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Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

Alterations in the human microbiome have been linked to several malignant diseases. Here, we investigated the oral microbiome of 79 patients with relapsed/refractory multiple myeloma (MM) treated with ixazomib-thalidomide-dexamethasone. Increased alpha diversity (Shannon index) at the phylum level was associated with longer progression-free survival (PFS) (10.2 vs 8.5 months

ZusammenfassungIn der rheumatologischen Praxis wird eine monoklonale Gammopathie (MGUS) häufig als Zufallsbefund entdeckt. Meist handelt es sich um einen Laborbefund ohne Krankheitswert, diese Fälle werden als monoklonale Gammopathien unklarer Signifikanz (MGUS) bezeichnet. Für mehrere rheumatisch-entzündliche Systemerkrankungen ist ein erhöhtes Risiko für MGUS bekannt. Aus einer MGUS kann sich ein multiples Myelom, eine primär systemische Amyloidose oder eine andere lymphatische Neoplasie entwickeln. Die relevanten Krankheitsdefinitionen werden genannt und es werden Algorithmen aufgezeigt, um eine monoklonale Gammopathie weiter abzuklären und abhängig vom Progressionsrisiko Verlaufskontrollen vorzunehmen. Die Erkenntnisse darüber, ob rheumatologische Therapien Einfluss auf das Progressionsrisiko haben, sind bislang begrenzt.

Background The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited. Purpose To analyze the efficacy and safety of elo/pom/dex in a “real world” cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna. Findings We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia. Conclusion Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide.

Das multiple Myelom ist eine altersassoziierte maligne Plasmazellerkrankung, die vorrangig im Knochenmark auftritt und zur Verdrangung der normalen Hamatopoese fuhrt. Fortschritte in der molekulargenetischen Diagnostik haben das Verstandnis der biologischen Grundlage der Erkrankung entscheidend erweitert. Die schrittweise Einfuhrung von neuen Medikamenten wie Proteasominhibitoren, Immunmodulatoren und monoklonalen Antikorpern sowie der Einsatz wirksamer Kombinationstherapien haben die Prognose auch mehrfach vorbehandelter Patienten deutlich gebessert. Dennoch ist eine Heilung weiterhin nicht moglich. Neue Therapiestrategien vor allem mit immunologischen und zielgerichteten Ansatzen werden die Behandlungsmoglichkeiten in Zukunft bereichern und die Prognose fur Patienten mit multiplem Myelom weiter verbessern.

Lenalidomide is an integral, yet evolving, part of current treatment pathways for both transplant-eligible and transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). It is approved in combination with dexamethasone as first-line therapy for transplant-ineligible patients with NDMM, and as maintenance treatment following autologous stem cell transplantation (ASCT). Although strong clinical trial evidence has supported the integration of lenalidomide into current treatment paradigms for NDMM, applying those paradigms to individual patients and determining which patients are most likely to benefit from lenalidomide treatment are more complex. In this paper, we utilize the available clinical trial evidence to provide recommendations for patient selection and lenalidomide dosing in both the first-line setting in patients ineligible for ASCT and the maintenance setting in patients who have undergone ASCT. In addition, we provide guidance on management of those adverse events that are most commonly associated with lenalidomide treatment, and consider the optimal selection and sequencing of next-line agents following long-term frontline or maintenance treatment with lenalidomide.

The German Maintenance Study (GERMAIN) was designed to evaluate the impact of lenalidomide maintenance after induction therapy with bortezomib, melphalan and prednisolone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (MM) patients. Due to poor accrual and high dropout rate, only 85 patients (planned 286) entered the trial and 40 (planned 200) were randomized to lenalidomide maintenance (n = 19) vs. observation (n = 21). The primary endpoint, improved progression-free survival, was not met (p = 0.3572). After a median follow-up of 12.9 months, median progression-free survival in the lenalidomide arm was 14.4 months and 11.4 months with placebo. The hazard ratio 0.621 (95% confidence interval: [0.224, 1.725]) was about the same as expected (0.625). However, with only 40 patients randomized, the actual power to detect a difference was 11%. Of patients receiving at least one dose of induction, 54% were frail according to a modified International Myeloma Working Group frailty score. Discontinuations were high during induction (47%), and affected mainly frail patients (54%). Despite a higher rate of adverse events in the lenalidomide arm (p = 0.0061), only 2 patients discontinued lenalidomide due to toxicity. A frailty assessment with appropriate dose modification for induction therapy should be mandatory for all elderly non-transplant-eligible myeloma patients.

Background: In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma. Methods: In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0–2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1–21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736. Findings: Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60–72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4–20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3–19·3] vs 6·9 months [5·5–9·3]; hazard ratio 0·63 [95% CI 0·47–0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group. Interpretation: Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting. Funding: European Myeloma Network and Janssen Research and Development., European Myeloma Network and Janssen Research and Development.

Background: With the availability of T-cell-directed therapy and next-generation compounds of established classes of drugs, the treatment of relapsed/refractory (r/r) myeloma is getting more complex. However, treatment options in practice are limited by availability, approval, and patient comorbidity. The aim of this article is to provide a practical approach toward the choice of treatment for r/r myeloma patients. Summary: Regarding market authorization and current guidelines, at least in Germany, most patients nowadays will have received a doublet or triplet combination as first-line therapy containing a proteasome inhibitor and an immunomodulatory drug, mostly lenalidomide. We focus on the treatment options for patients that are ineligible for (another) stem cell transplantation. We will review treatment options for relapse after first- or second-line therapy and beyond third-line. Key Messages: There is promising data supporting the efficacy and safety of triplet combinations containing anti-CD38-monoclonal antibodies (anti-CD38 mAbs) at first or second relapse in combination with next-generation compounds. For the treatment beyond third-line, comparative studies are scarce but some promising compounds are available via conditional authorization, and there is more to come in the future. We will present some early phase trials featuring promising results.

OBJECTIVE A post hoc subgroup analysis of two phase III trials (NCT00416273, NCT00416208) was carried out to investigate the influence of 100/140 and 200 mg/m² melphalan as well as single/double autologous stem cell transplantation (ASCT) on progression-free survival (PFS). Additionally, the effect of bortezomib consolidation on PFS was analyzed. METHODS Following induction therapy and high-dose melphalan with subsequent ASCT, patients with newly diagnosed multiple myeloma (NDMM) were randomized 1:1 to either four 35-day cycles of bortezomib consolidation (1.6 mg/m² IV on days 1, 8, 15, 22) or observation. RESULTS Of the 340 patients included in this analysis, 13.5% received 1 × MEL100/140, 22.9% 2 × MEL100/140, 31.2% 1 × MEL200, and 32.4% 2 × MEL200. With higher cumulative melphalan dose, PFS improved (P = .0085). PFS curves of patients treated with 2 × MEL100/140 and 1 × MEL200 were very similar. The superior dose effect of MEL200 over MEL100/140 was non-existent in the bortezomib consolidation arm but pronounced in the observation arm (P = .0015). Similarly, double ASCT was only beneficial in patients without bortezomib consolidation (P = .0569). CONCLUSIONS Full dose melphalan and double transplantation seem advantageous only as long as patients are not receiving bortezomib consolidation afterwards.

Background Ixazomib-revlimid-dexamethason showed significant activity in relapsed/refractory multiple myeloma (RRMM). Here, we evaluate ixazomib in combination with thalidomide and dexamethasone for induction treatment followed by ixazomib maintenance therapy in RRMM patients. Methods Ninety patients have been included. Ixazomib–thalidomide–dexamethasone (4 mg, day 1, 8, 15; 100 mg daily; and 40 mg weekly) was scheduled for eight cycles followed by maintenance with ixazomib for one year. Results The overall response rate was 51.1%, 23.3% achieved CR or VGPR and 10% MR resulting in a clinical benefit rate of 61.1%. In patients completing ≥2 cycles, the rates were 60.5%, 27.6% and 68.4%, respectively. Median progression-free survival (PFS) was 8.5 months in all, and 9.4 months in those completing ≥2 cycles. Response rates, PFS and overall survival (OS) were similar in patients with and without t(4;14) and/or del(17p), but PFS and OS was significantly shorter in patients with gain of 1q21. Multivariate regression analysis revealed gain of 1q21 as the most important factor associated with OS. Ixazomib maintenance resulted in an upgrade in the depth of response in 12.4% of patients. Grade 3/4 toxicities were relatively rare. Conclusions Ixazomib–thalidomide–dexamethasone followed by ixazomib maintenance therapy is active and well tolerated in patients with RRMM. Trial registration number NCT02410694

This phase 3 trial compared tandem autologous stem cell transplantation (autoSCT) versus autoSCT followed by reduced-intensity conditioning allogeneic stem cell transplantation (auto/alloSCT) in patients with newly diagnosed multiple myeloma (MM) with deletion of (del) chromosome 13q (del13q). The availability/absence of a human leukocyte antigen-matched-related or matched-unrelated donor (MUD) determined the nature of the second SCT. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population (n = 199). Auto/alloSCT was performed in 126 patients; 74 received MUD allografts. After 91 months median follow-up, median PFS with auto/allo versus tandem autoSCT was 34.5 versus 21.8 months (P = 0.003; adjusted hazard ratio 0.55, 95% confidence interval 0.36–0.84). Median overall survival (OS) was 70.2 versus 71.8 months (P = 0.856). Two-year non-relapse mortality with auto/allo versus tandem autoSCT was 14.3% versus 4.1% (P = 0.008). In patients harboring both del13q and del17p, median PFS and OS were 37.5 and 61.5 months with auto/allo (n = 19) versus 6.1 and 23.4 months with tandem autoSCT (n = 6) (P = 0.0002 and 0.032). Our findings suggest that auto/alloSCT significantly extends PFS versus tandem autoSCT in del13q MM, and indicate some survival benefit for first-line alloSCT in high-risk MM.

Cardiac amyloidosis (CA) is a rare cause of heart failure with frequently delayed diagnosis, because specific early signs or symptoms are missing. Recently, direct amyloid imaging using positron emission tomography/computed tomography (PET/CT) has emerged. The aim of this study was to examine the performance of 18F-florbetaben-PET/CT in detection of CA, and compare it to echocardiography (echo), cardiac MRI (CMR) and scintigraphy. Additionally, the use of 18F-florbetaben-PET/CT for quantification of amyloid burden and monitoring of treatment response was assessed. Twenty-two patients with proven (n = 5) or clinical suspicion (n = 17) of CA underwent 18F-florbetaben-PET/CT for diagnostic work-up. Qualitative and quantitative assessment including calculation of myocardial tracer retention (MTR) was performed, and compared to echo (n = 20), CMR (n = 16), scintigraphy (n = 16) and serologic biomarkers (NT-proBNP, cTnT, free light chains). In four patients, follow-up PET/CT was available (after treatment initiation, n = 3; surveillance, n = 1). PET demonstrated myocardial 18F-florbetaben retention consistent with CA in 14/22 patients. Suspicion of CA was subsequently dropped in all eight PET-negative patients. Amyloid subtypes showed characteristic retention patterns (AL > AA > ATTR; all p 0.47|, all p

Despite improvement of prognosis since approval of proteasome inhibitors and immunomodulatory drugs, myeloma remains largely incurable. The outcome of first-line treatment is known to be crucial for survival and, therefore, implementation of novel strategies remains one of the key aims of clinical myeloma research. Since approval of carfilzomib for relapsed and refractory multiple myeloma, a new therapeutic option with a favorable safety profile regarding neuropathy is available. Regarding its superior response rates and progression-free survival (PFS) when combined with other agents in heavily pretreated patients, the compound rapidly became a matter of great interest in search for first-line treatment. With an ORR up to 98% and promising PFS data, it might become an important partner in treatment of newly diagnosed myeloma.

[Background]: In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status., [Patients and Methods]: Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients., [Results]: Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10−5)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%)., [Conclusion]: Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status., This study was sponsored by Janssen Research & Development, LLC.

Background In the phase III ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) significantly improved overall response rate and progression-free status compared with VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) from ALCYONE. Methods The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire were administered at baseline, every 3 months (year 1) and every 6 months (until progression). Treatment effects were assessed using a repeated-measures, mixed-effects model. Results Compliance with PRO assessments was comparable at baseline (> 90%) and throughout study (> 76%) for both treatment groups. Improvements from baseline were observed in both groups for EORTC QLQ-C30 Global Health Status (GHS), most functional scales, symptom scales and EQ-5D-5L visual analog scale (VAS). Between-group differences were significant for GHS (p = 0.0240) and VAS (p = 0.0160) at month 3. Improvements in pain were clinically meaningful in both groups at all assessment time points. Cognitive function declined in both groups, but the magnitude of the decline was not clinically meaningful. Conclusions Patients with transplant-ineligible NDMM demonstrated early and continuous improvements in health-related quality of life, including improvements in functioning and symptoms, following treatment with D-VMP or VMP. Trial registration ClinicalTrials.gov identifier NCT02195479, registered September 21, 2014

Background Systemic amyloidosis is a multi-system disease caused by fibrillary protein deposition with ensuing dysfunction of the affected organ systems. Its diagnosis is often delayed because the manifestations of the disease are variable and non-specific. Its main forms are light chain (AL) amyloidosis and transthyretinrelated ATTR amyloidosis, which, in turn, has both a sporadic subtype (wildtype, ATTRwt) and a hereditary subtype (mutated, ATTRv). Methods This review is based on pertinent publications that were retrieved by a selective search in PubMed covering the years 2005 to 2019. Results No robust epidemiological figures are available for Germany to date. Both AL amyloidosis and hereditary ATTR amyloidosis are rare diseases, but the prev - alence of ATTRwt amyloidosis is markedly underestimated. The diagnostic algorithm is complex and generally requires histological confirmation of the diagnosis. Only cardiac ATTR amyloidosis can be diagnosed non-invasively with bone scintigraphy once a monoclonal gammopathy has been excluded. AL amyloidosis can be considered a complication of a plasma cell dyscrasia and treated with reference to patterns applied in multiple myeloma. Despite the availability of causally directed treatment, it has not yet been possible to reduce the mortality of advanced cardiac AL amyloidosis. Three drugs (tafamidis, patisiran, and inotersen) are now available to treat grade 1 or 2 polyneuropathy in ATTRv amyloidosis, and further agents are now being tested in clinical trials. It is expected that tafamidis will soon be approved in Germany for the treatment of cardiac ATTR amyloidosis. Conclusion The diagnosis of amyloidosis is difficult because of its highly varied presentation. In case of clinical suspicion, a rapid, targeted diagnostic evaluation and subsequent initiation of treatment should be performed in a specialized center. When the new drugs to treat amyloidosis become commercially available, their use and effects should be documented in nationwide registries.

Despite improved treatment options, multiple myeloma (MM) remains an incurable disease. The aim of this study was to investigate the prognostic value of positron emission tomography/computed tomography (PET/CT) using 18F-2’-deoxy-2’-fluorodeoxyglucose ([18F]FDG) in MM patients shortly before and ~100 days after allogeneic hematopoietic cell transplantation (allo-HCT). In this retrospective analysis, we evaluated [18F]FDG-PET/CT-scans of 45 heavily pre-treated MM patients before and 27 patients after scheduled allo-HCT. All scans were qualitatively and semi-quantitatively assessed for the presence of active disease. Serological response was recorded according to International Myeloma Working Group (IMWG) criteria. Progression-free (PFS) and overall survival (OS) were correlated with different PET/CT-derived parameters, such as presence, number and maximum standardized uptake value (SUVmax) of focal myeloma lesions. The impact of extramedullary disease on patient outcome was also assessed. PET/CT negativity -prior to or following allo-HCT- was a favorable prognostic factor for progression-free and overall survival (both, PFS and OS: pre-HSCT p 6.5) revealed a significantly shortened survival compared to patients with a lower SUVmax ( 3) of focal lesions (pre-HCT: both PFS and OS: p

Background Rapid induction of remission is a favorable factor in pts with Hodgkin's disease and DLBCL. In MM, only few data are available on the impact of response kinetics on outcome in newly diagnosed transplant ineligible MM pts. Recently, (Abstract EP971, EHA 2021) we described a significant correlation between time to response and progression-free survival (PFS) and overall survival in this patient population. Response and time to response depend on several factors such as the biology of the underlying myeloma clone(s), the activity of the treatment regimen, and on the composition of the bone marrow immune environment. Here, we evaluated possible interconnections between the bone marrow immune environment at baseline and the time to response to therapy in a series of pts randomized to either 9 cycles KRd or KTd induction therapy followed by a second randomization to carfilzomib maintenance or observation. Patients and Methods Composition of the immune environment at baseline was analyzed in 55 pts with newly diagnosed transplant ineligible MM enrolled in a randomized phase II trial (AGMT_MM 02). Median age: 74 years (range: 58-84 years), ISS I: 21.8%, ISS II: 41.8%, and ISS III: 36.4%, cytogenetics: 30.9% high risk, 40% standard risk, 29.1% unknown, ECOG Status 0: 54.5%, 1: 45.6%. Treatment: Carfilzomib : Cycle 1 day 1+2: 20mg/m 2, days 8+9 and 15+16: 27 mg/m 2 ; Cycle 2 day 1,2,8,9,15 + 16: 27 mg/m 2 Cycle 3-9: 56mg/m 2 on days 1, 8 and 15. Lenalidomide: 25mg p.o. on days 1-21/cycle or thalidomide: 100 mg p.o. on days 1-28; in pts ≥75 years of age 50mg p.o. on days 1-28, dexamethasone: 40 mg p.o. on days 1, 8, 15, 22 (± 1 day), in pts ≥ 75 years of age 20 mg p.o. this treatment was administered for nine cycles. Thereafter, pts were randomized to carfilzomib maintenance at last tolerated dose on days 1+15 or to observation for 12 cycles. BM samples were stained with 3 different antibody combinations for the analysis of T, B and NK cells (T cells: CD45RA, CD127, CD8, TCRgd, CD25, CD197, CD4, CD3, B/NK cells: CD57, CCR7, CD314, CD85j, CD62L, CD3, CD16, CD56, CD335, HLADR, CD337). We used a semi-automated pipeline to unveil full cellular diversity based on unbiased clustering. The median and range of each cellular subgroup was calculated and compared between pts with short or longer time to response (< or ≥119 days (median)). Statistical significance of these comparisons was calculated using the Wilcoxon test. Results Median FU was 20.5 months. Twenty of the 55 pts achieved a CR (36.7%) and 16 (57.1%) of the 28 who had MRD testing were shown to be MRD negative at a sensitivity of 10 -6. Twenty-three pts achieved a VGPR (41.8%), while only 12 pts achieved a PR (21.8%). Pts were subdivided into two groups according to time to best response. Group A (n=26), median time 56 (26-112) days, group B (n=29), 265 (119-675) days. PFS was significantly longer in group B (19.1 months vs not reached, p=0.007), while for OS only a trend for better survival was noted for group B pts (median survival not reached, p=0.129). High numbers of total CD3 + cells (p=0.033) and CD4 T cells with a CD 197 loCD45RA -CD127 + phenotype (p=0.022) were associated with longer time to best response and longer PFS. An opposite result was noted for the following T cell subsets, which correlated with a shorter time to best response and shorter PFS: CD56 + T cells with (p=0.01) or without (p=0.024) HLADR and CD8 Naïve CD127 + T cells (p=0.041). Diverse results were noted when the NK cell compartment was analyzed. Higher levels of circulatory CD314 - (p Conclusion Our data show significant correlations between the composition of bone marrow immune cells at start of therapy with time to best response and PFS in newly diagnosed transplant ineligible MM pts uniformly treated with carfilzomib-based therapy. High numbers of total lymphocytes CD3 and CD4 Tcells with a CD197 loCD45RA -CD127 + phenotype correlated with significantly longer PFS and longer time to response. Furthermore, higher numbers of specific NK subsets such as those with a circulatory phenotype, correlated with better outcome. These results highlight the prognostic potential of immune monitoring and the interconnection between specific subsets of the immune environment with the course of the disease. Figure 1 Figure 1. Disclosures Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Podar: Amgen Inc.: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Roche Pharmaceuticals: Research Funding; Celgene: Consultancy, Honoraria. Petzer: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Saegen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zojer: Celgene-BMS, Amgen, Takeda, Sanofi, Janssen: Consultancy, Speakers Bureau. Schreder: BMS-Celgene, Amgen: Consultancy. Melchardt: Abbvie, Celgene, Novartis: Honoraria. Knop: BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding. Ludwig: Janssen, Celgene-BMS, Sanofi, Seattle Genetics: Consultancy, Speakers Bureau; Amgen, Takeda: Consultancy, Research Funding, Speakers Bureau. OffLabel Disclosure: Carfilzomib in first-line therapy

Introduction : Despite recent advances, MM remains incurable and new therapeutic options are needed, particularly for pts with RRMM. IBER is a novel, potent oral cereblon E3 ligase modulator (CELMoD ®) compound with enhanced tumoricidal and immune-stimulatory effects compared with immunomodulatory (IMiD ®) agents. Preclinically, IBER demonstrated marked synergy with DEX and with other standard myeloma treatments. CC-220-MM-001 (NCT02773030) is an ongoing phase 1/2 study evaluating IBER with different treatment combinations in independent cohorts of pts with RRMM; in phase 1, the recommended phase 2 dose of IBER, when given in combination with DEX, was determined at 1.6 mg (Lonial S, et al. Blood 2019;134[suppl 1]:3119). Here we report results from the dose expansion of IBER + DEX in pts with heavily pretreated, triple-class exposed (including ≥ 1 IMiD agent, ≥ 1 proteasome inhibitor [PI], and ≥ 1 anti-CD38 monoclonal antibody [mAb]) RRMM. Methods : Eligible pts had RRMM; had received ≥ 3 prior lines of therapy, including lenalidomide (LEN), pomalidomide (POM), a PI, a glucocorticoid, and an anti-CD38 mAb; had experienced disease progression within 60 days of last myeloma therapy; and were refractory to an IMiD agent, a PI, a glucocorticoid, and an anti-CD38 mAb. Pts with central nervous system involvement were not eligible. Pts who had received prior anti-BCMA therapy were excluded, but included in a supportive cohort for safety and preliminary efficacy assessment. IBER (1.6 mg) was given orally on days (D) 1-21, in combination with DEX (40 mg; 20 mg if > 75 years of age) on D1, 8, 15, and 22 of each 28-day cycle. Thrombo-embolism prophylaxis was mandatory for all pts. Primary objective was to determine efficacy expressed as overall response rate (ORR). Secondary endpoints included additional efficacy and safety assessments. Exploratory endpoints included evaluation of health-related quality of life (HRQoL). Results : As of June 2, 2021, 107 pts had received IBER + DEX. Median age was 64 (44-83) years; median time since initial diagnosis was 6.9 (1.6-24.5) years. Extramedullary plasmacytomas were present in 25.2% of pts; 29.9% of pts had high-risk cytogenetics. Median number of prior regimens was 6 (3-23). All pts were triple-class exposed; prior therapies included autologous stem cell transplantation (78.5%), PIs (100%), IMiD agents (LEN [100%] and POM [100%]), and anti-CD38 mAbs (100%); 99.1% of pts were refractory to last myeloma regimen and 97.2% of pts were triple-class refractory. Median follow-up was 7.69 (0.5-17.5) months, with a median number of 4 (1-17) cycles received and 13 (12.1%) pts continuing treatment. Main reason for discontinuation was progressive disease (69.2%). ORR was 26.2%, with 1 (0.9%) stringent complete response, 8 (7.5%) very good partial responses, and 19 (17.8%) partial responses (Table); the clinical benefit rate (≥ minimal response) was 36.4% and disease control rate (≥ stable disease) was 79.4%. Median duration of response was 7.0 (4.5-11.3) months (Table), median progression-free survival was 3.0 (2.8-3.7) months, and median overall survival was 11.2 (9.0-not reached) months. Similar response rates were observed among a cohort of pts also exposed to BCMA therapies (N = 24, Table). Grade (Gr) 3-4 treatment-emergent adverse events (TEAEs) were reported in 88 (82.2%) pts. Most frequent (≥ 20% pts) hematologic Gr 3-4 TEAEs were neutropenia (44.9%; and 4.7% febrile neutropenia), anemia (28.0%), thrombocytopenia (21.5%), and leukopenia (20.6%). Gr 3-4 infections were reported in 27.1% of pts; Gr 3-4 pneumonia and COVID-19 occurred in 10.3% and 4.7% of pts, respectively. Occurrence of other Gr 3-4 non-hematologic TEAEs was generally low, including gastrointestinal disorders (5.6%), fatigue (2.8%), rash (1.9%). Fifty-six (52.3%) pts and 20 (18.7%) had IBER dose interruptions and reductions due to TEAEs, respectively. Five (4.7%) pts discontinued due to TEAEs. No pt discontinued IBER due to neutropenia. Overall, HRQoL was maintained in these pts. Conclusions : IBER + DEX demonstrated promising efficacy in pts with heavily pretreated, triple-class exposed and refractory RRMM, as well as in pts who had previously received anti-BCMA therapy; this combination was generally well tolerated and TEAEs were manageable with dose reductions and interruptions. These results support the further development of IBER in MM, including phase 3 trials in combination regimens. Figure 1 Figure 1. Disclosures Lonial: Abbvie: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Popat: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Abbvie, Takeda, Janssen, and Celgene: Consultancy; Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Janssen and BMS: Other: travel expenses. Hulin: Sanofi: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; abbvie: Honoraria. Jagannath: Legend Biotech: Consultancy; Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Oriol: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson: Karyopharm: Consultancy, Research Funding; Regeneron: Consultancy; AbbVie: Consultancy; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Protocol Intelligence: Consultancy; Janssen: Consultancy; Secura Bio: Consultancy; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Minnema: Cilag: Consultancy; Janssen: Consultancy; Alnylam: Consultancy; Celgene: Other: Travel expenses; Kite/Gilead: Consultancy; BMS: Consultancy. Badros: J&J: Research Funding; Janssen: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding. Knop: BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy. Stadtmauer: Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Chen: Bristol Myers Squibb: Current Employment. Nguyen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Amin: Bristol Myers Squibb: Current Employment. Kueenburg: Celgene a BMS company: Current Employment. Peluso: Celgene, a Bristol-Myers Squibb Company: Current Employment. van de Donk: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectis: Research Funding; Takeda: Consultancy; Roche: Consultancy; Novartis /bayer/servier: Consultancy.

Background Despite recent advances, new therapies are needed to deepen and extend remissions in early-line relapsed/refractory multiple myeloma (RRMM). Iberdomide (IBER) is a novel, potent oral cereblon E3 ligase modulator (CELMoD®) compound with enhanced tumoricidal and immune-stimulatory effects when compared with IMiD® agents. Preclinically, IBER overcomes IMiD resistance and has synergy with dexamethasone (DEX), daratumumab (DARA), and bortezomib (BORT). In a phase 1/2 trial in patients (pts) with RRMM, IberDd showed efficacy with favorable tolerability, and pharmacodynamic data demonstrated increased NK and T cell proliferation (Lonial S, et al. HemaSphere 2021; 5(S2):49). The EXCALIBER trial was initiated to compare efficacy and safety of IberDd with that of DVd, a globally approved regimen, in pts with early-line RRMM. Methods In this multicenter, open-label, phase 3 study ≈742 pts will be randomized 1:1 to receive IberDd or DVd. Pts will be stratified within each cohort by number of prior lines of therapy (1 vs 2), age (≤70 years vs >70 years), and ISS staging at study entry (I–II vs III). Key eligibility criteria include age (≥18 years), measurable disease treated with 1–2 prior lines of antimyeloma therapy where a partial response or better to ≥1 prior therapy was achieved, and disease progression during or after the last regimen. Prior treatment with anti-CD38 monoclonal antibodies and/or BORT is permitted under stringent conditions. Treatment in the IberDd arm will consist of 28-day (D) cycles (C) with 1.6 mg IBER on D1–21; 1,800 mg subcutaneous (SC) DARA on D1, 8, 15, and 22 of C1–2, D1 and 15 of C3–6, and D1 of ≥C7; and 40 mg oral DEX (20 mg if ≥75 years) on D1, 8, 15, and 22. Treatment in the DVd arm will consist of 21-D cycles for C1–8 and 28-D cycles for ≥C9; 1,800 mg SC DARA on D1, 8, and 15 for C1–3, D1 for C4–8, and D1 for ≥C9; 1.3 mg/m2 SC BORT on D1, 4, 8, and 11 for C1–8; and 20 mg oral DEX (10 mg if ≥75 years) on D1, 2, 4, 5, 8, 9, 11, and 12 for C1–8. Treatment will continue until confirmed progressive disease, unacceptable toxicity, or consent withdrawal. Primary efficacy endpoint is PFS, calculated as the time from randomization to progressive disease, or death. Assuming a decrease in the PFS risk by 25% (HR=0.75) with IberDd, under exponential distribution assumption of PFS (one-sided α=0.025) and adjusted for the 2 interim analyses, 441 PFS events will have 85% power to detect an improvement in treatment effect. Secondary efficacy endpoints include OS, duration of response, time to progression, overall response rate, measurable residual disease, and quality of life. Safety evaluations include treatment-emergent adverse events, laboratory parameters, and vital signs. Two interim analyses are planned for PFS, when ≈134 (30%) and ≈334 (75%) events have been accumulated, to examine futility and superiority, respectively. Enrollment is expected to begin in Q3, 2021. NCT number is pending.

Background CC-220-MM-001 (NCT02773030) is an ongoing phase 1/2 study evaluating the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, and preliminary efficacy of IBER, an oral, novel cereblon E3 ligase modulator (CELMoD®) compound, with different treatment combinations in independent cohorts, in pts with MM. Here we report results from the IBER+DARA+DEX (IberDd), IBER+BORT+DEX (IberVd), and IBER+CFZ+DEX (IberKd) cohorts in RRMM. Methods Eligible pts received ≥2 (IberDd and IberKd cohorts) or ≥1 prior regimens (IberVd cohort), containing lenalidomide or pomalidomide, and a proteasome inhibitor. All pts had progressed ≤60 days from last therapy. Escalating oral doses of IBER were given on day (D)1–21 of each 28-D cycle in the IberDd cohort and in the IberKd cohort with weekly CFZ, and on D1–14 of each 21-D cycle in the IberVd cohort. DEX was given weekly in all 3 cohorts. Results As of April 8, 2021, 43 pts had received IberDd, 25 IberVd, and 9 IberKd. Median age was 67, 64, and 61 years, and median time since diagnosis was 7.35, 7.1, and 6.7 years in the IberDd, IberVd, and IberKd cohorts, respectively. Extramedullary plasmacytomas were present in 7 (16%), 4 (16%), and 2 (22%) pts in the IberDd, IberVd, and IberKd cohorts, respectively. Exposure to prior regimens was heterogeneous; all pts were refractory to their last prior regimen and ≥33% pts in the 3 cohorts were triple-class refractory. IBER doses ranged from 1.0 to 1.6 mg. Median follow-up was 4.17, 4.86, and 5.03 months, 22 (51%), 6 (24%), and 5 (56%) pts continue on treatment, and median cycles received were 4, 6, and 5 with IberDd, IberVd, and IberKd, respectively. Hematologic grade (G) 3–4 treatment-emergent adverse events (TEAEs) of interest included neutropenia (67%), leukopenia (23%), anemia (21%), and febrile neutropenia (5%) with IberDd; neutropenia (28%) and thrombocytopenia (24%) with IberVd; and lymphopenia (44%) and neutropenia (33%) with IberKd. Neutropenia was manageable with G-CSF. Occurrence of non-hematologic TEAEs was low, with very few G3–4 fatigue, rash, and gastrointestinal disorders. The overall response rate was 46% with IberDd, 56% with IberVd, and 50% with IberKd, including a VGPR or better of 24%, 28%, and 38%, respectively. Median time to response was 4.1 (4.0–12.0), 3.6 (3.0–13.1), and 4.1 (4.1–8.1) weeks, in the IberDd, IberVd, and IberKd cohorts, respectively. Median duration of response is 35.7 weeks in the IberVd cohort (not reached in the other cohorts). RP2D was determined at 1.6 mg in the IberDd cohort; dose evaluation continues in the other cohorts. Conclusions In pts with heavily pretreated RRMM, IberDd, IberVd, and IberKd showed a tolerable safety profile and promising efficacy. These results support further development of IBER-based regimens in MM, including the initiation of phase 3 combination studies. Previously published in Lonial S, et al. HemaSphere 2021;5(S2):49.

Lenalidomide, adriamycin, dexamethasone for induction followed by stem-cell transplant in newly diagnosed myeloma

Autologous stem cell transplantation (ASCT) is a standard treatment for eligible multiple myeloma (MM) patients, but many patients will relapse after ASCT and require subsequent therapy. The proteasome inhibitor carfilzomib is approved for relapsed or refractory MM (RRMM). In phase 3 trials, carfilzomib-based regimens (ASPIRE, carfilzomib–lenalidomide–dexamethasone; ENDEAVOR, carfilzomib–dexamethasone) demonstrated superior progression-free survival (PFS) compared with standard therapies for RRMM (ASPIRE: lenalidomide–dexamethasone; ENDEAVOR, bortezomib–dexamethasone). This subgroup analysis of ASPIRE and ENDEAVOR evaluated outcomes according to prior ASCT status. In total, 446 patients in ASPIRE and 538 in ENDEAVOR had prior ASCT. Median PFS was longer for carfilzomib-based regimens vs non-carfilzomib-based regimens for patients with prior ASCT (ASPIRE: 26.3 vs 17.8 months (hazard ratio (HR)=0.68); ENDEAVOR: not estimable vs 10.2 months (HR=0.61)), those with one prior line of therapy that included ASCT (ASPIRE: 29.7 vs 17.8 months (HR=0.70); ENDEAVOR: not estimable vs 11.2 months (HR=0.46)), and those without prior ASCT (ASPIRE: 26.4 vs 16.6 months (HR=0.76); ENDEAVOR: 17.7 vs 8.5 months (HR=0.43)). Overall response rates also favored the carfilzomib-based regimens. No new safety signals were detected. This analysis suggests that carfilzomib-based treatment may lead to improvement in PFS and response rates regardless of prior transplant status. Further evaluation is warranted.

C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM). Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival. ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive. CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted. CA extern

\(^{11}\)C-methionine (MET) has recently emerged as an accurate marker of tumor burden and disease activity in patients with multiple myeloma (MM). This dual-center study aimed at further corroboration of the superiority of MET as positron emission tomography (PET) tracer for staging and re-staging MM, as compared to \(^{18}\)F-2`-deoxy-2`-fluoro-D-glucose (FDG). 78 patients with a history of solitary plasmacytoma (n=4), smoldering MM (SMM, n=5), and symptomatic MM (n=69) underwent both MET- and FDG-PET/computed tomography (CT) at the University Centers of Wurzburg, Germany and Navarra, Spain. Scans were compared on a patient and on a lesion basis. Inter-reader agreement was also evaluated. In 2 patients, tumor biopsies for verification of discordant imaging results were available. MET-PET detected focal lesions (FL) in 59/78 subjects (75.6%), whereas FDG-PET/CT showed lesions in only 47 patients (60.3%; p

Introduction: DARA is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. In the phase 3 ALCYONE study (median follow-up of 40.1 months), DARA in combination with VMP (D-VMP) reduced the risk of disease progression or death by 58% versus VMP alone (median 36.4 vs 19.3 months; HR, 0.42; 95% CI, 0.34-0.51; P Methods: Pts with TIE NDMM were randomized 1:1 to receive up to nine 6-week cycles of VMP (V 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, and 32 of Cycle 1 and Days 1, 8, 22, and 29 of Cycles 2-9; M 9 mg/m2 PO on Days 1-4 of Cycles 1-9; and P 60 mg/m2 PO on Days 1-4 of Cycles 1-9) ± DARA (16 mg/kg intravenously once weekly (QW) for Cycle 1 and Q3W for Cycles 2-9). Pts in the D-VMP group received DARA as maintenance therapy Q4W for Cycles 10+ until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included overall response rate (ORR), rate of ≥CR, rate of ≥very good partial response (VGPR), MRD-negativity rate (10-5), OS, and HRQoL. Outcomes were also examined at the time of best response at the beginning of DARA monotherapy (Cycle 10+) and 1 and 2 years after beginning DARA monotherapy. Results: A total of 706 (D-VMP, n=350; VMP, n=356) pts were randomized. Baseline characteristics were well balanced between groups. After a median follow-up of 40.1 months, D-VMP increased the ORR (90.9% vs 73.9%) and the rates of ≥CR (46% vs 25%), ≥VGPR (73% vs 50%), MRD-negativity (28% vs 7%; all P For patients in the D-VMP group who received DARA monotherapy in Cycle 10+, responses continued to deepen: rates of ≥CR improved from 44% at the beginning of maintenance to 64% and 68% at 1 and 2 years, respectively, after the start of DARA maintenance therapy. As in the full study population, improved PFS and OS were observed with deepening responses. Conclusions: D-VMP induced deep responses in TIE NDMM pts and improved PFS, regardless of response status. Depth of response improved PFS, OS, and time to subsequent therapy and responses continued to deepen for patients receiving DARA maintenance therapy. HRQoL was improved in both treatment groups over the course of the study as clinical response deepened. These findings suggest that the addition of DARA to VMP achieves and maintains deep responses for TIE NDMM pts, leading to better outcomes and HRQoL. Disclosures Rodriguez-Otero: Janssen, BMS: Other: Travel, accommodations, expenses; Janssen, BMS, AbbVie, Sanofi, GSK, Oncopeptides, Kite, Amgen: Consultancy, Honoraria; BMS, Janssen, Amgen: Honoraria; Celgene-BMS: Consultancy, Honoraria; Mundipharma: Research Funding. Boccadoro:Mundipharma: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Martinez-Lopez:Novartis: Consultancy; Incyte: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding. Lucio:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Nagy:MorphoSys AG: Patents & Royalties. Liberati:Onconova: Research Funding; Takeda: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Pfizer: Research Funding; Abbvie: Honoraria, Research Funding; Morphosys: Research Funding; Novartis: Research Funding; Incyte: Honoraria; Oncopeptides: Research Funding; Karyopharm: Research Funding; Verastem: Research Funding; Janssen: Honoraria, Research Funding. Takamatsu:Adaptive Biotechnologies: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Ono pharmaceutical: Honoraria, Research Funding; Janssen Pharmaceutical: Consultancy, Honoraria, Research Funding; SRL: Consultancy, Research Funding. Romejko-Jarosinska:Janssen: Honoraria; Celgene: Honoraria; Gilead: Honoraria, Other: travel expences ; Servier: Honoraria; Sanofi: Honoraria; Roche: Honoraria, Other: travel expences ; Macopharma: Other: travel expences ; Servier: Other: travel expences . Knop:Celgene; Bristol Myers Squibb; Sanofi; Janssen: Honoraria. Forsyth:Amgen: Consultancy; Janssen Pharmaceuticals Australia: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gries:Janssen: Current Employment, Current equity holder in publicly-traded company. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Kudva:Memorial Sloan Kettering Cancer Center: Other: non-paid consultancy; Janssen: Current Employment, Current equity holder in publicly-traded company. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Wroblewski:Susan Wrobleski: Current Employment, Current equity holder in publicly-traded company. Carson:Janssen: Current Employment. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau.

Background: Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. Methods: ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. Findings: 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4–43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46–0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2–82·0) in the D-VMP group and 67·9% (62·6–72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34–0·51]; p

A 63-year-old man with a 1-year course of IgA-λ multiple myeloma (MM) and a history of autologous stem cell transplantation presented with multiple nontender, nodular violaceous skin lesions that were located predominantly on his trunk. Diagnostic workup using F-FDG PET/CT revealed disseminated disease including highly hypermetabolic (sub)cutaneous lesions, consistent with active manifestations of MM. Histopathology confirmed monoclonal, λ-restricted plasma cell infiltrates with a high proliferation index (Ki-67) of about 80%. Cutaneous manifestation of MM is an uncommon observation in clinical practice portending poor prognosis.

This trial evaluated quality of life (QoL) using the EORTC QLQ-C30 and the EORTC QLQ-MY20 instruments in 90 patients with relapsed/refractory multiple myeloma during induction and maintenance therapy with eight cycles of ixazomib-thalidomide-dexamethasone, followed by 12 months of ixazomib maintenance therapy. When patient's baseline QoL was compared with data of the general population, a significant impairment in health-related QoL, physical, role, and social functioning and several other dimensions, as well as more pain and fatigue, was noted. Induction therapy resulted in significant improvement of pain and worsening of neuropathy, with no significant variation of other parameters. During maintenance treatment, scores for most dimensions including health-related QoL, physical functioning and pain, improved, while for neuropathy no improvement was observed. Time to deterioration (≥10 score points) of health-related QoL, physical functioning, pain, and neuropathy was distinctly shorter than time to progression. Health-related QoL and physical functioning at baseline correlated with overall survival.

Objective A post hoc analysis of two phase III trials was carried out to explore the influence of age and treatment factors on the effect of bortezomib consolidation on progression-free survival (PFS) post autologous stem cell transplantation (ASCT). Methods Patients with newly diagnosed multiple myeloma were assigned to one of two trials (ClinicalTrials.gov IDs: NCT00416273, NCT00416208), which were conducted in parallel, based on age (18-60 or 61-75 years, respectively). Following induction and ASCT, patients were randomized 1:1 to four 35-day cycles of bortezomib consolidation (1.6 mg/m2 IV on days 1, 8, 15, 22) or observation only. Results Median PFS with bortezomib consolidation vs observation was 33.6 vs 29.0 months (P = 0.3599) in patients aged 18-60 years (n = 202), and 33.4 vs 26.4 months (P = 0.0073) in patients aged 61-75 years (n = 155), respectively. Bortezomib consolidation post-ASCT appeared to equalize outcomes between older and younger patients who received prior treatment of differing intensity. This suggests that the effect of consolidation may be relative and may depend on the composition and intensity of induction and high-dose therapy. Conclusion Older patients receiving less intensive prior treatment could experience a larger PFS benefit from bortezomib consolidation.

Multiple myeloma (MM) is the second most common hematologic malignancy and occurs similar to cardiovascular diseases (CVD), in the sixth/seventh decade. The aim of this retrospective cohort study was to evaluate the prevalence and prognostic value of cardiovascular risk factors (CVRF) and CVD in 325 patients with MM undergoing autologous peripheral blood stem cell transplantation (PBSCT) at the University Hospital of Wurzburg between 03/2004 and 12/2011. Mean age in the total cohort was 61 years. Among CVRF, prevalence of arterial hypertension was highest (59.7%), followed by overweight (54.2%) and positive smoking history (18.2%). The prevalence of heart failure (3.1%) or coronary heart disease (4.8%) was low. During a median follow-up of 36 months, 18% of the patients died. Hypertension (HR = 1.83, p = 0.048) as well as positive smoking history (HR = 2.13, p = 0.02) were independently associated with increased mortality risk in multivariate analysis. In a subgroup analysis of 100 patients echocardiographic parameters were compared before and after PBSCT. Echocardiography revealed a significant reduction of left atrial diameters (-1.5 mm, p = 0.009) and septum thickness (-1.0 mm, p = 0.001), non-significant reduction of systolic function, and an increase of the prevalence of diastolic dysfunction (+14%; p = 0.01). In this study CVRF, especially hypertension and smoking, are strong predictors of poor survival in patients with MM undergoing autologous PBSCT. Echocardiography before and after treatment shows subtle changes in systolic function but an increase of the prevalence of diastolic dysfunction.

Background: Allogeneic (allo) following autologous (auto) stem-cell transplantation (SCT) has yielded conflicting results in newly diagnosed multiple myeloma (MM). In alloSCT, information is lacking regarding the impact of cytogenetic features except chromosome 13q deletion (del13q). Methods: This phase 3 trial compared tandem autoSCT versus autoSCT followed by reduced-intensity conditioning alloSCT (auto/alloSCT) in del13q MM. The availability/absence of a human leukocyte antigen-matched related or matched unrelated donor (MUD) determined the nature of the second SCT. The primary endpoint was progression-free survival (PFS) in the intent-to-treat population (n=199). Findings: Auto/alloSCT was performed in 126 patients; 74 received MUD allografts. After 91 months' median follow-up (range 2-143 months), median PFS with auto/allo versus tandem autoSCT was 34·5 versus 21.8 months (p=0·003; adjusted hazard ratio 0·55, 95% confidence interval [CI] 0·36-0·84). Median overall survival (OS) was 70.2 versus 71.8 months (p=0.856). Two-year non-relapse mortality (NRM) with auto/allo versus tandem autoSCT was 14·3% versus 4·1% (p=0·008). In patients harbouring both del13q and deletion of chromosome 17p, median PFS and OS were 37·5 and 61·5 months with auto/allo (n=19) versus 6·1 and 23·4 months with tandem autoSCT (n=6) (p=0·0002 and 0·032). Interpretation: Auto/alloSCT significantly extends PFS versus tandem autoSCT in patients with del13q MM. We believe this to be the first MM study demonstrating that MUD alloSCT can be performed with reasonable NRM. Furthermore, our data suggest some survival benefit for first-line alloSCT in high-risk MM. Funding: The trial was sponsored by Wurzburg University, Wurzburg, Germany. Declaration of Interest: MH reports personal fees from Amgen, Celgene, Janssen, Bristol-Myers Squibb, and Takeda. GH reports personal fees from Janssen, Roche, AbbVie, Gilead, Novartis, MorphoSys, and Celgene; and grants from Roche, Pfizer, and Celgene. SM reports non-financial support from EBMT/EHA, IACH, Celgene, Miltenyi, KIADIS, Bellicum, DGHO, Jazz Pharma, and ISCT; and personal fees from Celgene, Miltenyi, KIADIS, Bellicum, and Jazz Pharma. GM reports personal fees from Gilead, Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, and Merck-Serono; and non-financial support from Janssen-Cilag. LK reports honoraria for presentation at “MedIpdate” (OnkoUpdate, IntemistenUpdate, PraxisUpdate) and at “Medizin Aktuell”. Amgen and Celgene are sponsors of the “Biannual International Stem Cell Conference, Tubingen, Germany): Scientific chairman: LK. HE reports grants, personal fees, and other (advisory board) from Janssen, Celgene, Amgen, BristolMyers Squibb, Novartis, and Takeda. All other authors declare no competing interests. Ethical Approval: The trial protocol was approved by the Wurzburg University ethics committee. All patients provided written informed consent prior to trial entry, and all procedures were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Guidelines for Good Clinical Practice.

Background Bone marrow neovascularization is a hallmark of multiple myeloma and progression is associated with a substantial increase in pro-angiogenic factors that promote bone marrow angiogenesis, including vascular endothelial growth factor (VEGF-A) and hepatocyte growth factor (HGF). At present, anti-angiogenic agents are not part of treatment strategies in multiple myeloma, neither alone nor in combination with approved agents. MP0250 is a first-in-class, tri-specific multi-DARPin® drug candidate neutralizing VEGF-A and HGF as well as binding to human serum albumin to increase plasma half-life. This is a report on early safety and efficacy of MP0250 in combination with bortezomib plus dexamethasone (Vd) in RRMM patients that have previously been exposed to proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs). Aims To assess the efficacy and safety of MP0250 in combination with bortezomib and dexamethasone in patients with RRMM (MiRRoR, NCT03136653). Trial Design This trial is recruiting adults ≥18 years of age with RRMM who have progressed after at least two prior treatment regimens including bortezomib and an IMiD. Patients were enrolled to receive iv MP0250 on day 1 + subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8, 11, oral dexamethasone 20 mg on days 1-2, 4-5, 8-9, 11-12 of each 21-day cycle. Patients will receive treatment until there is documented disease progression or unacceptable toxicity. Methods The primary endpoint is efficacy in terms of overall response rate (ORR) per International Myeloma Working Group criteria. Secondary endpoints include safety, immunogenicity, progression-free survival (PFS) and duration of response (DOR). Exploratory endpoints include overall survival, and pharmacokinetics. Exploratory biomarkers for HGF and cMET in bone marrow biopsies are detected by IHC; MM specific markers, circulating HGF and VEGF levels are measured using patient plasma samples. Results As of 01 July 2019, 20 patients (7 ongoing) received a total of 137 doses (1-33 cycles) of MP0250 at the maximum tolerated dose of 8 mg/kg on Day 1 of each 21-day cycle in combination with Vd. Median age was 61 years (46-76), median time since diagnosis was 6.7 years. Median number of prior therapies was 4 (range, 2-9). All 20 patients had prior exposure to IMiDs and PIs and 9 patients received PI-based regimens as their immediate prior line of therapy before start of MP0250 + Vd. Importantly, 6 out of these 9 patients achieved responses ≥ Partial Response (PR). Treatment had been discontinued in 40% of patients due to PD, 15% due to Adverse Event (AE), 5% due to physician's decision and in 1 case at patient's request. The most frequent drug-related grade 3/4 AEs were hypertension in 7/1 patients, thrombocytopenia in 4/1 patients, grade 3 proteinuria in 4 patients and grade 3 anemia in 4 patients. There were no infusion-related reactions. No treatment-related deaths were reported. 20 patients received ≥ 1 dose of MP0250 + Vd and had at least 1 assessment of response and were included in the efficacy analysis. 1 patient (5%) achieved Complete Response, 4 patients achieved Very Good Partial Response (20%) and 3 patients achieved PR (15%) for an ORR of 40%. DOR at cutoff date is 6 months (range, 2-21). Pharmacokinetic data show sustained exposure over multiple cycles with a mean half-life of 11 days (range, 6-17). No indication of ADA-mediated drug clearance was observed. Summary Combining MP250 at 8 mg/kg with standard doses of bortezomib and dexamethasone was generally well tolerated with discontinuation due to AE in only 15% of patients. No unexpected toxicity was observed and AEs consistent with the toxicity profile of the individual agents. Analysis of the preliminary efficacy results showed an encouraging ORR of 40%. Recruitment to this Phase 2 study is ongoing. Disclosures Knop: Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Goldschmidt:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; John-Hopkins University: Research Funding; MSD: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; John-Hopkins University: Research Funding; Chugai: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Molecular Partners: Research Funding; Mundipharma: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dürig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene: Consultancy, Other: Travel or accommodations, Speakers Bureau. Bringhen:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gamberi:Amgen: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Castellano Acosta:Molecular Partners AG: Employment. Lang:Molecular Partners AG: Employment. Lemaillet:Molecular Partners AG: Employment. Sudhir:Molecular Partners AG: Employment.

Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex, VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was &gt, 30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. Results: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR &lt, 45 mL/min decreased from 7.3% at baseline to 1.9% PInd (p &lt, 0.0001). Thirty-seven point one percent of VCD versus 49% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined “renal complete response (CRrenal)” was achieved in 17/25 (68%) pts after VCD, 12/19 (63%) after RAD, and 14/27 (52%) after VRd (p = 0.4747). Conclusions: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment “renal fitness” in the latter group.

Although generally not applied as first-line treatment of multiple myeloma, allogeneic hematopoietic cell transplantation (allo-SCT) can still be chosen as ultimate escalation approach in high-risk patients, preferentially within the framework of clinical trials. In this study, we investigated whether decreasing donor chimerism (DC) is predictive for relapse. In addition, we comprehensively determined the impact of several other disease- and treatment-related factors on outcome. One hundred fifty-five multiple myeloma patients whose DC status was followed serially by the short tandem repeat–based techniques at a single lab were included in this retrospective study. Outcome variables were studied in univariate and multivariable analyses. Available were 2.324 DC samples (median, 12 per patient). Loss of full DC was associated with shorter progression-free survival (PFS) (HR, 1.7; 95% CI, 1.1 to 2.6) but did not impact overall survival. Two-thirds of patients with International Myeloma Working Group–defined relapses still displayed a full DC in peripheral blood or bone marrow. Extramedullary manifestations were observed in 33% of patients, accounting for the discrepancy between DC analysis and the actual disease status. In multivariable analysis, the 2 most relevant variables for an unfavorable PFS were progressive disease before allo-SCT (HR, 3.0; 95% CI, 1.5 to 5.9) and allo-SCT at least the second relapse (HR, 2.8; 95% CI, 1.5 to 4.9), whereas for overall survival progressive disease or partial response before allo-SCT had the strongest negative effects (HR, 4.2; 95% CI, 1.9 to 9, and HR, 2.0; 95% CI, 1.0 to 3.8, respectively). Adverse cytogenetics such as del17p, t(4,14) or amp(1q21) were not associated with shorter survival after allo-SCT. Extensive DC sampling beyond robust engraftment does not appear to provide additional information helpful for disease management in most patients and is challenged by a significant incidence of extramedullary disease. In our series, allo-SCT overcame unfavorable cytogenetics.

The management of multiple myeloma has fundamentally changed over the years and imaging techniques able to match the therapeutic advances are now much needed. Although many patients now achieve complete response after first-line treatment, relapse is common. Therefore, it would be important to improve the initial prognostic stratification and to detect minimal residual disease after treatment. 18F-FDG-PET/CT is a useful imaging tool which has a high prognostic value at baseline evaluation and can effectively differentiate active from inactive lesions during induction treatment or after autologous stem-cell transplantation. In combination with biological data, it improves the prediction of relapse. Other PET tracers may soon enter clinical practice and overcome some of the limitations of 18F-FDG, such as the low sensitivity in detecting early bone marrow infiltration. Excellent results with 11C-Methionine are reported by Lapa and colleagues in this issue of the Journal. 11C-Methionine uptake reflects the increased protein synthesis of malignant plasmocytes and correlates well with bone marrow infiltration. Other promising PET ligands include lipid tracers, such as 11C-Choline or 11C-acetate, and some peptide tracers, such as 68Ga-Pentixafor, that targets CXCR4 (chemokine receptor-4), which is often expressed with high density by myeloma cells. Malignant plasma cells are radiosensitive and thus potentially amenable to systemic radionuclide therapy. Indeed, excellent preclinical results were obtained with radioimmunotherapy targeting CD38. Also, preliminary clinical results with peptides targeting CXCR4 (e.g. 177Lu- or 90Y-Pentixather) are encouraging. Multiple myeloma may represent a renewal of the already strong partnership between hematologists and nuclear medicine physicians.

8521 Background: High-dose chemotherapy (HDT) followed by autologous stem cell transplant (SCT) remains a standard of care in patients (pts) with newly diagnosed (ND) multiple myeloma (MM). While lenalidomide (R) maintenance is acknowledged to improve outcomes, intensified consolidation (such as tandem-SCT) has yielded conflicting results. Allogeneic (allo) SCT holds the promise of curative potential at the cost of higher treatment-related mortality (TRM). In a previous phase 2 study, we showed a very low TRM rate (6.1%) and feasibility of 12 months (mos) of R maintenance (maint), with auto/allo SCT after R/adriamycin/dexamethasone (RAD). This prompted us to compare, on a randomized rather than a “biological assignment” basis, a second auto- versus (vs) an allo-SCT in pts with an unfavorable prognosis. Methods: The current protocol (DSMM XIV, NCT01685814) was set up according to a double 2x2-factorial design. Post-induction (PInd) CR rate was the efficacy endpoint for the comparison of RAD vs bortezomib (V)/RD (VRD; 3 cycles each). If pts had achieved >VGPR to HDT, a second randomization (2ndR) compared immediate R maint (arm A2) with a second auto-SCT (B2). In case of < VGPR, pts were randomized between a second auto- (C2) and allo-SCT (D2). Planned R maint. duration was 36 mos, except after allo (12 mos). Results: Between 05/2012-06/2016, 476 pts were randomized and 469 received at least one dose of study drug. Pts’ median age was 55 (range, 32–65) years. 11.3% of pts had FISH del17p; 11.6% had t(4;14); and 4.4% had t(14;16). PInd CR rate was 11.8% (90% CI, 7.9%-16.3%) with RAD and 13.0% (90% CI, 8.9-18.0) with VRD (P = .697). 382 pts underwent R2 with 279 pts. (73%) in >VGPR and 103 (27%) in < VGPR, respectively. Median duration of R maint (N = 298) was 21.2 mos for A2, 23.1 mos for B2, 27.4 mos for C2, and 11.0 mos. for D2. At a median follow-up of 40.2 (0.5-87.0) months, median PFS from first randomization with RAD was 41.7 (95% CI, 35.4-48.5) mos vs. 53.7 (95% CI, 46.2-63.1) mos with VRD (P = .0439). Median PFS from 2ndR was 38.7 (95% CI, 30.3-47.3) mos for the 181 RAD vs. 50.7 (95% CI, 44.4-64.9) mos for the 201 VRD pts (P = .0126). Median overall survival (OS) cannot be estimated. With 47 deceased RAD vs 36 VRD pts, HR was .671 (95% CI, .435-1.037; P = .0703). Conclusions: In this study, median PFS benefit was 12 mos in favor of VRD vs. RAD despite comparable PInd CR. We show for the first time a len-PI to be superior to a len-chemo triplet, confirmed with positive OS trends. 3-year PFS for all consolidation arms will be presented. Clinical trial information: NCT01685814 .

This study aimed to explore the value of cardiac biomarker [serum high sensitive troponin T (hs-TNT) and N-terminal pro-brain natriuretic peptide (NT-proBNP)] measurement in the differential diagnosis of infiltrative cardiomyopathy patients [Friedreich's ataxia (FA), Fabry disease (FD) and light-chain (AL) cardiac amyloidosis (CA)] with preserved left ventricular (LV) systolic function.Between 2012 and 2014, all consecutive patients presenting at our center with infiltrative cardiomyopathy and concomitant symmetrical LV hypertrophy as well as preserved LV systolic function were included in this study. Serum hs-TNT and NT-proBNP, morphologic and functional features derived from echocardiography and cardiac magnetic resonance imaging (cMRI) examinations were compared among these patients.A total of 57 patients (FA 20, FD 23 and CA 14) were included. Hs-TNT and NT-proBNP levels were significantly higher in the CA group [median: hs-TNT 98 pg/mL, NT-proBNP 4,110 pg/mL] than in the FA group [hs-TNT 14 pg/mL, NT-proBNP 40 pg/mL] and FD group [hs-TNT 18 pg/mL, NT-proBNP 131 pg/mL, both P0.001]. There was a negative correlation between NT-proBNP and estimated glomerular filtration rate (eGFR) in CA patients (r=-0.72, P=0.012). Both hs-TNT60 pg/mL (sensitivity 0.79, specificity 0.93) and NT-proBNP1,000 pg/mL (sensitivity 0.91, specificity 0.93) excellently differentiated CA from FA and FD.Increased hs-TNT and NT-proBNP levels are suggestive of CA diagnosis among patients with infiltrative cardiomyopathy and preserved LV ejection fraction.

Based on ELOQUENT-2, combination therapy with the monoclonal antibody elotuzumab was approved for relapsed/refractory multiple myeloma in the US and Europe. However, outside clinical trials, the optimal integration of elotuzumab into the sequence of treatment lines remains to be determined. Therefore, we analyzed safety and efficacy of elotuzumab/immunomodulatory drug combinations in a real-life cohort of 33 patients from our institution. The most frequent grade 3/4 adverse event was lymphopenia which did not increase the incidence of viral reactivations. After a median of four prior treatment lines, an overall response rate of 60% and a median progression-free survival (PFS) of 8 months were observed. The presence of cytogenetic high-risk status had no impact on PFS while low disease burden and high numbers of natural killer (NK)-cells at treatment initiation were associated with longer PFS. We observed an extramedullary relapse in three patients, associated with reduced expression of the elotuzumab target antigen SLAMF7 on extramedullary myeloma cells in one patient. Thus, biomarkers like disease burden, NK-cell count and SLAMF7 expression on myeloma cells may help to define myeloma patients with high likelihood to respond to elotuzumab treatment. Prospective trials investigating these biomarkers in larger patient cohorts are highly warranted.

Background Carfilzomib, the second-generation proteasome inhibitor, is still awaiting approval for the treatment of multiple myeloma in Europe. Results from clinical trials have demonstrated favorable efficacy in advanced disease but have opened an ongoing debate on cardiac complications related to carfilzomib treatment. ‘Real-life’ data are scarce. Methods/Patients At our institution, 22 patients were registered within the European Carfilzomib Access Program for treatment with carfilzomib, dexamethasone, and a third combination partner depending on patient characteristics and prior treatment. Patients had received a median of six previous lines of therapy, and most were refractory to bortezomib (77%) and immunomodulatory drugs (95%). Results Overall response rate was 65% with a median progression-free survival of 6.0 months and a median duration of response of 6.8 months. Median overall survival was 14.9 months. Grade 3/4 adverse events (AEs) occurred in 50% of patients with 23% experiencing left ventricular failure. The risk of cardiac AEs was markedly increased after previous radiotherapy of the thoracic spine and concomitant administration of doxorubicin. Conclusion Carfilzomib-based treatment is efficient in advanced multiple myeloma. In our ‘real-life’ patients, we found considerable cardiotoxic effects in some cases, indicating a need for careful patient selection and close monitoring of the at-risk population.

Relative apical sparing of longitudinal systolic strain (LSsys) with preserved LSsys at apical and significantly reduced LSsys at mid/basal segments is a typical echocardiographic feature in AL amyloidosis patients with cardiac involvement. The present study aims to evaluate the change of this typical feature over time by serial echocardiography and its impact on outcome in AL amyloidosis patients with cardiac involvement. Echocardiography was performed in 24 consecutive patients with biopsy-proven AL amyloidosis (mean age 64 ± 9 years; 50% male) at baseline and during a median of 257 (quartiles 103-651) days follow-up. Global and segmental LSsys were assessed by two-dimensional speckle-tracking-imaging in septal and lateral segments of the left ventricle (LV) from the apical 4-chamber view. Sixteen (67%) patients died during a median follow-up of 487 days (quartiles 223-872). LV global and segmental LSsys remained unchanged over time in survivors (all P > 0.05), while LV global, septal-apical and lateral-apical LSsys significantly decreased in non-survivors. A decrease in lateral-apical LSsys > 3.0% independently predicted a fivefold increased all-cause mortality risk after adjustment for age, gender, NYHA class, and treatment strategies. Further, baseline serum NT-proBNP, serum albumin decrease during follow-up, baseline septal apical-to-basal LSsys ratio and lateral-apical LSsys decrease during follow-up remained independently predictive of increased all-cause mortality risk. Serial monitoring of serological and echocardiographic parameters is valuable to predict outcome in AL amyloidosis patients with cardiac involvement. The best follow-up parameter to predict risk for imminent death is a decrease of longitudinal systolic strain at the lateral apical segment.

68Ga-pentixafor is a promising PET tracer for imaging the expression of the human chemokine receptor 4 (CXCR4) in vivo. The whole-body distribution and radiation dosimetry of 68Ga-pentixafor were evaluated. Methods: Five multiple-myeloma patients were injected intravenously with 90–158 MBq of 68Ga-pentixafor (mean ± SD, 134 ± 25 MBq), and a series of 3 rapid multiple-bed-position whole-body scans were acquired immediately afterward. Subsequently, 4 static whole-body scans followed at 30 min, 1 h, 2 h, and 4 h after administration of the radiopharmaceutical. Venous blood samples were obtained. Time-integrated activity coefficients were determined from multiexponential regression of organ region-of-interest data normalized to the administered activity, for example, the time-dependent percentages of the injected activity per organ. Mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM. Results: The effective dose based on 150 MBq of 68Ga-pentixafor was 2.3 mSv. The highest organ-absorbed doses (for 150 MBq injected) were found in the urinary bladder wall (12.2 mGy), spleen (8.1 mGy), kidneys (5.3 mGy), and heart wall (4.0 mGy). Other organ mean absorbed doses were as follows: 2.7 mGy, liver; 2.1 mGy, red marrow; 1.7 mGy, testes; and 1.9 mGy, ovaries. Conclusion:68Ga-pentixafor exhibits a favorable dosimetry, delivering absorbed doses to organs that are lower than those delivered by 18F-FDG– or 68Ga-labeled somatostatin receptor ligands.

The primary objective of this phase 1 study was to evaluate the safety and tolerability of the anti-glucose regulated protein 78 monoclonal immunoglobulin M antibody PAT-SM6 in subjects with relapsed or refractory multiple myeloma. Twelve heavily pretreated patients received four intravenous infusions of PAT-SM6 at doses of 0.3, 1, 3, and 6 mg/kg within 2 weeks. Efficacy, pharmacokinetics and immunogenicity were followed up until the end of the trial (day 36). In addition, immune cell patterns in peripheral blood were assessed by flow cytometry and glucose regulated protein 78 expression status was evaluated in bone marrow specimens by immunohistochemistry and flow cytometry at screening. All doses administered were found to be safe and well tolerated; the maximum tolerated dose was not reached. The most common treatment emergent adverse event was leukopenia (grades 1 and 2) in eight out of the 12 multiple myeloma patients. Pharmacokinetic analysis demonstrated dose-proportional increases in drug serum concentration. The terminal half-life ranged from 5.86 to 8.41 h, the apparent volume of distribution ranged from 101 to 150 mL/kg, and clearance ranged from 8.11 to 16.1 mL/h/kg. All patients showed glucose regulated protein 78 surface expression on multiple myeloma cells. Four out of the 12 patients (33.3 %) had stable disease, according to the International Myeloma Working Group criteria, after PAT-SM6 treatment across the doses 1, 3 and 6 mg/kg. In summary, single-agent PAT-SM6 was well tolerated with modest clinical activity in relapsed or refractory multiple myeloma. Further trials exploring the combination of PAT-SM6 with existing myeloma therapies are planned. Trial registration: clinicaltrials.gov identifier: NCT01727778