Introduction Of Novel Agents Research Articles

Thrombosis in Myeloma treated with IMiDs

Survival of myeloma patients has improved since the introduction of novel agents in the armamentorium, especially with the Immunomodulator drugs (IMiDs). However, this substantial benefit has been counterbalanced by the dramatic increase of the incidence rate of thromboembolic events, either venous and/or arterial. This observation has made compulsory a prophylactic treatment in myeloma treated with IMiDs. Although guidelines were proposed since, it is clear that several unanswered questions remain, starting with the choice of the thromboprophylaxis and the definition of risk factors. Further studies are warranted to help decide the optimal thromboprophylaxis.

Impediments to Curing Myeloma in 2012

SUMMARY Our understanding of multiple myeloma biology over the last two decades has led to a marked improvement in progression-free and overall survival for the majority of patients. The introduction of novel agents, improvement in administration of high-dose therapy with autologous stem cell support, along with supportive care measures have enabled the myeloma researchers to once again debate the curability of this disease. The present article is a succinct review of the progress that has been made and the impediments to curability of this disease.

Diagnosis and treatment of multiple myeloma and AL amyloidosis with focus on improvement of renal lesion

Multiple myeloma (MM) and AL amyloidosis are caused by the expansion of monoclonal plasma cells and secretion of dysproteinemia (Bence Jones protein and free light chain) and some patients require the hemodialysis. Myeloma kidney is mainly caused by the cast nephropathy of the distal tubuli, whereas, AL amyloid-protein is mainly deposited in glomeruli with massive fibrillar involvement. Therefore, almost MM patients presents a symptom of renal insufficiency, whereas, almost patients of AL amyloidosis present a nephrotic syndrome with severe hypoalbuminemia. These two diseases have some similar characteristics such as up-regulation of cyclin D1 gene by 11:14 chromosomal translocation. High-dose chemotherapy supported with autologous peripheral blood stem cells is effective for these two diseases. However, they are still difficult to be cured and require long-term disease control. In recent years, introduction of novel agents has changed their treatment strategies from the palliation therapy to the clinical cure.

Treatment patterns and outcomes in elderly patients with multiple myeloma

Treatment patterns and outcomes in elderly patients with multiple myeloma

How to select among available options for the treatment of multiple myeloma

The introduction of novel agents (thalidomide, bortezomib and lenalidomide) in the frontline therapy of multiple myeloma has markedly improved the outcome both in younger patients who are candidates for high-dose therapy plus autologous stem-cell transplantation (HDT/ASCT) and in elderly patients. In the HDT/ASCT paradigm, novel agents may be used as induction therapy or after HDT/ASCT as consolidation and/or maintenance therapy. It is now possible to achieve up to 70% complete plus very good partial remission after HDT/ASCT and 70% 3-year progression-free survival (PFS). However long-term non-intensive therapy may also yield high response rates and prolonged PFS. Randomized trials comparing these two strategies are underway. In elderly patients, six randomized studies show the benefit of adding thalidomide to melphalan-prednisone (MP). a large randomized trial has also shown that the combination of bortezomib-MP is superior to MP for all parameters measuring the response and outcome. Finally, the role of maintenance is currently evaluated and a randomized trial shows that low-dose lenalidomide maintenance prolongs PFS.

Emerging immunotherapies for renal cell carcinoma

In recent years, an improved understanding of renal cell carcinoma (RCC) tumour biology has resulted in major advances in the treatment of patients with metastatic RCC (mRCC). Although immunotherapy with interleukin-2 and interferon-α was once the standard of care for mRCC, the introduction of novel agents targeting angiogenesis and signal transduction pathways has markedly improved patient outcomes. However, targeted agents rarely induce complete responses, and patients eventually develop resistance to therapy, prompting consideration of novel therapeutic approaches and a resurgence of interest in immunotherapy for RCC. Phase I/II trials of vaccination with allogeneic dendritic cell/tumour fusions in patients with mRCC have demonstrated immunological and clinical responses in some patients, and T-cell modulating agents (e.g. antibodies against programmed death 1 and cytotoxic T lymphocyte-associated antigen-4, or soluble lymphocyte activation gene-3) and dendritic cell-activating toll-like receptor agonists have also shown encouraging evidence of efficacy in early-phase clinical trials. These early studies suggest that immunotherapy may continue to be an effective approach for patients with mRCC. As such, a number of other strategies are currently under investigation, including adoptive cell transfer (ACT) with T cells modified to target proteins expressed by renal tumours such as MAGE-A3/12, DR4 and TRAIL, and ACT with autologous natural killer cells. Results from trials of novel immunotherapies are encouraging, with data from other indications helping to facilitate development. To realise the full benefit for patients, it is likely that immunotherapy will need to be combined with targeted agents or other agents. Novel therapies used in combination or sequentially have the potential to improve outcomes in mRCC, and results from ongoing/planned trials will shape future therapy.

Management Strategies for Relapsed/Refractory Multiple Myeloma: Current Clinical Perspectives

In the last decade, the introduction of novel agents including the immunomodulatory drugs thalidomide and lenalidomide, and the first-in-class proteasome inhibitor bortezomib, has dramatically improved clinical outcome in patients with relapsed/refractory multiple myeloma (MM) compared to conventional chemotherapy alone. Although combination treatment approaches with traditional cytotoxic agents and novel agents have led to response rates as high as 85% in patients with relapsed/refractory disease, not all patients will respond to established novel agents, and even those who do respond will ultimately relapse or become refractory to currently available regimens. There is no generally accepted standard treatment for patients with relapsed/refractory disease; however, both disease-related (eg, quality and duration of response to previous therapies and the aggressiveness of the relapse) and patient-related (eg, preexisting toxicities, comorbid conditions, quality of life, age, and performance status) factors should be considered when selecting the best treatment option. This article will review up-to-date approaches for managing patients with relapsed/refractory MM, including the efficacy and safety of established novel agents, the use of adjunctive/supportive care, and strategies for tailored treatment.

Pharmacokinetic Considerations of Perinatal Antiretroviral Therapy

Antiretroviral therapy (ART) in pregnant women represents a unique combination of therapy and prophylaxis of HIV infection. Until the global epidemic of HIV and the discovery of efficient prevention of perinatal transmission through ART, the world has not witnessed a pharmacologic intervention of such a scale during pregnancy and delivery. The use of ART in pregnancy creates unique challenges in delivering therapeutic agents, targeting the HIV virus in both the pregnant woman and her unborn child, throughout dramatic changes in their physiologic state. With an increased complexity of perinatal ART and the introduction of novel agents into clinical practice, a better understanding of the pharmacokinetics (PK) and pharmacodynamics of ARV drugs is crucial for the safe and most effective use of ARV drugs in women during pregnancy and infants in the first months of life. While PK studies are already difficult to perform during pregnancy, they are particularly challenging in women with HIV infection due to multiple social, economic and cultural constrains. In this paper we provide an overview of published studies of ART disposition during pregnancy, labor, breastfeeding and in the newborn infant after delivery.

Long-term results in multiple myeloma treated with high-dose melphalan and autologous peripheral stem cell transplantation and achieving complete remission.

e18564 Background: Major progress has been made in the treatment of multiple myeloma (MM) in recent years, including the introduction of novel agents and transplant strategy. High-dose melphalan (HDM) followed by autologous haematopoietic stell cell transplantation (AHSCT) remains an integral component of upfront treatment strategy. Many studies stress the importance of achieving a deeper response as a surrogate for improved survival but, despite the improvements, MM remains incurable and long-term survival appears elusive. The aim of study is to establish the actual prognosis for the different response categories in the same original cohort of patients with MM treated with HDM and AHSCT after long-term follow-up. Methods: We evaluated a cohort of MM patients treated up-front in the Bone Marrow Transplant Unit of Reggio Calabria between 1994 and 2006. Disease response was assessed with the use of criteria from the European Group for Blood and Marrow Transplantation modified to include Complete Remission (CR) and near Complete Remission (nCR). Results: The study group was composed by 150 patients (age at 1st AHSCT M±SD 55±9 years, male 64%); 94 (63%) of them had 2 AHSCT. After treatments 22 (15%) patients have a CR, 32 (21%) a nCR and 90(64.0%) a PR. After a mean follow up of 50 months the cumulative probability of survival was 69% for patients with CR, 43% for those in nCR and 0% for patients in PR (log-rank test P PR vs nCR=0.006; CR vs nCR and nCR vs PR<0.001 ). The estimate mean survival for patients with CR, nCR and PR was respectively 166, 81 and 46 months. For patients with CR the survival curves showed a plateau of cumulative probability of survival after 134 months. Conclusions: In MM achieving a CR after HDM and AHSCT is a central prognostic factor. The relapse rate is low in patients with >11 years of follow-up, possibly signifying durable remission in patients in CR.

Characteristics and Clinical Course of Myeloma in Patients 40 Years of Age or Younger: A Study of the Greek Myeloma Study Group

Abstract 5085Multiple myeloma is a disease of the elderly, with a median age at diagnosis around 65 years of age. This disease occurs uncommonly in patients ≤40 years of age and thus the reports on these patients are limited. We analyzed the database of the Greek Myeloma Study Group and among 1750 unselected consecutive patients we identified 66 patients (3.7%) ≤40 years of age. Most of these young patients were males (67%), 80% had osteolytic bone disease at initial diagnosis, 49% had an ECOG performance status ≥2, 34% presented with anemia (hemoglobin less than 10 gr/dl), 10% with low platelet counts (≤130×109/L) and 14% had serum creatinine ≥2 mg/dl. When compared to patients older than 40 years, younger patients with symptomatic MM were more often males (67% vs. 55%, p=0.071), had less often renal impairment (eGFR < 60 ml/min; 22% vs. 49%, p<0.001), low serum albumin (< 3.5 gr/dl; 24% vs. 40%, p=0.013) and less often beta2-microglobulin ≥3.5 mg/dl (40% vs. 60%, p=0.013). Thus, there was a different disposition within ISS: 51% of young patients ≤40 years of age were ISS-1, 25% were ISS-2 and 25% ISS-3 compared to patients older than 40 years of age (27%, 35% and 37% for ISS-1, ISS-2 and ISS-3, respectively, p<0.001). IgD myeloma was more common in patients 40 years or younger than older patients (8% vs. 1.2%, p<0.001). Elevated serum LDH ≥300 IU/L was more common in patients ≤40 years that older patients (19% vs. 11%, p=0.061). There were no significant differences regarding performance status, the frequency of osteolytic bone disease, the frequency of anemia or low platelet counts or the degree of Bence Jones proteinuria when compared to older patients.Most patients ≤ 40 years of age received first line therapy based on conventional chemotherapy (82%) and 18% received novel agent based therapies – there was no significant difference in the treatment type when compared to patients older than 40 years. A response to first line therapy was achieved in 52% of younger patients compared to 63% for patients older than 40 years (p=0.093).The median survival for patients ≤40 years of age was 75 months, while for patients >40 years but ≤65 years was 50 months and for patients >65 years was 35 months (p<0.001). The survival for patients ≤40 years who started treatment before 1/1/2000 (i.e. before novel agents became available in Greece) was 60 months compared to 36.5 months for patients older than 40 years (p=0.003), while for patients who started treatment after 1/1/2000 (i.e. in the era of novel agents) the median survival for those ≤40 years has not been reached and is 49 months for patients >40 years (p=0.003).We then evaluated several factors which could be associated with survival within the cohort of patients ≤40 years: ECOG performance status ≥2 (66 vs. 154 months, p=0.03), low platelet counts <130×109/L (69 months vs. not reached, p<0.001), advanced ISS stage (154 vs. 69 vs. 33 months for ISS-1, ISS-2 and ISS-3, respectively, p=0.048) and LDH ≥300 IU/L (21 vs. 116 months, p<0.001) were associated with inferior survival. In multivariate analysis, ECOG performance status ≥2 (HR: 3.9, 95% CI 1.43–10.5, p=0.008) and elevated LDH ≥300 IU/L (HR: 6.230, 95% CI 1.72–22.5, p=0.005) were independently associated with inferior survival in patients ≤40 years of age.In conclusion, 3.7% of our myeloma patients were ≤40 years of age; these patients tend to be males, have more often IgD myeloma and ISS-1 disease. The median survival of these patients exceeds 6 years, and there is also a significant improvement after the introduction of novel agents with an expected survival of 10 years. Factors associated with tumor burden such as ISS-stage, low platelet counts and elevated LDH are associated with inferior survival in these young patients. Although there has been significant progress over the last decade, especially with the introduction of novel agents, efforts to further improve their outcome should be continued and perhaps cure should be the ultimate goal for as many as possible of these young patients. Disclosures:No relevant conflicts of interest to declare.

Trends in Incidence and Survival of Multiple Myeloma in the Netherlands in the Last Two Decades. Results From a National Population Based Study

Abstract 5071 Background:Multiple myeloma (MM) is de second most common haematological malignancy in adults worldwide. MM is common in the elderly. While the general life expectancy is increasing an ever increasing number of patients has to be expected. In the last decade treatment strategies are changed continuously because of the introduction of novel agents and allogeneic and autologous stem cell transplantation. In randomized controlled trials, overall survival in patients up to 65 years is improving convincing. In contrast with results in older patients. We studied data of patients treated outside clinical trials derived from the population based registry in the Netherlands to recognize trends in incidence en survival during 1989–2009. Patients and methods:We included all patients with newly diagnosed MM in the period 1989 – 2009 who were recorded in the Netherlands Cancer Registry (n =16.822 ). Follow-up was until January, 2010. We calculated the yearly age-standardised incidence rates for males and females and age-specific incidence rates in 10 year age groups for both sexes separately and combined. Changes in incidence were evaluated by calculating the estimated annual percentage change (EAPC). We then calculated relative survival, which may be interpreted as disease-specific survival within a cancer patient population. Traditional cohort-based, relative survival analysis was applied for patients diagnosed during 1989–2009. Since follow-up was available until 2010, 5 year relative survival for patients diagnosed in 2004–2009 was estimated using period-based relative survival analysis. Results:The number of newly diagnosed MM cases rose between 1989 and 2009 from 631 to 968 cases respectively. Significantly more males were diagnosed than females over time (p=0.01). Furthermore the proportion of male patients increased slightly over these time periods. However, the overall age standardised incidence rate for males and females remained stable over time but was higher among males than females.The median age at diagnosis was 71 years (p10-P90 range 53–84) and stable over time (p=0.07). Incidence was highest in the 70–79 age group for both sexes. However, because of the aging population the age-specific incidence rates (ASIR) were highest for patients aged 80+ years for both sexes.Within specific age groups significant changes were seen. In the population 50–59 years, the ASIR increased from 5.0 per 100,000 in 1989 to 6.9 in 2009 (EAPC 1989–2009 = + 0.7%; 95% CI: 0.0 –1.3). A decrease was seen in females aged 80+ years from 25.1 per 100,000 in 1989 to 22.4 in 2009 (EAPC 1989–2009 = −1,0; 95% CI: −1.8; −0.2). [Display omitted] [Display omitted] In the overall patient population the 1-year relative survival increased only slightly from 72% to 77% between 1989 and 2009. 5-year relative survival increased from 28% to 37%. Small improvements in survival were observed for all age groups in the past two decades except for patients aged 80+ years.Relative survival decreased with increasing age. In contrast, in the group aged 40–64 years improvements are already detectable from 1994 on. In 2004–2009 the highest 5-year relative survival, 62%, was seen in patients 40–49 year of age. However the strongest improvement over time was observed among the group 50–59 years. Conclusion:Although the average annual age-adjusted incidence rate remained stable from 1989–2009, the number of newly diagnosed MM patients increased because of the aging population.Relative survival increased slowly but continuously in time for patients until 80 years of age with strongest increase seen in patients up to 64 years of age. Improvement for these younger patients is most likely caused by the introduction of novel agents based regiments as well as by the introduction of high dose chemotherapy followed by stem cell transplantation. Our findings in trends of incidence and survival of MM are similar to those reported in other western populations. Disclosures:Sonneveld:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees.

Reversibility of the Resistance to Lenalidomide and Pomalidomide and Absence of Cross-Resistance in a Murine Model of MM

Abstract 134 Introduction:The introduction of novel agents has improved the outcome of MM patients, but MM is still considered an incurable disease and the emergence of resistance is the main responsible for this situation. The unraveling of the resistance mechanisms would help to design novel therapeutic strategies (combinations or sequencing treatments) to overcome this problem. Material and Methods:We have developed an in vivo model of acquired resistance to antimyeloma agents based in a model of subcutaneous plasmocytoma (MM1S) in CB17-SCID mice. For this purpose, mice were treated with Lenalidomide (25 mg/Kg) + Dex (1 mg/Kg) (LD), Pomalidomide (5 mg/Kg) + Dex (PD) or vehicle control, and after a period of initial sensitivity, tumors developed resistance to the administered combination. At this moment selected sensitive and resistant tumors were excised to analyze apoptosis, signaling pathways and gene expression profiling (GEP) changes. Moreover, some of these mice bearing resistant tumors were switched to receive the alternative combination (that is LD-PD or PD- LD), and, in selected mice, a second change of treatment was performed after secondary resistance to receive again the initial treatment (LD-PD-LD or PD-LD-PD). In order to evaluate TTP and to define the moment to change treatment we considered progression when tumor volume reached 1.700 mm3. Results:Both combinations (LD & PD) controlled the initial growth of the tumors, with a higher potency for the PD combination. Tumor volume reached 500 mm3 at a median of 8, 42 & 53 days for control, LD and PD respectively (p=0.01 and p=0.001). Nevertheless, after 30 days of continuous treatment, and despite maintaining the administration of the drugs, tumors started growing, and, once the tumors had reached 500 mm3, their growth kinetic was similar for the treated mice (despite still being treated) as compared to the untreated mice, indicating the emergence of complete resistance. This resistance was also confirmed ex vivo by in vitro culture with the corresponding drugs.In order to test the presence of cross-resistance, mice bearing big tumors resistant to LD or PD and already growing in an exponential phase (volume of 1.700 mm3), were at this point treated with the alternative combination. This sequential treatment change induced tumor stabilization and even a decrease of tumor volume. Again PD was significantly more potent at overcoming LD resistance as compared to the alternative situation, and this was verified both in terms of tumor growth inhibition (p=0.005) and in terms of time to progression (median of 16 vs 27 days for LD and PD respectively. p=0.004).Furthermore, mice that had been treated with LD-PD or PD-LD and had developed resistance to both combinations were again treated with the initial combination, and, surprisingly, they were again sensitive, indicating the reversibility of the acquired resistance. Similarly to previous experiments, PD was again significantly more potent than LD. This reversibility was also confirmed ex vivo after culture of the cells in medium without drugs.In order to investigate the resistance mechanisms, cells extracted from sensitive and resistant tumors were analyzed by Western Blot. Treatment with LD and PD induced a downregulation of pERK 1/2, nevertheless, when these cells developed resistance a very significant increase of pERK 1/2 levels (even higher than the basal levels) was observed. Moreover, these resistant cells also showed an upregulation of p-MEK, p-RAF and RAS. In this same line, the MEK inhibitor PD-98059 potentiated the in vitro activity of LD or PD in fresh MM1S cells, with high synergism (CI<0.1).Finally, changes in GEP were evaluated in extracted tumors. A significant change was observed in cells from tumors sensitive to PD and LD (with a higher gene deregulation with the former combination), as compared to untreated ones. Interestingly, when tumors became resistant, most of these changes disappeared and the GEP partially returned to a profile similar to that of active untreated tumors. Conclusion:The data presented would support treatment with alternative IMIDs if resistance was developed to one of them (specially PD was significantly more potent at rescuing resistance to LD), or even the retreatment with the same IMID after a wash up period. Moreover this study supports the evaluation of combinations of IMIDs with agents that abrogate the ERK pathway in order to increase efficacy or avoid resistance. Disclosures:Quintana:Celgene: Employment. García:Celgene: Employment. Pandiella:Celgene: Research Funding. San Miguel:Celgene: Consultancy, Research Funding.

Risk of Second Cancers Among Multiple Myeloma (MM) Patients in the Era of Novel Agents: Analysis Using the Surveillance, Epidemiology and End Results (SEER) Database

Abstract 1859 Introduction:Recent data have drawn interest in the potential association of lenalidomide and the risk of developing of second cancers in patients with MM. However, available data are limited. Though there is lack of chemotherapy specification, SEER data segregated into diagnosis periods may be useful as a surrogate to detect changes in the incidence of second cancers corresponding to the introduction of novel agents. Methods:Patients who had MM diagnosed as a first cancer from 1973–2008 were identified in the SEER 17 database. We included only patients who survived at least 2 years after diagnosis. Time segments were created based on the era of novel agents approved for MM: before January 2000 (Period 1; control), January 2000-April 2003 (Period 2; off-label thalidomide), May 2003-April 2006 (Period 3; bortezomib approval), May 2006-September 2006 (Period 4; thalidomide approval) and October 2006-December 2008 (Period 5; lenalidomide approval). The primary outcome measure was incidence of second cancer within 2 years of MM diagnosis. All second cancers were included except for myelodysplastic syndrome and in situ cancer that were not of breast and bladder. Odds ratios (ORs) were adjusted and P values < 0.05 were considered statistically significant. Results:There were 29,259 eligible patients. Majority were males (53%) and the mean age at MM diagnosis was 65 years (std.+/− 12). The incidence of second cancers was associated with period of diagnosis (P = 0.048), sex (P < 0.001), treatment (P < 0.001), and age (P < 0.001), but not with race (P = 0.108). Multivariate analyses showed that higher risk of second cancers was associated with older age (OR = 1.03; P < 0.001), male sex (OR = 1.41; P < 0.001), radiation and/or surgery as compared to neither treatment (radiation and surgery OR = 1.77, radiation only OR = 0.82, surgery only OR = 2.31; P values: 0.002, 0.040, and <0.001, respectively), and Periods 3 and 4 as compared to Period 1 (Periods 2–5 ORs: 1.11, 1.22, 1.63, and 1.53, respectively; P values: 0.260, 0.033, 0.011, and 0.096, respectively). Conclusions:Our population-based study suggests that the risk of developing second cancers in patients with MM may be increased in the recent decade wherein novel agents were introduced. A more specific study linking SEER to Medicare database is recommended in order to further define the risk specific to novel agents. Disclosures:No relevant conflicts of interest to declare.

Bortezomib Induction Followed by ASCT in Patients with Multiple Myeloma: Achievement of Response After Induction and Achieving CR Post-ASCT Are Both Important Prognostic Markers

Abstract 1866 Background:In multiple myeloma (MM), the association between the response to induction before autologous stem cell transplantation (ASCT) and long-term outcome is less clear but the situation may change with the introduction of novel agents. We therefore assessed the clinical relevance of response of bortezomib induction treatment or post-ASCT response for patients who received bortezomib-combined induction chemotherapy followed by ASCT. Methods:We retrospectively assessed 183 MM patients who received bortezomib-containing induction therapy (BTZ-IT) followed by ASCT in 24 institutions throughout Korea between 2003 and 2010. Records of these patients were reviewed using the Korean Myeloma Registry database (www.myeloma.or.kr). Each institution was requested to reconfirm the data using additional case report forms. Patients who had overt MM based on International Myeloma Working Group diagnostic criteria were selected. Results:One-hundred seventy eight patients were eligible. Their median age was 56 years (range, 28–69 years) and 96 (53.9%) were male. Forty nine (27.5%) received bortezomib as front-line therapy and 129 (72.5%) as second-line treatment. All patients underwent ASCT and 22 (12.4%) were treated with tandem ASCT. Ninety-seven (54.5%) patients were treated with maintenance therapy after ASCT. After BTZ-IT, the response rates in this selected series of patients were 37.6% CR, 12.4% VGPR, 41.0% PR, 7.3% SD and 1.7% PD (Figure 1A, 1B, 1C); the corresponding post-ASCT rates were 69.2% CR, 14.0% VGPR, 11.0% PR, 2.9% SD and 2.9% PD. At a median follow-up of 46.6 months, the 3-year overall survival (OS) and event-free survival (EFS) rates were 70.0% and 31.9%, respectively. Multivariate analysis showed that factors independently predictive of OS and EFS included achievement of BTZ-IT response °Ã PR (P=0.025 and P=0.014, respectively) and the treatment with maintenance therapy (P=0.048 and P=0.001, respectively). Post-ASCT CR vs. °Â VGPR was also an independent prognostic factor for OS and EFS (P=0.0001 and P=0.002, respectively). [Display omitted] Conclusion:At least PR to BTZ-IT and CR after ASCT were predictive of survival. These findings suggest that patients who responded to BTZ-IT may benefit from ASCT due to an enhanced quality of response. Maintenance therapy can also affect patient outcomes. Disclosures:No relevant conflicts of interest to declare.

Second Malignancies Among Elderly Multiple Myeloma Patients Exposed to Bortezomib and Other Treatments: An Analysis of the US SEER-Medicare Linked Database,

Abstract 3972Second hematologic malignancies have been found to occur at a higher rate among multiple myeloma patients compared to the general population. Although alkylating therapy has been suggested to play a role, the underlying causes remain largely unclear. Increased survival benefit has been documented with the introduction of novel agents over the past decade, and, as noted in other cancers, there may also be a higher occurrence of second malignancies in the era of novel therapies. Recently, data from Phase III studies suggest that patients treated with lenalidomide with prior exposure to melphalan may have an increased risk compared to placebo. However, the contribution of other specific agents has not been well characterized. Evaluation of second malignancies in clinical trial and product safety data for bortezomib has not revealed an increased incidence in bortezomib-treated patients. Additionally, our follow-up study of the VISTA clinical trial participants after 5 years showed no elevation in risk (San Miguel, et al. ASH 2011). To expand our current knowledge, we are conducting a population-based study using the NCI SEER-Medicare database (NCI SEER cancer registry linked with diagnostic and treatment claims data of Medicare beneficiaries) to evaluate bortezomib and other standard treatment exposures in relation to second malignancies subsequent to multiple myeloma.Using the NCI SEER-Medicare database, we identified all multiple myeloma patients with their first diagnosis between 1 Jan 2000 and 31 Dec 2007 aged 66 years or older. Exposure to chemotherapy was identified via Medicare claims, and second malignancies, defined as invasive cancers whose onset was after bortezomib-based therapy and occurring at least 2 months after the initial multiple myeloma diagnosis, were identified from the SEER registries. We identified the number of second malignancies among elderly patients with multiple myeloma and following bortezomib exposure; expanded multivariate analyses, adjusted for exposures, will be presented at the meeting.A total of 9,377 multiple myeloma patients were identified (median age 76 years; 50% males). During the study period, 2,285 (21%) patients had any documented exposure to bortezomib (with or without other treatments). Patients with bortezomib exposure had a median age of 73 years, and 55% were male. Among these 2,285 patients with bortezomib exposure, 33 patients (1.4%) developed a second malignancy (4 [0.2%] hematologic and 29 [1.3%] solid tumors) during the study period after their first documented bortezomib exposure. Hematologic tumors were non-Hodgkin lymphoma (n=3) and acute myeloid leukemia (n=1). Solid tumors were prostate (n=4), bladder (n=4), lung and bronchus (n=3), colon (excluding rectum) (n=3), breast (n=3), and other (n=12). Among the 7,092 multiple myeloma patients with no documented exposure to bortezomib, 320 (4.5%) developed a second malignancy (55 [0.8%] hematologic and 265 [3.7%] solid tumors) during the study period. Hematologic tumors were non-Hodgkin lymphoma (n=16), acute myeloid leukemia (n=7), chronic lymphocytic leukemia (n=2), acute lymphocytic leukemia (n=1), chronic myeloid leukemia (n=1), Hodgkin lymphoma (n=1), and other (n=27). Solid tumors were lung and bronchus (n=46), prostate (n=38), colon (excluding rectum) (n=33), melanoma (n=23), bladder (n=21), breast (n=17), and other (n=87).Based on more than 9,000 elderly multiple myeloma patients, we found a lower prevalence of second malignancies among persons exposed to bortezomib compared to those with no documented bortezomib exposure in our unadjusted analysis. To account for survival and adjust for other exposures, expanded analyses will be presented at the meeting, including standardized incidence ratios and calculations of absolute excess risk among patients exposed to bortezomib and other standard treatments compared to the general SEER population, cumulative incidence of second malignancy for each treatment group adjusting for death as a competing risk, and multivariate analyses to assess risk while adjusting for prior and concomitant treatments and other risk factors. Disclosures:Gifkins:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. McAuliffe:Millennium Pharmaceuticals, Inc.: Employment. Matcho:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Porter:Millennium Pharmaceuticals, Inc.: Employment. Chavers:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Ponsillo:Millennium Pharmaceuticals, Inc.: Employment. King:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Desai:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Cakana:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Esseltine:Millennium Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership.

Evolving Paradigms in the Treatment of Newly Diagnosed Multiple Myeloma

The treatment of multiple myeloma has undergone significant changes in the past few years. The introduction of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib, has dramatically improved the outcome of this disease and considerably increased the treatment options available. Several trials have shown the advantages linked to the use of novel agents both in young patients, who are considered eligible for transplantation, and elderly patients, for whom a conventional therapy should be considered. These novel agents may increase the efficacy of autologous stem cell transplantation with deeper and long-lasting response. In the transplant setting, different novel agent combinations have proved to be superior to the traditional vincristine-doxorubicin-dexamethasone. Similarly, novel agents have also changed the treatment paradigm of patients not eligible for transplantation, thus replacing the traditional melphalan-prednisone approach. Preliminary data also support the role of consolidation and maintenance therapy to further improve outcomes. This article provides an overview of the latest strategies, including novel agents used to treat patients with multiple myeloma, both in the transplant and nontransplant settings.

Guest editorial: understanding the pathogenesis and the evolving treatment paradigm for multiple myeloma in the era of novel agents

1 Shifts in the therapeutic paradigm The introduction of thalidomide, lenalidomide, and bortezomib has significantly improved the response rates and survival outcome in patients with myeloma (MM), and been integrated into MM treatment [1‐3]. These new agents target not only the intracellular mechanisms in MM cells but also the interaction between MM cells and the bone marrow microenvironment. Given the clinical benefit of these novel agents either alone or in combinatorial regimens, the treatment of MM is changing rapidly. A focus of clinical studies appears to be the evaluation and identification of novel combinations using these new agents to uniformly produce better outcomes in different clinical settings of patients with MM, and to further tailor treatment as appropriate to the clinical background as well as the biological characteristics of MM cells and their surrounding microenvironment in individual patients. High-dose therapy with autologous hematopoietic stem cell transplantation (ASCT) is the standard of care for newly diagnosed MM patients eligible for ASCT. Introduction of new drugs in the induction setting have markedly improved response rates, leading to increased survival rates after ASCT. For newly diagnosed elderly patients, or those not eligible for ASCT, the introduction of novel agents has also changed the management of this disease. The combination of melphalan, prednisone, and thalidomide, and that of bortezomib, melphalan, and prednisone are regarded as the new standards of care for elderly patients [4]. However, no standard treatments have been established for relapsed/refractory MM, although it has been suggested that the implementation of treatment regimens based on proteasome inhibitors and/or immunomodulatory drugs (IMiDs) improves response rates and survival in patients with relapsed/refractory MM [5, 6]. Overall, recent data suggest that the upfront combination of individual proteasome inhibitors and IMiDs is highly effective, and new approaches with these novel agents are currently being studied to further improve the response rates and duration of response, including the implementation of induction therapies with three or more drugs in combination, and consolidation and maintenance therapies featuring long-term administration of novel agents. 2 Risk-stratification by cytogenetic and molecular profiling

Cost differences among treatment options for patients with refractory myeloma previously treated with high-dose chemotherapy and autologous stem-cell transplantation: An analysis from the U.S. and Swiss perspectives.

e16569 Background: The introduction of novel agents has significantly improved clinical outcome for myeloma patients. While thalidomide, lenalidomide and bortezomib as well as autologous stem-cell ...

Optimal management of bone metastases in breast cancer patients.

Bone metastasis in breast cancer is a significant clinical problem. It not only indicates incurable disease with a guarded prognosis, but is also associated with skeletal-related morbidities including bone pain, pathological fractures, spinal cord compression, and hypercalcemia. In recent years, the mechanism of bone metastasis has been further elucidated. Bone metastasis involves a vicious cycle of close interaction between the tumor and the bone microenvironment. In patients with bone metastases, the goal of management is to prevent further skeletal-related events, manage complications, reduce bone pain, and improve quality of life. Bisphosphonates are a proven therapy for the above indications. Recently, a drug of a different class, the RANK ligand antibody, denosumab, has been shown to reduce skeletal-related events more than the bisphosphonate, zoledronic acid. Other strategies of clinical value may include surgery, radiotherapy, radiopharmaceuticals, and, of course, effective systemic therapy. In early breast cancer, bisphosphonates may have an antitumor effect and prevent both bone and non-bone metastases. Whilst two important Phase III trials with conflicting results have led to controversy in this topic, final results from these and other key Phase III trials must still be awaited before a firm conclusion can be drawn about the use of bisphosphonates in this setting. Advances in bone markers, predictive biomarkers, multi-imaging modalities, and the introduction of novel agents have ushered in a new era of proactive management for bone metastases in breast cancer.

Relapsed multiple myeloma in the UK prior to the introduction of novel agents - a response to Koleva et al. (2010)

Relapsed multiple myeloma in the UK prior to the introduction of novel agents - a response to Koleva et al. (2010)