Efficacy of Upfront Daratumumab Combination Regimen in Patients with Newly Diagnosed Multiple Myeloma

Introduction: Management of newly diagnosed multiple myeloma (NDMM), which accounts for 1% of all cancers, is an area in dire need of therapeutic innovation. In recent years, the introduction of novel agents is one of the major advances in the management of patients with NDMM, in both transplant- eligible and transplant- ineligible candidates. Studies have combined daratumumab, a human IgGκ monoclonal antibody that targets CD38 which is highly expressed on myeloma cells, with proteasome inhibitors and immunomodulatory agents-based regimens in the first-line treatment of NDMM. The purpose of our study is to explore and consolidate the efficacy of upfront daratumumab combination regimen in patients with NDMM. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with newly diagnosed/ untreated multiple myeloma were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) for overall response rate (ORR), including stringent complete response (sCR), CR and very good partial response (VGPR). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. Results: Three phase III RCTs with a total of 2,528 patients with NDMMwere included.Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, and DVd + thalidomide (T) vs VTd. The randomization ratio was 1:1 in all studies. The I2statistic for heterogeneity was 0, suggesting homogeneity among RCT. The pooled HR for PFS was statistically significant at 0.52 (95% CI: 0.44-0.61; P < 0.0001). The PFS benefit was observed in all ISS categories, types of immunoglobulin (Ig) and standard risk cytogenetic; ISS I cohort (HR, 0.55; 95% CI: 0.37- 0.82; P = 0.003), ISS II cohort (HR, 0.43; 95% CI: 0.33- 0.55; P < 0.0001), ISS III cohort (HR, 0.63; 95% CI: 0.48- 0.82; P = 0.0006), IgG cohort (HR, 0.56; 95% CI: 0.40- 0.77; P = 0.0003), non-IgG cohort (HR, 0.52; 95% CI: 0.28- 0.97; P = 0.04), and standard risk cytogenetic cohort (HR, 0.43; 95% CI: 0.35- 0.53; P < 0.0001). The pooled HR for PFS in high risk cytogenetic cohort was not statistically significant at 0.76 (95% CI: 0.53- 1.10; P = 0.15). The pooled RR for ORR was 1.13 (95% CI: 1.01-1.26; P = 0.03), sCR was 2.02 (95% CI: 1.33-3.08; P = 0.001), CR was 1.46 (95% CI: 1.20-1.79; P = 0.0002),and VGPR was 1.01 (95% CI: 0.82-1.25; P = 0.93). The pooled RR for negative minimal residual disease (MRD) was 2.54 (95% CI: 1.24-5.20; P = 0.01). Conclusions: Upfront combination regimen with daratumumab significantly improved PFS, ORR, sCR and CR along with negative MRD, compared to control arm in patients with NDMM. The improvement in PFS was noted across all subgroups except in high-risk cytogenetic group. More randomized studies are required to explore further novel agents and to formulate optimal combination regimen to improve survival in this high-risk cytogenetic subset. Disclosures No relevant conflicts of interest to declare.

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Analysis of 179 Patients with Newly Diagnosed Multiple Myeloma (MM) Treated with Novel Agents Followed by Autologous Stem Cell Transplantation (ASCT): a Retrospective Study

Blood ◽

10.1182/blood.v116.21.1343.1343 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1343-1343

Author(s):

Joyce Habib ◽

Neil Dunavin ◽

Gary Phillips ◽

Patrick Elder ◽

Meaghan Tranovich ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

Research Funding ◽

Progression Free Survival ◽

Novel Agents ◽

Genetic Profile ◽

Newly Diagnosed ◽

Free Survival

Abstract Abstract 1343 Background: Multiple myeloma (MM) is the second most common hematological malignancy in the United States with an estimated 20,580 new cases in 2009. Over the past decade, the introduction of novel agents (thalidomide, lenalidomide and bortezomib) have played a pivotal role in improving response rates, duration of response, overall survival (OS) and quality of life. In this study we describe a single center experience with novel agents used for induction followed by high dose chemotherapy (HDT) and first autologous stem cell transplant (ASCT) in patients with MM. Method: A retrospective review of the medical records of 179 newly diagnosed patients with MM seen between October 2006 and December 2009 at The Ohio State University was performed. All patients received novel therapy containing thalidomide, bortezomib or lenalidomide as part of an induction regimen followed by ASCT. All patients received melphalan 140mg/m2 or 200mg/m2 as preparative regimen. Kaplan-Meier estimates were used to plot progression free survival and overall survival. Results: Of the 181 patients seen, 2 were excluded because they did not receive a novel agent as part of induction treatment. Of the 179 patients analyzed, median age was 56.8 years (29-80) with 30% of patients older than 60 years. African American represented 19%. Fifty-nine percent were male, 80% had Durie-Salmon (DS) stage III while 25%, 28%, 18% represented International prognostic score (IPS) stage I, II, and III respectively with 27% unknown. Median comorbidity index score was 2 (2-7) and median Karnofsky performance score (KPS) was 90% (70-100). Thirty percent had high risk genetic profile, and 73% received one line of treatment before ASCT. The median time from diagnosis to ASCT was 8.33 months (4-58). The overall response rate (ORR) prior to transplant was 84% (9% complete (CR), 29% very good partial (VGPR), and 46% partial (PR)). The ORR post ASCT was 89% (CR 45%, VGPR 22%, PR 21%). Non relapse mortality was 1% and 3% at 100 days and 1 year respectively. At a median follow up of 31 months (7-90), 69 patients (38%) had relapsed. Median progression free survival (PFS) was 29 months with 1 and 3 years PFS of 79.3% and 61.5% respectively (Fig. 1). The OS was not reached. One and 3 years OS were 93% and 88% respectively (Fig. 1). Univariate analysis showed that time to transplant > 12 months was associated with poor outcome and decreased overall survival (HR 3.30, p = 0.008). High risk genetic profile was also found to be associated with decreased overall survival although this was not statistically significant (HR 2.31, p = 0.070). Multivariate analysis found that only time to transplant > 12 months was an independent predictor of decreased OS. Significant predictors for disease progression were high risk genetic profile and time to transplant > 12 months in patients receiving 2 or more treatments before ASCT. Conclusion: Induction with novel agents followed by HDT and ASCT improves CR rate, in our case from 9% to 45%. Median PFS (29 months) was comparable to other published data. OS was not been reached after a median follow up of 31 months. Predictors of progression include high risk genetic profile and time to transplant > 12 months. The only significant predictor for survival was time to transplant. Our study suggests that an early transplant may improve OS and PFS. An extended analysis will be presented at the meeting. Disclosures: Phillips: NCI/NIH: Research Funding; NCCM Grant: Research Funding; ARRA RC2 Grant: Research Funding. Byrd:Genzyme Corporation: Research Funding.

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Lower Plasma Mir-92a Levels Predict Shorter Progression-Free Survival In Newly Diagnosed Symptomatic Multiple Myeloma Patients

Blood ◽

10.1182/blood.v122.21.1879.1879 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1879-1879

Author(s):

Seiichiro Yoshizawa ◽

Tomohiro Umezu ◽

Junko H Ohyashiki ◽

Shinsuke Iida ◽

Kazuma Ohyashiki

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Chromosomal Aberrations ◽

Progression Free Survival ◽

Risk Groups ◽

Newly Diagnosed ◽

Lower Plasma ◽

Free Survival ◽

Cut Points ◽

Standard Risk

Abstract Background Current prognostic model for multiple myeloma (MM) is based on International Staging System (ISS) and presence of specific chromosomal abnormalities (CAs), especially by fluorescence in situ hybridization (FISH) analysis. MicroRNAs (miRNAs) play important roles in the development and progression in multiple myeloma (MM). Previously, we have described that plasma miRNA profiling has showed considerably lower plasma miR-92a levels in newly diagnosed MM patients (Yoshizawa et al. Blood Cancer Journal 2(1):e53, 2012). The aim of this study was to investigate the impact of plasma miR-92a levels to CAs and to prognosis in patients with newly diagnosed MM. Patients and methods From April 2004 to December 2012, 60 patients with newly diagnosed symptomatic MM (median age, 66 years; range, 34-93 years) were included in this study. We measured plasma miR-92a values (miR-92a/miR-638) by qRT-PCR. They were divided into high-risk and standard-risk by using FISH and conventional cytogenetic studies: high-risk cytogenetics was defined as translocations t(4;14), t(14;16), or del (17p13) detected by FISH, or del (13q) by Q-banding according to IMWG guidelines. All others, including t(11;14), were defined as standard-risk cytogenetics. We analyzed the clinical relevance of plasma miR-92a levels with respects to CAs. Furthermore we identified miR-92a expression cut points with the most impact on outcome to investigate which of the some disease characteristics and its cut-off value had prognostic influence in MM patients. Results Chromosomal aberrations were noted in 26 (43%) MM patients after diagnosis, including 12 patients with t(4;14), 5 with t(11;14), 3 with t(14;16), 2 with del (17p13), 2 with del (13q), and 1 with t(4;14) and del (17p13), 1 with t(11;14) and del (17p13). Between MM patients with and without high-risk cytogenetics, there were no significant differences in β2-microglobulin and albumin levels (P = 0.994 and 0.85, respectively), ISS staging (P = 0.583), age (P = 0.651), sex (P = 0.585), frequency of CRAB symptoms (hypercalcemia, P = 0.755; renal insufficiency, P = 0.75; anemia, P = 0.375; bone lesion, P= 0.65, respectively). The plasma miR-92a level was significantly lower in the newly diagnosed MM with high-risk groups than in those with standard-risk groups (P = 0.015). Patients with plasma miR-92a levels < 0.04 had a significantly shorter progression-free survival (PFS) than patients with plasma miR-92a levels ≥ 0.04 (median PFS: 48 vs 15.8 months, P = 0.011). In addition, some clinical parameters were associated with adverse PFS: high-risk cytogenetics (P = 0.001), high proportions of bone marrow plasma cells (P = 0.043), high levels of serum β2-microglobulin (P = 0.022) and not attaining ≥ very good partial response (VGPR) (P = 0.007). On multivariate analysis, lower miR-92a level was an independent prognostic factor for PFS. Using the same miR-92a cut points, there was a tendency towards significant difference among standard-risk myeloma patients (P = 0.077). Moreover, the combinations of chromosomal aberrations and plasma miR-92a were able to classify newly diagnosed MM patients with three risk groups with different probabilities. Conclusion The plasma miR-92a values vary across high- and standard-risk cytogenetics in newly diagnosed MM patients. We conclude that measurement of plasma miR-92a levels may not only function as novel biomarkers for diagnosis, but may also be helpful for prognostic stratification. Disclosures: Ohyashiki: Janssen Pharmaceutical co.: Research Funding.

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Prognostic Impact of Minimal Residual Disease By ASO-RQ-PCR in Multiple Myeloma: A Pooled Analysis of 2 Phase III Studies in Patients Treated with Lenalidomide after Front-Line Therapy

Blood ◽

10.1182/blood.v128.22.4409.4409 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4409-4409 ◽

Cited By ~ 4

Author(s):

Stefania Oliva ◽

Manuela Gambella ◽

Alessandra Larocca ◽

Stefano Spada ◽

Eleonora Marzanati ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Minimal Residual Disease ◽

Research Funding ◽

Residual Disease ◽

Tumor Burden ◽

Phase Iii ◽

Standard Risk ◽

Minimal Residual

Abstract Background: The prognostic utility of minimal residual disease (MRD) analysis in multiple myeloma (MM) patients has been well described in the last few years. The role of prolonged maintenance therapy even in persistent MRD negative patients is still unclear. The aim of this study is to evaluate the role of MRD by allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) as predictor of progression-free survival (PFS) in newly diagnosed MM (NDMM) patients receiving Lenalidomide maintenance after frontline treatment. Patients and Methods: NDMM patients enrolled in the RV-MM-EMN-441 (NCT01091831) and the RV-MM-COOP-0556 (EMN02/HO95 MM) phase III trials achieving ≥ very good partial response (VGPR) after consolidation/intensification were included in the pooled MRD molecular analysis. After induction therapy, patients in the RV-MM-EMN-441 study were randomized to Cyclophosphamide-Lenalidomide-Dexamethasone (CRD) or Autologous Stem Cell Transplantation (ASCT); patients in the RV-MM-COOP-0556 were randomized to Bortezomib-Melphalan-Prednisone (VMP) vs ASCT (Gay F et al Lancet Oncol 2016, Cavo M et al J Clin Oncol 34, 2016 abstr 8000). All patients received Lenalidomide maintenance until progression or intolerance. MRD analysis was performed on bone marrow (BM) aspirates after intensification/consolidation, after 6 courses of maintenance and then every 6 months until clinical relapse. Patient-specific IgH rearrangements were amplified and directly sequenced from genomic DNA at diagnosis. IgH-based MRD detection by ASO-RQ-PCR was performed using an AbiPrism7900HT.MRD analysis was interpreted following the Euro-MRD guidelines(van der Velden VH et al. Leukemia 2007). Molecular-CR (m-CR) was defined as two consecutive negative MRD results by ASO-RQ-PCR with minimal sensitivity of 10−5. PFS was analyzed using the Kaplan-Meier method, curves were compared with the log-rank test. Multivariate Cox model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: a total of 105 patients entered the molecular MRD pooled study: a specific IgH molecular marker was identified in 73 patients (70%), 32 (30%) did not obtain a successful sequencing. Median age was 57 years (37-65); 30 (41%) patients had International Staging System (ISS) stage I, 33 (45%) stage II and 10 (14%) stage III. FISH risk profile was standard in 43 (59%) patients, high in 24 (33%) and not available in 6 (8%). Thirty-eight (52%) patients did not receive ASCT consolidation and 35 (48%) underwent ASCT. After consolidation/intensification 33/73 (45%) patients achieved m-CR: 19/35 (54%) ASCT patients and 14/38 (37%) no ASCT patients. The impact of m-CR on outcome after consolidation was explored: after a median follow-up of 44 months, median PFS was 48.8 months versus not reached in no m-CR vs m-CR patients, respectively (p=0.01). Lenalidomide maintenance further improved depth of MRD response: 11/40 (27%) MRD positive patients after consolidation obtained a m-CR during maintenance and a median of 2 natural logarithms of tumor burden reduction was recorded. In multivariable Cox analysis the risk of progression/death was higher for ISS stage II/III versus I (HR, 2.91, CI: 1.01-8.41, p=0.048), high-risk FISH versus standard-risk (HR, 2.23 CI: 0.81-6.10, p=0.12), age > 60 years versus ≤60 years (HR: 3.55, CI: 1.26-10.04, p=0.017) and patients who did not achieve m-CR during treatment versus patients who did (HR, 7.65 CI: 2.77-21.11, p<0.001). We identified a very high risk group defined by high risk FISH at diagnosis and persistent MRD positivity, with a median PFS of 29.4 months (figure1). Conclusions: MRD status by ASO-RQ-PCR is a predictor of outcome significantly superior to standard risk factors in NDMM patients and the achievement of m-CR seems to overcome the high risk FISH status in PFS analysis. Molecular CR rate and reduction of tumor burden obtained after consolidation can be enhanced with Lenalidomide maintenance. Based on these preliminary results, the assessment and monitoring of MRD should be suggested as a better prognostic indicator than CR, and the potential role of a MRD-guided therapy should be investigated in future prospective trials. Figure 1 PFS of patients stratified by MRD status (molecular-CR vs no molecular-CR) and FISH (high risk vs standard risk) Figure 1. PFS of patients stratified by MRD status (molecular-CR vs no molecular-CR) and FISH (high risk vs standard risk) Disclosures Oliva: Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Larocca:Amgen, Celgene, BMS, Janssen-Cilag: Honoraria. Offidani:Janssen: Honoraria; Celgene: Honoraria, Research Funding. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Sanofi, Celgene, Amgen, Janssen, Novartis, Abbivie, BMS: Honoraria; Celgene, Janssen, Amgen, BMS, Mundipharma, Novartis, Sanofi: Research Funding.

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Contemporary therapy efficacy for high-risk multiple myeloma: A systematic review.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e19536 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e19536-e19536

Author(s):

Afia Ashraf ◽

Udhayvir Singh Grewal ◽

Prem Thirunagari ◽

Ahsan Wahab ◽

Ammara Majeed ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Residual Disease ◽

Pegylated Liposomal Doxorubicin ◽

Progression Free Survival ◽

Complete Response ◽

Outcome Data ◽

Drug Conjugates ◽

Car T ◽

Standard Risk

e19536 Background: Multiple Myeloma (MM) is a heterogeneous disease. High Risk (HR) MM is defined as the presence of abnormal cytogenetics i.e. t(4:14), t(14:16), t(14:20), del(17/17p), non hyperdiploidy and gain (1q). HR MM is a treatment challenge. We aim to explore efficacy of anti-myeloma therapy for newly diagnosed (ND) and relapsed/refractory (RR) HR MM. Methods: We used Pubmed, Ebsco and MBASE to select 18 trials with outcome data on ND (n = 598) and RR(n = 726) HR MM (n = 1321), after extensive review, treatment efficacy (CR, VGPR, ORR) and survival (mPFS, OS) data was extracted. Results: In HR MM the range of overall response rate (ORR) was 31%-100% (Standard Risk (SR): 56%-94.7%), complete response (CR) was 10%-58.3% (SR: 7%-38.1%) and very good partial response (VGPR) was 15%-88.3% (SR: 25%-63%). In ND HR patients, range of ORR was 71.2% - 86.2% (SR: 71.2% - 91.7%) and CR was 35% - 58.3% (SR: 22%-35%) and median progression free survival (mPFS) was 18 months (m) - 31.3m (SR: 31.3m – Not Reached). In RR HR patients, range of ORR was 31% – 85.2% (SR: 56%-94.7%) and CR was 10%-29.2% (SR: 7%-38.1%) and mPFS was 3.3m - 23.1m (SR: 4m - Not Reached). In RR HR MM, Daratumumab ( Dara) , lenalidomide (R) and dexamethasone (d) combination resulted in highest minimal residual disease (MRD) negativity 21.4%. In RR HR, Carfilzomib (Car)- R-d resulted in the longest mPFS of 23.1m (SR: 29.6m) followed by (Dara)-R-d of 22.6m (SR:NR) and Ixazomib (I)- R-d of 21.4m (SR:20.6). In ND HR, Bortezomib (V) with thalidomide (T)- d resulted in longest mPFS of 23.5m (SR: NR) and OS of 56.6m followed by Cyclophosphamide (Cy)-T-d of 20m (SR:34m) and (Dara)-V- Melphalan(M) and Prednisone of 18m (SR:NR). Quadruplet therapy in ND with Cy- V – d with pegylated liposomal doxorubicin resulted in the highest CR 58.3% and mPFS of 31.3m (~8m longer). Conclusions: Cytogenetically HR MM achieved high ORR, CR and VGPR similar to SR MM yet, the PFS and OS in HR (mPFS: 11.2m - 31.3m) was significantly shorter than SR (mPFS: 19m - Not Reached) representing poor prognosis. Promising strategies and targeted therapies that are currently evolving include antibody based combination therapy (3 or 4 drugs), various CAR-T cells constructs, targeted inhibitors, and antibody-drug conjugates.

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

Blood ◽

10.1182/blood-2018-99-119662 ◽

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.

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Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance

Blood ◽

10.1182/blood-2011-04-345801 ◽

2011 ◽

Vol 118 (17) ◽

pp. 4547-4553 ◽

Cited By ~ 46

Author(s):

María-Victoria Mateos ◽

Norma C. Gutiérrez ◽

María-Luisa Martín-Ramos ◽

Bruno Paiva ◽

María-Angeles Montalbán ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Dna Ploidy ◽

Progression Free Survival ◽

Newly Diagnosed ◽

Free Survival ◽

Cytogenetic Abnormalities ◽

High Risk Patients ◽

Risk Patients ◽

Standard Risk

Abstract Cytogenetic abnormalities (CAs) such as t(4;14), t(14;16) or del(17p), and nonhyperdiploidy are associated with poor prognosis in multiple myeloma. We evaluated the influence of CAs by FISH and DNA ploidy by flow cytometry on response and survival in 232 elderly, newly diagnosed multiple myeloma patients receiving an induction with weekly bortezomib followed by maintenance therapy with bortezomib-based combinations. Response was similar in the high-risk and standard-risk CA groups, both after induction (21% vs 27% complete responses [CRs]) and maintenance (39% vs 45% CR). However, high-risk patients showed shorter progression-free survival (PFS) than standard-risk patients, both from the first (24 vs 33 months; P = .04) and second randomization (17 vs 27 months; P = .01). This also translated into shorter overall survival (OS) for high-risk patients (3-year OS: 55% vs 77%; P = .001). This adverse prognosis applied to either t(4;14) or del(17p). Concerning DNA ploidy, hyperdiploid patients showed longer OS than nonhyperdiploid patients (77% vs 63% at 3 years; P = .04), and this was more evident in patients treated with bortezomib, thalidomide, and prednisone (77% vs 53% at 3 years; P = .02). The present schema does not overcome the negative prognosis of high-risk CAs and nonhyperdiploidy. This trial was registered with www.ClinicalTrials.gov as NCT00443235.

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Impact of Novel Agents on Young Patients with t(11;14) Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.2059.2059 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2059-2059

Author(s):

Jonas Paludo ◽

Nishanth Vallumsetla ◽

Shaji Kumar ◽

Rhett Ketterling ◽

Morie A Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Conflicts Of Interest ◽

Young Patients ◽

Novel Agents ◽

Prognostic Impact ◽

Cell Transplant ◽

Genetic Signature ◽

Normal Fish ◽

Standard Risk

Abstract Background: Outcome studies for the unique cohort of young patients with multiple myeloma (MM) are sparse. In general, MM is a heterogenous disease with the genetic signature being one of the major determinants of prognosis. We have recently reported on improvement in overall survival (OS) of young patients with the use of novel agents, but the maximal survival gain has been achieved by integrating autologous stem cell transplant (SCT) to our current approach. Herein, we report on outcomes of patients with MM who were 50 years or younger at diagnosis and stratified by fluorescence in situ hybridization (FISH) results. Our study focuses on t(11;14) myeloma as its prognostic impact remains unclear with the use of novel agents upfront. Methods: Out of 1384 patients with MM, evaluated consecutively at Mayo Clinic, Rochester, MN between 1/1/2000 and 12/31/2011, 290 (21%) were 50 years or younger at diagnosis. Interphase FISH, performed within 100 days of diagnosis of MM, was utilized to stratify patients as high-risk [deletion 17p, t(14;16), t(14;20) or t(4;14)] or standard-risk [normal FISH, trisomies, t(11;14), t(6;14) or monosomy13/deletion 13q]. FISH results were available in 125 young patients that comprise the cohort of interest in the current study. OS from diagnosis was estimated by the Kaplan-Meier method. Results: Median age at diagnosis of MM was 47 years (range: 22 to 50 years) and 58% of the patients were male. At the time of data cut-off (7/31/2014), 45 (36%) patients had died with 90% of all known causes of deaths (n=39) being MM related. FISH abnormalities were noted in 114 (91%) patients. At diagnosis, 46%, 30% and 24% patients were categorized as International Staging System (ISS) stage I, II and III, respectively. The estimated median follow up was 60 months (95% CI: 54-67) and the 5-year OS rate was 69% [median 86 months (95% CI: 76-108)]. Standard (n=100; 80%) and high (n=25; 20%) risk patients had a median OS of 89 months (95% CI: 76-108) and 77.6 months (95% CI: 42-130), respectively (p=0.87). In order to further investigate the similar outcomes between these broad risk-groups with typically diverse disease course, we assessed the outcomes based on the common genetic abnormalities (Table 1) within each of the 2 categories. Presence of t(11;14) (n=37; 29%) was associated with a significantly shorter median OS (76 months) compared to patients with trisomic and normal FISH profile (n=46) (91 months, p=0.01; Figure 1). Patients with t(11;14) also had a significantly shorter median OS compared to those with other standard-risk FISH abnormalities (median OS 96 months, p=0.02). Presence of t(11;14) was not associated with higher plasma cell labeling index (PCLI, p=0.29) or worse ISS stage (p=0.99) compared to patients without t(11;14). OS survival of patients with t(11;14) was similar to those with high risk features (median 76.2 vs. 77.6 months, p=0.32). Of 24 (65%) patients with t(11;14) who underwent SCT, 79% had early SCT (within 12 months from diagnosis). Median OS was 79.4 months (95% CI: 36-108) vs. not reached (NR) (95% CI: 27-NR), respectively (p=0.79) in early versus late SCT. Twenty-one (57%) and 13 (35%) patients with t(11;14) received initial immunomodulatory drugs or bortezomib-based therapies, respectively. Those receiving frontline bortezomib had a higher median OS (76.2 months, 95% CI 76-79) compared to 64.8 months (95% CI 32-108) with other initial agents although it did not reach statistical significance (p=0.78). Conclusion: Presence of t(11;14) is associated with an inferior OS compared to patients with normal FISH, trisomies, or other standard risk abnormalities in young patients with MM. Given, the inherent biases associated with a retrospective study from a referral institution, our findings require external validation. However, our data suggest that our current therapeutic approaches in managing young patients with this unique genetic signature are inadequate. Table 1FISHn(%)Median OS in months (95% CI)t(11;14)37(29)76.2 (53.5-107.7)Trisomies35(28)91.3 (76.4-NR)13/del(13q)11(9)NR (32-NR)Normal11(9)95.5 (45.4-95.6)t(4;14)11(9)NR (40.1-NR)del(17p)/-1710(8)42 (19.2-129.6)t(14;16)4(3)77.6 (42.4-NR)Others6(5)NR (11.5-NR) Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Prospective study to measure the impact of MMprofiler on treatment intention in newly diagnosed multiple myeloma patients (PROMMIS).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.8030 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 8030-8030

Author(s):

Parameswaran Hari ◽

Suzanne Lentzsch ◽

David Samuel DiCapua Siegel ◽

Saad Zafar Usmani ◽

Binod Dhakal ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Treatment Strategies ◽

Progression Free Survival ◽

Risk Classification ◽

Newly Diagnosed ◽

Treatment Paradigm ◽

Risk Patients ◽

The Impact ◽

Standard Risk

8030 Background: Multiple Myeloma (MM) is recognized as a heterogeneous group of patients with varying response and outcome of their disease, associated with various risk factors including genetic aberrations. Risk adapted treatment strategies are beginning to emerge (e.g. mSMART), which include gene expression signatures. SKY92, a 92-gene prognostic signature, classifies MM patients as “high” or “standard” risk. It has been reported to be a robust predictor for Overall and Progression Free Survival (Kuiper 2012, 2015). Here we report the preliminary impact of SKY92 on risk classification and treatment intention decisions in newly diagnosed MM patients enrolled in the PRospective Observational Multiple Myeloma Impact Study (PROMMIS). Methods: Patients with MM had their BM aspirate analyzed using the MMprofiler with SKY92. The physician completed questionnaires with his/her treatment intention, before and after knowing SKY92 results. Results: 39 MM patients were enrolled from 5 US centers. The SKY92 signature classified 15 patients (38%) as high risk. Prior to knowing SKY92 results, physicians regarded 20 (51%) patients as clinically high risk, for whom SKY92 indicated 12 patients to be standard risk. Upon revealing SKY92, 8 patients were then considered standard risk by the physician. For 2 patients with concordant high risk classification results, the confirmation of the risk classification was considered helpful. The impact of treatment intention decisions in clinical high risk patients was 40% (8 out of 20). In the 19 patients (49%) that were regarded clinically standard risk prior to knowing SKY92, SKY92 indicated 7 patients to be high risk. Physicians agreed to this classification. For 4 patients with concordant risk classification, the confirmation was found helpful. The impact of treatment intention decisions in clinical standard risk patients was 37% (7 out of 19). Conclusions: Preliminary results from the PROMMIS trial indicate that SKY92 impacts the physician’s treatment intention for 38% of patients with newly diagnosed MM. Moreover, the physicians found the SKY92 result useful for 54% of the patients. This underlines the relevance and need for assessment of SKY92 in MM patients, and associated risk stratified treatment paradigm. Clinical trial information: NCT02911571.

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Cohort Analysis of FISH Testing of CD138+ Cells in Relapsed Multiple Myeloma: Implications for Prognosis and Choice of Therapy

Blood ◽

10.1182/blood.v124.21.3399.3399 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3399-3399

Author(s):

Dean Smith ◽

Clemency Stephenson ◽

Anna Lach ◽

Steve Chatters ◽

Helena Kempski ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Conflicts Of Interest ◽

Risk Group ◽

Cohort Analysis ◽

Fish Analysis ◽

Newly Diagnosed ◽

Interphase Fish ◽

Line Of Therapy ◽

Standard Risk

Abstract Introduction: Interphase FISH on CD138-selected bone marrow cells enables genetic risk stratification in newly diagnosed multiple myeloma (MM), however as MM remains incurable, most centres still treat newly diagnosed MM uniformly, utilising the most active regimens available. At relapse an increasing choice of regimens, coupled with co-morbidities and treatment-emergent toxicities, means no uniform approach is possible. Instead, therapy is tailored to disease and patient related risk factors. In this setting, FISH testing may be particularly useful if not done at diagnosis and to identify progression events that may alter prognosis. Aim: To evaluate the outcome of FISH analysis in consecutive patients with relapsed MM undertaken at our centre: success rate, frequency of abnormalities, incidence of progression events and correlation of FISH abnormalities with treatment outcomes. Methods: FISH analysis was performed on 192 samples from 154 relapsed patients (2012-13). Plasma cells were selected using magnetic CD138 MicroBeads and interphase FISH carried out using probes as recommended by the EMN (Ross et al, 2012). If patients had no prior results, a full FISH MM panel was performed, using probes for t(4;14), t(14;16), t(11;14), deletion 17p (17p-), Chr 1 abnormalities (1p-/1q+) and deletion 13q (13q-). If patients had been previously tested for an IgH translocation (Tx), a progression event panel was used: 1p-/1q+, 17p- and 13q-. Patients underwent FISH testing prior to starting the next line of therapy. Results: 79% of samples were successfully analysed, with analysis limited in 16% and failed in 5%. Common reasons for failure were poor quality/aged slides, insufficient material and poor hybridisation. 17% of patients had no cytogenetic abnormality. The most common abnormality was 13q- (43.1%), followed by 1q+ (41.4%), t(11;14) (18.3%), t(4;14) (12.4%), 17p- (12.0%) 1p- (8.9%), and t(14;16) (5.6%) Progression events were more common in t(14;16) and t(4;14) groups. All patients with t(14;16) and 82% with t(4;14) had an additional genetic lesion. Only 21% of patients with t(11;14) and 54% with no IgH Tx had an additional event. 80 patients (51.3%) had prior FISH results and 13 (16.3%) had developed a new abnormality on the later test. In 9 cases the progression event was 17p-, in 2 it was 1q+ and 2 cases developed 17p- and 1q+. The patients developing 1q+ were previously standard risk, so repeat testing altered risk group. Acquisition of 17p- indicates especially poor outcome, thus in all 13 cases repeat FISH analysis altered risk. Among patients with progression events none harboured t(11;14), 8 (64%) had no IgH Tx, 3 had t(14;16) and 2 had t(4;14). FISH results were correlated with clinical outcome. Patients were stratified as having high risk genetics [t(4;14), t(14,16), 17p- in ≥50% cells, 1p-/1q+] or standard risk [t(11;14), normal cytogenetics]. 63 (41%) patients were high risk, 83 (54%) standard risk, with no information available for 8 (5%). Both groups had received a median of 2 prior lines of therapy. Response rates (≥PR) to the next line of therapy were similar (60.4% standard risk vs 56.0% high risk). PFS from time of FISH was significantly longer in the standard risk group (9.8 months vs 5.9, p<0.01) as was OS (not reached vs 17.1 months, p<0.01, Fig. 1). In the high risk group, PFS was significantly longer in patients receiving a proteasome inhibitor (PI) as the next line of treatment versus those receiving other therapies (9.6 months vs 4.6, p=0.01) as was OS (not reached vs 9.7 months, p<0.01, Fig. 2). In the standard risk group, PFS was similar if patients received PI or not (9.5 months PI vs 9.8 other) as was OS (not reached both groups, Fig. 2). Conclusions: FISH analysis on MM patients at relapse was achievable. 74/154 patients had no prior results and a further 13 developed new poor prognostic markers, thus FISH at relapse provided new information in 56% of patients. Progression events were more common in patients harbouring t(4;14) or t(14;16). FISH at relapse was prognostic with high risk abnormalities associated with significantly shorter PFS and OS. The use of PI appeared to abrogate this poor prognosis, suggesting FISH at relapse could be a predictive and prognostic marker. Given the availability of second generation PI and the option of bortezomib re-treatment, results of FISH testing at relapse could directly influence clinical practice. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Carfilzomib, lenalidomide, and dexamethasone plus transplant in newly diagnosed multiple myeloma

Blood ◽

10.1182/blood.2020007522 ◽

2020 ◽

Vol 136 (22) ◽

pp. 2513-2523 ◽

Cited By ~ 1

Author(s):

Jagoda K. Jasielec ◽

Tadeusz Kubicki ◽

Noopur Raje ◽

Ravi Vij ◽

Donna Reece ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Residual Disease ◽

Progression Free Survival ◽

Complete Response ◽

Newly Diagnosed ◽

Cardiac Events ◽

End Point ◽

Depth Of Response ◽

Grade 3

Abstract In this phase 2 multicenter study, we evaluated the incorporation of autologous stem cell transplantation (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma (NDMM). Transplant-eligible patients with NDMM received 4 cycles of KRd induction, ASCT, 4 cycles of KRd consolidation, and 10 cycles of KRd maintenance. The primary end point was rate of stringent complete response (sCR) after 8 cycles of KRd with a predefined threshold of ≥50% to support further study. Seventy-six patients were enrolled with a median age of 59 years (range, 40-76 years), and 35.5% had high-risk cytogenetics. The primary end point was met, with an sCR rate of 60% after 8 cycles. Depth of response improved over time. On intent-to-treat (ITT), the sCR rate reached 76%. The rate of minimal residual disease (MRD) negativity using modified ITT was 70% according to next-generation sequencing (<10−5 sensitivity). After median follow-up of 56 months, 5-year progression-free survival (PFS) and overall survival (OS) rates were 72% and 84% for ITT, 85% and 91% for MRD-negative patients, and 57% and 72% for patients with high-risk cytogenetics. For high-risk patients who were MRD negative, 5-year rates were 77% and 81%. Grade 3 to 4 adverse events included neutropenia (34%), lymphopenia (32%), infection (22%), and cardiac events (3%). There was no grade 3 to 4 peripheral neuropathy. Patients with NDMM treated with KRd with ASCT achieved high rates of sCR and MRD-negative disease at the end of KRd consolidation. Extended KRd maintenance after consolidation contributed to deepening of responses and likely to prolonged PFS and OS. Safety and tolerability were manageable. This trial was registered at www.clinicaltrials.gov as #NCT01816971.

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