMEA is encouraging as it suggests that more patients may benefit from earlier treatment.”

Multiple myeloma is the second most common blood cancer, representing approximately one percent of all cancers and two percent of all cancer deaths. In 2002, there were approximately 85,700 cases of multiple myeloma worldwide. Currently, only 30 percent of MM patients survive longer than five years with more than 18,000 people in the European Union dying each year from the disease.

VELCADE is the first proteasome inhibitor to receive worldwide regulatory approval for the treatment of multiple myeloma. Proteasome inhibitors are drugs that block the action of large protein complexes, called proteasomes. These enzymes break down proteins, like the p53, a key component in the regulation of cell division. When P53 is mutated, cells in many types of tissues become unregulated and divide out of control.

Clinical trials are underway to investigate the potential of VELCADE in additional settings and in combination with other anti-cancer drugs to enhance treatment effects or reverse resistance.

The most common side effects reported with VELCADE include fatigue, gastrointestinal adverse events, transient loss of blood-clotting platelet cells and nerve effectiveness neuropathy, which is reversible in the majority of patients.

SOURCE: news release issued by Janssen-Cilag / Ortho Biotech via PRNewswire.

VELCADE For Multiple Myeloma Receives Front-line Approval In Canada

VELCADE (bortezomib) for Injection has received Health Canada approval for front-line (first) treatment of multiple myeloma, a fatal blood cancer. As part of combination therapy, VELCADE is indicated for the treatment of patients with previously untreated multiple myeloma who are unsuitable for stem cell transplantation. With this new approval, patients with multiple myeloma can now receive VELCADE earlier following initial disease diagnosis, which may help to slow, reverse or halt disease progression.

“Living with this relentless type of cancer for the past year, I know firsthand how debilitating the rapid progression of the disease can be,” says Monique Racine, a Canadian patient diagnosed with multiple myeloma. “By receiving VELCADE earlier in this disease, other patients may have an even greater benefit from the treatment. This medication, which has done so much good for me, has empowered me and given me a stronger desire to fight my disease.”

“Having access to proven effective combination therapies upon disease diagnosis is very important in the fight against multiple myeloma because it gives patients of this fatal disease a chance to extend their life expectancy and their quality of life,” comments Dr. Andrew Belch, Hematologist, Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta. “Multiple myeloma is an aggressive disease that advances rapidly, with the patient’s condition deteriorating exponentially. The front-line approval of VELCADE is a positive step forward and should bring renewed hope to multiple myeloma patients and their families.”

VELCADE’s front-line approval is based on the phase III VISTA (VELCADE as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) trial, recently published in the New England Journal of Medicine (NEJM)1. VISTA is a randomized, international, open-label phase III trial that Canadian investigators participated in. The trial compared VELCADE in combination with the current standard of care versus the standard of care alone in 682 previously untreated patients who were unsuitable for stem cell transplantation. VISTA demonstrated that patients receiving the standard of care plus VELCADE achieved a greater overall survival rate at 24 months (83 per cent) compared to those who only received standard of care alone (70 per cent) 2. The complete response in the VELCADE combination arm was 30 per cent versus four per cent in the standard of care arm alone2.

“The approval of VELCADE as a front-line therapy is a great step forward in the fight against this challenging disease,” says Dr. Donna Reece, Hematologist, Toronto, Ontario. “As a physician, it is outstanding that we now have an effective treatment to offer our patients immediately following diagnosis that can not only help to improve their quality of life, but can also extend their life this is so meaningful for both the patients and their families.”

About Multiple Myeloma in Canada

As of 2003, an estimated 6,200 Canadians have multiple myeloma3. In 2008, new cases of multiple myeloma are estimated to reach 2,1004, an increase of 13.5 per cent since 20055. Furthermore, the number of deaths from this disease in 2008 is estimated at 1,3504, which demonstrates an increase of eight per cent since 20055.

About VELCADE (bortezomib) for Injection

VELCADE offers a completely novel approach to treating multiple myeloma by acting on a unique target in cells called the proteasome. The proteasome is a structure that exists in all cells and plays an important role in breaking down proteins that control how the cell lives and grows.

VELCADE was first approved in Canada under a Notice of Compliance with Conditions in January 2005 for the treatment of patients with multiple myeloma who have relapsed following front-line therapy and are refractory to their most recent therapy.

VELCADE was also recently approved for the treatment of patients with mantle cell lymphoma (MCL), who have relapsed or are refractory to at least one prior therapy. MCL is a type of non-Hodgkin’s lymphoma, which is a cancer of the blood that affects the white blood cells.

VELCADE is currently funded across Canada for the treatment of relapsed or refractory multiple myeloma. Ortho Biotech will seek funding across Canada for this new indication of front-line treatment of newly diagnosed previously untreated multiple myeloma patients.

The safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. In most cases side effects are manageable with appropriate monitoring and if necessary, dose modification. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or any of the excipients. In the VISTA clinical trial, the most commonly reported adverse events included thrombocytopenia (decrease in blood clotting cells), neutropenia, leucopenia, lymphopenia, anemia, nausea, diarrhea, constipation, vomiting, peripheral neuropathy (numbness of the hands, arms, feet or legs), neuralgia, fever, fatigue and asthenia.

In Canada, VELCADE is marketed by Ortho Biotech, a division of Janssen-Ortho Inc.

Ortho Biotech – Division of Janssen-Ortho Inc.

Ortho Biotech (Canada) is a biopharmaceutical healthcare company and the leader in the treatment of anemia with a commitment to developing treatments for Canadians suffering from cancer.

Trademark of Millennium Pharmaceuticals, Inc., all trademark rights used under license

References

(1) Jf San Miguel, R Schlag, NK Khuageva, MA Dimopoulos, O Shpilberg, M Kropff, I Spicka, MT Petrucci, A Palumbo, OS Samoilova, A Dmoszynska, KM Abdulkadyrov, R Schots, B Jiang, M-V Mateos, KC Anderson, DL Esseltine, K Liu, A Cakana, H van de Velde, PG Richardson; VISTA-MMY-3002 study investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. NEJM 2008 [August 28, 2008].

(2) Product Monograph VELCADE, updated as of August 29, 2008.

(3) Calculated Canadian estimate based on US prevalence (according to “Orphan Products: Hope for People With Rare Diseases” By Carol Rados, FDA Consumer magazine, November-December 2003 Issue, about 63,000 people in the United States are affected by multiple myeloma).

(4) Canadian Cancer Society/National Cancer Institute of Canada: Canadian Cancer Statistics 2008, available at: http://www.cancer.ca.

(5) Canadian Cancer Society/National Cancer Institute of Canada: Canadian Cancer Statistics 2004, available at http://www.cancer.ca.

Look Good Feel Better from Cancer.net 9/24/08

Look Good Feel Better

Cancer and cancer treatments, such as chemotherapy, radiation therapy, and surgery, may change your appearance and how you feel about yourself. Common changes include hair loss and skin problems. It is common for people with cancer to feel anxious or distressed when these changes happen. One resource, the Look Good…Feel Better program, can help you restore your appearance to boost how you feel about yourself.

Look Good…Feel Better offers free support programs across the country for women affected by cancer. Volunteer cosmetologists provide makeover tips and advice on creating an appearance that allow women to feel better about themselves so they can approach their cancer treatment with greater confidence.

The Personal Care Products Council Foundation—the charitable arm of the Personal Care Products Council, which is the national representative for the cosmetics and personal care products industry, started Look Good…Feel Better two decades ago. With the help of the National Cosmetology Association and the American Cancer Society, Look Good…Feel Better delivers support programs to 50,000 women in the United States each year.

Cancer treatment and emotional well-being

Look Good…Feel Better believes that how you feel about yourself and your appearance while coping with cancer can have a dramatic effect on your emotional well-being. In 2002, Look Good…Feel Better sponsored a survey among women who had been treated for cancer within the last five years to understand overall quality of life during cancer treatment and how a woman’s appearance affects her sense of well-being.

About 79% of women said that cancer treatment had a somewhat negative or greatly negative influence on their psychosocial (emotional and social) well-being.

Two-thirds of the women indicated that cancer treatment had a somewhat or significant negative effect on their appearance.

Seventy-eight percent (78%) said they experienced some or significant changes in their appearance during treatment, and 83% of these women said that their overall quality of life was affected by cancer treatment.
Cosmetic tips and solutions offered by Look Good…Feel Better help with many of the physical and emotional side effects of cancer treatment and allow women and others to look beyond their cancer. While some people with cancer may plan for possible side effects and body changes, such as cutting their hair short or shaving it if it begins to fall out from treatment, others may desire to portray the physical image they are used to and the one with which they are comfortable. Deciding how to manage your appearance after such changes is a personal decision and one that should make you feel comfortable.

How Look Good…Feel Better works

Cosmetologists certified by Look Good…Feel Better lead groups of five to ten women in nearly 2,000 hospitals and cancer centers around the country. They guide a 12-step skin care and makeup application lesson, in addition to demonstrating options for nail care techniques and options for managing hair loss, such as wigs, scarves, and accessories. Women in various stages of cancer treatment share their appearance concerns and favorite beauty tips with each other.

Search for a group near you by visiting Look Good…Feel Better or by calling 800-395-LOOK (5665). Bilingual groups are offered in some cities. Look Good…Feel Better is also offered in 18 other countries around the world. Learn more about these programs on Look Good…Feel Better’s website.

An individual consultation by a cosmetologist may also be available to women who are unable to attend a group. What’s more, women can check out helpful makeover tips on the Look Good…Feel Better website. Here are a couple examples:

A concealer that is slightly lighter than your skin color may help cover dark patches, such as under-eye circles.

For nail treatment, a light moisturizer, cuticle cream, or even olive oil may help moisturize dry nails, as brittle or discolored fingernails is a common side effect in women undergoing chemotherapy.

When selecting a wig, choose a lighter shade than your natural color for a face-brightening effect.
Support for teens and men

Look Good…Feel Better also offers group programs for teen girls and boys at hospitals in 18 cities across the United States, and produces 2bMe, a website where teens can read valuable tips on all of the non-medical aspects of cancer care, such as hair and skin care, fitness, and friendships. Teens can also check out interactive style finder quizzes, how-to demos, and fashion slide shows on 2bMe.

For adult men undergoing cancer treatment, Look Good…Feel Better for Men is a practical guide that gives advice on how deal with some side effects, such as skin changes, hair loss, and stress. For example, some men may not be aware that using a concealer to hide facial discolorations and dark circles under the eyes is common for men with hyperpigmentation (dark spots) and sallow skin.

For more information about Look Good…Feel Better, call the toll free number at 800-395-LOOK (5665) or visit the website at www.lookgoodfeelbetter.org.

Managing and Treating Cancer Pain from Cancer.Net 9/24/08

Managing and Treating Cancer Pain (Part I)

Many people don’t know that nearly all cancer pain can be treated successfully, either with or without the use of medication. In addition, many options are available to control or prevent pain related to cancer. In this two-part series, learn practical tips to better manage your pain. This article discusses basic facts about cancer-related pain, medications used to control it, and tips to document and communicate your pain issues with your health-care team.

Facts about cancer-related pain

Pain in people with cancer may occur due to (1) the effects of the cancer itself; (2) side effects of the cancer treatment; and (3) causes unrelated to the cancer, including other diseases, such as arthritis and diabetes. The following are some important facts for you to know about cancer pain and pain management:

Emotional distress can worsen pain, and pain can contribute to emotional distress.

Sleep deprivation can intensify pain, and uncontrolled pain can lead to sleep deprivation.

Lack of communication with health-care providers can result in pain not being managed as well as it could be.

The most complete and potentially successful approach often combines medical treatment with nonmedical treatment in an individualized plan.
Communication is important

After a thorough medical assessment of any pain, it is important to discuss your concerns and develop a plan with your health-care team. Some hospitals have professionals called pain specialists who are trained in helping people manage cancer pain. Nurses, pharmacists, and other health-care professionals can also help you learn about your options for controlling pain.

Although having cancer doesn’t mean you will always have pain, it is important to talk with your doctor about any pain you are experiencing. He or she can help determine the cause of your pain and help select the best treatment options with you.

Patients know their own pain best. So, it is important to discuss the pain you are feeling with your doctor in as specific terms as possible. In fact, a doctor’s role in managing pain is to listen to patients and offer an effective pain control solution.

Consider keeping a pain diary noting the date, time, and intensity level.

Keep a record of when the pain started, how long it lasted, and what activities aggravated the pain.

Make sure you communicate to a member of your health-care team where the pain started and if the pain was specific to one area or spread to other parts of the body.

It may be helpful to describe pain on a scale of 0 to 10, in addition to using words that describe the type of pain, such as “burning,” “stabbing,” or “throbbing.”

Note what type of pain control method you tried for relief and its level of effectiveness.
Every person’s need for pain relief is different

The intensity, type, and location of pain experienced differs from person to person. Therefore, the options used to treat and manage pain should also be individualized and should remain flexible. When choosing a pain management strategy, the doctor, patient, and patient’s family need to consider the stage, location, and type of cancer; the intensity of the pain, the patient’s tolerance for pain (called pain threshold), personal preferences, and previous responses to treatment. Finding an effective pain management solution is a collaboration between the cancer care team, the patient, and the family.

Controlling cancer pain

Controlling pain caused by cancer should be part of the overall cancer treatment plan. Preventing pain from occurring or worsening is one of the most effective ways to treat pain caused by cancer. When using medications to treat pain, patients should receive the medication at regular, scheduled intervals, with “rescue” doses for breakthrough pain (pain that surges suddenly through regular pain medications). Rarely is addiction to pain medication a problem. However, if it becomes a problem, there are still ways to manage the pain, even if pain medications called opioids (also called narcotics) are needed. When pain is not managed correctly, a person may experience fatigue, depression, anger, worry, and stress. With effective pain management, people can remain active, sleep better, improve their appetite, and enjoy activities and time spent with family and friends.

Doctors can treat pain in several ways.

Treating the source of the pain (such as the tumor or inflammation)

Changing the perception of pain (usually with pain medications)

Interfering with pain signals sent to the brain (through techniques such as spinal treatments or nerve blocks, whereby pain medication is injected into a nerve or surrounding a nerve to interfere with a pain signal)
Often, if pain control is not achieved, switching the dose or type of medication may be helpful, as there are many different drugs and ways to give them, depending on the source of the pain and the person’s overall health.

You may experience some side effects while taking pain medication. Opioids, which are used for moderate to severe pain, can cause constipation, nausea, sleepiness, confusion, or hallucinations. Several opioids are marketed under various brand names, but the generic names include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Opioids used for breakthrough pain include fentanyl and fentanyl citrate. Also, short-acting versions of hydrocodone, hydromorphone, morphine, oxycodone, and oxymorphone may be used. Be sure to tell your doctor if you experience any side effects from your pain medication, as most side effects are easily treatable, sometimes by changing the timing, dose, or type of drug.

Managing and Treating Cancer Pain (Part II)

Many people have found that other methods besides drugs help control pain. This second article of a two-part series discusses other pain management techniques and ways to track their success.

Your doctor should be able to help you manage pain using more than one method. Share with your doctor any methods that have worked well for you. Ask if they have any suggestions for nonmedical treatment, and if there are any special considerations when selecting techniques in your situation. Make your pain management a priority in your care; you deserve to feel your best.

Self-care and support techniques as a supplement to medical care

The following techniques have helped many people with cancer achieve better pain management:

Counseling and support groups. Talking with a trained counselor or attending a cancer support group may provide a valuable forum for addressing worries about cancer and pain and help you develop coping strategies. Hearing about techniques that have worked for others in the same situation may help you identify what might work for you. Discussing concerns and getting support may also help relieve some of the physical and emotional tension that can make pain worse.

Imagery and visualization. Many imagery techniques are useful for pain and discomfort associated with treatment. The “magic glove” is a technique in which you imagine putting on a glove before getting a needle stick, and visualize that the glove protects your hand from the sensation of pain. The “light switch” method involves visualizing a light switch that you can control and that has the power to turn off pain signals. Or, you may benefit from simple visualization exercises in which you imagine a peaceful scene or a favorite memory, listen to music and imagine that music melting away your discomfort or lifting your pain away, or create a mental picture of a healing light that takes pain up and away.

Massage. A qualified massage therapist who has experience working with people with cancer can provide gentle therapeutic massage to alleviate tension, discomfort, and pain. Simple massage techniques including gentle, smooth, circular rubbing of feet, hands, or back can be done at home by a caregiver. You can also massage yourself by applying light, even pressure to your hands, arms, neck, and forehead.

Heat and cold. Many people with cancer find that applying hot or cold compresses, heating pads, or ice packs to aching, sore, or painful areas of the body can diminish discomfort. Discuss this approach with a health-care provider and follow any special instructions, particularly during or after radiation therapy or chemotherapy. Start with short applications of 5 to 10 minutes at moderate temperatures. Make sure not to apply heat or cold directly on bare or injured skin or to areas that have received recent radiation therapy. Wrap ice packs and compresses in a towel to protect skin and use heating pads over clothing, a sheet, or a towel. Gradually experiment with temperatures to find a method that provides relief comfortably. A warm bath is another way to get heat evenly applied to a large area at once.

Breathing exercises. Gentle breathing exercises can enhance relaxation, reduce tension, and decrease pain. They can be done while sitting up in a chair, arms relaxed gently at the sides, or while lying down in a reclining chair or bed. Try breathing in through the nostrils, counting one, two; then breathing out through the mouth, counting one, two. Continue for five minutes initially, gradually working up to 20 minutes. Or, while breathing gently in and out, repeat a calming word such as “peace” or “relax” with each inhalation.

Distraction. Activities such as taking a warm bath, reading a book, watching television or a movie, drawing, doing needlework, listening to music, or taking a short walk outdoors can provide an engaging way to distract the mind from pain. Choose an activity or media that will create the mood desired: relaxing, upbeat, soothing. While the mind is actively engaged in the chosen activity, many people find that their pain is diminished.

Table to track pain reduction

Health-care providers are often interested in tracking your success with pain management techniques. One idea is to create a table (see below) with the days of the week across the top and things you would like to track down the side, such as time of day, supportive techniques, activity level, or anything else you can think of. It’s not necessary to fill in every box every day. Simply write down what you can remember from your days and look for the trends of what is working for you. Pick a level you would like to reach; for example, a pain rating of 3 or less. At the end of the week, highlight all days in which you had that score or lower, and you will be able to see which situations and techniques are helping you on the road toward being pain-free.