Abstract: Lenalidomide is an immunomodulatory drug that is active in newly diagnosed as well as relapsed multiple myeloma (MM). The goal of this study is to describe patients with newly diagnosed MM remaining on lenalidomide for more than 3 years (long term responders) as well as patients that after discontinuing lenalidomide were able to maintain disease control while only on observation (LenO group). Methods We retrospectively reviewed 283 patients with newly diagnosed MM that were treated with lenalidomide between January 2003 and January 2011. We excluded patients that underwent early autologous stem cell transplant (n=102) or had less than 3 years of follow-up (n=6), leaving 175 patients for the current analysis. Results Long term responders Thirty-three patients (19%) received lenalidomide for more than 3 years. When compared to patients receiving lenalidomide for less than 3 years, at baseline, long term responders were more likely to have standard risk disease (64% versus 44%, p=0.03) and less likely to have high risk disease (18% versus 4%, p=0.04). They were more likely to have achieved a deeper response (VGPR versus PR, p 〈 0.001) and had a longer median time to best response (6 versus 4 months, p 〈 0.001). When considering the 12 patients who received lenalidomide for more than 5 years, this group was more likely to have achieved a deeper response (CR versus PR, p 〈 0.0001) and had a longer median time to achieving best response (9 versus 4 months, p 〈 0.0001) than those 163 patients who remained on lenalidomide for fewer than 5 years. Observation group Thirty-three patients (19%) discontinued lenalidomide for reasons other than progression and were observed without receiving further treatment (LenO group). Prior to moving to observation, five patients had received lenalidomide for more than three years. Indications for stopping in the LenO group included: prolonged disease stability (n= 20); and toxicity (n=13). The only differences in baseline characteristics between the LenO group and patients that were not observed off any treatment was depth of response, with 61% (n=20) of LenO in VGPR or better versus 23% (n=23) in the remainder, p=0.0003. Median PFS from the time of discontinuing lenalidomide was significantly longer in those patients who took lenalidomide for more than 1 year (n=24) when compared to patients taking it for less than one year (n=9) (median PFS off therapy was 38.5 months versus, 14.9 months log rank 0.08; Wilcoxon p 〈 0.05), figure 1a; PFS for those treated for 1-2 years (n=11) as compared to 2 years or greater (n= 13) were comparable to each other (data not shown). Among those taking lenalidomide for at least a year, PFS from time of discontinuing lenalidomide was superior in patients who had achieved a VGPR/CR (n=20) as compared to those who achieved only a PR (n=13) (Median 48.4 months versus 14.8 months, log-rank p 〈 0.05; Wilcoxon p=0.01), figure 1b. Conclusion Approximately one out of five patients with newly diagnosed MM can achieve responses lasting more than three years while on treatment with lenalidomide. Patients with standard risk FISH and those achieving at least VGPR are more likely be long-term responders. Furthermore, long-term responders were more likely to be slow responders. We also demonstrate that suspension of lenalidomide therapy after 1 year among those patients achieving a VGPR or better can result in long-term disease control and can be considered as a therapeutic strategy. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Gertz:Celgene: Honoraria. Lacy:Celgene: Honoraria. Dispenzieri:Celgene: Research dollars Other.

Abstract: Introduction Cyclophosphamide, bortezomib, and dexamethasone (CyBor-D) is considered a standard induction regimen for transplant eligible patients with newly diagnosed multiple myeloma (MM) based primarily on phase 2 data. It has not been directly compared to bortezomib and dexamethasone (Bor-Dex) alone. Therefore, we sought to compare the efficacy CyBor-D and Bor-Dex induction in transplant eligible patients treated at a tertiary care center. Methods A retrospective observational study was performed from a single tertiary care center between January 1, 2008 and April 30, 2016. All transplant eligible patients with MM who received induction chemotherapy with CyBor-D or Bor-Dex and were included. The primary outcome was progression free survival (PFS). Secondary outcomes were response to induction, toxicity, stem cell collection yield and failures, and response to autologous stem cell transplant (autoSCT). Continuous variables were reported as median and compared using Mann-Whitney test. Categorical variables were compared using Pearson's chi-square test. PFS was estimated with Kaplan-Meier. Results One hundred and fifty nine patients were included, 82 (51.6%) treated with CyBor-D and 77 (48.4%) treated with Bor-Dex. The relative proportion of patients treated with CyBor-D increased annually: 1/23 (4%) in 2012, 20/30 (66%) in 2013, 33/34 (97%) in 2014, and 28/28 (100%) in 2015. Patient demographics and disease characteristics were similar between all groups for sex, subtype of MM and stage by the International Staging System. The Bor-Dex group was significantly younger than the CyBor-D group (mean age 56 vs. 61 years, p 〈 0.001). Median number of cycles was the same for both groups (4, p= 0.73); however, the Bor-Dex group was more likely to have treatment held, reduced or discontinued than the CyBor-D group (19.7% vs. 6.4%, p=0.017). The overall response rate (ORR) was similar between both groups, 88.5% for CyBor-D and 82.7% for Bor-Dex (p=0.36), but patients treated with CyBor-D had deeper responses to induction with 57.5% achieving ≥VGPR whereas 38.7% in the Bor-Dex group achieved ≥ VGPR (p=0.02). The stem cell mobilization regimen was predominantly Cyclophosphamide and GCSF for both groups. Plerixafor use was more common in the CyBor-D cohort, 14.6% vs. 1.3% in Bor-Dex (p=0.002), and there were more collection failures in the CyBor-D group compared to Bor-Dex (6.1% vs. 0%, p=0.03). The median number of CD34 cells collected was higher in the Bor-Dex compared to CyBor-D (9.88 x 106 cells/kg vs. 7.66 x 106cells/kg, p=0.004), however median collection days was similar (1 in both groups, p=0.175). The mobilization toxicity was similar between both groups with a trend towards increased hospitalizations in the CyBor-D group (26% vs. 14%, p=0.075). The conditioning regimen was the same in both groups, predominantly Melphalan 200 mg/m2. Day 100 response was similar, with 76.7% of CyBor-D patients achieving ≥ VGPR vs. 71.21% for Bor-Dex (p= 0.25). The median PFS was 36.5 months in the Bor-Dex group and not yet reached in the CyBor-D group, due to shorter follow up time. However, the percentage of patients free from relapse was similar at 1 year (92.8% for CyBorD vs 98.7% for Bor-Dex) and at 2 years (69.4% for CyBor-D vs 72.9% for Bor-Dex). Conclusions CyBor-D and Bor-Dex appear to have similar overall efficacy for newly diagnosed transplant eligible patients with multiple myeloma in our cohort. CyBor-D was associated with deeper response to induction, but after autoSCT there was no difference in the depth of response between the two cohorts. Longer follow up is required to detect if the deeper response to induction with CyBor-D leads to differences in PFS. When used with Cyclophosphamide-GCSF mobilization, CyBor-D appears to result in more collection failures and a trend towards increased hospitalizations. Further prospective studies are required to examine this relationship. Disclosures Kew: Celgene: Honoraria. McCurdy:Celgene: Honoraria.

Abstract: Background: Belantamab mafodotin (belamaf) is a first-in-class antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA) that has shown clinically meaningful activity as a single agent in relapse/refractory multiple myeloma (RRMM). Pre-clinical studies demonstrate that the immune mediated anti-myeloma activities of belamaf are enhanced by immunomodulatory drugs (IMiDs) providing the rationale for combining Belamaf with pomalidomide (POM). The Algonquin study is an ongoing Phase 1/2 trial designed to evaluate the recommended Part 2 dose (RP2D), safety, and preliminary efficacy of belamaf in combination with POM and dexamethasone (DEX) (B-Pd) in patients (pts) with RRMM. The initial data from the dose-escalation phase of the study identified 2.5 mg/kg in combination with standard dosing of POM/DEX as the maximum tolerated dose (MTD) (Trudel et al. ASH 2020). Here we report updated safety and efficacy data and additional dosing cohorts used to identify the RP2D. Methods: Eligibility required & gt; 1 prior lines of treatment (LoT), lenalidomide (LEN) and proteasome inhibitor (PI) exposure and refractoriness to the last LoT. POM was administered at 4 mg days 21/28 days, DEX 40 mg (20 mg age & gt; 75 years) weekly in conjunction with IV belamaf SINGLE (1.92 or 2.5 mg/kg) Q4W, 2.5 mg/kg LOADING dose followed by 1.92 mg/kg Q4W from cycle 2+, 2.5 mg/kg dosed Q8W (BIMONTHLY) or Q12W (TRIMONTHLY), or belamaf SPLIT (2.5 or 3.4 mg/kg), split equally on days 1 and 8 Q4W. Dose escalation was accomplished using a standard 3+3 dose escalation design. Responses were assessed by International Myeloma Working Group (IMWG) criteria and adverse events (AEs) were graded by CTCAE criteria except for corneal findings which were also graded by the pre-specified keratopathy and visual acuity (KVA) scale. Up to 12 pts could be enrolled at dose levels not exceeding the MTD to inform the R2PD. Results: At cut-off (July 15, 2021), 60 pts had been enrolled in the following dose levels and schedules: 1.92 SINGLE (n=12), 2.5 SINGLE (n=7), 2.5 LOADING (n=5), 2.5 BIMONTHLY (n=12), 2.5 TRIMONTHLY (n=11), 2.5 SPLIT (n=8) and 3.4 SPLIT (n=5). The median age was 65 years (range 36-81) and median prior LoT was 3 (1-5). Prior therapies (exposed/refractory) included stem cell transplant (57%), PI (100%/82%), LEN (100%/90%) and daratumumab (DARA) (58%/100%). 76% were refractory to LEN and a PI and 48% to LEN, a PI and DARA. The most frequent AEs regardless of attribution were keratopathy (an ophthalmologic finding) (96.9%), blurred vision (87.5%), fatigue (59.4%), neutropenia (62.5%), thrombocytopenia (50%), fever (46.9%), diarrhea (34.4%), constipation (34.4%), and dry eye (28.1%). Grade 3/4 AEs reported in & gt;20% of pts across all cohorts, were keratopathy (56.7%), neutropenia (38.3%), thrombocytopenia (35%) and blurred vision (30%). Corneal safety profile by dosing cohort as well as dose reductions and dose delays used to manage corneal AEs are listed in Table 1. Two patients discontinued treatment due to AEs (one G4 decreased visual acuity and one G3 elevated ALT) while no grade 5 AEs were observed. At cut-off, 54/60 patients were evaluable for response. Across all cohorts the ORR was 88.9% (11 PR, 24 VGPR, and 13 sCR). Responses by dosing cohort are summarized in Table 1. At a median follow up of 8.6 months (range 0.9-27.9) the median PFS was 24.2 months (95% CI: 14.1, NYR). Conclusions: The safety profile of B-Pd is consistent with that observed for Pd or Belamaf individually. All dosing cohorts demonstrate deep and durable responses however the 2.5 mg/kg dose appears to have better efficacy. The 2.5 BIMONTHLY dosing schedule has been selected for the Part 2 cohort expansion based on optimized safety and efficacy. Figure 1 Figure 1. Disclosures Trudel: Genentech: Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Honoraria; Roche: Consultancy; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. McCurdy: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi: Honoraria; Celgene: Consultancy, Honoraria. Sutherland: Amgen: Consultancy; Janssen: Consultancy, Research Funding; GSK: Research Funding; Karyopharm: Research Funding; Celgene: Consultancy. Louzada: Celgene: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Venner: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; BMS: Research Funding; GSK: Research Funding; Sanofi: Research Funding. Mian: Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Kotb: Pfizer: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company; Takeda: Honoraria; Sanofi: Honoraria, Research Funding; Celgene: Honoraria; Merck: Honoraria, Research Funding; Janssen: Honoraria; Amgen: Honoraria; Akcea: Honoraria; BMS: Honoraria. Othman: Sanofi: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Roche: Honoraria. Camacho: Janssen: Consultancy; AbbVie: Consultancy; Bausch-Health: Consultancy. Reece: Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Honoraria; Amgen: Consultancy, Honoraria; Millennium: Research Funding; BMS: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria. White: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; Forus: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Karyopharm Therapeutics Inc.: Consultancy, Honoraria. OffLabel Disclosure: belantamab and pomalidomide in combination

Abstract: Background: Carfilzomib is effective in the treatment of relapsed and refractory multiple myeloma (RRMM). Questions remain regarding optimal dosing strategies and combinations. The MCRN-003/MYX.1 single arm phase II clinical trial of high-dose once weekly carfilzomib in combination with dexamethasone and cyclophosphamide (wCCD) in RRMM met its primary endpoint with an overall response rate (ORR) ≥ 80% after 4 treatment cycles [Venner, Blood 2018 132:1984]. This abstract focuses on previously unreported protocol specified secondary and exploratory endpoints including progression free (PFS) and overall survival (OS). Methods: This multi-centre clinical trial is run through the Myeloma Canada Research Network (MCRN) with support from the Canadian Cancer Trials Group (CCTG). Patients who had 1-3 prior lines of therapy and without proteasome inhibitor (PI) refractory disease were eligible. Treatment consists of carfilzomib (20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28-day cycle, plus weekly oral dexamethasone 40 mg and cyclophosphamide 300 mg/m2 capped at 500 mg. Treatment continues until progression or intolerance, except for cyclophosphamide which is discontinued after 12 cycles. Secondary endpoints included toxicity, depth of response, PFS and OS as defined by International Myeloma Working Group Uniform Response Criteria (2016). Exploratory endpoints included the impact of cytogenetics (CG) and prior PI or lenalidomide exposure on efficacy, and the novel endpoint of serum free light chain (sFLC) escape, defined as a 〉 25% change in the difference of involved to uninvolved light chain with the absolute rise 〉 100mg/L, in individuals with disease previously measurable by serum or urine protein electrophoresis. This analysis is based on the locked database of 19 June, 2019. Results: Of 76 patients accrued, 75 were included in the analysis. One was ineligible due to prior bortezomib refractoriness. Thirty-nine percent received 1 prior line, 44% two prior lines and 17% three prior lines of therapy. High-risk cytogenetics (t(4;14), t(14;16) and/or del P53, considered positive at any level above local accepted threshold) were identified in 32%. Twenty percent had ISS stage III disease. The majority of participants were previously exposed to PI (87%) and lenalidomide (83%). The median duration of follow-up was 25 months. The ORR at any time was 85% (1 patient achieved a response after 4 cycles) with ≥ VGPR achieved in 68% and ≥ CR in 29%. The presence of high-risk CG conferred a worse ORR (75% vs 97% respectively, p = 0.013). Thirty-one patients have died with a median OS and median PFS of 27 months and 17 months respectively (figure 1). High risk CG conferred a worse median OS (18 months vs NR, p = 0.002) and a trend toward a worse median PFS with high risk CG (14 months vs 22 months, p = 0.06; figure 1). For patients with prior PI exposure the median OS and PFS were 27 and 17 months respectively. For patients with prior lenalidomide exposure median OS and PFS were 26 and 16 months respectively. Free light chain escape events were noted in 11 patients (15%) but was the only progression event in 3 (4%). For the remaining 8 patients the sFLC rise was a harbinger of traditional relapse by electrophoresis. The median PFS when sFLC escape was included as a progression event was 17 months. With updated toxicity data the most common ≥ grade 3 non-hematologic events were infection (40%), cardiac (15%, including 5 dyspnea and 1 pulmonary edema) and vascular (17%, including 7 with hypertension and 3 with thrombotic microangiopathy). To date 57 (76%) patients have discontinued carfilzomib, including 34 due to disease progression and 14 due to toxicity. Conclusion: This phase II trial demonstrates that wCCD remains a safe and effective regimen for RRMM. The survival data presented here is comparable to current phase II and III studies examining the weekly dosing strategy. No new toxicity signals are observed but cardiovascular risks remain an important factor in the use of carfilzomib-based therapies. Using sFLC escape does not negatively affect PFS outcomes but likely better characterizes progression as a harbinger of more traditional events detected by electrophoresis. This regimen will be a useful triplet-based option for RRMM especially in patients refractory to lenalidomide and otherwise ineligible for the carfilzomib-lenalidomide-dexamethasone combination. Disclosures Venner: J & J: Research Funding. Leblanc:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sandhu:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; gilead: Honoraria. White:Celgene: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Reece:Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding. Chen:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Louzada:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bayer: Honoraria. McCurdy:Janssen: Honoraria; Celgene: Honoraria. Hay:Janssen: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Kite: Research Funding; Takeda: Research Funding; Roche: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; MorphoSys: Research Funding; Gilead: Research Funding. OffLabel Disclosure: While Carfilzomib is approved for use in relapsed and refractory myeloma the combination with cyclophosphamide is not approved.

Abstract: MRD negativity has become an important goal of the initial treatment of MM pts. Our phase 2 multi-center clinical trial, conducted in 10 major Canadian transplant centers, was designed to increase the MRD negativity rate after ASCT by using conditioning with 2 high-dose alkylating agents followed by len maintenance. In addition to conventional response criteria, this trial evaluated serial bone marrow aspirate (BMA) samples for MRD analysis by 8-color multiparameter flow cytometry (MFC) along with serum Hevylite™ assays of the involved HLC that were obtained before and after ASCT and during maintenance therapy. After bortezomib (btz)-based induction therapy off study, pts without MM progression received BuMel (busulfan 3.2 mg/kg IV days -5 to -3 or days -6 to -4 + melphalan 140 mg/m2 day -2 or day -3) conditioning, followed by ASCT on day 0. On day 100 post-ASCT, len 10 mg/day was started, escalated after 3 cycles to 15 mg/day if appropriate, and continued until progression. BMA and serum samples were shipped centrally for MRD and Hevylite analysis before induction therapy, before ASCT, on day 100 post-ASCT, every 3 mos for the 1st year and every 6 mos until progression. Between 03/2013 - 05/2016, 125 newly diagnosed pts provided BMA samples for MRD analysis. To date, 76 pts (target 78), have completed induction therapy and undergone ASCT; 2 pts have provided initial samples and are expected to be enrolled. 46 of the 125 (36.8%) who provided BMA samples did not proceed to BuMel due to: poor samples - 4 (3.2%); MM not confirmed - 3 (2.4%); prior therapy - 1 (0.8%); death during induction - 1 (0.8%); consent withdrawal/opted for standard conditioning - 21 (16.8%); and no ASCT - 16 (12.8%) (8 were unfit, 4 had comorbidities, 2 progressed, 1 failed mobilization and 1 underwent preferential tandem ASCT). Median follow-up is 27.4 mos (range: 10.4-37.6). Median age is 57 (34-69); 65.8% are male. Median serum β2-microglobulin level is 3.07 mg/L (1.5-20) and albumin 37 g/L (2.8-48.1); 34 pts have ISS stage I; 21 stage II; 17 stage III MM and 5 have missing data. Ig isotype includes IgGκ in 34 (44.7%), IgGλ in 16 (21.1%), IgAλ in 10 (13.2%), IgAκ in 9 (11.8%) and κ in 7 (9.2%). Post-ASCT, 26 SAEs have occurred: Grade 2: atrial fibrillation (1) and URI (1); Grade 3: atrial fibrillation (1), acute kidney injury (4), infectious enterocolitis (2), gallbladder infection (1), URI (1), febrile neutropenia (3), bacteremia (1), pain in extremity (1), hypoxia (1), pleural effusion (1), and 3 lung infection (4); and Grade 4: sepsis (1), AML [with spontaneous regression] (1), respiratory distress (1) and acute kidney injury (1). There have been no ASCT-related deaths; 11(14.4%) pts have progressed. The best conventional Ig response post-induction in the 76 evaluable pts is CR in 6 (7.9%), VGPR in 29 (38.2%), PR in 35 (46.1%), MR in 5 (6.6%) and SD in 1 (1.3%). At day 100 after ASCT, the Ig response in the 73 evaluable pts is CR in 9 (12.3%), VGPR in 41 (56.2%), PR in 22 (30.1%) and MR in 1 (1.4%). The rates of MRD negativity also increased from 29% after btz-based induction to 41%, while the rates of achievement of a normal HLC ratio were 50% after induction and 48% at day 100 (Table 1). Among evaluable pts, 77.3% of those after induction and 53.3% of those at day 100 who were MRD-negative also had had normal involved HLC ratios, while 38.9% and 44.2% of those, who were MRD-positive, respectively, had had normal involved HLC ratios. At month 6 and 12 post-ASCT, 43% and 35% of evaluable pts, respectively, are MRD-negative. Individual patient patterns of len dose, MRD negativity and involved HLC ratios are under assessment and will be presented. Conclusions: 1) IV BuMel conditioning + ASCT is well-tolerated with few SAEs and no ASCT-related deaths; 2) at day 100 post-ASCT, 98.6% had achieved ≥ PR (≥ VGPR in 68.5% and CR in 12.3%); 3) MRD negativity rates improved from 29% to 41% after ASCT; 4) the rates of normalization of the involved HLC ratio remained stable (50% to 48%) pre- and post-ASCT; 4) conventional Ig and MRD responses were often discordant as only 41% of CR pts were MRD-negative at day 100; 5) the majority of MRD-negative patients (53.3%) also had normalization of their involved HLC ratios; 5) with a median follow-up of over 2 years, only 14% of pts have progressed; 6) the serial marrow samples mandated by this study will allow determination of relationships between len dose, conventional Ig response rates, MRD status and involved HLC ratios as these pts are followed for longer periods of time. Disclosures Reece: Takeda: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Research Funding; BMS: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. White:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria. Venner:Takeda: Honoraria; Celgene: Honoraria, Research Funding; J+J: Research Funding; Janssen: Honoraria; Amgen: Honoraria. Stakiw:Roche: Research Funding; BMS: Honoraria; Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Jansen: Honoraria, Speakers Bureau. Sebag:Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria. Comeau:Seattle Genetics: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy. Song:Otsuka: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Louzada:Pfizer: Honoraria; Bayer: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. McCurdy:Celgene: Honoraria. Kukreti:Celgene: Honoraria. Trudel:Glaxo Smith Kline: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Honoraria; Oncoethix: Research Funding. Prica:Janssen: Honoraria; Celgene: Honoraria. Tiedemann:Novartis: Honoraria; Takeda Oncology: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; BMS Canada: Honoraria. Chen:Takeda: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Abstract: Smoldering multiple myeloma (SMM) bridges the gap between monoclonal gammopathy of undetermined significance (a mostly premalignant disorder) and active multiple myeloma (MM). Until recently, no interventional study in patients with SMM showed improved overall survival (OS) with therapy as compared with observation. A report from the PETHEMA-GEM (Programa Español de Tratamientos en Hematologica) group described both fewer myeloma-related events and better OS among patients with high-risk SMM who were treated with lenalidomide and dexamethasone. This unique study prompted us to review current knowledge about SMM and address the following questions: (1) Are there patients currently defined as SMM who should be treated routinely? (2) Should the definitions of SMM and MM be reconsidered? (3) Has the time come when not treating is more dangerous than treating? (4) Could unintended medical harm result from overzealous intervention? Our conclusion is that those patients with the highest-risk SMM (extreme bone marrow plasmacytosis, extremely abnormal serum immunoglobulin free light chain ratio, and multiple bone lesions detected only by modern imaging) should be reclassified as active MM so that they can receive MM-appropriate therapy and the paradigm of careful observation for patients with SMM can be preserved.