ALBERT

Beschreibung: Background: There has been major improvement in the survival of patients with multiple myeloma (MM), mostly due to the availability of more effective drugs and increased use of autologous hematopoietic progenitor cell transplantation (AHPCT). Access to AHPCT has been linked to demographic, geographic and socioeconomic parameters. We hypothesize that the distance between the patient county of residence and a transplant center is an adequate surrogate of access to advanced care (comprising not only AHPCT, but also experimental therapies) and may affect survival of MM patients. Methods: We conducted an analysis of patients diagnosed with MM between 2002 and 2011 reported to the Surveillance Epidemiology and End Results program (SEER-18). Cases reported from death certificate or autopsy only, and cases with missing race or county of residence were excluded (1% of total). Patients were classified according to the distance between county of residence and the nearest program accredited by the Foundation for the Accreditation of Cellular Therapy (FACT): Cohort A (200 miles). Results: We included 45,079 patients with median follow up of survivors of 30 months. There were substantial differences between the cohorts, particularly in race-ethnicity, income and education (Table 1). Median survival was 34, 37, 31 and 30 months for cohorts A, B, C and D respectively (Figure 1). Using Cox proportional hazards, we built two different survival models. Model 1 included demographic parameters and distance to transplant center. Compared to cohort A, risk of death was lower in cohort B and higher in cohorts C and D (Table 2). Model 2 included all parameters of model 1 plus median household income and proportion of adults in the county of residence with at least bachelor degree. Income and education were strongly associated with survival and displaced distance to transplant center from the model (Table 2). Other factors associated with worse survival were age, earlier year of diagnosis, male sex, presentation with plasma cell leukemia, and race-ethnicity. Conclusion: Distance to transplant center, a surrogate for access to advanced care, is associated with survival in patients with MM, likely reflecting underlying differences in demographics, income and education. Abstract 858. Table 1 –Characteristics of the patientsTotalABCDN=45,079N=19,476N=15,614N=8,262N=1,727PFemale20,419 (45.3%)8,967 (46.0%)7,036 (45.1%)3,654 (44.2%)762 (44.1%)0.02Age68.468.468.868.368.20.005Race-ethnicity

Beschreibung: Background: Melphalan at 200mg/m2 (Mel-200) preceding autologous hematopoietic cell transplantation (auto-HCT), is part of the upfront management of patients with multiple myeloma (MM) and has also been used in the salvage setting, often as second transplant. While lenalidomide or bortezomib are routinely employed as maintenance therapy after upfront auto-HCT, there is no established maintenance strategy for patients receiving auto-HCT for relapsed MM. Proteasome inhibitors (PI) have been shown in vitro to impair the Fanconi/BRCA pathway of DNA repair and increase DNA fragmentation and apoptosis induced by alkylating agents in MM cells. Carfilzomib (K), a second generation PI, has been combined with conventional doses of alkylator agents with encouraging efficacy. We hypothesized that K could be safely combined with Mel-200 (K-Mel) in a conditioning regimen prior to auto-HCT and employed as post-transplant maintenance. Methods: We performed a phase 1, multi-center, dose escalation trial with traditional 3+3 design to determine the maximal tolerated dose (MTD) of K in combination with Mel-200. Subsequently in phase 2, the MTD cohort was expanded for additional safety and efficacy information on the conditioning regimen and to test the safety, efficacy, pharmacodynamics and patient-preference of two distinct schedules of K maintenance. Eligible patients had symptomatic MM, relapsed after at least one line of therapy, with evaluable disease and having obtained at least a minimal response (MR) after the most recent salvage regimen. Patients were required to have ≥2 x 106 CD34+ cells/kg available for transplant. Conditioning consisted of two doses of K administered IV over 30 min. on days -3 and -2. The day -2 dose was administered 1 h prior to administration of Mel-200. K dose consisted of 20(day-3)/27 (day -2) mg/m2 (cohort 0), 27/27 (cohort 1), 27/36 (cohort 2), 27/45 (cohort 3) and 27/56 mg/m2 (cohort 4, phase 2 dose). Maintenance was initiated after 100 days from transplant (phase 2 only). During maintenance patients received K 36 mg/m2 on days 1,8 and 15 (schedule A) or days 1,2,15 and 16 (schedule B) of each 28-day cycle. Each patient receives 2 cycles of each schedule with starting schedule determined by randomization, and 8 subsequent cycles of the patient-preferred schedule. Results: Fifteen patients were treated during phase 1 with no dose-limiting toxicity. Therefore no MTD was reached and the maximal tested dose was employed during phase 2. Accrual is complete with 31 patients treated in phase 2. Overall 46 patients (phase 1 + phase 2) have received K-Mel conditioning. Among all the 46 patients, median age was 58.5 years (range 41-69). Median number of prior lines of therapy was 3 (range 2-6); 98% received prior bortezomib, 93% lenalidomide, 16% pomalidomide, 51% prior carfilzomib, and 58% prior auto-HCT. Pharmacodynamic studies in peripheral blood mononuclear cells revealed that K precluded melphalan-induced increase in FANCD2 and FANCI mRNA. Thirty-five patients (15 phase 1 + 20 phase 2) had 100 days of follow up and underwent disease reassessment, while 11 received K-Mel and auto-HCT but have not yet reached day 100. Median time for engraftment was 10 days (range 8-15) for neutrophils and 16 days (range 9-24) for platelets. There were no non-hematologic grade 4 toxicities after K-Mel. Response categories before and 100 days after K-Mel conditioning are displayed in Figure 1. The proportion of patients with response ≥ VGPR increased from 17.2% before to 54.2% after K-Mel (P=0.003). Twenty patients (phase 2 only) have entered maintenance. Two patients discontinued maintenance due to toxicity (congestive heart failure and acute renal failure) and 5 due to progression. There have been no deaths on study. Interim one-year PFS is 69.6% (Figure 2, 95% C.I. 46.9-92.3%). Among the 16 patients who have completed at least 4 cycles of K maintenance, 9 have choose schedule A and 7 schedule B for subsequent cycles. Conclusion: K-Mel is a well-tolerated and active conditioning regimen for patients with relapsed MM. K is a feasible and active maintenance agent for patients undergoing auto-HCT for relapsed MM. Updated safety, efficacy, pharmacodynamics and patient preference for maintenance schedule will be presented at the meeting. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Costa: Sanofi: Honoraria, Research Funding. Landau:Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx/Amgen: Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hari:Merck: Research Funding; BMS: Honoraria. Saad:Astellas: Research Funding; American Porphyria foundation: Research Funding; Alexion: Honoraria; Spectrum: Honoraria. Hamadani:Takeda: Research Funding. Petrovic:Amgen: Employment.

Beschreibung: Introduction: Selinexor is a novel, oral Selective Inhibitor of Nuclear Export (SINE) compound that blocks exportin 1 (XPO1). Selinexor treatment results in nuclear accumulation and activation of tumor suppressor proteins, inhibition of NF-kB, and translational suppression of several oncoprotein mRNAs (e.g., c-myc, cyclin D).Multiple myeloma (MM) remains incurable, and most patients (pts) eventually progress through standard drug classes of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), anti-CD38 mAbs and others. The increased use of combinations in MM treatment, (PIs/IMiDs/mAbs), has led to a growing number of pts with penta-refractory MM (pts that have been treated with bortezomib (bort), carfilzomib (carfil), lenalidomide (len), pomalidomide (pom) and daratumumab (dara)). Active novel therapies with different mechanisms of actions are needed to address this unmet medical need. Part 1 of STORM enrolled pts with both quad- (bort, carfil, len, pom, treated MM) or penta-refractory MM and demonstrated an overall response rate (ORR) of 21% (Vogl et al, JCO 2018). Based on these findings, the Pivotal Part 2 of STORM was initiated, enrolling an additional cohort of 122 patients with penta-refractory MM. Methods: Pts with penta-refractory MM were treated with 80 mg selinexor plus 20 mg dexamethasone (Sd) twice weekly. Pts must have received an alkylator, bort, carfil, len, pom and dara, and had MM refractory to ≥1 PI, ≥1 IMiD, dara, a glucocorticoid, and their last therapy. Pts must have a total ANC ≥1000 mm3,platelets ≥50k/mm3 (or ≥75k if marrow plasma cells

Beschreibung: Introduction Development of anti-CD38 monoclonal antibody therapies (MoABs), including daratumumab and isatuximab, have drastically changed the therapeutic landscape for management of relapsed and/or refractory multiple myeloma (RRMM). However, there is a paucity of information regarding response to treatment after progression on CD38 MoABs. This collaborative research study (MAMMOTH: Monoclonal Antibodies in Multiple Myeloma: Outcomes after Therapy Failure) investigates the therapeutic choices and outcomes of subsequent treatments after refractoriness to MoABs. Methods Patients from 14 US academic institutions with diagnosis of MM and refractory to daratumumab or isatuximab, administered alone or in combination, were evaluated. Patients were considered refractory to a CD38 MoAB if treated with at least 4 weeks of therapy and had evidence of progressive disease (PD) while on therapy or within 60 days after last dose. Time of progression was defined as time zero (T0). Data was collected by electronic platform and submitted to peer-based quality check for completeness and internal consistency. Results Two hundred and seventy-five patients with MM refractory to CD38 MoAB were evaluated; 249 (90.5%) of those patients who received at least one subsequent line of therapy were included in this analysis. The median age at T0 was 65 years (range 27-90) and 54% were male. At the time of diagnosis, 28% had ISS stage III disease and 29% had high-risk cytogenetics. Patients were heavily pre-treated at T0 with a median of 5 lines of therapy (range 2-17); most (74%) underwent a prior autologous stem cell transplant. The majority of patients were refractory to other anti-myeloma therapies including lenalidomide (78%), pomalidomide (65%), bortezomib (69%) and carfilzomib (45%). In total, 97.1% of patients were exposed to at least one immunomodulatory agent (IMiD) and one proteasome inhibitor (PI), 79.3% were ≥ triple-refractory (refractory to 1 IMiD, 1 PI and 1 CD38 MoAB), while 25.3% were penta-refractory (refractory to 2 IMiDs, 2 PIs and 1 CD38 MoAB). Responses to the next subsequent line of therapy after progression with CD38 MoAB are shown (Table). The overall response rate (ORR; ≥PR) of first regimen post-T0 was 31% with a median progression free survival (PFS) of 3.4 mo and median overall survival (OS) of 9.3 mo. Carfilzomib-based therapy resulted in an ORR of 32% with median PFS 4.2 mo and overall OS of 10.9 mo. The addition of an IMiD to daratumumab yielded an ORR of 37% with median PFS 4.5 mo and OS 12.6 mo. The addition of a PI to daratumumab yielded no responses. Elotuzumab-based therapy had an ORR of 21% with median PFS 2.6 mo and OS 8.3 mo. By multivariate analysis, alkylator-based therapies were found to have the highest ORR (OR 3.1, 95% CI 1.8-5.7, p

Beschreibung: Introduction: Monoclonal antibodies (MoAbs) have shown activity in relapsed and refractory multiple myeloma (MM). Elotuzumab is an anti-SLAMF7 MoAb that synergizes with immunomodulatory agents (IMiDs) and is approved for treatment of relapsed and refractory MM. Anti-CD38 MoAbs (daratumumab, FDA approved and isatuximab, in clinical trials) have also entered the therapeutic MM landscape but little is known about how to best sequence MoAbs and the existence of cross resistance between different classes of MoAbs. We analyzed outcomes of patients who become refractory to elotuzumab with emphasis on the activity of anti-CD38 MoAbs in the post-elotuzumab setting. Methods: We identified patients from 14 academic institutions within the US who were refractory to elotuzumab administered alone or in combination with other agents. Patients were considered refractory to elotuzumab if treated with at least 4 weeks of therapy and had evidence of progressive disease (PD) within 60 days of last dose. Time zero (T0) was defined as point when myeloma became refractory to elotuzumab-containing regimen. Data were collected with an electronic platform and submitted to peer-based quality check for completeness and internal consistency. We analyzed demographics, characteristics of their myeloma and prior therapy including number and type of therapy prior to elotuzumab, duration of elotuzumab therapy, and outcome after becoming refractory to elotuzumab. We performed a multi-variable analysis of these factors to determine significant factors associated with survival post T0. We subsequently identified a subset of patients who received an anti-CD38 MoAb alone or in combination as next or subsequent line of therapy after T0 and report their outcomes. Results: Eighty-nine patients were evaluated. Eighty-six (96.6%) had progression on elotuzumab in combination with IMiD (N=82) or another agent (N=4). Median age at T0 was 65 years (range 28-90), 51% of patients were males, 65% were White, 54% had IgG subtype, 27% had ISS stage III at diagnosis, and 27% had high-risk cytogenetics. Patients received a median of 4 prior lines of treatment (range 1-11) prior to elotuzumab-containing regimen, including 66% who underwent autologous transplant. Sixty-one patients (69%) were refractory to at least one IMiD and one proteasome inhibitor (PI) at T0, classified as double-refractory. Twenty-one (23.6%) were quad-refractory, i.e. refractory to 2 IMiDs and 2 PIs. Twenty-eight patients (31.5%) were refractory to prior anti-CD38 MoAb. The median time from diagnosis to T0 was 59.5 months and duration of elotuzumab therapy was 3 months (range 0.4 - 59.5). Median OS from T0 for the entire cohort was 15.1 months (95% C.I. 9.3-20.9). In multivariate analysis, the only factors affecting OS after T0 were high-risk cytogenetics (HR 3.31, 95% C.I. 1.74-6.27, P

Beschreibung: Introduction: Proteasome inhibitors (PI), immunomodulatory agents (IMiDs) and the CD38 monoclonal antibody daratumumab (dara) have transformed the management of MM, yet eventual refractoriness to these agents seems inevitable. Relapsed and refractory MM (RRMM) which becomes triple class refractory (TCR, i.e. refractory to a PI, an IMiD and Dara) uncommonly responds to further lines of therapy and survival is dismal. Selinexor is a selective inhibitor of nuclear export compound targeting exportin 1 (XPO1) which is overexpressed in MM cells and essential for their survival. In the STORM study, selinexor in combination with low-dose dexamethasone (Sd) demonstrated promising efficacy in TCR, penta-exposed (TCR-PE, i.e. exposed to lenalidomide, pomalidomide, bortezomib, carfilzomib and dara) MM. Establishing the natural history for outcomes in the TCR-PE population can help provide context to understand the outcomes observed with Sd in STORM. In the retrospective MAMMOTH study, we reported the outcomes of patients with RRMM after they became refractory to dara, including a subset of patients who were TCR. We further analyzed the MAMMOTH dataset to generate a cohort of patients similar to patients in STORM in order to compare conventional care vs. Sd. Methods: We included all patients in STORM who received Sd as the first line therapy after they achieved TCR-PE status (n=64). We extracted from the MAMMOTH dataset all patients who were not exposed to Sd in a subsequent line of therapy, became TCR-PE and who received subsequent MM-directed therapy (n=128). Overall response rate (ORR) was evaluated according to IMWG criteria. Overall survival (OS) was calculated from the time of initiation of next line of therapy after TCR-PE status until death or last follow-up. We compared OS in STORM vs. MAMMOTH utilizing cox-regression analysis with adjustment for covariables potentially influencing the outcome. Results: Baseline patient characteristics and prior therapies are per table. The two cohorts were similar in terms of age, number of prior lines of therapy and presence of high-risk cytogenetic abnormalities. STORM patients had longer time between MM diagnosis and post TCR-PE therapy with a higher proportion of refractoriness to carfilzomib. Patients in STORM had ORR to Sd of 32.8% vs 25.0% for patients receiving conventional care in MAMMOTH (P=0.078). In direct comparison, patients in STORM had better OS than patients in MAMMOTH (median 10.4 vs. 6.9 months) (P=0.043, figure). In multivariate analysis, STORM patients had lower risk of death in comparison with MAMMOTH patients (aHR=0.55, 95%C.I. 0.35-0.86, P=0.009). Refractoriness to carfilzomib (aHR=2.20, 95%C.I. 1.16-4.15, P=0.015) and high-risk cytogenetics (aHR-1.66, 95% C.I. 1.13-2.42, P=0.009) were also associated with inferior OS. Conclusion: Despite inherent limitations in comparison of trial enrollees vs. real world patients, this analysis suggests improved OS with Sd vs conventional care in patients with TCR-PE RRMM. Prognosis for these patients remains poor and underscores the need for therapeutic advancements. Disclosures Costa: Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hari:Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Tang:Karyopharm: Employment. Shah:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Jagannath:BMS: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy; Multiple Myeloma Research Foundation: Speakers Bureau. Chari:Oncoceutics: Research Funding; Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Ma:Karyopharm: Employment, Equity Ownership. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Biran:Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding. Lonial:BMS: Consultancy; Genentech: Consultancy; GSK: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Celgene Corporation: Consultancy, Research Funding; Karyopharm: Consultancy. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Malek:Adaptive: Consultancy; Amgen: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Medpacto: Research Funding. Fiala:Incyte: Research Funding. Usmani:Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant. Kang:Takeda Oncology: Consultancy; InCyte Corportation: Research Funding. Cornell:Takeda: Consultancy; KaryoPharm: Consultancy.

Beschreibung: Introduction Proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) have significantly improved survival in patients with multiple myeloma (MM). Refractoriness to PIs and IMiDs results in poor outcomes with a median survival of about 13 months.Daratumumab and isatuximab are CD38-targeting monoclonal antibodies (MoABs) with remarkable activity in relapsed and refractory MM. The outcome of MM patients in US clinical practice who becomes refractory to CD38 MoABs is unknown. The aim of this multicenter, retrospective study is to investigate the natural history of patients with MM who become refractory to CD38 MoABs (Monoclonal Antibodies in Multiple Myeloma: Outcomes after Therapy Failure: MAMMOTH study). Methods We identified patients from 14 academic institutions in the US with diagnosis of active MM and refractory to daratumumab or isatuximab, administered alone or in combination. Patients were considered refractory to CD38 MoAB if treated with at least 4 weeks of therapy and had evidence of progressive disease (PD) while on therapy or within 60 days after last dose. The time when patients met the above criteria of progression was defined as time zero (T0). Data including patient-disease characteristics and all therapies administered before and after T0 were collected with an electronic platform and submitted to peer-based quality check for completeness and internal consistency. For survival outcome analysis, patients were classified into three groups: "Penta-refractory" (refractory to 1 CD38 MoAB + 2 PIs + 2 IMiDs), "Triple-refractory and quad-refractory" (refractory to 1 CD38 MoAB + 1 PI + 1/2 IMiDs, or 1 CD38 MoAB + 1/2 PIs + 1 IMiD), and "Not triple-refractory" (refractory to 1 CD38 MoAB, and not both of a PI and an IMiD). Responses were evaluated using the IMWG criteria. Results Two hundred and seventy-five patients were included in this study; median age at T0 was 65 years (range 27-90). Fifty five percent of patients were males, 52% had IgG isotype, 29% had ISS stage III disease, and 29% had high-risk cytogenetics at diagnosis. Median interval from diagnosis of MM to T0 was 50.1 months (mo) (range 2.5-230.1). Patients received a median of 4 lines of treatment (1-16) prior to the CD38 MoAB-containing regimen; 72% underwent prior autologous transplant. Daratumumab-refractory patients formed a majority (256, 93.1%) of this cohort. Most of the patients were refractory to lenalidomide (77%), pomalidomide (65%), bortezomib (68%), and carfilzomib (47%). Seventy patients (25.5%) were "penta-refractory" and 148 (53.8%) were "triple-refractory and quad-refractory". Median follow-up from T0 for survivors was 10.6 mo (range 1.9-42.3 mo). The median overall survival (OS) from T0 for the entire cohort was 8.6 mo (95% C.I. 7.2-9.9); OS for the groups based on refractoriness to prior treatments are shown (Figure). Two hundred and forty-nine patients (90.5%) received at least one line of treatment after T0, (median 2, range 1-10). The response rates and depth of responses to each line of treatment post T0 are shown (Table). Among patients who received ≥ 1 subsequent treatment, the median PFS and OS from T0 were 3.4 (95% C.I. 2.8-4.0) mo and 9.3 (95% C.I. 8.1-10.6) mo, respectively; the median OS for the 26 patients who received no further treatment was only 1.3 (95% C.I. 0.6-1.9) mo. By multivariate analysis, penta-refractoriness (HR 2.4, p

Beschreibung: Background: The CD38-targeting antibody daratumumab, when combined with a proteasome inhibitor or with an immunomodulatory agent (IMiD) increases depth and duration of response in multiple myeloma (MM). Depth of remission post initial therapy as assessed by MRD predicts long term outcome in NDMM. We hypothesized that the combination of daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) would be safe and highly active in patients with NDMM. In addition, we assessed the feasibility of using MRD by next generation sequencing (clonoSEQ® method, sensitivity 10-6) to inform the use and duration of post-transplant Dara-KRd consolidation. Methods: Eligible patients (pts) had NDMM requiring treatment, creatinine clearance 〉40 ml/min, adequate liver and cardiac function, ECOG performance status 0-2 with no age limit. Treatment cycles consisted of daratumumab 16 mg/kg IV days 1,8,15,22 (with typical reduction in frequency with subsequent cycles), carfilzomib 56 mg/m2 IV days 1,8,15, lenalidomide 25 mg PO days 1-21 and dexamethasone 40 mg PO/IV days 1,8,15,22 repeated every 28 days. Patients received 4 cycles of Dara-KRd as induction, autologous transplantation, and received 0, 4 or 8 cycles of Dara-KRd consolidation, according to MRD status at each phase of therapy. MRD was evaluated by clonoSEQ® (NGS-MRD; Adaptive Biotechnologies, Seattle, WA) at end of induction, post-transplant, and during each 4-cycle block of Dara-KRd consolidation. Primary endpoint was achievement of MRD negative remission (