 Early detection offers the best chance for a cure. Screening guidelines vary; talk to your healthcare provider to determine what is right for you based on your individual risk factors. The Seattle Cancer Care Alliance supports the American Cancer Society’s recommendation that women begin annual mammography screening at age 40.

 Numerous studies show that doctors who specialize in mammography are more accurate at interpreting the images when compared to physicians with less experience. Get your mammogram read by a doctor who specializes in reading them. The American College of Radiology offers an online search for accredited facilities and “Breast Imaging Centers of Excellence.”

 Centers that specialize in digital mammography are best for women with dense breast tissue and for women under age 50. Digital scans can do a better job of detecting cancer in these women than traditional film mammography.

4. Don’t put off screening because of discomfort.

 A mammogram should never be painful. Fear that the exam will be uncomfortable is one reason women put off scheduling a mammogram. To reduce discomfort, try to schedule the exam after your monthly period, when breast tissue is less sensitive. You may benefit by taking an over-the-counter anti-inflammatory such as ibuprofen or acetaminophen before your mammogram. Above all, tell the mammography technologist about any discomfort you may be experiencing.

5. Don’t put off screening because of fear.

 Most abnormalities found after a mammogram are not cancer. However, in some cases additional mammography or ultrasound is needed to confirm the area on the screening mammogram is normal. That’s why you may be asked to return for a follow-up exam.

6. Consider getting results while you wait.

 Particularly for your first mammogram, you may want to schedule your exam so you receive your results before you leave the imaging center. Or if you have found that you are frequently called back to your mammography center for a second scan, you can ask that your appointment include getting results to you while you wait.

 Know how your breasts feel normally. Your healthcare provider can show you how to do a breast self-exam. If you notice a change in your breasts, such as a lump or swelling, skin irritation, or dimpling, talk to your healthcare provider.

 The American Cancer Society recommends that women aged ≥40 years should receive annual clinical breast exams. Women in their 20s and 30s should have a clinical breast exam as part of a periodic health exam by a health professional at least every 3 years.

 If you have family members who had breast cancer, especially a mother or sister, and if they had breast cancer before reaching menopause, tell your doctor, as your own risk of cancer may be higher than average. For example, a 20% increase in risk could mean that you should have an annual MRI in addition to a screening mammogram.

 The Breast Cancer Risk Assessment Tool, designed by the National Cancer Institute, is a questionnaire to help women determine their chances of developing invasive breast cancer. You can find it online at 

Dr Lehman is the director of Breast Imaging and the Medical Director of Radiology at the Seattle Cancer Care Alliance in Washington. Reprinted with permission from the Fred Hutchinson Cancer Research Center. 

Articles

Early detection offers the best chance for a cure.

10 Tips for Breast Cancer Screening and Early Detection

It was a cloudless January day in Los Angeles, and Ron Rogers was zipping right along.

	Out of bed at 6:30 am, the chief executive officer was in his Century City office at The Rogers Group, his public relations firm, for breakfast by 8 am. It was a Wednesday, so he didn’t have his usual workout, a 2-mile hike through the Santa Monica Mountains followed by weightlifting.

	His schedule was full: a morning of strategy meetings with clients and staff, of planning for fundraisers, and of “talking to my friends in the media”—PR-speak for lobbying&mdash; then lunch at Ivy at the Shore in Santa Monica. After that it was back to the office for a board meeting of the Los Angeles Fire Department Foundation, some desk work, then a plane ride to a northern California horse auction, followed by several more days at his 1200-acre cattle ranch in Colorado, where an untold number of his 200 cows were due to give birth.

	Mention of the ranch launched Rogers into a happy description of how cows give birth at all hours, requiring countless visits to snowy pastures every 3 or 4 hours, and of how he had been recently trying to rope a friend into going to Colorado with him.

	“I want to see if I can work him for 3 or 4 days,” Rogers says. “When I am up there it’s the only time our foreman gets a break. I told [my friend], ‘I have a chore for you that involves a very long glove.’”

	Rogers seems in the prime of his life, a 67-year-old, happily married, highly energetic and successful businessman whose biggest gripe on this particular day was waiting in a doctor’s office for 15 minutes for a treatment. “I never understand,” he says, “why you end up waiting in a doctor’s office. I don’t keep my clients waiting… It’s an old peeve of mine.”

	You’d never know that Rogers has had multiple myeloma for almost 11 years—and that’s just the way he likes it.

	“It’s a minor inconvenience,” Rogers says of the cancer. “There were maybe 2 or 3 times where I didn’t feel good. [Yet] I can still say the whole thing is a minor inconvenience compared to what I have seen other people, friends, parents, go through. I have been very fortunate.”

	Living with a disease that may be terminal within 5 years of diagnosis was for Rogers a slow climb out of a well of fear into what today feels more like an occasional splash of anxiety. A patient of oncologist James Berenson, MD, he is tested monthly at Berenson’s Institute for Myeloma & Bone Cancer Research in West Hollywood and always feels, he says, some nervousness before an exam.

	“There have been times when I have been on some of the chemotherapies that Dr Berenson has brewed up that have knocked me for loop for 2 or 3 months,” Rogers says. “I’ll be tired, leaving the office at 2:30 pm and generally dragging my tail, but those times have been very few. The rest of the time, when he is not trying to do me in, I am pretty active.”

	Exactly why Rogers has done so well is something of a mystery to him and his wife, 65-year-old Los Angeles attorney Lisa Specht. Their reasons are, medically speaking, nonspecific: Rogers’ good physical shape and positive attitude and Berenson’s cocktail of antimyeloma drugs and therapies.

	“Everything he has done for Ron has been right. Everything,” Specht said of Berenson. “Yes, there have been some side effects. Once in awhile Ron gets a side effect that’s really unpleasant, but he doesn’t go into major depression. His idea of major depression is to go read a book by himself. He is not a weeper. He is not having a pity party for himself.”

	Rogers’ stoicism might come from his having had a pretty full and satisfying life. The son of a Hollywood press agent, he has what was later found to be dyslexia and left school in the eleventh grade. Always business- and ranching-minded, and introduced to horses when he was 13, Rogers was buying and selling stallions at age 17. He started his own car parking business at 19.

	A brief stay in the mailroom at his father’s press agency followed. Alfred Bloomingdale, heir apparent of the department store fortune, hired him as a sort of business mechanic. Rogers spent several years guiding many Bloomingdale-bought businesses into the black before returning to his father’s agency, Rogers & Cowan. He worked as a set publicist on television programs such as The Andy Griffith Show, Ron Rogers with wife Lisa Specht and their cat Tigger at their Colorado cattle ranch.Gunsmoke, and Walt Disney’s Wonderful World of Color. Still, Hollywood wasn’t really his thing.

		Ron Rogers with wife Lisa Specht and their cat Tigger at their Colorado cattle ranch.

	“I just didn’t like the lack of ethics and loyalty of many of the people I came in contact with at the time, except for a few people I worked for when I was a kid,” Rogers says.

	Rogers had formed his own agency, then called Rogers & Associates, serving clients such as Dole, Raytheon, and Whole Foods, when multiple myeloma struck. A week passed before he could break the news to his wife. The initial horror lasted months. Then a sort of calm ensued that puzzled him, he says.

	“After about 6 months, I went to see a shrink because I thought, ‘Maybe I am handling this all too well, and maybe it’s not real.’ After a couple of sessions, he told me to get out of his office because I was dealing with it in its proper place,” Rogers says. “I remember thinking, am I doing what I really want to do? You don’t know how sick or ill you will be feeling and how long you are going to live, so there’s this big question mark going through your mind. But today I don’t think about what I have, unless I am on my way to Dr Berenson, or I am taking some kind of a test.”

	“I have absolutely no fear of dying,” he adds. “I have a fear of being uncomfortable, or of not doing what I would like to do.”

	Specht is less sanguine about their future, but pretty sure of one thing.

	“I think that Ron is going to die from something else,” she says, “and not this disease.”

You'd never know that Rogers has had multiple myeloma for almost 11 years -- and that's just the way he likes it.

Back on the Horse: Ron Rogers

	Multiple myeloma (MM) is a clonal plasma cell malignancy with a highly heterogeneous genetic background, characterized by bone marrow (BM) plasmacytosis, production of monoclonal proteins, osteolytic bone lesions, hypercalcemia, renal disease, anemia, and immunodeficiency. Several advances in diagnosis and treatment have been achieved during the past years. More sensitive imaging techniques, cytogenetic evaluations, and novel assays to measure paraprotein levels help to discern monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) from MM, and thereby enable the selection of patients who need treatment. Progress in our understanding of MM pathogenesis has led to the identification of new therapeutic targets. The introduction of derived agents, including thalidomide, bortezomib, and lenalidomide, into conventional chemotherapeutic regimens has fundamentally changed treatment strategies in MM during the last decade and steadily improved patient outcome.

	Multiple myeloma (MM) is the second most common hematologic malignancy in the United States. Age-adjusted incidence and mortality rates of MM in the United States are 5.6 and 3.6 cases per 100,000 persons per year, respectively.

 MM is a disorder of terminally differentiated B lymphocytes, called plasma cells, that are preferentially located within the bone marrow and secrete monoclonal immunoglobulin (IgG in about 60%, and IgA in about 20%) or light chains (κ or λ). Deregulated tumor cell growth and paraprotein production induce myelosuppression, bone destruction and hypercalcemia, immunodeficiency, hyperviscosity, and renal failure. Other plasma cell disorders include monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and solitary plasmacytoma. MGUS and SMM, also referred to as indolent or asymptomatic MM, are characterized by the absence of symptoms and require regular follow-up but no treatment. The rare solitary plasmacytoma occurs as a single lesion and benefits from local therapies. Recent advances in the diagnostic workup helped to distinguish these forms of disease from symptomatic MM, and thereby helped to select patients who needed treatment. Improvements have been achieved also by the identification of tumor microenvironment-directed agents, including thalidomide, bortezomib, and lenalidomide. Their inclusion in current MM treatment regimens has extended median overall survival (OS) from 3 to at least 7 years, especially in the younger patient population.

 In addition, novel effective supportive therapies have improved patients’ quality of life.

	Despite therapeutic advances, MM ultimately relapses and remains an incurable disease. Current research goals aim to further increase our knowledge, to identify additional targeted therapies, and to define patient-specific sequence and combination regimens in order to reduce adverse effects and improve response rates. Here, we summarize recent advances in both diagnosis and treatment strategies.

		Table 1. Staging Systems in Multiple Myeloma

		- Serum calcium value normal or ≤12 mg/dL

		- Bone x-ray, normal bone structure, or solitary bone plasmacytoma only

		- Low M-component production rate (IgG value <5 g/dL; IgA value <3 g/dL Bence Jones protein <4 g/24 h)

		Stage II: Neither stage I nor stage III

		Stage III: one or more of the following:

		- High M-component production rate (IgG value >7 g/dL; IgA value >5 g/dL, Bence Jones protein >12 g/24 h).

		Patients are further subclassified in either A or B:

		A: Relatively normal renal function (serum creatinine value <2.0 mg/dL)

		B: Abnormal renal function (serum creatinine value ≥2.0 mg/dL)

		Stage I: β-2 microglobulin <3.5 mg/L and albumin ≥3.5 g/dL

		Stage III: β-2 microglobulin ≥5.5 mg/L

	Plasma cell disorders are characterized by bone marrow infiltrate of monoclonal tumor cells and paraprotein production. MGUS is defined by the absence of symptoms and a lower grade of bone marrow infiltration compared to SMM and MM (MGUS: <30g/L paraprotein, BM clonal plasma cells <10%). MM in contrast to SMM presents with symptoms related to calcium levels above 10.5 mg/dL, renal impairment with creatinine levels >2 mg/dL, anemia with Hb <10 g/dL, and/or bone disease (CRAB-criteria). MM requires prompt antitumor and supportive treatment. MGUS and SMM are managed by regular clinical follow-up and serum and/or urine paraprotein determination. In order to predict survival and choose the most appropriate treatment, patients are categorized according to the Durie-Salmon Staging System and the International Staging System (ISS) (

 Advances in cytogenetic analysis pro-vides additional prognostic features. The recommended current diagnostic workup of MM patients is summarized in 

		Table 2. Recommended Diagnostic Workup in Multiple Myeloma

		• Serum and urine protein electrophoresis and immunofixation

		Evaluation of plasma cell infiltrates and cytogenetic abnormalities

		Bone marrow aspiration and biopsy with flow cytometry, immunohistochemistry, and cytogenetics

		Assessment of organ function and tumor burden

		Complete blood cell count, serum creatinine, calcium level, lactate dehydrogenase, albumin, and β2-microglobulin

 Recently, diagnostic advances have been made in the detection of bone lesions. Up to 80% of MM patients at diagnosis present with osteolytic lesions, often complicated by pain, bone fractures, and hypercalcemia. Malignant plasma cells stimulate activity of bone-resorbing cells (osteoclasts) while inhibiting bone-producing cells (osteoblasts). The resulting unbalanced bone destruction leads to the development of lytic bone lesions. Due to the absence of osteoblastic activity, bone scintigraphy scans and serum alkaline phosphatase levels are normal in MM patients. The recommended test to assess bone involvement at diagnosis and in the relapsed setting is conventional radiography, although techniques with higher sensitivity are currently under evaluation.

 Specifically, MRI and the new whole-body MRI (wbMRI) are more sensitive than skeletal survey to detect focal lesions, as they assess bone marrow involvement rather than bone destruction. MRI identifies lesions in up to 30% of patients with negative skeletal survey, and is therefore recommended in symptomatic patients with normal radiography in order to determine either treatment or follow-up. It is also recommended in cases of solitary bone plasmacytoma to determine the need for aggressive systemic chemotherapy versus local therapy.

 MRI or CT without contrast is critical to confirm cord compressions in the emergency setting.

	In contrast to conventional skeletal survey, focal lesions identified by MRI at diagnosis worsen patients’ prognosis. However, their resolution after therapy is associated with longer survival.11 Moreover, wbMRI in patients with asymptomatic MM is a strong predictor for progression to symptomatic MM.

 Due to the prognostic value of focal lesions identified by MRI, a modification of the Salmon-Durie Staging System has been proposed that includes MRI instead of conventional x-ray results (Salmon-Durie Plus). By using this new system, diagnosis of MGUS and plasmacytoma and staging of MM patients are upgraded in most cases. Derived therapeutic decisions are still a matter of debate.

	PET-CT, which demonstrates high sensitivity to detect tumor active sites and bones at risk for fractures, is performed in the context of clinical trials. Suppression of PET activity after induction therapy or after autologous stem cell transplantation (ASCT) may confer longer survival, suggesting its potential use as an indicator of response.

 Genetic testing, including fluorescence in situ hybridization (FISH) on primary bone marrow samples of MM patients, has become increasingly important for its prognostic relevance and therapeutic implications. Nearly 45% of MM patients present with hyperdiploid genetic anomalies, which are associated with older age at presentation, IgGκ paraprotein, and a more indolent form of MM. Standard risk is determined by the presence of translocation t(11;14).

 In contrast, hypodi-ploid subtypes are related to more aggressive disease, young-er age at presentation, and IgAλ paraprotein secretion.

 Genetic events associated with poor prognosis and shorter survival include translocation t(4;14), deletions of chromo- some 13 (del 13) and 17 (del 17), and amplification or deletion of chromosome 1.

 The presence of either of these genetic abnormalities characterizes the high-risk patient population whose OS after treat- ment with conventional chemotherapeutic regimens is shorter than in patients with standard-risk disease.

 Specifically, upfront treatment with bortezomib overcomes the negative prognostic impact of t(4;14) in MM patients compared to conventional chemotherapy, but provides no benefits to patients bearing the del 17.

 In the relapsed/refractory setting, lenalidomide with or without bortezomib improves the outcome of patients with del 13 or t(4;14). In contrast, outcome remains poor in patients with del 17 or chromosome 1 abnormalities.

 Therefore, patients with high-risk cytogenetic features, especially del 17 and chromosome 1 abnormalities, should be enrolled in clinical trials assessing novel agents.

 In 90% of MM patients, a paraprotein can be detected in serum or urine using electrophoresis and immunofixation techniques. The remaining 10% without a detectable paraprotein have been classified as oligosecretory or nonsecretory MM patients. In these cases, tumor response can be assessed only by bone marrow plasma cell infiltration. Most recently, the availability of the serum immunoglobulin-free light chain (FLC) assay, now a routine assay for screening of plasma cell disorders, has greatly improved diagnostic procedures. Along with serum electrophoresis and immunofixation, FLC increases the sensitivity to diagnose plasma cell disorders.

 Moreover, baseline light chain measurements and κ/λ ratio may be used as independent prognostic factors together with ISS index to improve prognostic evaluation.

 Importantly, an abnormal FLC ratio is associated with a higher risk of MGUS and SMM progression to MM, therefore requiring closer follow-up.

	Not all patients with a new diagnosis of plasma cell disorder require treatment. Patients with SMM or MGUS should be closely monitored to initiate a therapy in case of progression. If treatment is needed, regimens now include new nonchemotherapeutic agents. Indeed, thalidomide, bortezomib, and lenalidomide have dramatically changed the course of disease by improving remission rates, duration of response, and survival, and overcoming, at least in part, adverse genetic features.

 Therapies are tailored to patients’ age, comorbidities, and preferences. Current standard of care for patients with good performance status and without severe comorbidities is high-dose therapy and autologous stem cell transplant (HDT/ASCT). In contrast, therapies achieving the longest remission without excessive toxicity should be offered to patients aged <65 years, or older if in good performance status (eg, Eastern Cooperative Oncology Group [ECOG] >3, New York Heart Association [NYHA] >3). The role of long-term treatment to maintain a remission status after induction therapy or ASCT is currently under evaluation. In case of relapse or progression, regimens that include new drug combinations and novel anti-MM agents should be given within clinical trials.

		Table 3. Clinical Trials on Recommended Induction Strategies in Transplant-Eligible Patients

		ASCT indicates autologous stem cell transplant; CR, complete remission; IFE, immunofixation electrophoresis; NA, not available; nCR, near CR; OS, overall survival; PAD, bortezomib plus doxorubicin plus dexamethasone; PR, partial remission; Rd, lenalidomide plus low-dose dexamethasone; RD, lenalidomide plus high-dose dexamethasone; TD, thalidomide plus dexamethasone; VAD, vincristine plus adriamycin plus dexamethasone; VBMCP/VBAD, vincristine plus carmustine plus cyclophosphamide plus melphalan plus prednisone/vincristine plus carmustine plus doxorubicin plus dexamethasone; VD, bortezomib plus dexamethasone; VTD, bortezomib plus thalidomide plus dexamethasone.

 Treatment of the young patient population, aged <65 years or older if in good performance status, should be based on HDT/ASCT. After initial induction therapy, stem cells are collected to perform HDT/ASCT. Subsequent consolidation and maintenance strategies are still not recommended outside of clinical trials.

 The aim of induction therapy is maximal disease control to collect tumor-free peripheral blood stem cells (PBSCs). Recommended induction regimens include bortezomib- and lenalidomide-based combinations (

). Alkylating agents should be avoided for their negative impact on stem cell collection. Specifically, bortezomib plus dexamethasone (VD) versus standard chemotherapeutic induction strategies (VAD; vincristine, adriamycin, and dexamethasone) achieves higher response rate before and after ASCT, and shows a trend towards improvement of progression-free survival (PFS).

 In contrast, the combination of thalidomide plus dexamethasone (TD) failed to maintain the response rate advantage after ASCT when compared to VAD.

 Other strategies achieving high remission rates before transplant include bortezomib plus dexamethasone plus doxorubicin (PAD), and bortezomib plus thalidomide plus dexamethasone (VTD). PAD is superior to VAD in terms of response rate after ASCT.

 VTD is significantly superior to TD in terms of response rates before and after ASCT, although with higher toxicity.

 To overcome this problem, a regimen with low-dose bortezomib plus thalidomide plus dexamethasone (vTD) has been proposed. Compared to VD, vTD achieves a significantly higher response rate before ASCT, with comparable toxicity.

 Lenalidomide plus dexamethasone is considered to be another standard induction regimen for transplant candidates.

 Due to the positive results obtained with bortezomib- and lenalidomide-based regimens, their combination (VRD) is currently being evaluated. Preliminary data suggest an overall response rate of 96% before ASCT and 13% complete remission (CR).

 After 3 to 4 months of induction therapy, peripheral blood stem cell collection using granulocyte-colony stimulating factor (G-CSF), with or without cyclophosphamide follows. Importantly, with the exception of lenalidomide, novel agents do not influence stem cell yield.

 In order to overcome the negative influence of lenalidomide on stem cell collection, early harvesting and priming with cyclophosphamide is recommended.

 More recently, a new chemokine receptor inhibitor has been studied for its effects on stem cell mobilization: plerixafor in combination with G-CSF facilitated optimal stem cell collection at earlier time points than G-CSF alone, without major toxicity. Plerixafor in combination with G-CSF has been successfully used in patients failing previous mobilization attempts. Importantly, it overcomes negative effects of lenalidomide on stem cell mobilization.

 These positive results led to the FDA and European Medicines Agency (EMA) approval of plerixafor in combination with G-CSF in 2008 and 2009, respectively, in patients with non-Hodgkin lymphoma and MM.

	The backbone of conditioning therapy is melphalan, administered at doses ranging from 100 to 200 mg/m

, dependent on age and preexisting comorbidities.

 A second ASCT is recommended by the NCCN Guidelines within 6 months of the initial ASCT for those patients who did not achieve at least a very good partial remission (VGPR) after the first ASCT.

 Although allogeneic stem cell transplantation remains the only potential curative treatment for MM patients, high toxicity rates and transplant-related mortality limit this approach to young patients with high-risk features or a relapse within 12 months of ASCT. The graft versus myeloma effect obtained with allogeneic transplantation after reduced-intensity conditioning has been evaluated as consolidation strategy after ASCT, but due to controversial data this treatment strategy remains restricted to clinical trials.

 With the purpose of increasing depth of response after ASCT, consolidation strategies have been explored. Thalidomide plus prednisone for 12 months after first ASCT prolongs both PFS and OS compared to prednisone alone; 3-year OS is 86% versus 75%, respectively.

 Two cycles of VTD after the second transplant induce high rates of durable molecular response associated with a better outcome.

 Four cycles of lenalidomide together with prednisone as consolidation therapy and thereafter alone as maintenance strategy increase the CR rate from 38% after ASCT to 66%.

 These promising data need further confirmation in randomized trials to assess the effective benefits on response and survival in light of increased toxicity.

 Older patients with reduced performance status, defined as ECOG performance status or NYHA class >3, have higher morbidity and mortality if they undergo HDT/ASCT because of increased therapy-related toxicity.

 Therefore, this patient group should be offered alternative strategies that achieve disease control while limiting therapy-induced adverse events. According to the most recent guidelines, any upfront therapies in this setting should include thalidomide, lenalidomide, or bortezomib in doublet or triplet combination with conventional therapies, such as melphalan and/or prednisone (

 The choice is based on comorbidities and preference. Ongoing clinical trials explore quadruplet regimens and novel agents to further improve patient outcome.

		Table 4. Clinical Trials on Recommended Induction Strategies in Transplant-Ineligible Patients

		CR indicates complete remission; Mel100, melphalan 100 mg/m

; MP, melphalan plus prednisone; MPT, melphalan plus prednisone plus thalidomide; MPV, melphalan plus prednisone plus bortezomib; NA, not available; nCR, near CR; OS, overall survival; PR, partial remission; Rd, lenalidomide plus low-dose dexamethasone; RD, lenalidomide plus high-dose dexamethasone; Tm, thalidomide maintenance; VGPR: very good partial remission.

	Since 2006, thalidomide in combination with melphalan and prednisone (MPT) belongs to the standard treatment in newly diagnosed transplant-ineligible MM patients.

 Several consecutive studies supported the superiority of this regimen to melphalan plus prednisone (MP) in terms of response rate.

 Two meta-analyses of 6 randomized controlled trials comparing MPT versus MP as initial therapy for transplant-ineligible patients showed a superior response rate and PFS with minimal additional toxicity in patients treated with MPT. A 6.6-month increase in OS has also been reported.

 Common side effects associated with thalidomide treatment are constipation, fatigue, dose-dependent neuropathy, and thrombosis. Notably, the combination with dexamethasone (TD) is poorly tolerated by patients aged >75 years, with increased toxicity-related deaths compared to MP and reduced OS (19.8 mo in TD arm vs 41.3 mo in MP arm).

 This study raises important questions on the safety profile of the novel nonchemotherapeutic agents, suggesting cautious use in the older population.

	Similar to thalidomide, bortezomib in combination with melphalan plus prednisone (MPV) achieved significantly higher survival rates than MP and complete remission rates comparable to those obtained with HDT/ASCT. The VISTA trial demonstrated that at a median follow-up of 36.7 months, OS was not estimable in the MPV group versus 43.1 months in the MP group.

 Due to the observed significant benefit on OS, MPV is also considered a standard upfront regimen for older patients. Common bortezomib-associated dose-limiting adverse side effects include peripheral neuropathy, gastrointestinal toxicity, and thrombocytopenia. Bortezomib-containing therapies are especially recommended for patients with renal disease, since elimination of bortezomib is independent of renal clearance and bortezomib may even help to normalize MM-associated renal dysfunction in selected patients.

 Due to the high response rates achieved with thalidomide and bortezomib, the combination of both agents with prednisone (VTP) has been investigated. Compared to MPV, VTP induced similar CR rates but showed a different toxicity profile that was predominantly hematological for MPV and cardiac for VTP.

 Further studies are needed to confirm the safety and efficacy of this new regimen.

	Positive results have also been demonstrated using lenalidomide in combination with low-dose dexamethasone (Rd) versus high-dose dexamethasone (RD). The higher toxicity rate observed with RD translates to a shorter OS, with a 2-year OS of 75% for the RD arm versus 87% of the Rd arm.

 Adverse side effects of the combination include neutropenia and thromboembolic events (deep vein thrombosis and pulmonary emboli) requiring antithrombotic prophylaxis in all lenalidomide-treated patients.

 The combination of lenalidomide plus melphalan plus prednisone (MPR) in the upfront setting of elderly transplant-ineligible patients has also been explored. In a dose-determining study, after 9 cycles of MPR, 24% of the patients obtained a complete immunofixation-negative response. Grade 4 adverse events were mainly hematologic.

 Several trials have explored the benefits of maintenance strategies after ASCT or after induction therapy in transplant-ineligible patients in terms of response rate and survival. Maintenance therapy aims to prolong remission in long-term tumor control and to reduce the risk of relapse.

 However, data are still preliminary and maintenance strategies do not yet belong to the standard of care. In the post-ASCT setting, long-term treatment with thalidomide and prednisone is superior to placebo in terms of response and disease-free survival (DFS); however, no effects on OS have been demonstrated. In addition, thalidomide-related toxicity, neuropathy in particular, reduces patients’ quality of life.

 It therefore represents a limitation to long-term use. In contrast, lenalidomide may overcome this problem due to better tolerability.

 Compared to placebo, lenalidomide maintenance significantly delays the time to progression (TTP). Specifically, McCarthy and colleagues

 showed an estimated median TTP of 42.3 months for the lenalidomide arm versus a TTP of 21.8 months for the placebo arm at 17.5 months from ASCT. Similarly, Attal and associates

 observed a median PFS from diagnosis of 52 versus 34 months in lenalidomide versus placebo-maintained patients. Advantages in terms of PFS by lenalidomide maintenance have also been demonstrated by Palumbo and colleagues

 in the nontransplant setting.At a median follow-up of 9.4 months, PFS for MPRm (MPR plus lenalidomide maintenance) was not reached; for MP, PFS was 13 months; and for MPR, PFS was 13.2 months. In contrast to thalidomide, bortezomib is better tolerated as maintenance therapy. Sonneveld and associates

 noted a rate of discontinuation of 9% in bortezomib-treated patients versus 31% in thalidomide-treated patients. In addition, a survival advantage in patients with negative prognostic features, such as gain 1q21 and t(4;14), was observed.

 Improved response rates have also been demonstrated in patients not eligible for transplant, although a longer follow-up is needed to assess any survival advantage.

 Finally, long-term treatment with bortezomib in combination with thalidomide has also been explored. Preliminary data confirm the advantage at PFS and suggest a favorable safety profile.

 Salvage treatment regimens are proposed for patients with progressive disease or relapse after induction therapy, ASCT, or allo-SCT.

 If possible, patients with relapsed/refractory disease should be enrolled in clinical trials. Treatment choices depend on previous therapies, duration of response and toxicities, and presence of high-risk cytogenetic features.

 Patients relapsing more than 6 months after completion of induction therapy may be rechallenged with the same initial treatment regimen or a combination of previous therapies. If relapse occurs after a shorter period of time from induction, treatment options include HDT/ASCT or the switch to a new regimen.

 Allo-SCT may be offered to a selected population of young patients with preferably HLA-matched donors.

 Strategies approved in the relapsed setting include bortezomib alone or in combination with pegylated liposomal doxorubicin, and lenalidomide in combination with dexamethasone.

 The combination of bortezomib and doxorubicin versus bortezomib alone significantly prolonged TTP (9.3 mo vs 6.5 mo, respectively), however, with more grade 3/4 toxicities. Similarly, TTP was improved by adding lenalidomide to dexamethasone in relapsed/refractory patients, from 4 to 11 months.

	Ongoing studies are evaluating double, triple, and quadruple combinations, as well as additional targeted novel agents. Thalidomide has been combined with a variety of agents, such as dexamethasone, cisplatin, cyclophosphamide, and etoposide (DT-PACE).

 Safety and efficacy of lenalidomide plus pegylated liposomal doxorubicin or cyclophosphamide and dexamethasone have been additionally evaluated.

	Among the novel agents currently tested in myeloma, pomalidomide, carfilzomib, and bendamustine are the most promising. In the relapsed/refractory setting, an overall response of 30% was achieved by the new immunomodulatory drug pomalidomide, alone or in combination with dexamethasone. The dose-limiting adverse effect was myelosuppression.

 Notably, activity of pomalidomide was also observed in patients refractory to thalidomide, lenalidomide, or bortezomib.

 Ongoing phase II clinical trials are assessing the combination of pomalidomide plus bortezomib.

	Carfilzomib is a highly active new proteasome inhibitor targeting both the chymotrypsin-like and immuno- proteasome activities. In contrast to bortezomib, carfilzomib has an irreversible mechanism of action.

 Higher doses twice weekly seem to be better tolerated than lower doses administered for 5 days.

 Although high response rates were demonstrated in patients previously treated with lenalidomide, bortezomib, and HDT/ASCT, even higher response rates were observed in bortezomib-naïve patients.

 Reported toxicity was mainly hematologic; in contrast to bortezomib, neuropathy was not a major problem. A larger randomized phase III trial is planned to assess the combination of carfilzomib plus lenalidomide plus dexamethasone in the setting of relapsed disease.

	Bendamustine hydrochloride is a DNA alkylating anticancer agent, approved for the treatment of chronic lymphocytic leukemia.

 In heavily pretreated patients, bendamustine in combination with thalidomide and prednisone conferred median PFS and OS of 11 and 19 months, respectively.

 Similar results have been observed with the combination of bendamustine with bortezomib and dexamethasone.

 Supportive therapies in MM aim to prevent and treat bone disease and its complications, thromboembolic events, renal impairment, hyperviscosity, infections, and anemia (

). Patients with symptomatic bone disease or asymptomatic patients whose bone imaging suggests decreased bone density benefit from therapy with bisphosphonates.

 Indeed, monthly infusions with zoledronate or pamidronate reduce skeletal complications (hypercalcemia, fractures, and pain).

 Discontinuation after 2 years of treatment is recommended in patients with responsive or stable disease.

 Bisphosphonates have also been used in patients with MGUS and SMM and concomitant bone loss. However, although improved bone mineral density was observed, no data suggest prevention of skeletal complications or antitumor effects in this patient population; therefore, the use of bisphosphonates is questionable.

 Patients undergoing thalidomide- and lenalidomide-based therapies are at high risk for thromboembolic events and benefit from the regular use of anticoagulants. Based on risk-stratification analysis, aspirin, low-molecular-weight heparin, or warfarin may be administered.

		Table 5. Supportive Therapies in Multiple Myeloma

		• Surgery (kyphoplasty and vertebroplasty)

		Hydration and bisphosphonates, eventually calcitonin

		Herpes zoster prophylaxis in case of bortezomib-based regimens

Progress in our understanding of multiple myeloma pathogenesis has led to the identification of new therapeutic targets.

Updates on Multiple Myeloma Diagnosis and Treatment Strategies

	Osteoporosis is characterized by low bone mass, deterioration of bone tissue and architecture, compromised bone strength, and an increase in fracture risk.

 The World Health Organization (WHO) defines osteoporosis as a bone mineral density (BMD) at the hip or spine ≤2.5 standard deviations below the young normal mean reference population. It affects nearly 10 million Americans and nearly 34 million are at risk, according to the National Osteoporosis Foundation. Although there is a greater incidence in women, men can also be affected.

 Postmenopausal women require special attention due to the decrease in estrogen levels, with an increase in the rate of bone remodeling causing an imbalance between osteoblasts and osteoclasts. Several measures are key techniques in both the prevention and treatment of osteoporosis, including but not limited to adequate intake of calcium and vitamin D, weight-bearing exercises, fall prevention techniques, bisphosphonate administration, nasal calcitonin, estrogen/hormonal replacement therapies, and parathyroid hormone supplementation.

	In patients with bone metastases secondary to malignancy, there is an imbalance between osteoclast and osteoblast activity that results in local bone destruction. It is estimated that approximately 80% of all patients with diagnoses of breast cancer, prostate cancer, or multiple myeloma will develop bone metastases at some time during the course of their disease. The goal of treating these patients is to reduce the risk of developing a skeletal-related event (SRE), which is defined as spinal cord compression, a pathologic fracture, and a need for radiation therapy for skeletal stabilization or hypercalcemia.

	Denosumab is a human IgG2 monoclonal antibody that inhibits binding of the receptor activator of nuclear factor kappa-B ligand (RANKL, part of the tumor necrosis factor family) to RANK receptors located on the surface of osteoclasts and their precursors. This inactivation prevents the formation, function, and survival of osteoclasts, which then reduces bone resorption, allowing for growth in cortical and trabecular bone.

 Improvements in BMD have been demonstrated with the use of denosumab.

	Serum type I C-telopeptide (CTx), a bone resorption marker, adequately reflects denosumab activity. Three days following a single injection, CTx levels were reduced by 83%. A maximum reduction was noted in 1 month, with ranges of 45% to 80% during the 6-month dosing interval. Bone formation markers such as osteocalcin and procollagen type I N-terminal peptide (PINP) were also observed to decrease, indicating the coupled action of bone remodeling.

 Unlike the bisphosphonates, dose reductions were not required in renal or hepatic impairment. Clearance occurred through the reticuloendothelial system, ending with renal filtration and excretion.

 Studies have shown that denosumab is not incorporated into bone; therefore, accumulation is not a factor.

	In 2009, results were published for the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial, a large international, randomized, placebo-controlled study.

 In this trial, patients were randomly assigned to either denosumab 60 mg subcutaneously (SC) or placebo every 6 months for 36 months. All patients received daily supplements containing at least 1000 mg of calcium and vitamin D supplementation as determined by the baseline labs. Patients were eligible for the trial if they were aged 60 to 90 years with a BMD T-score of <—2.5 at the lumbar spine or total hip. Patients who had previously used bisphosphonates for <3 years were eligible for the study if they had not received bisphosphonate therapy for the previous 12 months. Exclusion criteria for the study included previous oral bisphosphonate use for >3 years; intravenous (IV) bisphosphonate use within the previous 5 years; fluoride or strontium use within the previous 5 years; or a vitamin D level <12 ng/mL. The primary endpoint for the trial was the presence of new vertebral fractures, evaluated by annual lateral spine radiographs. Secondary endpoints were the time to the first nonvertebral fracture and time to the first hip fracture. The efficacy endpoints were evaluated based on the intention-to-treat analysis and safety analyses included all patients who had received ≥1 dose of a study drug. A total of 7868 women were enrolled in the study. The average age in both groups was 72.3 ± 5.2 years, and the groups were well matched in terms of baseline characteristics. At the end of the 36-month study period, 82% of patients had completed the study and 76% had completed all planned injections. The study’s end-point results are shown in 

. The risk reduction for vertebral fractures seen in the denosumab group is similar in magnitude to IV zoledronic acid and greater than the oral bisphosphonates. The denosumab group had a similar risk reduction to alendronate, risedronate, and zoledronic acid in regard to nonvertebral fractures. There were no significant differences between the denosumab and placebo groups in terms of adverse events (AEs), but there were significantly more patients in the denosumab group that developed eczema (3% vs 1.7%, respectively). The incidence of selected AEs is shown in 

	Also in 2009, the results of a phase III randomized, double-blind study comparing 12 months of therapy with either denosumab (60 mg SC every 6 months) to alendronate (70 mg orally every week) was published.

 Eligible patients were postmenopausal women with a T-score ≤2.0 at the total hip or lumbar spine. Patients were excluded if they had previously received treatment with IV bisphosphonates, fluoride, or strontium. In addition to the study treatment, patients were instructed to take daily calcium supplements with ≥500 mg calcium and vitamin D supplements based on the baseline 25(OH)D levels. The primary endpoint of the study was the percentage change from baseline of the total hip BMD at month 12. Secondary endpoints included the percentage change from baseline in BMD at the femoral neck, trochanter, lumbar spine, and one-third radius at month 12. A total of 1189 subjects were enrolled in the study. The groups were similar in regards to baseline characteristics. The mean BMD percentage change at the total hip from baseline was significantly higher in the denosumab group (3.5%) compared to the alendronate group (2.6%; 

 <.0001) at month 12. Patients treated with denosumab had significantly greater increases in BMD compared to patients treated with alendronate at the trochanter (4.5% vs 3.4%; 

 <.0001) and one-third radius (1.1% vs 0.6%; 

 = .0001), in addition to the gains at the total hip. These results were consistent between the intention-to-treat analysis and per protocol populations. There were no significant differences in overall AEs between patients treated with denosumab and patients treated with alendronate (80.9% vs 82.3%, respectively; 

 = .60). The incidence of serious AEs was also similar between groups.

	In addition to the current FDA-approved indication for denosumab use in the management of osteoporosis, Amgen, the manufacturer of denosumab, has also recently obtained FDA approval for an indication for the prevention of SREs in patients with breast and prostate cancers that have metastasized to the bones.

 Results of several phase II and III trials have recently been published, leading to these new approvals. A detailed discussion of those studies will follow under the appropriate indication.

	Fizazi and colleagues performed a randomized phase II study in patients with bone metastases from prostate, breast, and other malignancies that had elevated urinary N-telopeptide levels (uNTx) despite receiving IV bisphosphonate therapy. Elevated NTx levels represent excessive bone resorption, and these are the patients at greatest risk for developing SREs, cancer progression, and cancer-associated death.

 The study was a randomized, open-label, multicenter trial conducted at 26 centers in Europe and North America. A total of 111 patients were randomized to 3 different treatment arms: continuation of an IV infusion of a bisphosphonate every 4 weeks (n = 37), denosumab 180 mg SC either every 4 weeks (n = 38) or every 12 weeks (n = 36). Patients were required to have a uNTx level >50 nmol/L/mM at screening despite having received IV bisphosphonate therapy for at least 8 weeks. The primary endpoint of the study was the proportion of patients with a uNTx level <50 nmol at week 13 (treatment phase). Secondary endpoints included a variety of other assessments of uNTx levels in terms of time to response and percentage change of this marker. Time to first on-study SRE and safety were also secondary endpoints of the study. Besides breast and prostate cancers, multiple myeloma was the next most common malignancy, with 8% of the patients having the diagnosis.

	At week 13, the primary endpoint of a uNTx level <50 was achieved in 71% of the patients treated with denosumab, compared to 29% in the IV bisphosphonate arm. The median percentage reduction in uNTx levels at 13 weeks also favored denosumab, with a 78% reduction for denosumab compared to 33% for the bisphosphonate group. Finally, the estimated median time to obtaining a reduction in uNTx levels <50 was 9 days in the denosumab arm compared to 65 days for the IV bisphosphonate arm. All other measurements of marker activity favored the patients treated with denosumab.

	During the 25-week treatment period, the percentage of patients experiencing a first on-study SRE was 8% in the denosumab treatment arm compared to 17% for the bisphosphonate arm. Rates of AEs were similar between the study arms, with grade 3 to 5 AEs being reported in 55% of the patients treated with denosumab and 71% of the patients treated with bisphosphonate. The authors concluded that denosumab normalized elevated uNTx levels more frequently than bisphosphonate treatment in patients with bone metastases who have elevated uNTx levels despite bisphosphonate therapy. The ability of denosumab to further suppress markers of bone resorption despite previous bisphosphonate therapy indicates a different mechanism of action responsible for these effects.

	To date there has been 1 large, randomized phase III study and several phase II trials that have evaluated the efficacy of denosumab in women with breast cancer that has metastasized to the bone. In these patients there is increased osteoclast activity at the site of bone metastases, resulting in local bone destruction and the potential for skeletal complications.

	A multicenter, randomized, blinded phase II trial conducted by Lipton and associates evaluated the efficacy and safety of 5 different dosing levels of denosumab compared to IV bisphosphonates in patients with breast cancer and bone metastases that had not received prior IV bisphosphonate therapy.

 The primary endpoint of this study was the percentage change in uNTx (corrected for urine creatinine, uNTx/Cr), which is a marker for bone turnover, from baseline to week 13. Patients with elevated levels of NTx have been shown to be at an increased risk of developing SREs, disease progression, and death. In the trial, 255 patients were randomized to either denosumab 30 mg SC every 4 weeks (n = 42), 120 mg every 4 weeks (n = 42), 180 mg every 4 weeks (n = 43), 60 mg every 12 weeks (n = 42), or 180 mg every 12 weeks (n = 43); 43 patients were randomized to receive an IV bisphosphonate, zoledronic acid, pamidronate, or ibandronate, depending on site-specific labeling and commercial availability. Patients were also instructed to take 500 mg of oral calcium and 400 IU of vitamin D daily.

 Secondary endpoints of efficacy assessed at 25 weeks (end of treatment) included the percentage change from baseline in uNTx levels, the proportion of patients with a >65% reduction in uNTx from baseline, the median time to a >65% reduction in NTx from baseline, the percentage of patients with at least 1 on-study SRE, and the overall incidence of AEs and safety through the end of the follow-up period (57 weeks). The use of a 65% reduction in levels was chosen as the study endpoint because that number is the average decrease reported in the literature for patients with bone metastases treated with an IV bisphosphonate.

	A total of 255 women with bone metastases secondary to advanced breast cancer were enrolled in the study. Demographics were generally well balanced, although the patients treated with denosumab were slightly older than the patients in the bisphosphonate group. The majority of patients had skeletal metastases at more than 2 separate sites. Suppression of NTx occurred at all doses of denosumab administered, but the 120 mg dose given every 4 weeks resulted in the greatest overall median suppression of NTx at 13 weeks, with computer estimations that approximately 95% of patients treated at a dose of 120 mg every 4 weeks would achieve >90% suppression of NTx. Overall, a >65% reduction in NTx/Cr occurred in 74% of all patients treated with denosumab, compared to 63% of those treated with an IV bisphosphonate. The median time from randomization to achievement of a >65% reduction in NTx/Cr was 13 days in the denosumab cohorts compared to 29 days for the bisphosphonate cohort. Time to first on-study SRE was similar between the 2 groups, with 9% of patients treated with denosumab and 16% of patients treated with bisphosphonate experiencing a first on-study SRE. The most commonly experienced SRE was fracture.

 The incidence and severity of reported AEs were similar between the groups, and there was no apparent relationship between the dose of denosumab administered and the development of AEs. Pyrexia, arthralgias, and asthenia more commonly reported in the bisphosphonate group, while nausea and fatigue were more common in the denosumab cohorts.

	The authors concluded that denosumab and IV bisphosphonates appeared similar in regard to the suppression of uNTx/Cr. However, the 120 mg dose of denosumab administered every 4 weeks resulted in a numerically greater degree of suppression of uNTx/Cr than the other doses or dosing-interval combinations of denosumab. The authors also concluded that the 120 mg dose should be further studied in future phase III trials.

	A randomized, double-blind phase III trial was conducted by Stopeck and colleagues in patients with advanced breast cancer and bone metastases to evaluate the impact of denosumab in preventing or delaying SREs.

 In this study an SRE was defined as either a pathological fracture, a need for radiation or surgery to the bone for an impending fracture, or spinal cord compression. The study was designed as a noninferiority trial comparing denosumab to zoledronic acid, with time to first SRE (on-study) as the primary endpoint. Secondary endpoints included a demonstration of superiority of denosumab over zoledronic acid with respect to time to first SRE (on-study) and time to first and subsequent SREs, and a safety and tolerability assessment. Patients were required to be naïve to previous treatments with IV bisphosphonates, and were encouraged to take a minimum of 500 mg of calcium and 400 IU of vitamin D daily.

	A total of 1026 patients were randomized to the denosumab/zoledronic acid placebo arm, and 1020 were randomized to the zoledronic acid/denosumab placebo arm. Denosumab was administered every 4 weeks at a dose of 120 mg SC, while zoledronic acid was administered on the same 4-week dosing schedule at a dose of 4 mg. At an average follow-up period of 34 months, denosumab was found to be superior to zoledronic acid in preventing first on-study SREs (primary outcome), with an 18% reduction in their incidence (

 = .01). In the zoledronic acid group, the median time to first on-study SRE was determined to be 26.5 months; in the denosumab arm, median time to first on-study SRE had not yet been reached at the time of the analysis. The secondary endpoint of time to first and subsequent SREs was also found to be superior in the patients treated with denosumab, with a 23% improvement in this study outcome favoring denosumab (

 = .001). There were no differences noted in time to disease progression or overall survival (OS) between the 2 treatment arms.

	In terms of safety and tolerability, there were no differences in the overall reporting of AEs, with 96% of patients treated with denosumab and 97% of patients treated with zoledronic acid experiencing at least 1 on-study adverse event. There were also no differences in the rates of serious AEs reported (44% vs 46%), infection rates (46% vs 49%), or serious infections (7% vs 8%) in comparing denosumab with zoledronic acid, respectively. The reported incidence of osteonecrosis of the jaw (ONJ) was similar between the 2 arms, with a 2% incidence in the denosumab arm and a 1.4% incidence in the zoledronic acid arm (

It is estimated that approximately 80% of all patients with diagnoses of breast cancer, prostate cancer, or multiple myeloma will develop bone metastases at some time during the course of their disease.

Summer 2011 | Contemporary Oncology®

10 Tips for Breast Cancer Screening and Early Detection

Back on the Horse: Ron Rogers

Updates on Multiple Myeloma Diagnosis and Treatment Strategies

Denosumab: A Review of Its Pharmacology and Clinical Implications

Evolving Strategies Using Hematopoietic Stem Cell Transplantation in Diffuse Large B-Cell Non-Hodgkin Lymphoma

Accelerating Changes in Oncology