Initial Therapy For Multiple Myeloma Research Articles

Factors determining utilization of stem cell transplant for initial therapy of multiple myeloma by patient race: exploring intra-racial healthcare disparities

Multiple myeloma (MM) therapeutics have evolved tremendously in recent years, with significant improvement in patient outcomes. As newer treatment options are developed, stem cell transplant (SCT) remains an important modality that provides excellent disease control and delays the progression of disease. Over the years, SCT use has increased overall in the U.S., but two distinct gaps remain, including suboptimal use overall and racial-ethnic disparities. We evaluated the National Cancer Database (NCDB) to study what sociodemographic factors might play a role within a given racial-ethnic group leading to disparate SCT utilization, such that targeted approaches can be developed to optimize SCT use for all. In nearly 112,000 cases belonging to mutually exclusive categories of non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB), Hispanics, non-Hispanic Asians (NHA), and others, we found certain factors including age, comorbidity index, payor type, facility type (academic vs. community) and facility volume to be uniformly associated with SCT use for all the racial-ethnic groups, while gender was not significant for any of the groups. There were several other factors that had a differential impact on SCT utilization among the various race-ethnicity groups studied, including year of diagnosis (significant for NHW, NHB, and Hispanics), income level (significant for NHW and Hispanics), literacy level (significant for NHW and NHB), and geographic location of the treatment facility (significant for NHW and NHA). The suboptimal SCT utilization overall in the U.S. suggests that there may be room for improvement for all, even including the majority NHW, while we continue to work on factors that lead to disparities for the traditionally underserved populations. This study helps identify sociodemographic factors that may play a role specifically in each group and paves the way to devise targeted solutions such that resource utilization and impact can be maximized.

Main Treatment Choices in the 2 First Lines of Therapy for Multiple Myeloma in Patients with High Risk Cytogenetics: Lesson from the Real World in the EU5 Countries and the USA

Background Typical approach to initial therapy in multiple myeloma (MM) includes more aggressive combinations early on with triplets. To further improve response rates and survival, quadruplets are moving to frontline, in both stem cell transplant (SCT) eligible and ineligible patients (pts). Defining high risk features is crucial; current international NCCN and IMWG clinical practice guidelines stratify pts based on those criteria proposing more aggressive therapy in this setting. Definitions of high risk are: cytogenetic abnormalities incl. del(17p), some laboratory factors with ISS III and increased LDH, some clinical features including plasma cell leukaemia, extramedullary involvement or age and functional assessment with primary refractory disease and rapid progression within 18 months of diagnosis. Aims Identify in real world setting the main regimens used in first line SCT eligible and ineligible pts as well as in 2nd line high risk pts with MM in EU5 countries (France, Germany, Italy, Spain, UK) and in the USA. Methods Anonymous patient charts were analysed based on data reported by onco-haematologists treating MM pts in EU5 countries and USA. A total of 1,575 unique patient charts in 1st line (530 SCT eligible and 1,045 SCT ineligible pts) and 1,665 unique pts in 2nd line were included in the analysis, from Oct. to Dec. 2022. The analysis focused on pts with high risk cytogenetic features and regimens used in accordance with international clinical practice guidelines. D= daratumumab; V=bortezomib; T=thalidomide; d= dexamethasone; R=lenalidomide; M= melphalan; p= prednisone; K=carfilzomib; Isa=isatuximab Results Mean age in 1st line SCT eligible pts was 59.0 years (n=441) in EU5 and 60.9 years (n=89) in the USA. In 1st line SCT ineligible pts, mean age was 74.0 years (n=838) in EU5 and 65.9 years (n=207) in the USA. Among all 1st line SCT eligible pts, 34% in EU5 and 29% in US had high risk cytogenetic features, with del17p identified in 12% of EU5 cases and 16% of US cases. In 1st line SCT ineligible pts in the EU5 and in the US 14% and 17% respectively were high risk, including 9% and 13% del17p. In the 2nd line setting, 1,208 unique pts were included in the EU5 and 457 in the US with 17% and 14% classified at high risk, respectively, del17p was identified in 9% and 11% of pts. The most frequently used regimens in 1st line SCT eligible pts in EU5 are D-VRd (n=56), VRd (n=69) and D-VTd (n=136) with 41% and 39% of high-risk pts. In the US, the most frequent regimens used in this subset were D-VRd (n=17) and VRd (n=33) with 35% and 39% of pts belonging to the high-risk group. For 1st line SCT ineligible pts in EU5, 40% of patients were high risk, with the most common regimen being VRd (n=67). Pts with del17p were also overrepresented in this subgroup with 15% of total population receiving VRd. Other frequently used regimens were D-VMP (n=95), DRd (n=188), Rd (n=148) and VMP (n=80) but none was preferred in high-risk pts. In the US, the most frequently-used regimen in 1st line SCT ineligible population was VRd (n=73) with 27% of pts with high-risk features (vs. 17% in the overall population). For 2nd line treatment in the EU5, carfilzomib-based combinations are more frequently used in high-risk pts, particularly DKd (n=42) and KRd (n=118), both associated with 35% of pts with high-risk features. Kd was also regularly used in this subset (n=76) with 32% of high-risk pts. Despite a small number of pts (n=29), Isa-Kd triplet is more regularly used in pts with del17p (21% of all pts). In 2nd line setting in the USA, the most frequently used regimen was DKd (n=37) with 30% high-risk pts. In pts with del17p, Kd was regularly used (n=14) with 21% of pts presenting this abnormality. Among other regimens, such as DPd (n=38), Dd (n=30), DRd (n=35) and KRd (n=21), none was preferred in high-risk pts. Conclusion This real-world study reveals quite heterogeneous treatment choices in 1st and 2nd line pts with high-risk cytogenetic features with no large consensus, especially between EU5 and the US. Some trends can be identified between different pts subsets: quadruplets with D-VRd and D-VTd in EU5 and D-VRd in the US are preferred as induction treatment prior to SCT. VRd is regularly used in 1st line SCT ineligible pts in the EU5, particularly in case of del17p. Carfilzomib-based regimens are more common in 2nd line pts in both EU5 and US, especially DKd, KRd and Kd. Those are in line with the main international guidelines and expert recommendations for high-risk pts.

Autologous Stem Cell Transplant in Initial Therapy for Multiple Myeloma

Autologous Stem Cell Transplant in Initial Therapy for Multiple Myeloma

Impact of achieving a complete response to initial therapy of multiple myeloma and predictors of subsequent outcome.

Achievement of a complete response (CR) in multiple myeloma (MM) correlates with improvement in survival outcomes; however, its impact on prognostic variables at baseline outside of clinical trial settings is not well described. We sought to determine the impact of achieving a CR within 2 years from diagnosis, its effect on the prognostic value of fluorescence in situ hybridization (FISH) and International Staging System (ISS) risk, and examined additional predictors of outcome among those achieving a CR in a routine clinical setting. We evaluated 1869 newly diagnosed MM patients who had ≥ 2 monoclonal protein immunofixation studies in the serum and urine available within 24 months from diagnosis, categorizing those with ≥ 2 negative serum and urine immunofixations as achieving CR. With a landmark at 24 months, median progression-free survival (PFS) for CR versus non-CR patients was 29.8 versus 20.9 months (p≤ .0002); median overall survival (OS) was 104 versus 70 months (p< .0001). The impact of achieving a CR was retained after adjusting for FISH, ISS, sex, transplant status, and involved heavy chain. Baseline FISH and ISS stage were not associated with PFS or OS among patients achieving a CR. The following variables were found as predictors of inferior OS within the CR cohort: age > 75 years, male gender, hypoalbuminemia, and non-immunoglobulin G involved heavy chain. Our study confirms that achievement of CR within 2 years from diagnosis is associated with improvement in survival outcomes and neutralization of the impact of FISH and ISS risk, thereby confirming observations from the clinical trial setting among a clinical practice cohort.

Utilization of Radiation Therapy in Multiple Myeloma: Trends and Changes in Practice

Background: Radiation therapy (XRT) has been used effectively for the spectrum of plasma cell disorders including plasmacytomas (PLA) and multiple myeloma (MM). Several reports have shown a change in practice for MM therapy including earlier use of combination agent regimens and increased overall utilization of stem cell transplant (SCT) but the role of XRT in the setting of novel therapeutic landscape has not been explored.Methods: The 2016 National Cancer Database (NCDB) for MM with patients diagnosed between 2004-2013 was studied. Cases without information on the selected patient or facility characteristics evaluated in this analysis, including XRT use, race, median income (2008-2012 dats), insurance status or facility type of initial MM diagnosis and/or treatment were excluded. The association between utilization of XRT as part of initial MM therapy and socio-demographic or treating facility characteristics was studied using multivariate logistic regression analysis.Results: Of the 123480 unique MM patients in NCDB diagnosed between 2004-2013, 111281 met the inclusion criteria with 7792 patients having osseous PLA (PLA-O; ICD-O 9731), 101919 having MM (ICD-O 9732) and 1570 having extraosseous PLA (PLA-E; ICD-O 9734). Of these, 28232 patients (25.4%) received XRT as a part of their initial therapy. These included 5399 PLA-O (69.3% of all PLA-O), 21891 MM (21.5% of all MM) and 942 PLA-E (60% of all PLA-E). Significant differences were noted for XRT use by most characteristics analyzed. Decreased XRT use was seen with progressively advancing patient age (≥85 year age OR 0.55, 95% CI 0.51, 0.61; ref=<50 year age). Similarly there was a decrease in XRT utilization over time from 2004-2005 (Ref) to 2012-2013 (OR 0.72, 95% CI0.68, 0.77). Men were more likely to receive XRT than women (OR 1.13, 95% CI 1.09, 1.16). There was a significant difference by race where non-Hispanic Blacks were least likely to receive XRT as part of initial therapy for MM (OR 0.89, 95% CI 0.84, 0.93, Ref=non-Hispanic Whites). Socioeconomic factors associated significantly with XRT use included income, where patients with a high income (median income quartile $63000+) were less likely to receive XRT as compared to lower income levels (OR 0.90, 95% CI 0.83, 0.97, Ref=<$38000) and literacy level, where an increasing literacy was associated with a higher likelihood of receiving XRT (OR for <7% no high-school degree 1.10, 95% CI 1.02, 1.19, Ref=≥21% no high-school degree). Insurance payer type influenced XRT utilization as patients with Medicare were less likely (OR 0.86, 95% CI 0.78, 0.94) while those with “Other Government” payer were more likely (OR 1.34, 95% CI 1.12, 1.60) to receive XRT as compared to the reference group of uninsured. There was an interaction with distance from treating facility as patients living between 10-45 miles away were slightly more likely to receive XRT. Patients with a higher Charlson-Deyo Comorbidity Score (Score 2+) were less likely to get XRT (OR 0.72, 95% CI 0.68, 0.77, Ref=Score 0). Treating facility characteristics significantly associated with increased XRT utilization included geographical location in Mountain (OR 1.17, 95% CI 1.01, 1.35) or Pacific (OR 1.18, 95% CI 1.07, 1.30) regions, while characteristics associated with decreased XRT utilization included high-volume facilities (OR for 50+ MM diagnoses seen/year 0.76, 95% CI 0.64, 0.91, Ref=<5 MM diagnoses seen/year) and facilities performing stem cell transplants (SCT) (OR 0.82, 95% CI 0.76, 0.87). There was no statistical difference in XRT utilization between academic and non-academic facilities.Conclusions: We provide the largest and most comprehensive analysis so far regarding XRT utilization in initial therapy of MM and PLA. We noted an expected higher XRT utilization for PLA as compared to MM and an overall decrease in utilization in recent years, possibly due to advent of highly efficacious systemic agents used as initial MM therapy. Decreased XRT utilization with advancing age may suggest its use as an adjunct to systemic therapy rather than a sole palliative measure since patients with increasing age can now be treated effectively and safely with systemic agents. Centers with higher MM volume and those involved in SCT were less likely to use XRT initially, possibly due to expertise with systemic therapy. Heterogeneity in XRT use based on gender, race and other socioeconomic factors needs to be explored prospectively. DisclosuresAilawadhi:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Research Funding. Sher:LAM Therapeutics, Inc: Research Funding.

Timeliness of Initial Therapy in Multiple Myeloma: Trends and Factors Affecting Patient Care.

Multiple myeloma (MM) treatment has advanced significantly over the last 2 decades. In most patients, the disease course has been altered from early fatality to chronic morbidity with multiple lines of treatment. The MM treatment paradigm has shifted toward treating patients before end-organ damage occurs. Thus, timeliness of treatment initiation in this era might improve patient outcomes. This is the first report to our knowledge analyzing disparities and trends in treatment timeliness of patients with MM using the National Cancer Database. Multiple factors affected the timing of treatment initiation in MM and disparities were found. We noted that initiation of treatment was delayed in women (odds ratio [OR], 1.15; 95% CI, 1.1 to 1.2) and blacks (OR, 1.21; 95% CI, 1.14 to 1.28; reference, whites) and in patients diagnosed in more recent years (2012-2015; OR, 1.15; 95% CI, 1.1 to 1.22; reference, 2004-2007). Patients were likely to start treatment earlier if they were age ≥ 80 years (OR, 0.83; 95% CI, 0.76 to 0.9; reference, age < 60 years), were uninsured (OR, 0.81; 95% CI, 0.72 to 0.91; reference, private insurance), had Medicaid (OR, 0.87; 95% CI, 0.79 to 0.95; reference, private insurance), were treated in a comprehensive community cancer program (OR, 0.7; 95% CI, 0.65 to 0.77; reference, community cancer program), lived in a location other than the US Northeast, or had a higher Charlson comorbidity score. Patient education and income levels did not affect time to treatment initiation. Particular aspects of these disparities could be explained by our current health care system and insurance rules, whereas others need to be investigated more deeply.

The impact of response kinetics following initial therapy for multiple myeloma in the era of novel agents

The impact of response kinetics following initial therapy for multiple myeloma in the era of novel agents

Factors Determining Utilization of Stem Cell Transplant (SCT) for Initial Therapy of Multiple Myeloma (MM) By Patient Race: Exploring Intra-Racial Healthcare Disparities

Background: SCT is a standard therapeutic approach for patients with MM and has contributed to improved outcomes. While SCT utilization in MM has increased for all racial-ethnic subgroups over time, population-based studies have repeatedly shown that racial minorities are less likely to receive it. We explored factors that determine SCT utilization among patients within a given race to understand intra-racial disparities and how to address them in order to maximize the use of this imperative treatment among eligible patients.Methods: The 2016 National Cancer Database (NCDB) for MM with patients diagnosed between 2004-2013 was studied. Cases without information on the selected patient or facility characteristics evaluated in this analysis, including SCT use, race, median income, insurance status or facility type of initial MM diagnosis and/or treatment were excluded. The association between utilization of SCT as part of initial therapy of MM and socio-demographic factors was studied stratifying patients into mutually exclusive racial-ethnic subgroups non-Hispanic Whites (NHW), non-Hispanic Blacks (NHB), Hispanics, non-Hispanic Asians (NHA) and others using multivariate GEE logistic regression analysis (clustered on facility ID). Interactions between race and patient/facility characteristics and SCT utilization were tested using similar methods but including all races.Results: Of the 123480 unique MM patients in NCDB diagnosed between 2004-2013, 111799 met the inclusion criteria. Of these, 15021 patients (13.4%) received SCT as part of initial MM therapy. Of those who received SCT, 77.5% were NHW (14.4% of all NHW), 15.1% NHB (10.3% of all NHB), 5.2% Hispanics (13.2% of all Hispanics), 2% NHA (15.5% of all NHA) and <1% others. There was no difference by gender but significantly reduced odds of receiving SCT were noted for every 10-year increase in age at diagnosis for all racial subgroups. NHA were the only subgroup not to have a significant year-wise increase over time in odds of receiving SCT between 2004-2013. A significant increase in SCT utilization was seen with increasing median income (quartiles; 2008-2012 data), for NHW and Hispanics but not for NHB and NHA, while increased education (% population with high-school degree; 2008-2012 data) was associated with a significant increase in SCT use for NHW and NHB, but not among Hispanics or NHA. An increase in great circle distance (GCD) from the treating facility as well as a lower Charlson-Deyo comorbidity index (CCI) was associated with significantly increased odds of receiving SCT for all racial groups. Insurancepayer status significantly affected odds of receiving SCT among all races with those having private insurance to be most likely to receive SCT among NHW, NHB and Hispanics while those with “other government” insurance payer type being most likely among NHA. Among treating facility characteristics, patients of all races were more likely to receive SCT if treated at an academic/researchfacility (including NCI-designated centers) or centers with highest quartile of patientvolume seen. For analysis by geographicalregion, NHW and NHA had the highest odds of receiving SCT in mountain region but there was no impact of geography on SCT for NHB or Hispanics. Odds ratio (OR) of receiving SCT as part of initial MM therapy by socio-demographic and facility characteristics for patients of individual racial subgroups are shown in Table 1. A significant interaction between odds of receiving SCT and various racial subgroups was noted for patient age at diagnosis (p<.001, decreased odds among NHW and NHA), GCD from treating facility (p=0.013, increased odds among NHB and NHA), CCI (p=0.043, decreased odds among NHA) and treatment facility volumes (p=0.046, increased odds among NHA and Hispanics).Conclusions: In the largest analysis exploring socio-demographic factors affecting SCT utilization in MM we note a significant disparity within races for who gets SCT as a part of initial MM management and who does not. While some of these factors are non-modifiable, others including access to healthcare, income, insurance and literacy levels, proximity to treatment center, treating facility type as well as volumes are modifiable and appear to be barriers to SCT among in some races, while not in others. These must be addressed to minimize disparities within racial subgroups, especially the minorities and realize maximal benefit of SCT for MM. [Display omitted] DisclosuresAilawadhi:Novartis: Consultancy, Honoraria; Pharmacyclics: Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Sher:LAM Therapeutics, Inc: Research Funding.

Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents.

Outcomes for patients with multiple myeloma (MM) have improved in recent years owing to use of novel agents and high-dose therapy followed by autologous stem cell transplant (ASCT). We analyzed the outcomes of 511 consecutive patients treated with novel therapies at our institution between 2006 and 2014 to determine the impact of relapse within 12 months of initiating treatment. A total of 82 patients (16.0%) experienced early relapse, with median time to relapse of 8.0 months (95% confidence interval (CI); 6.3, 8.9). Median overall survival (OS) was significantly worse for this group at 21.0 months (95% CI; 16.3, 27.2) vs not reached (NR) (95% CI; 96.3, NR) for those with late relapse (P<0.001). Survival outcomes remained poor among early relapse patients irrespective of depth of response to initial therapy. In multivariate analysis, low albumin and high-risk cytogenetics predicted early relapse. Outcomes of early relapse from early ASCT were also considered; median OS from ASCT for those relapsing within 12 months was 23.1 months (95% CI; 15.7, 32.4) vs 122.2 months (95% CI; 111.5, 122.2) for the remaining patients (P<0.001). Early relapse remains a marker of poor prognosis in the current era, and such patients should be targeted for clinical trials.

Utility of serum free light chain measurements in multiple myeloma patients not achieving complete response to therapy.

Normalization of the serum free light chain ratio (FLCr) with the absence of bone marrow monoclonal plasma cells following achievement of a complete response (CR) to therapy denotes a stringent CR in multiple myeloma (MM), and is associated with improved overall survival (OS). However, its value in patients achieving <CR is not clear. We hypothesized that patients achieving a normalization of FLCr with initial therapy of MM will have an improved outcome, even in the absence of a CR. We retrospectively evaluated 449 patients with newly-diagnosed MM with measurable disease at baseline, who did not achieve a CR with initial therapy. One hundred fifty three patients (34%) had a normal FLCr while 296 (66%) had an abnormal ratio. Patients with a normal FLCr had a longer progression-free survival (PFS) (29 vs. 16 months, P <.001) and OS (91 vs. 58 months, P <.001). Normalization of FLCr retained its prognostic value in a multivariable model. Our results suggest an important role for sFLC measurement in disease monitoring even in patients who achieve only a partial response to therapy. Obtaining a normal FLCr confers a favorable prognosis independent from other factors, supporting the inclusion of sFLC in all levels of response criteria.

Use of autologous hematopoietic cell transplantation as initial therapy in multiple myeloma and the impact of socio-geo-demographic factors in the era of novel agents.

Very effective combination chemotherapy using novel agents has become available in multiple myeloma (MM). Its impact on the use of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHCT) as part of initial therapy is unknown. Using the National Cancer Data Base, we studied the rate of upfront AHCT use among 137,409 newly diagnosed MM patients from 1998 to 2010 in the United States and determined whether disparity exists among various sociodemographic as well as geographic subgroups. Overall, 12,378 (9.0%) patients received AHCT as part of initial treatment. The use of upfront AHCT increased steadily from 5.2% in 1998 to 12.1% in 2010 (trend test, P < 0.001), with no sign of plateau. This was seen across all socio-geo-demographic subgroups except among patients treated in the Northeast where the rate fell from 8.7% in 1998 to 6.6% in 2010. In multivariable analysis, patients with the following characteristics were the least likely to receive AHCT (odds ratio): year of diagnosis from 1998 to 2003 before the era of novel agents (0.67), older age (0.35), Black race (0.58), Hispanic ethnicity (0.78), low level of education or annual household income (0.55), residence in a metro area (0.66), no or unknown medical insurance (0.30), treatment at a community cancer center (0.16), and treatment facility located in the Northeast region (0.54). Even after the introduction of novel agents, the rate of upfront AHCT in MM continues to increase annually. Significant disparities exist dependent on demographic, social, and geographic factors.

The Choice Of Regimens Based On Bortezomib For Patients With Newly Diagnosed Multiple Myeloma

Bortezomib significantly improved response rates in the treatment of patients with multiple myeloma (MM). However, the process of selecting an optimal bortezomib based regimen as the initial therapy of MM remains ambiguous due to a lack of modern clinical trials demonstrating the efficacy of various bortezomib based treatments. Here, we report four bortezomib-based regimens for treatment of MM patients from three hematological treatment centers in China. MethodsNewly diagnosed MM patients in three hematological centers in China between February 1, 2006 and May 31, 2013 were treated with combination therapies including bortezomib plus dexamethasone (PD), or triple combinations of PD with adriamycin (PAD), cyclophosphamide (PCD), and thalidomide (PTD) every 28 days. ResultsThe overall response rate (≥ partial response, ORR) of all the 215 eligible patients was 90.2%. The ORR for PCD, PAD, PTD and PD were 97.4%, 93.2%, 85.3% and 77.8% respectively, while the effects with VGPR or better were 63.7%, 62.7%, 44.2% and 37.8% respectively. The effect of ORR, VGPR and CR/nCR for PCD regimen was significantly better than PD scheme (P = 0.009, 0.011, 0.005 ). The median PFS of all the patients was 29.0 months with significant differences observed between groups (P =0.047). The median OS of all the patients was not reached, but triple combinations of PD with adriamycin (PAD), cyclophosphamide (PCD), and thalidomide (PTD) were more efficient in treatment of MM patients compared to PD (P =0.005). The frequently observed toxicities were neutropenia, thrombocytopenia, fatigue, infection, herpes zoster, and peripheral neuropathy. Incidence of peripheral neuropathy (PN) in PTD group was significantly higher than other three groups, especially grade 2-3 PN. Treatment with anti-viral agent acyclovir significantly reduced the incidence of herpes zoster. ConclusionsOur study demonstrated that bortezomib-based regimens were active and well-tolerated in the Chinese MM patients, and triple combinations of PD with adriamycin (PAD), cyclophosphamide (PCD), and thalidomide (PTD) were more efficient for treatment of MM patient, and the patients received PCD or PAD demonstrated significant higher ORR compared to PD. Disclosures:No relevant conflicts of interest to declare.

Therapy Related MDS/AML In Multiple Myeloma Patients In The Era Of Novel Agents

Introduction With the introduction of novel agents, survival in multiple myeloma has successively increased in the past decade. This improved survival increases the risk for late complications. Patients continue to receive melphalan therapy as a standard induction for those over the age of 65. Lenalidomide is considered a standard component of induction therapy in the United States for patients who are transplant candidates. Stem cell transplantation remains the standard of care for patients eligible to receive it. As a consequence of exposure to lenalidomide, stem cell transplant, and melphalan, the risk of late myelodysplasia and acute leukemia remains significant. We reviewed the Mayo Clinic experience with therapy-induced myelodysplasia beginning with the advent of novel agents. Patients and Methods All patients that carry the diagnosis of multiple myeloma between January 1, 2000, and September 1, 2011, were included. Patients with a synchronous diagnosis of a myeloproliferative or a myelodysplastic disorder or those who developed the myelodysplastic disorder within 15 months of first chemotherapy exposure were excluded. The date of diagnosis for the purpose of this abstract was based on first exposure to chemotherapy and not first detection of a monoclonal protein or smoldering multiple myeloma. All patients had to have morphologic verification in the bone marrow of dysplastic change consistent with therapy-related myelodysplasia. Results Of 3111 patients who had a myeloma diagnosis and first treatment after January 1, 2000, through September 1, 2011, 22 patients were identified to fulfill the criteria of myelodysplasia. There were 13 men and 9 women with a median age of 67 (46 to 82). At the time of this report, 17 have died. Prior to the development of myelodysplasia, exposure to an alkylating agent, lenalidomide, or an auto stem cell transplant was seen in 13, 15, and 10, respectively. Only one patient had been exposed to lenalidomide alone. Eighteen patients were classified as myelodysplasia. Four had acute non-lymphocytic leukemia. Metaphase cytogenetics was available in 19 and only one was normal. Twelve were hypodiploid. Trisomy 8 or abnormalities of chromosome 5 and 7 were present in 13. Seven patients received a hypomethylating agent with no clear evidence of response in any. Four patients had an allotransplant to manage the MDS/AML and only one survives 487 days after a matched-related donor allogeneic transplant. The median time from initial therapy of multiple myeloma to recognition of MDS or AML was 50.9 months (range: 15.2-146.5 months) fig 1. The median overall survival of the 22 patients is 6.5 months. Fig 2 Six of the 22 had active myeloma at the diagnosis of MDS/AML. Conclusion Myelodysplasia during the era of novel agents is a devastating complication of therapy with a very short survival and low response rate. As a time-dependent complication, the overall risk cannot be accurately estimated but has occurred in &lt;1% of our patient population to date. Hypomethylating agents were ineffective in the seven that received it. One of four allotransplant patients remains alive. Ongoing surveillance for MDS/AML in this population is warranted and more effective therapies are needed. Disclosures: Kumar: Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Phase 2 trial of intravenously administered plerixafor for stem cell mobilization in patients with multiple myeloma following lenalidomide-based initial therapy

Initial therapy of multiple myeloma with lenalidomide-based regimens can compromise stem cell collection, which can be overcome with the addition of plerixafor. Plerixafor is typically given subcutaneously (SQ), with collection approximately 11 hours later for maximum yield. Intravenous (IV) administration may allow more rapid and predictable mobilization. This trial was designed to assess the efficacy and feasibility of IV plerixafor in patients receiving initial therapy with a lenalidomide-based regimen. Patients received G-CSF at 10 μg/kg/day for 4 days followed by IV plerixafor at 0.24 mg/kg/dose starting on day 5; plerixafor administered early in the morning with apheresis 4–5 hours later. Thirty-eight (97%) patients collected at least 3×106 CD34+ cells/kg within 2 days of apheresis. The median CD34+ cells/kg after 1 day of collection was 3.9×106 (range; 0.7–9.2) and after two days of collection was 6.99×106 (range: 1.1–16.5). There were no grade 3 or 4 non-hematological adverse events and one patient experienced grade 4 thrombocytopenia. The most common adverse events were nausea, diarrhea and abdominal bloating. IV plerixafor is an effective strategy for mobilization with low failure rate and is well tolerated. It offers flexibility with a schedule of early morning infusion followed by apheresis later in the day.

Evolving Strategies in the Initial Treatment of Multiple Myeloma

Until the advents of novel agents, partial response (PR) or better was the established gold standard to initial therapy of multiple myeloma (MM), and treatment goals were focused on relieving symptoms, prevention of organ damage, and modest improvements in survival. With the introduction of autologous stem cell transplant (ASCT), deeper responses, including complete responses (CRs) were more frequent, and contributed to longer survival. In the era of novel therapies, ASCT remains commonly used and its impact on outcome appears superior, albeit less so than when compared with conventional therapy, and its survival benefit is yet to be established in either setting. In addition, in non-transplant candidates, novel therapies have now significantly improved the overall response rates, depth of response, and clinical benefit, to the levels previously only observed with ASCT, which now increasingly challenges the role and timing of ASCT in eligible patients. Nevertheless, the two approaches of treatment, transplant or no transplant, remain commonly accepted. With an improvement in the tolerability of newer regimens and the deferral of ASCT in transplant candidates, the debate has emerged whether the two-pathway approach to the treatment of newly diagnosed myeloma should be re-evaluated. At the same time, treatment goals are also shifting. Many believe that MM can be converted into a chronic disease and that a functional cure maybe a realistic goal, for at least a proportion of patients. This contribution will review these points of discussion and the evolving approach to treatment of newly diagnosed MM.

Novel Agents for Multiple Myeloma to Overcome Resistance in Phase III Clinical Trials

The incorporation of novel agents such as bortezomib and lenalidomide into initial therapy for multiple myeloma has improved the response rate of induction regimens. Also, these drugs are being increasingly used in the peri-transplant setting for transplant-eligible patients, and as part of consolidation and/or maintenance after front-line treatment, including in transplant-ineligible patients. Together, these and other strategies have contributed to a prolongation of progression-free survival (PFS) and overall survival (OS) in myeloma patients, and an increasing proportion are able to sustain a remission for many years. Despite these improvements, however, the vast majority of patients continue to suffer relapses, which suggests a prominent role for either primary, innate drug resistance, or secondary, acquired drug resistance. As a result, there remains a strong need to develop new proteasome inhibitors and immunomodulatory agents, as well as new drug classes, which would be effective in the relapsed and/or refractory setting, and overcome drug resistance. This review will focus on novel drugs that have reached phase III trials, including carfilzomib and pomalidomide, which have recently garnered regulatory approvals. In addition, agents that are in phase II or III, potentially registration-enabling trials will be described as well, to provide an overview of the possible landscape in the relapsed and/or refractory arena over the next 5 years.

Implications of rapidity of response to initial therapy in multiple myeloma.

8606 Background: The rapidity of response to initial therapy in multiple myeloma (MM) depends on a variety of factors. There is limited data on its implications on long term outcomes in patients (pts) with newly diagnosed MM. Methods: We retrospectively examined the outcomes in a cohort of 454 pts with newly diagnosed MM between Jan 2000- Dec 2011 undergoing induction therapy. Results: The median age at diagnosis was 66 yrs (29-92). Pts had measurable serum M-spike (&gt;= 1 g/dL), dFLC (&gt;=10 mg/dl) or 24 hour urinary M protein excretion (UrM; &gt;=200 mg) in 70, 63 and 39% respectively. We first examined the relationship between the response to first cycle of therapy and overall survival (OS). We divided pts into quartiles based on their % reduction in the serum M spike, dFLC or UrM. The median OS (Table) was poorest for pts with the least reduction of serum M protein (P&lt;0.001) and of dFLC. The cutoffs for Q1 was 25, 40and 40% decrease for serum M spike, dFLC and 24 hr UrM respectively. Among various baseline characteristics only higher age was predictive of a poor (Q1) response. Given the trend toward worse OS among the Q 4 group (maximum decrease in serum M spike), we examined the relationship to cytogenetic risk. Among 232 pts with FISH data available, proportion of pts with high-risk disease was 27, 12, 22 and 31% respectively in quartiles 1 - 4). In a multivariate analysis, quartile 1 and 4 of serum M-protein response and the high-risk FISH were independent risk factors associated inferior OS. Conclusions: Both shallow and very deep response to therapy in cycle 1 is a strong indicator of eventual disease outcome and should be considered as marker of high-risk disease, likely through different mechanisms. For the shallow responders, prospective trials should assess if a change in therapeutic management will alter the outcome of these pts. The rapid deep responders also appear represent a different high-risk biology, emphasizing the fact that pts with high-risk disease often have excellent initial responses, but poor long term outcomes. [Table: see text]

Use of stem cell transplantation (SCT) as initial therapy in multiple myeloma (MM) and impact of sociodemographic factors in the era of novel agents: Analysis of 137,409 patients using the National Cancer Data Base (NCDB).

8580 Background: Novel agents for MM became available in the past decade. Our study aim was to determine whether the rate of SCT utilization as part of initial therapy in patients with MM had changed in the US after the introduction of novel agents. We also determined the impact of various sociodemographic factors. Methods: De-identified patient level data were obtained from the NCDB bParticipant User File. NCDB is a nationwide oncology outcomes database, which comprises approximately 70% of all newly diagnosed cancer cases in the United States. Results: A total of 137,409 MM patients were included in the study. The median age was 68 years (range, 18-90+). The population was predominantly male (54%), white (79%), non-Hispanic (87%), and living in a metro (78%), low- or middle-income (annual income &lt; $46,000; 63%), and low- or moderate-education (&gt; 14% without high school diploma; 66%) areas. Most patients had minimal or no co-morbidities (Charlson-Deyo score of 0-1; 93%) and treated in the community setting (62%). The rate of SCT use as initial therapy consistently increased annually from 5% in 1998 to 12% in 2010. This was true for all socio-demographic subgroups except for those who were age &gt; 75 years, treated in the Northeast, and the medically uninsured. Multivariate logistic regression showed that the following characteristics were significant main predictors of lower likelihood of SCT use (odds ratio): age &gt; 65 years (0.18), non-white race (0.57), Hispanic ethnicity (0.68), lack of high education (0.89), annual income &lt; $30,000 (0.76), diagnosed before the era of novel agents (1998-2003) (0.70), covered by a non-managed care insurance (0.57), treatment in a non-academic facility (0.28), residence at a non-metro area (0.88), and treatment facility located outside of the Midwest or West (0.62). In contrast, sex was not significant. Conclusions: Even after the introduction of novel agents, the rate of SCT as initial therapy in MM continues to increase annually in the US. Significant disparity exists in the rate of SCT use by demographic, social, and geographic factors as well as the type of treatment facility.

Update on the Initial Therapy of Multiple Myeloma

Advances in myeloma biology and the identification of new anti-myeloma agents have resulted in improved management of younger, transplant-eligible, and older patients. The first novel agents-thalidomide, bortezomib, and lenalidomide-have been integrated into induction therapy before autologous stem cell transplant (ASCT) as well as into first-line therapy in elderly individuals; phase III trials have established the superiority of these approaches in terms of better response rates, progression-free survival (PFS), and, in some studies, overall survival. With more experience, improvements in dosing have decreased the toxicity of these regimens. Before ASCT, four phase III studies have shown that bortezomib-based regimens confer better outcomes than older regimens. Posttransplant consolidation and maintenance strategies with novel agents provide additional benefit, particularly in terms of a longer PFS. In the elderly population, novel agents can be combined with melphalan plus prednisone (MP). MP plus thalidomide and MP plus bortezomib are commonly utilized, and the regimen of MP plus lenalidomide with lenalidomide maintenance (MPR + R) produces superior response rates and longer PFS compared with MP alone. Prolonged maintenance with bortezomib plus thalidomide also appears to extend PFS when given following combinations of MP plus bortezomib. Treatment of very elderly patients, however, remains challenging due to comorbidities and side effects. Lenalidomide plus weekly dexamethasone is also effective in elderly patients, and results of a trial comparing this regimen with MP plus thalidomide should be available soon. Finally, better methods of risk stratification and the availability of even newer drugs will allow future refinements in myeloma treatment.

Update on the Initial Therapy of Multiple Myeloma

Advances in myeloma biology and the identification of new anti-myeloma agents have resulted in improved management of younger, transplant-eligible, and older patients. The first novel agents-thalidomide, bortezomib, and lenalidomide-have been integrated into induction therapy before autologous stem cell transplant (ASCT) as well as into first-line therapy in elderly individuals; phase III trials have established the superiority of these approaches in terms of better response rates, progression-free survival (PFS), and, in some studies, overall survival. With more experience, improvements in dosing have decreased the toxicity of these regimens. Before ASCT, four phase III studies have shown that bortezomib-based regimens confer better outcomes than older regimens. Posttransplant consolidation and maintenance strategies with novel agents provide additional benefit, particularly in terms of a longer PFS. In the elderly population, novel agents can be combined with melphalan plus prednisone (MP). MP plus thalidomide and MP plus bortezomib are commonly utilized, and the regimen of MP plus lenalidomide with lenalidomide maintenance (MPR + R) produces superior response rates and longer PFS compared with MP alone. Prolonged maintenance with bortezomib plus thalidomide also appears to extend PFS when given following combinations of MP plus bortezomib. Treatment of very elderly patients, however, remains challenging due to comorbidities and side effects. Lenalidomide plus weekly dexamethasone is also effective in elderly patients, and results of a trial comparing this regimen with MP plus thalidomide should be available soon. Finally, better methods of risk stratification and the availability of even newer drugs will allow future refinements in myeloma treatment.