scholarly journals Treatment of Smoldering Multiple Myeloma: Expectant Observation Should Still Be the Standard

2020 ◽  
pp. 364-370 ◽  
Author(s):  
Rafael Fonseca ◽  
Miguel Gonzalez-Velez
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Progression Free Survival ◽  
Organ Damage ◽  
Underlying Disease ◽  
Current Data ◽  
Patient Specific ◽  
Free Survival ◽  
Smoldering Multiple Myeloma ◽  
Disease Biology

Recent clinical trials have addressed the notion of early treatment of smoldering multiple myeloma (SMM). The results evidence improvement in progression-free survival and, in one study, overall survival. Although the treatment of SMM can be considered under specific circumstances, we propose here that careful interpretation of the clinical trials and the patient-specific data are needed before recommending therapy. In particular, many questions remain regarding the best regimen to be used as well as how to adapt based on the underlying disease biology. Hematologists should have a very thorough understanding of models designed to predict the progression from SMM to multiple myeloma, because their correct interpretation is paramount to establish proper care. Although there is no doubt that treatment should be started before overt end-organ damage, we do not believe that the current data support the widespread treatment of all SMM.

scholarly journals Randomized Trial of Lenalidomide Versus Observation in Smoldering Multiple Myeloma

2020 ◽  
Vol 38 (11) ◽  
pp. 1126-1137 ◽  
Author(s):  
Sagar Lonial ◽  
Susanna Jacobus ◽  
Rafael Fonseca ◽  
Matthias Weiss ◽  
Shaji Kumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Early Intervention ◽  
Randomized Trial ◽  
Progression Free Survival ◽  
Organ Damage ◽  
Hazard Ratio ◽  
Response To Therapy ◽  
Free Survival ◽  
End Organ Damage ◽  
Smoldering Multiple Myeloma

PURPOSE Observation is the current standard of care for smoldering multiple myeloma. We hypothesized that early intervention with lenalidomide could delay progression to symptomatic multiple myeloma. METHODS We conducted a randomized trial that assessed the efficacy of single-agent lenalidomide compared with observation in patients with intermediate- or high-risk smoldering multiple myeloma. Lenalidomide was administered orally at a dose of 25 mg on days 1 to 21 of a 28-day cycle. The primary end point was progression-free survival, with disease progression requiring the development of end-organ damage attributable to multiple myeloma and biochemical progression. RESULTS One hundred eighty-two patients were randomly assigned—92 patients to the lenalidomide arm and 90 to the observation arm. Median follow-up is 35 months. Response to therapy was observed in 50% (95% CI, 39% to 61%) of patients in the lenalidomide arm, with no responses in the observation arm. Progression-free survival was significantly longer with lenalidomide compared with observation (hazard ratio, 0.28; 95% CI, 0.12 to 0.62; P = .002). One-, 2-, and 3-year progression-free survival was 98%, 93%, and 91% for the lenalidomide arm versus 89%, 76%, and 66% for the observation arm, respectively. Only six deaths have been reported, two in the lenalidomide arm versus four in the observation arm (hazard ratio for death, 0.46; 95% CI, 0.08 to 2.53). Grade 3 or 4 nonhematologic adverse events occurred in 25 patients (28%) on lenalidomide. CONCLUSION Early intervention with lenalidomide in smoldering multiple myeloma significantly delays progression to symptomatic multiple myeloma and the development of end-organ damage.

Efficacy of Daratumumab Based Regimens Compared to Standard of Care for Transplant Ineligible Newly Diagnosed Multiple Myeloma in Phase III Clinical Trials: A Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Zahoor Ahmed ◽  
Karun Neupane ◽  
Rabia Ashraf ◽  
Amna Khan ◽  
Moazzam Shahzad ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Standard Care ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Control Group ◽  
Two Phase ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Phase Iii Clinical Trials

Introduction: Daratumumab (Dara) is a human anti-CD38 monoclonal antibody approved for multiple myeloma (MM) treatment. Dara has a promising efficacy and a favorable safety profile in newly diagnosed MM (NDMM) patients. This study is focused on the efficacy and safety of Dara when added to the standard care regimen in transplant ineligible NDMM in phase III clinical trials. Methods: We performed a comprehensive database search on four major databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). Our search strategy included MeSH (Medical Subject Headings) terms and key words for multiple myeloma and Dara including trade names and generic names from date of inception to May 2020. Initial search revealed 587 articles. After excluding review articles, duplicates, and non-relevant articles, two phase III clinical trials were included which reported overall response rate (ORR), and progression free survival (PFS) of transplant ineligible NDMM patients with Dara addition to standard care regimen. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using a fixed effect model in RevMan v.5.4. Results: A total of 1453 transplant ineligible NDMM patients were enrolled and evaluated in two phase III randomized clinical trials. Seven hundred and eighteen patients were in Dara group and 735 patients were in control group. Bahlis et al. (2019) studied Dara + lenolidamide (R) and dexamethasone (d) vs Rd in NDMM pts (n=737) in MAIA phase III trial. Similarly, Mateos et al. (2018) reported the role of Dara + bortezomib (V) + melphalan (M), and prednisone (P) vs VMP in NDMM pts (n=706) in a phase III trial (Alcyone). A pooled analysis of these phase III trials showed ORR (OR: 3.26, 95% CI 2.36-4.49; p < 0.00001, I2 = 0%), and progression free survival (PFS) (HR: 0.53, 95% CI 0.43-0.65; p < 0.00001, I2 = 0%). Achievement of minimal residual disease (MRD) negative status was significant in Dara based regimen as compared to control group (OR: 4.49, 95% CI 3.31-6.37; p < 0.00001, I2 = 0%). Dara addition to standard care regimen (Rd and VMP) decreased the risk of progression/death to 42% (HR: 0.58, 95% CI 0.48-0.70; p < 0.00001, I2 = 0%). The addition of Dara increased the risk of neutropenia (OR: 1.41, 95% CI 1.07-1.85; p < 0.02, I2 = 44%), and pneumonia (OR: 2.25, 95% CI 1.54-3.29; p < 0.0001, I2 = 37%) vs control group. However, decreased risk of anemia (OR: 0.64, 95% CI 0.49-0.85: p < 0.002, I2=30%) was observed in Dara group vs control group (Figure 1). Conclusion: Addition of Dara to the standard care regimen for transplant ineligible NDMM achieved the surrogate end points with improved efficacy and MRD negative status with manageable toxicity. However, data from more randomized controlled trials is needed. Table Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Hispanic or Latin American Ancestry Is Associated with a Similar Genomic Profile and a Trend Toward Inferior Outcomes in Newly Diagnosed Multiple Myeloma As Compared to Non-Hispanic White Patients in the Multiple Myeloma Research Foundation (MMRF) CoMMpassstudy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4117-4117
Author(s):  
Louis Williams ◽  
Patrick Blaney ◽  
Eileen M Boyle ◽  
Hussein Ghamlouch ◽  
Yubao Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Latin American ◽  
Copy Number ◽  
African Ancestry ◽  
Progression Free Survival ◽  
Driver Mutations ◽  
Advisory Committees ◽  
Free Survival ◽  
Disease Biology

Abstract Introduction Large clinical data sets suggest that the natural history and prognosis of newly diagnosed multiple myeloma (NDMM) differs between patients of European and African ancestry, with the latter group exhibiting an earlier age at onset and poorer overall prognosis in some studies. The use of next generation sequencing (NGS) to characterize the genomic landscape of multiple myeloma (MM) suggests that the observed phenotypic differences between these groups of patients may reflect distinct underlying genomic profiles and mutational processes. Thus far, characterizations of this type have focused principally on patients of African ancestry (AA). Here, we characterize the genomic features and outcomes of a large series of patients of Hispanic or Latin American ancestry (HL) as compared to their Non-Hispanic white (NHW) counterparts. Methods Subjects were selected from the MMRF CoMMpass SM trial, a study that includes 1,154 patients with updated outcome data as of March, 2020. Within this data set, 760 patients had information on race and ethnicity. Among these, 55 HL patients and 478 NHW patients possessed complete clinical and genomic information. We analyzed baseline whole exome sequencing (WES) and long insert whole genome sequencing (WGS) as previously described (Walker, et al. Blood 2019). Our analysis focused on 63 known driver mutations in multiple myeloma and 39 sites of common copy number variation across the study population. Complex structural variants and tumor telomere length were called using previously described bioinformatic tools (Boyle et al. Leukemia 2021). Survival analysis was undertaken using the Kaplan-Meier method with hazard ratios determined by the Cox proportional hazards model. Results In a comparison of clinical features between the Hispanic and NHW population, we did not identify any differences in age of onset, gender, presenting cytogenetics, International Staging System Score (ISS), and IMWG Risk Category. The proportion of patients undergoing autologous stem cell transplantation was similar between groups. We identified no statistically significant differences in the presence of characteristic translocations involving IgH locus or in hyperdiploidy status. No statistically significant differences in tumor mutational burden or loss-of-heterozygosity percentage emerged between HL and NHW patients. We examined non-synonymous variations (NSV) and copy number variations at the loci of known MM driver genes and encountered no statistically significant differences in NSV, copy number, or biallelic status. We further categorized genes into pathways relevant to the pathogenesis of MM and discovered no difference in the proportions of patients harboring mutations in genes related to the MEK/ERK and NF-κB pathways, cell cycle regulation, and epigenetic modification. We were unable to the distinguish either population based on the presence of chromothripsis or in the overall preponderance of an APOBEC mutational signature. Tumor telomere length was not significantly different between the populations. An analysis of overall and progression free survival (PFS) with a median duration of follow up of 44 months revealed a trend toward poorer outcomes among the HL population that did not reach statistical significance. Median PFS was 24 months in HL patients and 35 months in the NHW population (p = 0.19). Median OS was not reached in either ethnic subgroup. In terms of overall survival, age, ISS score, overall number of driver mutations, and the presence of chromothripsis emerged with a negative impact on outcome (Figures 1a, 1b). These variables with the exception of chromothripsis retained their significant impact on progression free survival (Figure 2a, 2b). Conclusion The correlation between Hispanic or Latin American ancestry and underlying disease biology in MM has yet to be fully elucidated. In our analysis, which was based on self-declared ancestry as opposed to admixture, no obvious differences in significant measures of genomic variation known to impact prognosis in MM emerged between HL and NHW patients. These results may help to inform the future large-scale studies to ascertain the impact of genomics, disease biology and socioeconomic factors on outcomes in this heterogeneous patient population. Figure 1 Figure 1. Disclosures Walker: Bristol Myers Squibb: Research Funding; Sanofi: Speakers Bureau. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Biological Significance and Prognostic Value of Cytogenetics in 160 Patients with Multiple Myeloma: Predictivity of 13 and/or 14 Monosomies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4735-4735
Author(s):  
Jolanda Donatella Vincelli ◽  
Antonio Scopelliti ◽  
Angela Violi ◽  
Corrado Mammi' ◽  
Maria Grazia D'Errigo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Diagnostic Criteria ◽  
Plasma Cell ◽  
Bone Disease ◽  
Molecular Classification ◽  
Organ Damage ◽  
Disease Biology ◽  
Risk Of Progression

Abstract Until recently, MM was defined using strict clinical pathological criteria that required evidence of specific end-organ damage (CRAB) attributable to the underlying clonal plasma cell disorder. In the case of absence of end-organ damage, patients with clonal plasma cell proliferation were diagnosed either with monoclonal gammopathy of undetermined significance (MGUS) or with smoldering multiple myeloma (SMM). Further, on one hand there have been on-going revisions of the diagnostic criteria for MM and SMM, on the other there have also been revisions of the molecular classification of these disorders; namely, staging and risk. These revisions regarding both the diagnostic criteria and the molecular classification of these disorders are very important because recent advances in understanding these disorders have led to significant progress in the treatment of MM and SMM, in our understanding of disease biology, and in prognostic evaluation for cancer patients. The Revised International Staging System (RISS) combines elements of tumor burden (ISS) and disease biology (presence of high-risk cytogenetic abnormalities or elevated lactate dehydrogenase level) to create a unified prognostic index that helps in clinical care, comparing clinical trial data. The RISS will be of importance in the clinic in terms of counseling patients regarding prognosis, as well as in clinical trials to compare outcomes across clinical trials. The initial cytogenetic classification of SMM also has implications for prognosis as patients with t(4;14) translocation, 17p deletion, and 1q amplification have a higher risk of progression from SMM to MM. Although patients with trisomies are considered to have a better prognosis when diagnosed with MM, they have a higher risk of progression from SMM to MM compared to patients with t(11;14). It is possible that trisomic MM manifests earlier with more obvious bone disease, producing in essence a lead-time bias. Thus, the time from SMM to MM is shortened while the time from MM to death appears longer. There are several molecular subtypes of MM, associated with several unique differences in disease presentation and prognosis. For example, trisomic MM appears to respond particularly well to lenalidomide-based therapy, while t(4;14) MM requires bortezomib-based induction and maintenance for good outcome. In terms of clinical presentation, t(4;14) MM appears to have a lower propensity for bone disease at diagnosis, while t(14;16) MM is often associated with high levels of serum free light chains (FLC) and a higher risk of acute renal failure at diagnosis. Disease biology in MM is best reflected based on the molecular subtype of the disease and the presence or absence of specific cytogenetic abnormalities. The abnormalities such as t(4;14), t(14;16), t(14;20), gain(1q), del(1p), and del(17p) influence disease course, response to therapy, and prognosis in MM. In our center we evaluated the cytogenetics data at the onset of the disease, after 1st line therapy, after transplantation and during maintenance therapy to analyze any changes in the cytogenetic panel and additional anomalies and if all this is correlated with the characteristics of the disease, patient, and risk predictor. In particular, we evaluated 160 patients and analyzed the clinical evolution in patients in which monosomies 13 and/or 14 were present, currently not classifiable in prognostic terms. The significance of these monosomies was evaluated based on the various stages of the disease and the type of therapy administered. Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficacy and Toxicity Profile of Ibrutinib Based Regimens for Refractory Multiple Myeloma: A Systematic Review

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1948-1948
Author(s):  
Faiza Jamil ◽  
Madeeha Shafqat ◽  
Ali Younas Khan ◽  
Seren Durer ◽  
Ceren Durer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
High Risk ◽  
Respiratory Infections ◽  
Progression Free Survival ◽  
Toxicity Profile ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Muscle Spasms ◽  
Combination Regimens

Abstract BACKGROUND: Despite recent advancements in treatment for multiple myeloma (MM) there is a constant need for newer therapies to tackle the complex issue of relapse and therapy after relapse for patients with MM. Ibrutinib is an oral inhibitor of Bruton tyrosine kinase (BTK), which is overexpressed in the plasma cells. We conducted a comprehensive literature search to analyze the efficacy, dosing and toxicity profile of ibrutinib in relapsed MM. METHODS: Database search using PubMed, EMBASE, Cochrane Library, Web of Science and Clinicaltrials.gov was performed on 06/05/18 (last update) . All clinical trials that used ibrutinib either as monotherapy or in combination regimens in the setting of relapsed and refractory multiple myeloma (RRMM) were included. RESULTS: A total of 388 articles were found on the initial search and after screening, three phase I and II clinical trials qualified for inclusion. Ibrutinib based regimen data (n=155 patients) was analyzed (Table 1). Majority (68%) of the patients were refractory to their previous line of therapy. Ibrutinib Monotherapy: Monotherapy (n=31) with a dose of 420 mg/d to 840 mg/d demonstrated a 0% ORR (overall response rate). A median PFS (progression-free survival) of 0.9 to 2.8 months was noticed with ibrutinib monotherapy. Most common hematological adverse events (HAE) noted were anemia (32%), thrombocytopenia (29%) and neutropenia (13%). All-grade gastrointestinal disturbances (GI) were observed in 90% of cases, fatigue and respiratory infections (RI), each in 39% and muscle spasms in 23% of cases. Ibrutinib + Dexamethasone: The addition of 40 mg dexamethasone to 560 mg/d (n=18) and 840 mg/d (n=43) ibrutinib showed an ORR of 6% and 5% and reported median PFS of 3.7 months and 4.6 months, respectively. Side effects included anemia (26%), thrombocytopenia (23%), and neutropenia (2%). GI toxicity was noted in 82% patients, fatigue in 46%, RI in 15% and muscle spasms reported in 15% patients. Ibrutinib + Carfilzomib: At 560 mg/d dose of ibrutinib, the addition of 27 mg/m2 (n=3) and 36 mg/m2 of carfilzomib (n=5) showed a response of 67% and 40%, respectively. The best response was elicited when 20 mg of dexamethasone was added to 36 mg/m2 of carfilzomib and ibrutinib at a dose of 840 mg/d (n=18; ORR: 71%) and 560 mg/d (n=17; ORR: 71%). The median duration of responses was 12.9 months. Minimal responses were observed in an additional 4 patients giving an overall clinical benefit rate of 76%. At a dose of 36 mg/m2 of carfilzomib, median PFS was reported as 8.1 and 6.4 months at 560 mg/d and 840 mg/d doses of ibrutinib, respectively. Most common HAE were anemia (35%), thrombocytopenia (28%) and neutropenia (9%). Eighty-six percent of patients developed GI disturbances while fatigue and muscle spasms were noted in 53% and 19%, respectively. RI were observed in 51% of patients. Ibrutinib + Bortezomib: The combination of ibrutinib given at 840 mg/d dose with a twice weekly dose of bortezomib 1.3 mg/m2 elicited a response in 46% (n=20) patients, and minimal responses in 4 (21%) patients. Most common GI disturbance was diarrhea (50%). Upper respiratory infections were noted in 30% cases while, asthenia and peripheral edema seen in 20% of cases. Bortezomib/IMiD Refractory Cohort: Patients refractory to prior bortezomib (n=27) showed an encouraging ORR of 73% that was durable for a median of 9.1 months when ibrutinib+carfilzomib+dexamethasone regimen was used. Similarly, another cohort (n=25) of double refractory patients treated with a combination of ibrutinib and dexamethasone demonstrated minimal response in 4 (16%) and disease stabilization in another 5 (20%) patients. High-Risk Cohort: In a population of high-risk cytogenetics (del 17p and/or t[4;14]; n=11) treated with 560 mg/dl to 840 mg/dl of ibrutinib, 36 mg/m2 of carfilzomib and (+/-) 20 mg of dexamethasone showed an ORR of 78%, response was durable for a median of 9.1 months, and achieved a median progression free survival (PFS) of 8.1 months . CONCLUSION: Ibrutinib has demonstrated a promising efficacy (70-80% of ORR in combination regimens) along with an acceptable toxicity profile in the heavily pre-treated and dual drug refractory MM patients. Larger prospective clinical trials are needed to further evaluate its efficacy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of Newer Agents on Progression Free Survival of Multiple Myeloma in the 2nd 3rd and 4th Line Setting- a Systematic Review

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5645-5645
Author(s):  
Muhammad Sardar ◽  
Jemin Aby Jose ◽  
Zunairah Shah ◽  
Chaudhry Saad Sohail ◽  
Insija Ilyas Selene ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Conflicts Of Interest ◽  
Case Series ◽  
Progression Free Survival ◽  
Novel Agents ◽  
Control Group ◽  
Combination Regimen ◽  
Free Survival ◽  
Line Setting

Abstract Background: Multiple Myeloma (MM) remains incurable. Majority of the patients ultimately relapse with a lower median event free survival after each successive line of therapy. For newly diagnosed MM patients, the median progression free survival (PFS) has improved drastically with the advent of novel agents. Aim of our review is to discuss median PFSnwith novel agents in the 2nd 3rd and 4th line of treatment in MM. Methods: A comprehensive literature search was done in accordance with the PRISMA guidelines from Jan 1st 2010 to May 30th 2018 using the following 4 databases: PubMed/ Medline, Elsevier/Embase, Wiley/Cochrane and clinicaltrials.gov. Inclusion criteria consisted of all prospective clinical trials that a) included patients with 1-3 prior lines of therapies b) received novel therapeutic agents as an intervention c) outcome was reported as median PFS. We excluded case series, retrospective/observational studies, systematic reviews/meta-analysis. We identified 4777 records through initial database search. After removing duplicates and further screening, 59 full-text articles were assessed for eligibility. 50 articles were subsequently excluded with reason and 9 articles constituting 4937 patients were selected for data extraction and final analysis. Result In a randomized clinical trial (RCT) by Dimopolous et al (2017), 396 patients (median age: 64) in the carfilzomib, lenalidomide and dexamethasone (KRD) arm had median PFS of 26.3 m. In comparison, 396 patients in the control group (median age: 65) that received RD regimen had a median PFS of 17.6 m. Percentage of patients with prior bone marrow transplant (BMT) and high-risk (HR) cytogenetics was 54.8% and 12.1% respectively in the KRD regimen and 57.8% and 13.1% respectively in the RD regimen. The median prior number of therapies was 2 in each group. In the trial by Avet-Loiseau et al 2017, patients in the Ixazomib-RD arm (n=360; HR cytogenetics=21%) had a median PFS of 20.6m as compared to 14.7 m in the control group (RD) arm (n=362; HR cytogenetics=17%). Median prior number of therapies was 2 in each group and 59% and 57% of the patients had prior BMT respectively. Lonial et al (2015) showed that the group (n=321; median age 67) that received elotuzumab-RD regimen had median PFS of 19.4m compared to 14.5m in the control group (n=325; median age 66) that received RD regimen. Prior median therapies were 2 in each arm and BMT was done in 52% and 57% of the patients respectively. A RCT of two drug regimen by Chang et al (2017) showed that patients (n= 464) who received KD had a higher median PFS (18.7m) as compared to patients (n= 465) who received bortezomib(V)-D (9.4 m). KD arm had 37.2% patients with prior BMT as compared to 49.6% in the VD arm whereas the median prior number of therapies was 2 in each arm. HR cytogenetics were present in 21% and 24% respectively. In the trial by Orlowski et al (2015), there was no improvement in the median PFS with the addition of Siltuximab to V as compared to V alone. Similarly, no significant improvement in median PFS was noted by Dimopolus et al (2017) in the combination regimen of Vorinostat-V as compared to placebo-V. In the trial by white et al (2017), the median PFS was 6.2 with bevacizumab-V as compared to 5.1m with placebo-V. In a trial by Richardson et al (2016), Panobinostat-VD had a median PFS of 11.99 which was higher than 8.08 with placebo-VD. Conclusion: Regimen consisting of KRD has the highest median PFS in MM patients with multiple prior lines of therapy followed by IRD based regimen. Limitations of our analysis include a heterogeneous patient population and exclusion of data with daratumumab based regimen because of unavailability of median PFS specifically in the 2nd 3rd and 4th line setting in the published clinical trials. Disclosures No relevant conflicts of interest to declare.

Investigation of the Association Between Treatment Effects On Progression Free Survival and Overall Survival in Multiple Myeloma Using Data From Published Literature

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4241-4241
Author(s):  
Bin Zhang ◽  
Shannon Cartier ◽  
Virginia Rosen ◽  
April Teitelbaum ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Clinical Trials ◽  
Linear Regression ◽  
Regression Models ◽  
Treatment Effects ◽  
Geometric Mean ◽  
Progression Free Survival ◽  
Linear Regression Models ◽  
Free Survival

Abstract Abstract 4241 Background: The primary goals in the development of new oncology therapies are treatments that improve quality of life and overall survival (OS). In recent years, advances in the treatment of multiple myeloma (MM) have led to improvements in OS. However, with improved treatment options and multiple rounds of therapy it is becoming an increasing challenge to demonstrate OS improvements in clinical trials. Thus, progression free survival (PFS) is widely used as a surrogate endpoint to demonstrate long term clinical benefit. However, to our knowledge, there has been very limited analysis of the association between treatment effects on PFS and treatment effects on OS in patients with multiple myeloma (MM). Purpose: To evaluate whether observed treatment effects on PFS are positively associated with treatment effects on OS in MM based on published data from clinical trials in patients with MM. Methods: A systematic literature review of MM identified 13 published clinical trials that reported HRs for the effects of treatment on PFS and separately on OS. The patients in 12 of the studies were previously untreated, and one study included patients with relapsed/refractory disease. The Pearson correlation coefficient (Pearson r) was used to estimate the association between the reported hazard ratios (HRPFS and HROS), as well as the log-transformed HRs (log(HRPFS) and log(HROS)), for the treatment effects on PFS and OS. Linear regression models were used to evaluate the relationship between the HR, and log(HR), of PFS and OS. A log transformation of the HRs for PFS and OS was used in order to minimize any skewness and normalize the data. R-squared values were estimated from the regression models. 95% Confidence intervals around the R-squared values were estimated using Olkin and Finn's approximation (I. Olkin and J. D. Finn, Psychological Bulletin, Vol 118(1), Jul 1995, 155–164) of the standard error and Student's T distribution. Sensitivity analyses included the estimation of additional weighted regression models to investigate the robustness of the R-squared estimates using two weighting methods. Individual study sample sizes were used as weights in one method to allocate more precision to studies with larger sample sizes. Estimates of the geometric mean of the variance of the HRs were also utilized as weights to account for the multi-directional error around the two HRs. The geometric mean estimates were calculated as the inverse of the product of the width of the two HRs. Results: Pearson r estimates between the HRs for the treatment effects on PFS and OS showed a strong positive correlation between HRPFS and HROS r=0.815 (CI: 0.53–0.93; p<0.0001), and between log(HRPFS) and log(HROS) r=0.80 (CI:0.50–0.92; p=0.0001), indicating that the treatment effects on PFS and treatment effects on OS in MM are positively associated. The HRPFS and log(HRPFS) were significantly associated with the HROS and log(HROS), respectively, based on the linear regression models. The R-squared values for these models were 0.66 (CI: 0.43–0.89) for the regression of HROS on HRPFS and R-squared values of 0.64 (CI: 0.40–88) for the regression of log(HROS) on log(HRPFS). Figure 1 displays the association between the log-transformed HRs. The sensitivity analysis results for the Pearson r and R-squared values were generally consistent with the primary analysis. Pearson r estimates ranged from 0.67 to 0.84, and the weighted regressions between HROS and HRPFS produced the extremes for the R-squared estimates: 0.71 and 0.45 when weighting by sample size and geometric mean of the variances, respectively. A separate regression model was considered that also adjusted for available covariates (age, population, length of follow-up). These covariates were not statistically significant predictors at the alpha = 0.05 level. With the addition of these covariates, the R-squared value for the linear regression of log(HROS) on log(HRPFS) was 0.695. Conclusion: This analysis based on published MM clinical trial results indicate that treatment effects on PFS may be positively associated with treatment effects on OS. Further studies involving patient-level data would be necessary to confirm these results. Disclosures: Zhang: BMS: Employment. Cartier:OptumInsight: Consultancy. Rosen:BMS: Consultancy. Teitelbaum:Optum Insight was hired to do literature review: Employment. Bartlett:Bristol-Myers Squibb: Employment. Kroog:Bristol-Myers Squibb: Employment. Mukhopadhyay:BMS: Employment. Wagner:Bristol-Myers Squibb: Employment.

scholarly journals What Is New in the Treatment of Smoldering Multiple Myeloma?

2021 ◽  
Vol 10 (3) ◽  
pp. 421
Author(s):  
Niccolo’ Bolli ◽  
Nicola Sgherza ◽  
Paola Curci ◽  
Rita Rizzi ◽  
Vanda Strafella ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
High Risk ◽  
Early Treatment ◽  
Individual Case ◽  
Symptomatic Disease ◽  
Plasma Cell Neoplasm ◽  
Smoldering Multiple Myeloma ◽  
Wide Range ◽  
Critical Issues

Smoldering multiple myeloma (SMM), an asymptomatic plasma cell neoplasm, is currently diagnosed according to the updated IMWG criteria, which reflect an intermediate tumor mass between monoclonal gammopathy of undetermined significance (MGUS) and active MM. However, SMM is a heterogeneous entity and individual case may go from an “MGUS-like” behavior to “early MM” with rapid transformation into symptomatic disease. This wide range of clinical outcomes poses challenges for prognostication and management of individual patients. However, initial studies showed a benefit in terms of progression or even survival for early treatment of high-risk SMM patients. While outside of clinical trials the conventional approach to SMM generally remains that of close observation, these studies raised the question of whether early treatment should be offered in high-risk patients, prompting evaluation of several different therapeutic approaches with different goals. While delay of progression to MM with a non-toxic treatment is clearly achievable by early treatment, a convincing survival benefit still needs to be proven by independent studies. Furthermore, if SMM is to be considered less biologically complex than MM, early treatment may offer the chance of cure that is currently not within reach of any active MM treatment. In this paper, we present updated results of completed or ongoing clinical trials in SMM treatment, highlighting areas of uncertainty and critical issues that will need to be addressed in the near future before the “watch and wait” paradigm in SMM is abandoned in favor of early treatment.

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