Induction Therapy For Multiple Myeloma Research Articles

Resource Utilization Analysis of Two Algorithms for Hematopoietic Progenitor Cell Mobilization in Multiple Myeloma

Background: Autologous hematopoietic cell transplantation (HCT) is a standard of care after induction therapy for multiple myeloma (MM). A key step in this procedure is the mobilization and collection of hematopoietic progenitor cells (HPC). HPC mobilization typically uses G-CSF with or without the CXCR4 antagonist Plerixafor (P). Although P increases the effectiveness of mobilization and may reduce the number of apheresis sessions, it is associated with significantly increased cost per dose. There is significant heterogeneity to HPC collection algorithms across institutions and there is no clear standard. At the Cleveland Clinic, our HPC collection algorithm was updated in an effort to reduce the use and associated cost of P. The criteria for initiating P became more stringent and far fewer patients were initiated on P prior to their first session of HPC collection apheresis. Prior to October 2017, patients were initiated on P if any 1 of the following criteria were met: age>60 years, prior treatment with melphalan or other alkylating therapy, prior treatment with lenalidomide >2 cycles, extensive bone marrow disease, or platelet count <100K. Starting October 1, 2017, patients were preemptively initiated on P prior to first collection only if all 3 of the following criteria were met: age > 65 years, lenalidomide > 6 cycles, and platelet count < 100K. However, P was added after the first apheresis session if peripheral blood CD34+ cell count was <20/uL or HPC yield was unsatisfactory (<2 x 10^6 CD34+ cells). Furthermore, target CD34 yield was decreased from 5 to 4 x 10^6 CD34+ cells. Herein, we perform a comparative resource utilization analysis of HPC collection at our center. Methods: We retrospectively collected HPC mobilization data on patients undergoing HCT for MM from 1/12014 to 12/31/2020. We determined the number of P doses, number of apheresis sessions, and HPC collection totals per patient. Patient characteristics were summarized in median, interquartile range (IQR), or frequencies and percentages as appropriate. Fisher's exact test and Wilcoxon rank sum test were used to compare variables in patients undergoing mobilization prior to versus after 10/1/2017. All tests were two-sided and p-values of 0.05 or less were considered statistically significant. Results: 219 patients underwent HPC mobilization from 1/1/2014 to 9/30/2017 and 251 patients underwent mobilization after algorithm change from 10/1/2017 to 12/31/2020. As anticipated, the protocol change decreased the number of patients receiving P prior to their first apheresis session. 91% received P prior to the first apheresis session before the change while 14% received this initial dose of P after the change. Prior to the change 51% of patients completed collection in 1 day, 30% completed in 2 days, 12 % completed in 3 days, and 7% completed in 4 days or more. These figures changed to 20%, 41%, 23%, and 17% respectively following the change (p<0.0001) Median day 1 peripheral blood CD34 count decreased from 63 to 19 cells/uL while median day 1 CD34 collection yield fell from 4.8 to 1.46 x 10^6 after the change (p<0.0001) (Table 1). Total CD34 collection yield also decreased from a median of 6.64 to 4.6 x 10^6 CD34+ cells (p<0.0001). However, the target yield was decreased from 5 to 4 x 10^6 CD34+ cells as described above. The number of doses of P per patient decreased after the change (pre-change median dose / patient = 1, IQR = 1-2) (post-change median dose / patient = 1, IQR = 0-2) (p=0.004). The average number of apheresis sessions required per patient increased following the change (pre-change median apheresis sessions = 1, IQR = 1-2) (median post change apheresis sessions = 2, IQR = 2-3) (p<0.0001) (Figure 1). Conclusion: Changes to our institutional HPC mobilization algorithm led to a substantial decrease in the use of preemptive P prior to day 1 of collection by design. The resulting decrease in total doses of P per patient was smaller than expected, although still statistically significant. However, this was offset by a concomitant significant increase in the number of apheresis sessions required per patient despite a lower collection target. Based on these results, a cost analysis is ongoing in order to re-evaluate our institutional algorithm.

Benefit-risk preferences for treatments for newly-diagnosed multiple myeloma.

320 Background: Clinical studies are generating evidence on benefits and risks of emerging, novel treatments, including bispecifics and CAR-T, for newly diagnosed patients with multiple myeloma (MM) who are not candidates for stem-cell transplant (SCT). This study quantified the extent to which patients would accept short-term risks following MM therapy for the potential benefit of a longer, treatment-free interval. Methods: Adult patients with MM from the Duke Cancer Institute Tumor Registry were invited to complete an online discrete-choice experiment (DCE) survey in which they were to suppose they had a friend (same age and gender) recently diagnosed with MM who is not a candidate for SCT. Respondents chose the better post-induction therapy treatment for their friend from pairs of experimentally designed hypothetical treatments. In each question, treatments varied in terms of time until relapse (3, 5, or 10 years), impact of treatment-related side effects on daily activities (no, minor, or moderate limits), treatment-related mortality (0% to 10% in the first 3 months), and risk of reversible, short-term side effects (described as neurotoxicity or cytokine release syndrome) resulting in a 10-day hospitalization (0% to 20% risk in the first 3 months). DCE data were analyzed with a random-parameters logit model to estimate preference weights (PW) which were used to estimate the maximum level of short-term mortality risk acceptable to patients for longer time to relapse and less impact on daily activities. Results: The survey was completed by 176 patients (mean age; 66 yrs; 51% female, 22% Black) of whom 80% had a transplant and 31% had at least one relapse. Responses to the DCE were logically ordered (patients preferred lower levels of risks and better levels of benefit). For the levels specified, avoiding treatment-related mortality was most important (PW: 3.69), followed by gaining relapse-free years (PW: 3.32), and reducing impact on daily activities (PW: 2.04). Risk of reversible, short-term side effects was relatively least important (PW: 0.58). All else equal, patients would accept 5.7% mortality (95% CI: 3.8-7.2) for a 2-year gain in time to relapse (from 3 to 5 yrs) or 6.0% mortality risk (95% CI: 4.5-7.3) to avoid side effects that moderately limit their daily activities. Conclusions: Patients considering initial treatment following induction therapy for MM assigned least importance to reversible, short-term side effects that may be associated with CAR-T. Specified levels of treatment mortality were acceptable in exchange for longer relapse free intervals and fewer impacts on daily activities.[Table: see text]

Advantage of achieving deep response following frontline daratumumab-VTd compared to VRd in transplant-eligible multiple myeloma: multicenter study.

The goal of induction therapy for multiple myeloma (MM) is to achieve adequate disease control. Current guidelines favor triplet (bortezomib-lenalidomide-dexamethasone; VRd) or quadruplet regimens (daratumumab, bortezomib-thalidomide-dexamethasone; D-VTd). In the absence of a direct comparison between two treatment regimens, we conducted this study to compare the outcomes and safety of VRd and D-VTd. Newly diagnosed MM patients aged ＞18 years who underwent induction therapy followed by autologous stem cell transplantation (ASCT) between November 2020 and December 2021 were identified. Finally, patients with VRd (N=37) and those with D-VTd (N=43) were enrolled. After induction, 10.8% of the VRd group showed stringent complete remission (sCR), 21.6% showed complete response (CR), 35.1% showed very good partial response (VGPR), and 32.4% showed partial response (PR). Of the D-VTd group, 9.3% showed sCR, 34.9% CR, 48.8% VGPR, and 4.2% PR (VGPR or better: 67.6% in VRd vs. 93% in D-VTd, P=0.004). After ASCT, 68.6% of the VRd group showed CR or sCR, while 90.5% of the D-VTd group showed CR or sCR (P=0.016). VRd was associated with an increased incidence of skin rash (P=0.044). Other than rashes, there were no significant differences in terms of adverse events between the two groups. Our study supports the use of a front-line quadruplet induction regimen containing a CD38 monoclonal antibody for transplant-eligible patients with newly diagnosed MM.

Serum microRNA Signature Predicting Poor Therapeutic Response to Bortezomib-Based Therapy and Clinical Outcome in Newly Diagnosed Multiple Myeloma: A Result of miRNA Profiling By Deep Sequencing

Introduction Bortezomib-based regimens are the preferred induction therapy for multiple myeloma (MM) in resource limited regions. Response to bortezomib is inconsistent across patients, and impact of disease heterogeneity on treatment failure remains an unpredictable challenge. Circulating/cell-free miRNA (cfmiRNA) have been shown to contribute to disease prognostication and response monitoring in relapse/refractory setting, serving as an auxiliary biomarker. However, data on real world utility of cfmiRNA in prediction of therapeutic response in newly diagnosed MM (NDMM), treated without transplant is scarce. Aim To identify MM-specific cfmiRNA signature and investigate its utility in prediction of initial therapeutic response (ITR) to Bortezomib-based regimens in NDMM. Further, we aimed to study the kinetics of cfmiRNA during induction therapy as a tool for disease monitoring and predicting clinical outcome. Methods We prospectively enrolled 141 NDMM patients diagnosed and treated at Tata Memorial Centre, India. Small RNA sequencing for miRNA profiling was performed in 65 NDMM and 10 age-matched control and validated by quantitative PCR (qPCR). cfmiRNA levels were evaluated by qPCR at diagnosis, at the end of 3 cycles (follow up1-FU1) and 6 cycles (follow up2-FU2) of chemotherapy. Changes in cfmiRNA expression at FU1 and FU2 was represented as fold change (FC) relative to baseline. Samples were grouped as high or low expressors using median FC of individual miRNAs as cut-off. Patients received bortezomib-based treatment. ITR was monitored at the end of FU2. Results Median age of patients was 55 years (range:27-81 years; M:F-2:1). Median follow-up was 35 months (1-71 months). ITR post FU2 included 7.09% CR, 43.97% VGPR, 33.33% PR, 2.84% SD, 2.84% PD and 9.93% deaths during initial therapy. BM clonal plasma cells (CPC) were detected in 134/141 patients (median, range:97.8%, 1.5-100%). Small RNA sequencing identified 36 miRNAs differentially expressed (DEMs) in MM serum (FC≥2; p-adj<0.05) at diagnosis, the greater majority being upregulated (31/37). DEMs with Log2FC≥2 was confirmed by qPCR (n=21). There was significant correlation between miRNA levels measured by RNA-seq and qPCR (R2=0.78; p<0.001), with a near-constant bias of 0.6361 for miRNA with Log2FC≥4 (n=13; Upper, lower limits of agreement:2.463, -1.191). Results were validated in additional 76 NDMM and 10 control samples. Of the 13 DEMs, high expression (Log2FC>6.01; p=0.0047) of miR-4665-5p at diagnosis was significantly associated with poor ITR at FU2 (OR:2.92; p=0.01), however, no association with OS or PFS was observed. We studied changes in cfmiRNA levels at FU1 and FU2 for therapeutic monitoring. Univariate analysis identified 5 miRNA - miR-92b-5p, miR-4775, miR-103a-2-5p, miR-4665-5p and miR-365a-3p significantly associated with poor ITR at FU1 and FU2. Multivariate logistic regression yielded a model (Hosmer-Lemeshow p=0.9) with high expression of miR-92b-5p (Log2FC>2.04; p=0.006; OR:5.9; p<0.0001) and miR-103a-2-5p (median Log2FC=1.65; p=0.0329; OR:2.54; p=0.0106) at FU2 significantly associated with poor ITR (p=0.0049). A combination of these miRNAs could differentiate good and poor responders with area under ROC curve of 0.87, 83.64% sensitivity and 75% specificity. Among these, miR-92b-5p demonstrated an association with poor PFS (27 vs. not reached; HR:2.4; p=0.0005) and OS (52 months vs. not reached; HR:2.88; p=0.0056). Univariate analysis also showed high risk cytogenetics, high LDH and CPC>90% of total plasma cells to be associated with poor PFS. Expression of miR-92b-5p at FU2 was independently associated with poor PFS (HR:1.4; p=0.0005) on Cox proportional hazards regression. Conclusion: We studied the kinetics of serum miRNA and demonstrated that changes in levels of miR-92b-5p and miR-103a-2-5p are useful in prediction of poor response to Bortezomib-based regimen. Increase in levels of miR-92b-5p at follow up time points post induction was found to be an indicator of poor ITR and shorter PFS. The role of miR-92b-5p in the biology of MM is yet to be evaluated. Herein, we highlight the utility of cfmiRNA assays as non-invasive biomarker in prediction of initial therapeutic response to Bortezomib-based protocol. Determining clinical relevance of these findings could expand applications of cfmiRNA as a biomarker. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Three Cases of Lenalidomide Therapy for Multiple Myeloma and Subsequent Development of Secondary B-ALL.

Multiple myeloma (MM) is the second most common hematological malignancy, accounting for 1% of all cancers, with median age of diagnosis between 66-70 years. MM remains incurable despite advances in treatment over time. Lenalidomide is an important medication used in induction therapy for MM and is also used for maintenance therapy for standard risk patients. With its increasing use, data is emerging about its use being associated with increased risk of secondary primary malignancies (SPM), especially when used as maintenance therapy. In this case series, we describe three patients with refractory MM treated with lenalidomide maintenance who later developed sALL. All had a common presentation of pancytopenia. They developed cytopenias while being on lenalidomide which was refractory to lenalidomide cessation, prompting bone marrow biopsy. Lenalidomide was subsequently stopped, and patients were treated for secondary B-ALL. However, all passed away either due to relapse of disease or complications arising from treatment. The mechanism of lenalidomide associated SPMs is not well understood however its incidence is well documented. At least 13 cases of ALL (predominantly B-cell ALL) following Immunomodulator imide drugs (IMiDs) have been reported in literature. An analysis of a larger cohort of patients is required to determine causality of lenalidomide with sALL. However, benefits of maintenance lenalidomide in patients with MM outweighs the risk of developing SPMs. Albeit persistent pancytopenia on lenalidomide therapy should be evaluated with bone marrow biopsy since it could be caused by secondary B -cell ALL.

Impact of Induction Treatment on Stem Cell Collection: A COVID Related Study

Introduction: Standard induction therapy for multiple myeloma consists of 3-6 cycles of bortezomib, lenalidomide, and dexamethasone (VRd) or carfilzomib, lenalidomide and dexamethasone (KRd). Receiving greater than 6 cycles of a lenalidomide containing regimen is thought to negatively impact the ability to collect sufficient CD34+ stem cells for autologous stem cell transplant (Kumar, Dispenzieri et al. 2007, Bhutani, Zonder et al. 2013). Due to the COVID-19 pandemic, at least 20 patients at University of Maryland Greenebaum Comprehensive Cancer Center (UMGCC) had transplant postponed, potentially resulting in prolonged exposure to lenalidomide containing induction regimens. Here, in the context of modern stem cell mobilization methods, we describe a retrospective study that suggests prolonged induction does not inhibit adequate stem cell collection for transplant.Methods: By chart review, we identified 56 patients with multiple myeloma who received induction with VRd or KRd and underwent apheresis or stem cell transplant at UMGCC between 10/1/19 and 10/1/20. Patients were excluded if they received more than 2 cycles of a different induction regimen, had a past medical history of an inborn hematological disorder, or participated in a clinical trial of novel stem cell mobilization therapy. We defined 1 cycle of VRd or KRd as 1 cycle of “lenalidomide containing regimen”. In accordance with routine clinical practice, we defined standard induction as having received 3-6 cycles of lenalidomide containing regimen and prolonged induction as having received 7 or more cycles.Results: 29 patients received standard induction (Standard induction cohort) and 27 received prolonged induction (Prolonged induction cohort) with lenalidomide containing regimens. The median number of cycles received by the Standard cohort was 6 (range 4-6), and the median number of cycles received by the Prolonged cohort was 8 (range 7-13). The frequency of KRd use was similar between patients who received standard induction and prolonged induction (27.58% vs. 25.93%, respectively). Standard induction and Prolonged induction cohorts were similar with respect to clinical characteristics (Fig 1), as well as the mobilization regimen used for stem cell collection (p = 0.6829).55/56 patients collected sufficient stem cells for 1 transplant (≥ 4 x 10 6 CD34 cells/kg), and 40/56 patients collected sufficient cells for 2 transplants (≥ 8 x 10 6 CD34 cells/kg). There was no significant difference in the total CD34+ stem cells collected at completion of apheresis between standard and prolonged induction (10.41 and 10.45 x 10 6 CD34 cells/kg, respectively, p = 0.968, Fig 2). Furthermore, there was no significant correlation between the number of cycles of lenalidomide containing regimen a patient received and total CD34+ cells collected (R 2 = 0.0073, p = 0.5324).Although prolonged induction did not affect final stem yield, prolonged induction could increase the apheresis time required for adequate collection or result in more frequent need for plerixafor rescue. There was no significant difference in the total number of stem cells collected after day 1 of apheresis between patients who received standard or prolonged induction (8.72 vs. 7.96 x 10 6 cells/kg, respectively, p = 0.557). However, patients who received prolonged induction were more likely to require 2 days of apheresis (44% vs. 25%, p = 0.1625) and there was a trend toward significance in which patients who received prolonged induction underwent apheresis longer than patients who received standard induction (468 vs 382 minutes, respectively, p = 0.0928, Fig 3). In addition, longer apheresis time was associated with more cycles of lenalidomide containing regimen, which neared statistical significance (R 2 = 0.0624, p = 0.0658, Fig 4). There was no significant difference between standard and prolonged induction with respect to the frequency of plerixafor rescue.Conclusions: Prolonged induction with lenalidomide containing regimens does not impair adequate stem cell collection for autologous transplant. Prolonged induction may increase the apheresis time required to collect sufficient stem cells for transplant, but ultimately clinicians should be re-assured that extending induction when necessary is not likely to increase the risk of collection failure. [Display omitted] DisclosuresBadros: Janssen: Research Funding; J&J: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding.

Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma Benefits Patients with Persistent Disease and Results in a High Rate of Residual Disease Clearance

Introduction: Residual disease (RD) after autologous transplantation as well as following induction therapy in multiple myeloma (MM) patients ineligible for transplant is associated with inferior survival. The significance of RD quantified by multiparameter flow cytometry (MFC) in the setting of allogeneic hematopoietic stem cell transplantation (HCT) for MM has not been reported. Using MFC we assessed the likelihood of RD clearance after HCT and assess whether RD status before HCT and at 1 and 3 months after HCT was associated with survival.Methods:We include 51 consecutive patients who underwent HCT for high-risk relapsed MM at our center between January 2014 and October 2016. All received CD34+ selected peripheral blood stem cell grafts. Donors included matched related (n=15), matched unrelated (n=20) and HLA 9/10 mismatched unrelated (n=16). The preparative regimen included busulfan (0.8mg/kg x 10 doses), melphalan (70mg/m2 x 2days), fludarabine (25mg/m2 x5days) and rabbit ATG (2.5mg/kg x 2 days).RD was assessed using MFC at 3 time points (TP) including TP0: median of 28 days (14-64) before transplantation (n=51), TP1: median of 28 days (range 26-55 days) after HSCT (n=48) and TP2: median 97 days (range 90-180days) after HSCT (n=43). MFC RD analysis was performed on marrow aspirate samples using 8-color flow analysis with sensitivity of 0.01% of white cells in 2013-till December 2015 and 10-color flow analysis with sensitivity of 0.0005% subsequently.Standard criteria were used to define categorical MM disease response. Overall survival (OS) was assessed using the Kaplan-Meier method and groups were compared using the log rank test. A landmark analysis was performed to assess the significance of MRD status at TP1 and TP2, with patients who relapsed or progressed within 30 days of the respective TP excluded from the landmark analysis.Results:Themedian age was 55 years (range 35-67). All patients had undergone prior autograft. Twelve experienced disease progression or relapse and 21 died, including 7 deaths due to relapsed MM and 14 due to transplant related mortality. The median follow-up amongst survivors (n=30) was 524 days (97-1089 days). Categorical disease status at HCT included: CR (n=9), VGPR (n=12), PR (n=21) and SD/PD (n=9) and this was associated with RD status. Detected RD was noted in 2/9 (22%), 8/12 (67%), 18/21 (86%) and 6/9 (67%) patients in CR, VGPR, PR and SD/PD, respectively (p=0.01).At TP0 34/51 had RD including all 13 with ≥5% marrow plasma cells. At TP1 31/48 were RD- (3 did not undergo RD assessment at TP1 due to TRM 49, 50 and 122 days after HCT). Of the 31 who were RD+ at TP0 and had assessment at TP1, 15 became RD- (48%). Sixteen of 17 who were RD- at TP0 remained RD- at TP1 and only 1 became RD+. Between TP1 and TP2 the concordance of MRD status among 43 patients who had assessment at both time points was 81% (RD+ at TP1 and TP2 n= 12, RD- at TP1 and TP2 n=23). Two became RD- at TP2 and 6 (14%) became MRD+, 4 of whom died due to MM.Categorical disease status before HCT was associated with RD status at TP1 and TP2. At TP1, 3/20 (15%) evaluable patients who were in CR or VGPR before HCT were RD+, compared to 14/28 (50%) who were in PR/SD or PD (p=0.016). At TP2, 3/19 (16%) evaluable patients who were in CR/VGPR prior to HCT were RD+ compared to 15/24 (63%) who were in PR/SD or PD (p=0.004). (Table 1)Conclusions: HCT resulted in the clearance of RD at TP1 in 48% of patients. Unlike autologous transplantation and pharmacologic therapy, HCT benefited MM patients irrespective of pre HCT RD status. Recurrence of RD by MFC was identified in 14% of patients between TP1 and TP2 suggesting this may be an optimal time to intervene with post transplant maintenance strategies. Improved RD sensitivity may be needed to better assess progression risk of MM post HCT. [Display omitted] DisclosuresKoehne:Atara: Consultancy, Patents & Royalties.

Efficacy and Toxicity Profile of Carfilzomib Based Regimens for Treatment of Multiple Myeloma, a Systematic Review

Background: Standard induction therapy for Multiple Myeloma (MM) is triple combination therapy based on three classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has serious issues of peripheral neuropathy (PN) with incidence of grade ≥ 3 PN reported between 2% to 23%. A novel proteasome inhibitor, carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PN. CFZ has been approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. We conducted comprehensive literature search to summarize efficacy, dosing and toxicity profile of CFZ in newly diagnosed and relapsed MM.Methods: Database search using PubMed, EMBASE, Cochrane library, Scopus, Web of Science, CINAHL, and Clinicaltrials.gov was performed on 6/5/2017. Phase II/III clinical trials from last 10 years and focusing on CFZ as primary drug therapy were included.Results: Literature search identified a total of 1839 articles. Twenty-six articles met the inclusion criteria (15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group) with a total of 5980 patients (4205 in RRMM and 1775 in NDMM group).For heavily pre-treated RRMM patients with median 5 prior lines of therapy, 20/27 mg/m2 of single agent CFZ produced outcomes ranging from 3.5 to 5.1 months of progression free survival (PFS), 16.7% to 23.7% of overall response rate (ORR) and 16% to 18.3% of partial response (PR). Higher dose 20/56 mg/m2 of CFZ in Kd (carfilzomib + dexamethasone) regimen produced PFS of 4.1 months and ORR of 55% in patients with 5 prior lines of therapy. Even higher 20/70 mg/m2 dose of CFZ in Kd regimen produced ORR of 77% and PFS of 12.6 months in patients with 1 prior therapy. ENDEAVOR and ASPIRE trials reported PFS of 18.7 months with Kd vs 9.4 months with Vd (bortezomib and dexamethasone) and 26.3 months with KRd (carfilzomib, lenalidomide and dexamethasone) vs 17.6 months with Rd (lenalidomide and dexamethasone) respectively, in patients with median 2 prior lines of therapy.CFZ in front line setting achieved high response rates. In NDMM, most commonly studied regimen was CFZ in combination with lenalidomide and dexamethasone (KRd) with 4 phase II and 1 phase I/II trial (n= 268). Their outcomes range from 96% to 98% ORR, 83% to 97% overall survival (OS) and 92% to 97% of 2-year PFS. Likewise, outcomes of other CFZ based regimens, 6 phase II and 3 phase I/II trials (n= 552) range from 72% to 97% ORR. Data on overall survival (OS) and progression free survival (PFS) was either not reported or reported at 2 or 3-year interim analysis. Observed PFS in a recent phase III trial comparing CFZ, melphalan and prednisone (KMP) with bortezomib, melphalan and prednisone (VMP) was 22.3 months vs 22.1 months respectively.Most common grade ≥3 AE were hematologic. Incidences of non-hematologic grade ≥ 3 AE include heart failure (3.4% to 20%), acute renal failure (3.4% to 9%), HTN (4.3% to 25%) and PNP (<1% to 1.1%). ENDEAVOR reported significantly higher incidence of ≥2 PNP in bortezomib group (32%) vs 6% in carfilzomib group. ENDEAVOR trial using serial echocardiograms reported no increased risk of cardiotoxicity and ventricular dysfunction with CFZ vs bortezomib.Conclusion: CFZ demonstrates comparable if not higher efficacy to bortezomib with much favourable adverse effect (AE) profile. Most common grade ≥ 3 AE were hematologic that usually don't require dose changes or discontinuation of therapy. High incidence of grade ≥3 HTN deserves attention and underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20/27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20/56 and 20/70mg/m2 dose of CFZ vs standard 20/27mg/m2 dose.All trials except one on CFZ for NDMM were phase II clinical trials with data available mostly as abstracts. So, there was insufficient data available to compare studies. Deep, rapid and sustainable response with KRd with lower incidence of crippling PN strongly supports extension of KRd therapy to frontline setting. More data from phase III trials is needed for head to head comparison of KRd vs other regimens like bortezomib, lenalidomide and dexamethasone (RVd) for treatment of NDMM. CFZ should be tested in combination with other available drugs like daratumumab and pomalidomide. [Display omitted] DisclosuresAbraham:Janssen Oncology (Johnson & Johnson, LLC): Consultancy.

Daratumumab (DARA) maintenance therapy following DARA + cyclophosphamide, bortezomib, and dexamethasone (CyBorD) induction therapy in multiple myeloma (MM): End-of-study analysis of LYRA.

8035 Background: LYRA is a community practice-based, phase 2, single-arm study (NCT02951819) evaluating DARA + CyBorD as an immunomodulatory drug-sparing regimen in MM. The primary analysis demonstrated the safety and efficacy of DARA + CyBorD in newly diagnosed MM (NDMM) and relapsed MM (RMM), and an update showed that DARA maintenance therapy deepened responses. We present the final end-of-study analysis of LYRA. Methods: US pts aged ≥18 years with MM per IMWG criteria and ≤1 prior line of therapy received 4-8 induction cycles of DARA + CyBorD (cyclophosphamide 300 mg/m2 PO weekly [QW]; bortezomib 1.5 mg/m2 SC on Days [D] 1, 8, and 15; dexamethasone 40 mg PO or IV QW every 28 days; DARA IV 8 mg/kg on D1 and D2 of cycle [C]1, 16 mg/kg QW C1D8-C2, 16 mg/kg Q2W C3-6, and 16 mg/kg Q4W C7-8). After induction, eligible pts could receive autologous stem cell transplantation (ASCT). Pts received up to 12 maintenance cycles with DARA 16 mg/kg IV Q4W and were followed for up to 36 months after induction. Results: In total, 101 (NDMM, n = 87; RMM, n = 14) pts were enrolled; 36% of pts had high-risk cytogenetics. NDMM and RMM pts received a median of 6 and 8 induction cycles, respectively. Among NDMM pts, 44.8% (39/87) underwent ASCT and 72.4% (63/87) completed 12 months of maintenance. Rates of ≥VGPR and ≥CR were 82.1% and 48.7% in NDMM pts who underwent ASCT, and 70.2% and 29.8% in NDMM pts who did not (Table). With a median follow-up of 35.7 months, median progression-free survival (PFS) and overall survival (OS) were not reached for NDMM pts. Estimated 36-month PFS rates were 69.3% and 72.6% for NDMM pts who did and did not receive ASCT, respectively; estimated 36-month OS rates were 94.9% and 84.3% (Table). Among RMM pts, 7.1% (1/14) underwent ASCT and 50.0% (7/14) completed 12 months of maintenance; efficacy outcomes are shown in the Table. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 62.0% of all pts, with the most common (≥10%) being neutropenia (14.0%). Serious TEAEs occurred in 33.0% of pts, the most common being pneumonia (4.0%) and pulmonary embolism (3.0%). TEAEs led to death in 2.0% of pts, all unrelated to study treatment. Infusion-related reactions occurred in 56.0% of pts; the majority were mild (4.0% of pts had grade 3/4 events). Conclusions: DARA used for induction with CyBorD and maintenance as monotherapy resulted in durable, deep responses in pts with NDMM or RMM, with a 3-year PFS rate of 70% in NDMM irrespective of ASCT status. With longer follow-up, no new safety concerns were identified. Clinical trial information: NCT02951819. [Table: see text]

Prolonged Lenalidomide Therapy Does Not Impact Autologous Peripheral Blood Stem Cell Mobilization and Collection in Multiple Myeloma Patients: A Single-Center Retrospective Analysis

Since the introduction of lenalidomide into induction therapy for multiple myeloma (MM), there have been conflicting reports about its impact on autologous peripheral blood stem cell (PBSC) mobilization. We evaluated the impact of previous lenalidomide exposure in a large cohort of patients with MM undergoing mobilization and collection at a tertiary stem cell transplantation center. We hypothesized that collection of PBSCs is feasible even with a prolonged duration of previous lenalidomide therapy. We examined patients with MM who attempted stem cell mobilization and collection, seen at our center between January 2012 and July 2015. The patients were categorized into 3 groups for analysis: (1) patients with previous receipt of >6 cycles lenalidomide, (2) patients with previous receipt of ≤6 cycles of lenalidomide, and (3) patients without previous lenalidomide exposure. We compared collection yields and days of apheresis among the 3 groups using linear regression analysis. We identified 297 patients with MM who underwent mobilization of PBSCs. Of these, 35 had received >6 cycles of lenalidomide (median, 8 cycles; range, 7 to 25 cycles), 156 had received ≤6 cycles of lenalidomide (median, 4 cycles; range, 1 to 6 cycles), and 106 had received no lenalidomide. Prior lenalidomide exposure did not have a statistically significant impact on the absolute number of CD34+ cells collected or on the duration of collection based on a multivariate linear regression analysis for association between receipt of >6 cycles of lenalidomide. In this retrospective analysis of MM patients undergoing autologous PBSC transplantation, we show that the duration of previous lenalidomide exposure does not impact the total number of PBSCs collected or the number of days of apheresis. These data suggest that longer courses of induction therapy with lenalidomide-containing regimens to achieve a maximum response can be safe without impairing the ability to collect PBSCs, and that limiting lenalidomide use before mobilization does not appear warranted in all cases.

Daratumumab-based induction therapy for multiple myeloma: A systematic review and meta-analysis.

This study aims to evaluate the efficacy and safety of Daratumumab-based induction therapy (DBI) in newly diagnosed multiple myeloma (MM). We identified four eligible RCTs including 2735 patients. The primary outcomes of RCTs involving transplant eligible (TEMM) and non-transplant eligible MM (NTEMM) were stringent complete response (sCR) and progression-free survival (PFS) respectively. Meta-analysis was performed using random-effects models. DBI improved sCR rates for standard risk (SR) (OR 1.86, 95 % CI 1.41-2.46) but not HiR (high risk) (OR 0.78, 95 % CI 0.41-1.48) (interaction P = 0.01) TEMM. In NTEMM, DBI improved PFS in SR (HR 0.44, 95 % CI 0.35-0.55) but not HiR patients. (HR 0.81, 95 % CI 0.52-1.27) (interaction P = 0.02). In conclusion, while DBI is efficacious in SR patients, there is insufficient data to support a benefit in HiR-MM.

Outcomes with different administration schedules of bortezomib in bortezomib, lenalidomide and dexamethasone (VRd) as first‐line therapy in multiple myeloma

Induction therapy for multiple myeloma with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (d) (VRd) was traditionally administered as bortezomib given twice weekly on a 3 week cycle. A modified schedule of weekly bortezomib has been adopted over time to decrease treatment burden for patients and reduce treatment-emergent neuropathy. This study evaluates the response rates and outcomes with different schedules of bortezomib in VRd administered for first-line treatment for patients with newly diagnosed MM (NDMM). We retrospectively analyzed patients treated with upfront VRd from June 30th 2008 to December 31st 2018, for variations of bortezomib administration. Five hundred and fifty-five (555) NDMM patients met inclusion criteria; median age 63 years and 61% men. Bortezomib was administered twice weekly every 21 days in 43%, once weekly every 21 days in 41% and once weekly every 28 days in 16%. Though peripheral sensory neuropathy was more frequent with twice weekly dosing (P = .002), this group achieved shorter time to best response (P = .01). Weekly every 21-day treatment saw higher VGPR or better rates (P = .02). However, with median follow up time of 37 months (IQR 22-56), we found no difference in PFS or OS among the groups. While small differences in response rates were found among the varying administration schedules of bortezomib administration, there was no significant effect on PFS or OS. Given that VRd remains a first line standard of care option for newly diagnosed MM, in the absence of a large trial comparing bortezomib dosing schedule modifications, these results are helpful in supporting current practices of once weekly administration.

Successful Treatment of Concurrently Diagnosed Multiple Myeloma and Myelodysplastic Syndrome with Isolated Del(5q) with Lenalidomide, Bortezomib, and Dexamethasone

Lenalidomide is known to be an effective therapy for multiple myeloma (MM) and for myelodysplastic syndrome with isolated del(5q). However, there have been very few reports of treatment of both conditions using lenalidomide when they are diagnosed concurrently. A review of the literature revealed two reports of MM and del(5q) MDS treated with lenalidomide. We report the case of a patient simultaneously diagnosed with multiple myeloma and myelodysplastic syndrome with isolated del(5q) who was treated successfully with lenalidomide. The patient is a 74 year old female who was referred to hematology for worsening chronic macrocytic anemia with a hemoglobin of 9.4 g/dL. A serum protein electrophoresis (SPEP) was obtained during her workup and demonstrated an IgG kappa monoclonal spike of 4.7 g/dL. Free light chain analysis demonstrated a kappa/lambda ratio of 36.7. The patient was mildly hypercalcemic at 10.6 g/dL but had no renal insufficiency. Platelet and white blood cell counts were normal. There were no osteolytic lesions on skeletal survey and a whole body PET scan identified no bony disease or plasmacytomas. A β-2 microglobulin level was 3.7 mg/L and albumin was 3.3 g/dL. Bone marrow biopsy revealed 60% plasma cells in a 70% cellular marrow. Granulocytic and megakaryocytic dysplasia was identified. Fluorescence in situ hybridization returned showing a 4:14 translocation in 72% of analyzed nuclei and monosomy 13 in 61% of nuclei analyzed consistent with an unfavorable risk profile. Chromosome analysis also revealed a 5q deletion in 15 of 20 analyzed cells. Bone marrow blasts were measured at 1%. Therefore, the patient concurrently met diagnostic criteria for stage II IgG kappa multiple myeloma per the International Staging System and low risk myelodysplastic syndrome with isolated del(5q) per the 2016 WHO classification of MDS with a Revised International Prognostic Scoring System Score (IPSS-R) of 2. She was started on lenalidomide 25 mg daily, bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 and dexamethasone 20 mg on days 1, 8, and 15 of a 21 day cycle. After 3 cycles of therapy, serum immunofixation electrophoresis showed an unquantifiably low IgG kappa monoclonal spike and the patient's kappa/gamma light chain ratio had normalized to 1.1. Hemoglobin and calcium returned to normal. On repeat bone marrow biopsy, there was normocellular marrow with 4% polytypic plasma cells by kappa/lambda immunohistochemistry. No dysplasia was identified and bone marrow blasts were 1.5%. Therefore, the patient achieved a very good partial response (VGPR) to therapy for multiple myeloma according to International Myeloma Working Group criteria within 3 months. She met National Comprehensive Cancer Network criteria for response of her MDS to lenalidomide by normalization of hemoglobin. The patient's case demonstrates successful treatment of concurrently diagnosed multiple myeloma and MDS with isolated del(5q) using lenalidomide. Among the two other similar cases we discovered in the literature, one patient was treated with low-dose lenalidomide and dexamethasone [Nolte, et al. Eur J Haematol. 2017 Mar;98(3):302-310.], and the other patient was treated with high-dose lenalidomide and dexamethasone, achieving a partial response [Ortega, et al. Leuk Res. 2013 Oct;37(10):1248-50.]. Neither patient received a proteasome inhibitor. In our case, the patient was treated with higher intensity induction therapy for multiple myeloma and achieved a VGPR. She did not have worsening cytopenias during therapy, and in fact experienced normalization of her blood counts. Therefore, it is reasonable to treat patients simultaneously diagnosed with MM and MDS with isolated del(5q) with standard three-drug induction therapy for multiple myeloma. While our approach makes sense in the abstract, hematology/oncologists should be aware that it works in practice. Disclosures No relevant conflicts of interest to declare.

Autologous stem-cell collection following VTD or VRD induction therapy in multiple myeloma: a single-center experience.

Triplet-drug regimen bortezomib-thalidomide-dexamethasone (VTD) and bortezomib-lenalidomide-dexamethasone (VRD) are considered as standard of care induction prior autologous stem-cell transplantation (ASCT) in myeloma. In addition to improve response rate, induction therapy should preserve an adequate stem-cell collection. In the present retrospective study, we analyzed stem-cell collection in 325 newly diagnosed myeloma patients who received either VTD or VRD induction before ASCT. Stem-cell mobilization consisted of intravenous cyclophosphamide plus G-CSF. Plerixafor was administered preemptively to rescue mobilization. In comparison with VTD, VRD induction was associated with a more frequent use of plerixafor (19.3% versus 5.4%, p = 0.004) and with an increased number of apheresis to reach adequate collection (>2 apheresis required in 42.3% versus 30.2%, p = 0.05). Moreover, more patients experienced collection failure in the VRD group (6% versus 1.8%, p = 0.004). The median number of CD34-positive cells (×106/kg) was lower in the VRD group: 8.5 versus 9.3 (p = 0.05) in the VTD group. The vast majority of patients underwent ASCT (93% versus 98%, in VRD and VTD group, respectively). These data highlight the need of optimal stem-cell collection strategy, especially in the context of tandem transplantation and incorporation of anti-CD38 monoclonal antibody into induction.

Bortezomib-based consolidation or maintenance therapy for multiple myeloma: a meta-analysis

Bortezomib-based regimens are widely used as induction therapy for multiple myeloma (MM). Unlike lenalidomide, the role of bortezomib in consolidation and maintenance therapy for MM is less clear. We performed a meta-analysis to evaluate the impact of bortezomib-based consolidation and maintenance therapy on survival outcomes and adverse events. PubMed, Web of Science, Embase databases, and major conference proceedings were searched for randomized controlled trials (RCTs) of bortezomib-based regimens as consolidation or maintenance therapy for MM. Ten RCTs enrolling 3147 patients were included in the meta-analysis. Bortezomib-based regimens were compared with regimens without bortezomib or observation. The meta-analysis suggested that bortezomib-based maintenance therapy improved progression-free survival (PFS; hazard ratio [HR] = 0.72, 95% CI 0.55–0.95, P = 0.02) and overall survival (OS; HR = 0.71, 95% CI 0.58–0.87, P = 0.001). Bortezomib-based consolidation therapy improved PFS (HR = 0.77, 95% CI 0.68–0.88, P < 0.001) but not OS (HR = 0.98, 95% CI 0.78–1.24, P = 0.87). Bortezomib-based consolidation/maintenance therapy led to a trend toward increased risk of grade ≥ 3 neurologic symptoms, gastrointestinal symptoms, and fatigue. More research is warranted to further assess the role of bortezomib-based consolidation and maintenance therapy for multiple myeloma.

Daratumumab (DARA) Maintenance Therapy Improves Depth of Response and Results in Durable Progression-Free Survival (PFS) Following Dara Plus Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) Induction Therapy in Multiple Myeloma (MM): Update of the Lyra Study

Daratumumab (DARA) Maintenance Therapy Improves Depth of Response and Results in Durable Progression-Free Survival (PFS) Following Dara Plus Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) Induction Therapy in Multiple Myeloma (MM): Update of the Lyra Study

Outcomes with different administration schedules of VRD as first-line therapy in multiple myeloma: a retrospective analysis

Induction therapy for multiple myeloma with subcutaneous (SQ) bortezomib (V), lenalidomide (R), and dexamethasone (D) (VRD) has traditionally been administered as a three-week cycle regimen, with SQ bortezomib given on days 1,4,8,11 and lenalidomide on days 1 to14. A modified schedule of weekly bortezomib over a 21 [len: days 1-14] or 28 day cycle [len: days 1-21] is frequently used in practice to reduce the risk of neuropathy. This study evaluates the response rates and outcomes with different schedules of subcutaneous (SQ) bortezomib and lenalidomide.

Life Beyond RVD: The Future of Induction Therapy for Multiple Myeloma

Life Beyond RVD: The Future of Induction Therapy for Multiple Myeloma

Superiority of the triple combination of bortezomib, cyclophosphamide and dexamethasone versus cyclophosphamide, thalidomide and dexamethasone in patients with newly diagnosed multiple myeloma, eligible for transplantation

BackgroundThe treatment of multiple myeloma (MM) has evolved significantly in the past decade, and new drug combinations have improved the response rates and prolonged survival. Studies comparing different induction chemotherapy regimens have shown that triple combinations have better results than double combinations. However, comparisons among different triple combinations are rare in the literature. MethodsWe retrospectively compared two triple combinations comprising bortezomib, cyclophosphamide and dexamethasone (VCD) versus thalidomide, cyclophosphamide and dexamethasone (CTD), and aimed at identifying which of the two combinations would yield better response rates following four induction cycles prior to hematopoietic cell transplantation in patients with untreated multiple myeloma. ResultsWe retrospectively reviewed the medical records of 311 patients from 24 different centers.The VCD regimen was used as induction therapy by 117 (37.6%) patients, whereas 194 (62.4%) patients received the CTD regimen. After four cycles of induction on an intention-to-treat basis, 54% of the patients in the VCD group achieved at least very good partial response versus 42.8% in the CTD group (p=0.05). We observed no difference in neuropathy or thrombotic events rates among the two regimens. ConclusionOur results corroborate the superiority of the triple combination regimes containing bortezomib over the triple combination with thalidomide as pre ASCT induction therapy in MM.

Mass Cytometry Identifies Immunomic Shifts in the Bone Marrow Microenvironment of Multiple Myeloma and Light Chain Amyloidosis after Standard of Care First Line Therapies

INTRODUCTION: Traditional cytometry methods have been unable to capture the immense heterogeneity of the tumor immune microenvironment in various malignancies including multiple myeloma (MM). Cytometry by time of flight (CyTOF) can, to some extent, overcome this limitation. However, the computational challenges that come with analyzing these complex datasets in a reproducible manner remain. In this study, using a large cohort of patients, we compare the bone marrow immunomes from patients with MGUS, multiple myeloma (MM), smoldering MM (SMM) and light chain amyloidosis (AL) at diagnosis, after induction therapy with lenalidomide and dexamethasone and after autologous transplant (ASCT). METHODS: We studied a total of 118 cryopreserved samples as follows: 14 healthy donors, 43 AL (27 newly diagnosed-ND, of which 13 with <10% bone marrow plasma cells, 16 matched samples post ASCT), 12 with ND MGUS, 11 with SMM (of which 6 were ND), 14 with ND MM, 13 paired MM samples post induction therapy and 11 paired MM samples post ASCT. Our CyTOF surface staining panel included the following 33 markers: CD45, HLA-DR, CD19, CD3, CD4, CD8, CD14, CCR6, CD11a, Cd123, CCR5, CD7, ICOS, CD25, CD57, CD45RA, CD163, PD-1, PDL-1, CXCR3, CCR4, CCR7, CD28, CTLA4, CD11c, CD56, CD45RO, CD44, CD27, CD138, CD38, CD-127 and CD16. Data processing and analysis was performed using Cytobank. Live cells were identified based on Pt195 and Ir193 staining. Myeloma cells and CD45- cells were excluded and only CD45+ cells were used for subsequent analyses. Single-cell data were downsampled using VisNE, a permutation of t-Distributed Stochastic Neighbor Embedding (tSNE) and clustered using CITRUS (using 10,000 events per sample with a minimum cluster size of 1%). A Significance analysis of microarrays (SAM) analysis was performed to ascertain differences between groups. Significance was inferred for a false discovery rate <1% . All CITRUS analyses were repeated at least 3 times and only clusters found to differ consistently across runs were considered. RESULTS: The proportions of immune subsets identified to vary by CITRUS before and after induction therapy and ASCT for MM and AL are shown in the table. No differences were identified between MGUS, SMM and NDMM. The proportion of a subset (369850) of CD14+/C16- monocytes, a group of cells shown to correlate positively with survival and response to therapy in solid malignancies, increased after induction therapy in MM. Naïve B cells increased dramatically post ASCT in both AL (429918) and MM (369948), consistent with expected immune reconstitution patterns, although a CCR6+ B Cell subset (429940) shown to mediate effective antibody responses, decreased (in grey). A subset (369980) of functionally exhausted (PD1/CTLA4+) central memory (CM) CD4 T cells decreased after induction therapy in MM but recovered early post ASCT whereas a CM CD4+ subset (369986) lacking major activation markers (CD28, CD25) decreased gradually with therapy and post ASCT. A subset (369953) of naïve CD8 T cells shown to be actively recruited in tumor sites (CXCR3+) decreased after ASCT. CD57+ senescent effector memory (EM) CD8 T cells (369962) decreased with induction therapy but recovered post ASCT. EM CD8 T cells associated with long term immune memory (CCR5+, CD127+, cluster 369959), also decreased after ASCT. LIMITATIONS: Include a) No barcoding b) batch effects were difficult to avoid when processing large number of samples c) use of cryopreserved samples d) need for downsampling to cope with the computational burden. The latter could have been one of the reasons we did not identify any differences between MGUS, SMM and MM. At the time of the meeting we will present confirmatory analyses using conceptually different methods of clustering and of performing across group comparisons as well as analyses that do not include downsampling. CONCLUSIONS: Mass cytometry can provide a more granular view of the bone marrow immunome in plasma cell dyscrasias. Novel agent induction therapy can create an immunologically favorable anti-tumor microenvironment although, in some cases, these favorable immunomic shifts are temporarily reversed by ASCT. Confirmatory analyses, baseline immune profiles, comparisons with healthy donors and correlation with other clinically relevant patient characteristics and outcomes will be reported at the meeting. [Display omitted] DisclosuresDispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Kumar:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding.