Key Points• MRD monitoring is one of the most relevant prognostic factors in elderly MM patients, irrespective of age or cytogenetic risk.• Second-generation MFC immune profiling concomitant to MRD monitoring also helped to identify patients with different outcomes.The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible patients than in elderly patients. Because an optimal balance between treatment efficacy and toxicity is of utmost importance in patients with elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used second-generation 8-color multiparameter-flow cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study. The transition from first-to second-generation MFC resulted in increased sensitivity and allowed us to identify 3 patient groups according to MRD levels: MRD negative (<10 25; n 5 54, 34%), MRD positive (between <10 24and ‡10 25 ; n 5 20, 12%), and MRD positive ( ‡10 24 ; n 5 88, 54%). MRD status was an independent prognostic factor for time to progression (TTP) (hazard ratio [HR], 2.7; P 5 .007) and overall survival (OS) (HR, 3.1; P 5 .04), with significant benefit for MRDnegative patients (median TTP not reached, 70% OS at 3 years), and similar poorer outcomes for cases with MRD levels between <10 24 and ‡10 25 vs ‡10 24 (both with a median TTP of 15 months; 63% and 55% OS at 3 years, respectively). Furthermore, MRD negativity significantly improved TTP of patients >75 years (HR, 4.8; P < .001), as well as those with high-risk cytogenetics (HR, 12.6; P 5 .01). Using second-generation MFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate, and favorable outcomes (25%, 61%, and 100% OS at 3 years, respectively; P 5 .01), the later patients being characterized by an increased compartment of mature B cells. Our results show that similarly to transplant candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM patients, irrespectively of age or cytogenetic risk. This trial was registered at www.clinicaltrials.gov as #NCT01237249. (Blood. 2016;127(25):3165-3174)

Key Points• The sequential and alternating administration of VMP and Rd have equal efficacy and toxicity.• The greatest benefit of this total therapy approach was observed for patients aged 65 to 75 years.Bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus low-dose dexamethasone (Rd) are 2 standards of care for elderly untreated multiple myeloma (MM) patients. We planned to use VMP and Rd for 18 cycles in a sequential or alternating scheme. Patients (233) with untreated MM, >65 years, were randomized to receive 9 cycles of VMP followed by 9 cycles of Rd (sequential scheme; n 5 118) vs 1 cycle of VMP followed by 1 cycle of Rd, and so on, up to 18 cycles (alternating scheme; n 5 115). VMP consisted of one 6-week cycle of bortezomib using a biweekly schedule, followed by eight 5-week cycles of once-weekly VMP. Rd included nine 4-week cycles of Rd. The primary end points were 18-month progression free survival (PFS) and safety profile of both schemes. The 18-month PFS was 74% and 80% in the sequential and alternating arms, respectively (P 5 .21). The sequential and alternating groups exhibited similar hematologic and nonhematologic toxicity. Both arms yielded similar complete response rate (42% and 40%), median PFS (32 months vs 34 months, P 5 .65), and 3-year overall survival (72% vs 74%, P 5 .63). The benefit of both schemes was remarkable in patients aged 65 to 75 years. In addition, achieving complete and immunophenotypic response was associated with better outcome. The present approach, based on VMP and Rd, is associated with high efficacy and acceptable toxicity profile with no differences between the sequential and alternating regimens. This trial was registered at www.clinicaltrials.gov as #NCT00443235. (Blood. 2016;127(4):420-425) IntroductionMultiple myeloma (MM) is the second most frequent hematologic disease. Two-thirds of newly diagnosed patients are older than 65 years. 1Treatment options for this patient population have previously been limited to alkylators, but new up-front combinations based on novel drugs, with or without alkylating agents, have significantly improved outcomes.2 Findings from 6 randomized trials showed that melphalan, prednisone, and thalidomide (MPT) was better than melphalan plus prednisone in terms of response rate and progression-free survival (PFS), with increased overall survival (OS) reported in 3 out of 5 trials. To date, MPT has been considered a standard of care.3 Bortezomib plus melphalan and prednisone (VMP) is another standard of care for elderly MM patients based on the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial, in which VMP proved to be superior to melphalan and prednisone with an OS 4 benefit of 13 months. Moreover, bortezomib was subsequently optimized through weekly administration, which significantly improved tolerability but had no impact on the efficacy; this VMP "lite" is widely used in clinical practice.5 Concerning lenalidomide, the FIRST (Frontline Investigation of Lenalidomide plus dexamethasone vs Standard ...

Introduction: Carfilzomib dosed at 56 mg/m2 twice a week in combination with dexamethasone (Kd) is a standard of care for RRMM after 1-3 prior lines (PL) based on the ENDEAVOR study. Later, the ARROW study showed Kd dosed at 70 mg/m2 weekly to be superior to Kd dosed at 27 mg/m2 twice a week on RRMM patients (pts) after 2-3 PL. On the other side, Cyclophosphamide is an alkylating agent that has been widely combined with proteasome inhibitors and immunomodulatory drugs in MM, improving their efficacy with a good safety profile. In this phase 2 randomized study, we have compared Kd plus cyclophosphamide (KCyd) with Kd in RRMM after 1-3PL, both with K dosed weekly at 70 mg/m2. Patients and methods: RRMM after 1-3 PL of therapy were included in the trial. Consistently with the ENDEAVOR population, previous therapy with proteasome inhibitors was allowed but refractory patients were excluded. Pts were randomized 1:1 to receive K at a dose of 70 mg/m2 iv on days 1, 8 and 15 plus dexamethasone at a dose of 20 mg PO the day on and the day after K plus/minus KCyd at a dose of 300 mg/m2 IV on days 1, 8 and 15 of each 28 days-cycle, as continuous treatment until progressive disease or unacceptable toxicity. The primary endpoint was PFS and key secondary endpoints included response rates, safety profile, and OS. Results: Between January 2018 and February 2020, 198 RRMM pts were included. 97 pts were randomized to KCyd and 101 to Kd. The baseline characteristics of the patients were well balanced between both groups. The median age was 70 years, and 70% and 28% of pts were older than 65 and 75. The median number of PL was one; 61% of pts had received 1 prior line. 94% and 92% of patients had been exposed to bortezomib in the KCyd and Kd and all of them were sensitive. 72% and 67% of patients had been exposed to IMiD's and 51% and 55% of them were IMiD's-refractory in the KCyd and Kd. Only 4 and 6 patients in KCyd and Kd, had received anti-CD38 antibodies being all refractory. After a median f/u of 15.6 months, median PFS was 20.7 m and 15.2 m in KCyd and Kd (p=0.2). In pts after 1PL, median PFS has not been reached in any arm (p=0.4) and in patients after 2-3PL, KCyd resulted in a median PFS of 20.7 vs 11m for Kd (p=0.4). Of note, in the IMiD-refractory population, the addition of Cy to Kd resulted in a significant benefit in terms of PFS: 26.2 months vs 7.7 months in the Kd arm (p=0.01). OS is immature with 23 and 25 events so far in KCyd and Kd, respectively. The ORR was 78% for KCyd and 73% for Kd: 20% of patients in both arms achieved at least complete response, 33% and 28% very good partial response, respectively, and 25% partial response in both arms. The MRD-ve rate was 4% and 5%. As far as toxicity is concerned, neutropenia was the only hematological adverse event more frequently reported in KCyd compared with Kd, of any grade (24% vs 11%) and grade 3-4 (13% vs 7%). This did not translate into more infections and the rate was comparable in both arms (5% G3-4 in both arms). Thrombocytopenia of any grade and grade 3-4 occurred in 14%/1% and 18%/10% in KCyd/Kd. Cardiovascular events of any grade occurred in 22% and 30% of patients in KCyd and Kd. Nine pts in KCyd developed G3-4 cardiovascular events, these included atrial fibrillation (1pt), cardiac failure (2 pts), myocardial infarct (2 pts), and hypertension (4 pts). In the Kd arm, 11 patients developed G3-4 cardiovascular events and consisted of hypertension in most of them (9 pts). Conclusion: Cyclophosphamide added to Kd 70 mg/m2 weekly in RRMM pts after 1-3 PL prolonged the PFS as compared to Kd particularly in the lenalidomide-refractory population. The administration of K at a dose of 70 mg/m2 weekly was safe and more convenient and overall, the toxicity profile was manageable in both arms. Disclosures Mateos: Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; PharmaMar-Zeltia: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Takeda: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ocio:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Asofarma: Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria; GSK: Consultancy; MDS: Honoraria; Secura-Bio: Consultancy; Oncopeptides: Consultancy. Sureda Balari:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; BMS: Speakers Bureau; Incyte: Consultancy; Celgene: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria. Oriol:Celgene/Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Rosinol Dachs:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Blade Creixenti:Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Infections remain a common complication in patients with multiple myeloma (MM) and are associated with morbidity and mortality. A risk score to predict the probability of early severe infection could help to identify the patients that would benefit from preventive measures. We undertook a post hoc analysis of infections in four clinical trials from the Spanish Myeloma Group, involving a total of 1347 patients (847 transplant candidates). Regarding the GEM2010 > 65 trial, antibiotic prophylaxis was mandatory, so we excluded it from the final analysis. The incidence of severe infection episodes within the first 6 months was 13.8%, and majority of the patients experiencing the first episode before 4 months (11.1%). 1.2% of patients died because of infections within the first 6 months (1% before 4 months). Variables associated with increased risk of severe infection in the first 4 months included serum albumin ≤30 g/L, ECOG > 1, male sex, and non-IgA type MM. A simple risk score with these variables facilitated the identification of three risk groups with different probabilities of severe infection within the first 4 months: low-risk (score 0–2) 8.2%; intermediate-risk (score 3) 19.2%; and high-risk (score 4) 28.3%. Patients with intermediate/high risk could be candidates for prophylactic antibiotic therapies.

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