Expert Review of Hematology ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierr20 Advances in maintenance strategy in newly diagnosed multiple myeloma patients eligible for autologous transplantation Ahsan Wahab , Abdul Rafae , Muhammad Salman Faisal , Kamran Mushtaq , Hamid Ehsan , Maria Khakwani , Afia Ashraf , Tayyab Rehan , Zahoor Ahmed , Zunairah Shah , Aslam Khan & Faiz Anwer To cite this article: Ahsan Wahab , Abdul Rafae , Muhammad Salman Faisal , Kamran Mushtaq , Hamid Ehsan , Maria Khakwani , Afia Ashraf , Tayyab Rehan , Zahoor Ahmed , Zunairah Shah , Aslam Khan & Faiz Anwer (2020): Advances in maintenance strategy in newly diagnosed multiple myeloma patients eligible for autologous transplantation, Expert Review of Hematology, DOI: 10.1080/17474086.2020.1839886 To link to this article: https://doi.org/10.1080/17474086.2020.1839886 Accepted author version posted online: 20 Oct 2020. Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ierr20 Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group Journal: Expert Review of Hematology DOI: 10.1080/17474086.2020.1839886 IP T Review Advances in maintenance strategy in newly diagnosed multiple myeloma patients eligible for R autologous transplantation SC Ahsan Wahab1, Abdul Rafae2, Muhammad Salman Faisal3, Kamran Mushtaq4, Hamid Ehsan5, Maria Khakwani6, Afia Ashraf7, Tayyab Rehan8, Zahoor Ahmed9, Zunairah Shah10, Aslam Khan8 & Faiz U Anwer11 Baptist Medical Centre South/University of Alabama at Birmingham, Montgomery, AL, USA 2 McLaren Regional Medical Center, Flint, MI, USA 3 Allegheny Health Network, Pittsburgh, PA, USA 4 Northeast Internal Medicine Associates, LaGrange, IN, USA 5 Georgetown University, Washington, DC, USA 6 Anne Arundel Medical Center, Annapolis, MD, USA 7 Lahore Medical and Dental College, Lahore, Pakistan 8 Allama Iqbal Medical College, Lahore, Pakistan 9 King Edward Medical University, Lahore, Pakistan EP TE D M AN 1 Louis A. Weis Memorial Hospital, Chicago, IL, USA 11 Hematology Oncology, Stem Cell Transplantation Multiple Myeloma Program, Cleveland Clinic, C 10 AC Cleveland, Ohio, USA Corresponding author: Ahsan Wahab Baptist Medical Center South, 2105 E South Blvd, Montgomery, AL, 36116, USA Tel.: +1 334 286 3585 Email: drahsan.wahab@gmail.com Information Classification: General Abstract Introduction: Multiple myeloma (MM) lacks curative therapy. Therefore, researchers continue to conduct studies in an effort to improve progression-free survival (PFS) and overall survival (OS). Maintenance therapy (MT) after autologous stem cell transplant (ASCT) was extensively studied in the IP T last decade and now considered a standard approach. Areas covered: This review evaluated the evidence and updates on various maintenance agents in newly diagnosed multiple myeloma (NDMM) after ASCT. Articles were searched on PubMed and Embase that R were published in last 10 years. Both clinical trials and observational studies were evaluated. SC Expert opinion: Maintenance strategy after ASCT has consistent PFS benefit but lacks conclusive OS improvement. Lenalidomide is superior to thalidomide given reduced neurotoxicity. OS advantage is U controversial for both due to inconsistent evidence. Lenalidomide may confer a PFS advantage even at lower doses due to toxicity with higher doses. Bortezomib-based maintenance has some evidence for OS AN benefit in high-risk MM (HRMM) and renal dysfunction. Ixazomib has preliminary promising results. Two or three drug combinations for MT are potentially safe and more effective, particularly in HRMM M although data on this subject is still evolving. Efficacy of various MT regimens in terms of minimal D residual disease status needs to be further investigated. TE Keywords AC C survival EP maintenance therapy, minimal residual disease, Multiple Myeloma, progression-free survival, overall Information Classification: General Article highlights box  Maintenance therapy (MT) after ASCT is extensively studied in the last decade and now considered a standard approach.  Thalidomide maintenance has consistent PFS benefit but non-uniform OS benefit, with adverse IP T survival in high-risk cytogenetics.  Lenalidomide maintenance improves PFS after ASCT and has some evidence of OS benefit.  Bortezomib improves OS in patients with renal failure and high-risk cytogenetics. Ixazomib, a  R newer proteasome inhibitor, has preliminary promising results as maintenance. Two or three drug combinations for MT are potentially safe and more effective, particularly in RVD lite may improve PFS and OS in HRMM. Role of lenalidomide alone in HRMM is limited. U  SC HRMM although data on this subject is still evolving. AN 1. Introduction Despite advances in therapeutics, achieving a cure for multiple myeloma (MM) remains challenging. Therefore, research continues with the goals of finding improved disease responses, progression-free M survival (PFS) and superior overall survival (OS). In newly diagnosed MM (NDMM) after induction therapy, front line use of high-dose chemotherapy (HDCT) followed by ASCT is a standard of care in D suitably fit candidates due to better response outcomes, higher complete-response (CR) rates and TE longer PFS [1-4]. Usually, after 4-6 cycles of induction therapy (IT), ASCT-eligible patients receive HDCT followed by ASCT-rescue [5,6]. Following ASCT, disease relapse or progression eventually occurs in virtually all patients [1,4]. It was observed that after HDCT/ASCT, median event-free survival (EFS) and EP median OS (m-OS) do not extend beyond a few years when compared with conventional therapy and only a few patients are disease-free after ten years. Therefore, investigators use additional approaches C such as second consolidation using conventional drugs and single or multi-agent maintenance therapies AC (MT) to prevent disease relapse [7]. The rationale of such therapies is to achieve deepening response, preferably achieve a minimal residual disease (MRD)-neg (negative) status, and maintain such a response for a longer period [8,9]. Even after achieving a CR following ASCT, the majority of relapses occur due to MRD-positivity [9]. MRD-detection is now possible via several sophisticated methods such as polymerase chain reaction, multiplanar flow cytometry, and next-generation sequencing [10]. Achievement of MRD-neg status has prognostic value as it is associated with significantly improved PFS and OS and is a better predictor of survival compared Information Classification: General to conventional CR rates with MRD-pos (positive) disease [9]. MT in post-ASCT is associated with achievement of a negative MRD-status in almost one-third of patients who had positive MRD after HDCT [8]. Studies have proven the impact of MT in terms of PFS following ASCT; however, its role in OS improvement remains controversial [11-13]. IP T MT in post-ASCT patients does not adversely impact the quality of life (QoL) and the has potential to reduce healthcare-related costs [14,15]. MT may cause 1) hematologic adverse events (AEs) such as neutropenia, thrombocytopenia, anemia, 2) non-hematologic AEs such as fatigue, infections, peripheral R neuropathy (PN), thromboembolism and 3) second primary malignancies (SPM) [12,13]. Historically, MT involved the use of a single agent such as immunomodulators (IMiDs), i.e., lenalidomide (Lena) or SC thalidomide (Thal) and proteasome inhibitors (PIs), i.e., bortezomib (Bort) [16]. Recently, data on combination MT and newer agents are becoming available. This review intends to summarize, analyze, U interpret, and present the last 10 years of updates in terms of safety and efficacy of post-ASCT MT in AN NDMM to improve patient-related outcomes. M 2. Thalidomide Maintenance Thalidomide has consistent PFS benefit but non-uniform OS benefit [17-20]. Since 2010, five randomized D controlled trials (RCTs) (Table 1) compared the safety and efficacy of Thal-MT (alone or in combination) TE with no-MT or some other drug [17-22]. In the HOVON-50 trial, Lokhorst et al. randomized NDMM patients to VAD arm (vincristine-doxorubicin-dexamethasone) or TAD arm (thalidomide-doxorubicin- EP dexamethasone) followed by HDM (high-dose melphalan) and single/double ASCT. TAD arm received Thal maintenance, and VAD arm received IFN-α. Thalidomide improved EFS (34-mo (months) vs. 22-mo, HR:0.60, CI:0.48-0.75, p<0.001) and PFS for TAD arm (34-mo vs. 25-mo, HR:0.67, CI:0.55-0.82, p <0.001) C compared with VAD arm that received IFN-α [22]. Median-OS was longer but insignificant for TAD arm AC vs. VAD arm, 73-mo vs. 60-mo, HR: 0.96, CI: 0.74-1.25, p: 0.77. PFS benefit was mainly seen among patients who achieved at least a PR, but the benefit was not exclusively limited to these patients. The achievement of CR after 12 months correlated with better PFS and OS but did not demonstrate a statistical significance for OS [20,22]. Van de Donk et al. published the updates of HOVON-50 in 2018. EFS at 129-mo was superior in Thal-group compared to IFN-α, HR: 0·66, CI: 0·54–0·81, p<·0001. PFS was better for Thal-group compared to IFN-α (HR: 0.64, CI: 0.52-0.79, p<.0001) but OS was similar (HR: 0.81, CI: 0.65-1.02, p: .075). Elevated lactate dehydrogenase (LDH), international staging system (ISS) and poor Information Classification: General performance status were predictors of poor survival. With longer follow-ups, there was a trend toward a better OS in Thal-group but that remained insignificant. After first relapse or progression, survival was the same for both groups, HR: 1.20, CI: 0.93-1.53, p: 0.16. With shorter follow-up, post-relapse survival was inferior for Thal-group but later this finding faded with longer follow-ups, aborting the measured difference. Discontinuations were more frequent due to toxicity in Thal-group than in IFN-α (42% vs. IP T 27%); SPM rates were 4% in both the groups at 5 years [20]. The MRC Myeloma-IX study randomized patients to Thal-MT or no-MT after intensive and non-intensive inductions (Table 1) [18]. Median-PFS was better for Thal-MT (23-mo vs. 15-mo, HR: 1.45, CI: 1.22-1.73, p<0.001), but m-OS (HR: 0.91, CI: 0.72- R 1.17, p: 0.40) was the same. The PFS benefit due to thalidomide maintenance was consistently present SC across all subgroups. While dissecting the benefit of induction from maintenance, the intensive induction group had superior PFS following maintenance (30-mo with Thal vs. 23-mo in no-MT, HR: 1.42, U p: 0.003) compared to the non-intensive induction group (11-mo with Thal vs. 9-mo in no-MT, HR: 1.35, p: 0.014). There were some unique findings in this trial, i.e., patients with favorable interphase AN fluorescence-in-situ-hybridization (iFISH) who received Thal maintenance showed improved PFS and non-significantly prolonged OS. Patients with adverse iFISH (t(4:14), t(14:16)) showed an adverse OS due M to adverse tumor biology and had no PFS benefit. The post-relapse survival was poorer in Thal-group as a whole vs. no-MT group, especially among patients with adverse iFISH. Treatment-emergent AEs D caused Thal discontinuation in 52.2% of cases. Morgan et al. pooled the survival data of the Myeloma-IX study and 4 other trials in a meta-analysis and found an OS benefit (odds ratio: 0.75, CI: 0.64-0.87, TE p <.001) showing 25% lower odds of death with thalidomide maintenance favoring its survival benefit [18]. Maiolino et al. randomized patients to Thal-dexamethasone (Dexa) maintenance or Dexa alone EP after ASCT and both groups had comparable features except for a higher median-age and a higher percentage of ISS stage-III in Dexa-group. At 27-mo (median) follow-up, the two-year (Yr.) PFS was C double for Thal-Dexa compared with Dexa alone, 64% vs 30%, p: 0.002. Median-PFS was longer in ThalDexa group compared to Dexa-group, whereas two-year-OS and response rates were similar for both AC the groups. The PFS benefit after thalidomide-dexamethasone was mainly seen among those who did not respond to ASCT. Grade (G)-3/4 AEs were more frequent with Thal-Dexa combination than Dexa alone [17]. The Myeloma.10 (MY.10) trial sponsored by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) compared the combination of Thal-prednisone (Pred) maintenance with observation after ASCT. Myeloma-specific PFS and PFS were superior for Thal-Pred combination compared to observation. But there was no OS-benefit. At four-year follow-up, PFS estimate was 35% for Thal-Pred vs. 14% for Information Classification: General observation (HR: 0.56, CI: 0.43-0.73, p: 0.001), whereas 4-Yr OS estimates were similar, HR: 0.77, CI: 0.53-1.14, p: 0.18 (Table 1). Thal-Pred maintenance was associated with inferior QoL, increased incidence of DVT (7.3% for Thal-Pred vs. 0% for observation) and more frequent non-hematologic AEs. Those with high-risk cytogenetics (t(4;14) or del17p) had the worst PFS (HR: 2.23, CI: 1.34-3.69, p: 0.002) and OS (HR: 2.24, CI: 1.11-4.54, p: 0.02) on multivariate analysis. After progression, the survival was IP T shorter in Thal-Pred group compared to observation [19]. One multicenter phase-II trial evaluated the efficacy of thalidomide-dexamethasone maintenance in 43 Korean NDMM patients who had at least a PR after induction and ASCT. EFS at one-year was 60.47% (CI: 44.34-73.26%) while 1-Yr PFS and 2-Yr PFS R were 86.05% and 72.09%, respectively. Similarly, 1-Yr OS and 2-Yr OS were 90.70% and 88.37%. SC Following maintenance, four of 21 patients achieved a CR while the others could not achieve a CR after ASCT. Common G-3/4 AEs were upper respiratory infections and PN[21]. U In the HOVON-50 trial and MRC Myeloma-IX trial, thalidomide caused significant neurotoxicity in large AN proportions of participants, 42% and 26.6% respectively, and resulted in maintenance discontinuation [18,20]. Maiolino et al. recorded a relatively lower rate of neuropathy (21%) and a subsequently lower proportion of discontinuation due to AEs (6.1%). The investigators of this trial however resumed M thalidomide at smaller doses as soon as neuropathic symptoms were resolved and this might be the reason for fewer discontinuations in the trial [17]. SPM rates in Thal-group were similar to observation TE D or placebo. Table 1 provides a detailed account of thalidomide toxicity as maintenance. EP 3. Lenalidomide Maintenance Between 2010 and 2019, lenalidomide maintenance was evaluated in 13 studies [11,23-34]. In the IFM2005-02 trial, lenalidomide maintenance (10-15 mg) was given in NDMM after ASCT and was C compared with placebo. Lenalidomide increased CR/VGPR rate from 61% to 84% and showed superior AC m-PFS/m-EFS compared to placebo but no OS benefit. As there was an increased incidence of SPMs due to lenalidomide (8%) maintenance vs. placebo (4%), lenalidomide was prematurely stopped in this trial. OS, therefore, may be lacking due to premature termination of maintenance. PFS improved due to lenalidomide among patients with VGPR (64% for Lena vs. 49% for placebo) and among those without VGPR (51% for Lena vs. 18% for placebo). The benefit, however, was much larger if patients had VGPR. At five year, the OS was equivalent, 68% for Lena vs. 67% for placebo, HR: 1. Following first progression, the median OS was much shorter for Lena-group (29-mo) vs. placebo (48-mo), p: <0.0001 [22]. Adverse Information Classification: General survival was related to age, ISS-stage, and poor cytogenetics (t(4;14) and chromosome 17 del) in multivariate analysis [11,23]. McCarthy et al. in the Cancer and Leukemia Group B (CALGB)-100104 trial showed improved PFS (58.4-mo for Lena vs. 28.9-mo for placebo, HR: 0.579) and OS (not reached (NR) vs. 79.0-mo, HR: 0.565) with lenalidomide maintenance vs. placebo and recorded a trend toward a longer gap before disease progression if patients received Lena during both the induction and IP T maintenance phases compared to when they received lenalidomide during maintenance phase but not during induction. PFS due to lenalidomide maintenance was much longer for patients who achieved a CR or VGPR after ASCT compared to those who did not. The benefit, however, was not exclusively limited R to those who achieved a CR or VGPR [31]. According to the Palumbo et al. study, Lena maintenance SC provides superior results and a longer m-PFS when used after HDM/ASCT compared to when used after melphalan-prednisone-lenalidomide consolidation. Lenalidomide imparted consistent PFS benefit across U various subgroups except for stage-III disease but lacked an OS benefit [33]. A meta-analysis of IFM200502, CALGB100104, and GIMEMA-RV-MM-PI-209 with patient-level data on 1208 patients showed an OS AN benefit of lenalidomide maintenance (HR: 0.75) apart from its PFS benefit (HR: 0.48) [12]. The OS benefit of lenalidomide maintenance was more pronounced among patients with better responses after ASCT M and those with lenalidomide-based induction but no benefit was identified in certain subgroups such as stage-III disease, elevated LDH, low creatinine clearance, and high-risk cytogenetics. The PFS benefit in D these 3 RCTs was seen irrespective of different dosing schedules of lenalidomide. In one retrospective study, almost 70% of patients underwent lenalidomide-MT dose reduction for various reasons. The PFS, TE however, did not differ among patients with dose reductions and those without dose reductions, conferring PFS advantage even at smaller doses [34]. EP In the GMMG-MM5 phase III trial, Goldschmidt et al. randomized transplant patients into PAD (bortezomib-Adriamycin-dexamethasone) or VCD (bortezomib-cyclophosphamide-dexamethasone) C arms and subdivided them based on Lena-MT duration either for 2 years or until CR. Arms that received AC Lena for 2 years (A1, A2) beyond the CR had similar PFS but superior VGPR-rates and OS compared to those who received Lena until CR only (B1, B2), favoring the longer use of lenalidomide maintenance. Toxicity, on the other hand, was worse in 2 year arms given the longer use of lenalidomide, 77.6% vs. 58.2% [27]. As MRD-status is associated with better PFS, the NCRI Myeloma XI trial evaluated the influence of MRD on PFS in association with lenalidomide maintenance vs. no-MT. Patients who were MRD-neg after ASCT and remained negative throughout had the best PFS whereas those who were MRD-pos after ASCT and remained positive despite maintenance had the worst PFS. The MRD-negativity conversion rate was eight times higher among those receiving lenalidomide vs. those receiving no-MT, Information Classification: General 32% vs. 4%, p: 0.0045 [8]. In the Finnish Myeloma Group (FMG-MM02) phase-II trial, NDMM patients who received lenalidomide after ASCT had a significantly improved paraprotein response with sCR (stringent CR) of 22%,24%, and 30% at the start of MT and at one year and two years after the maintenance, respectively [35]. Sixty-seven percent of patients on maintenance had achieved MRDnegativity at least once during treatment. PFS estimates at 1, 2, and 3 years were 94%, 80%, and 65%, IP T and OS estimates were 100%, 96%, and 87%, respectively [35]. Retrospective studies have also explored the role of lenalidomide maintenance. Fonseca et al. analyzed R nationally representative data through Flatiron Health and found that a smaller proportion of patients who received lenalidomide maintenance progressed to second line of therapy compared to those who SC received no maintenance, i.e., 22.1% vs. 34%, HR: 5.46, CI: 3.34-8.95, p: <0.001). Time-to-next-line of treatment was longer for lenalidomide group vs. no-MT group [26]. Another retrospective review by U Cherniawsky et al. evaluated the survival impact of lenalidomide maintenance following Bort-based AN induction and ASCT and showed a positive impact on both PFS (55-mo for Lena vs. 32-mo for no-MT, p: 0.002) and OS (NR for Lena vs. 89-mo for no-MT, p: 0.01) [24]. Retrospective review of a communitybased registry also demonstrated superior m-PFS (50.3-mo for Lena vs. 30.8-mo for no-MT, HR: 0.62, p: M 0.0009) and m-OS (NR for both, HR: 0.54, p: 0.005) in lenalidomide maintenance [30]. Cote et al. found that lenalidomide maintenance also impacted the relapse pattern. Patients who received lenalidomide D developed clinical relapse more often whereas those without maintenance developed biochemical TE response more often with biochemical response being the most common overall. It is important to note that patients who relapsed despite lenalidomide maintenance had a shorter m-OS following relapse EP than no-MT group [25]. Lenalidomide has been successfully combined with other agents [36-38]. In a pooled study of two RCTs (GIMEMA-RV-MM-PI-209 and RV-MM-EMN-441), lenalidomide combination with prednisone was better C in terms of m-PFS (71% vs. 41%) and OS (86% vs. 75%) compared to lenalidomide alone [36]. AC Elotuzumab, a monoclonal antibody, has been successfully combined with lenalidomide in postmyeloablative phase. The preliminary results of this phase-II trial (3-Yr PFS:81%, OS:96%) support future trials on this combination [38]. Lenalidomide was also safely combined with vorinostat in 2015 in a doseescalation phase-I trial which showed improved responses in 7 of 15 participants [37]. Sharma et al. reported long term results of this trial with m-PFS of 64.3 months (range: 21.7-months-NR) at a median follow-up of 89.8 months. Median-OS was not reached but 2, 4 and 6 year OS estimates were 94%, 88% and 69%, respectively [39]. Information Classification: General Lenalidomide has greater rates of hematologic AEs (48 % vs 17% in CALGB-100104, 69% vs. 35% in IFM2005-02) and thrombosis (6.2% vs. 2% in IFM-2005-02), when compared with placebo [11,12,23,31]. Neutropenia and thrombocytopenia are the most common hematologic AEs of lenalidomide that often require dose reductions [28,34]. Infections and dermatologic AEs are also common [33]. Goldschmidt et al. noted more frequent toxicity with longer use of lenalidomide compared to limited use [27]. In a real- IP T world study, the average duration of lenalidomide spanned up to 33.2 months and 50% of patients required dose reductions. Common reasons of dose reductions were cytopenia, rash, fatigue and infection. Progressive disease was a more common cause of lenalidomide discontinuation than its AEs R [34]. SC In terms of secondary malignancies, SPM rates are significantly higher in Lena compared to placebo. In the IFM2005-2 trial, the authors reported 44 SPMs in Lena vs. 28 SPM in placebo and incidence of 2.3 U SPM for Lena vs. 1.3 in placebo per 100 patient-years [23]. SPM rates in the CALGB-100104 trial were AN also significantly higher in lenalidomide group vs. placebo, 8% vs. 1% for hematologic and 6% vs. 4% for solid SPMs, respectively [28]. The author of this trial observed that solid SPMs mainly occurred within a few years after exposure to lenalidomide whereas hematologic SPMs continued to emerge later on after M extended follow-ups. The cumulative incidence risk of developing an SPM (2.34, CI: 1.29–4.23. p: 0.0073) and dying from it (3.23, CI: 1.06–9.84, p: 0.031) was much bigger in lenalidomide maintenance D vs. placebo. SPM rate in another RCT was 4.3% for both lenalidomide maintenance and no-MT group TE [33]. Though these SPM rates are quite high, Cherniawsky et al. reported a relatively lower SPM rate of 1.7% in their retrospective review [24]. This may be due to a smaller number of patients in their study compared to RCTs. Both hematologic [MDS/AML, B-cell ALL, Hodgkin's lymphoma], and non- EP hematologic SPMs [skin, breast, colon, prostate, esophageal, kidney, bladder, endometrial, and melanoma] are reported in these studies. Major studies on lenalidomide maintenance are summarized AC C in Table 2. 4. Proteasome Inhibitors Maintenance Bortezomib has limited data as maintenance in post-ASCT. Because of its parenteral route and twiceweekly schedule, the best dose and optimal duration of Bort maintenance are not adequately explored. Bort-based induction and maintenance when combined with double HDM/ASCT resulted in significantly improved PFS and OS among high-risk myeloma (HRMM) patients and those with renal dysfunction Information Classification: General (Creatinine>2 mg/dl). The HOVON-65/GMMG-HD4 trial which focused on the role of bortezomib both as induction and maintenance has shown its promising efficacy as maintenance as well [40,41]. In this trial, PAD (bortezomib-doxorubicin-dexamethasone) induction and Bort maintenance were compared with VAD induction (vincristine-doxorubicin-dexamethasone) and Thal maintenance as control in HDM/ASCT patients (Table 3). CR rate was 49% for Bort maintenance vs. 34% for Thal, p<0.001. Bort-based arm as a IP T whole had significantly longer m-PFS, i.e., 34-mo vs. 28-mo in control arm, HR: 0.7, CI: 0.65-0.90, p<0.001. Median-OS though initially better for Bort-based arm at 66 months and 91.4 months later became similar after 96 months, 48% for Bort-arm vs. 45% for control, HR: 0.89, CI: 0.74-1.08, p: 0.24. R SPM rates (7% each, p: 0.85) and OS after relapse or progression (HR: 1.02, p: 0.85) were similar in both SC the arms [40-42]. As this trial focused on the joint efficacy of Bort-based induction and maintenance compared with control, it is difficult to precisely quantify the beneficial influence of bortezomib U maintenance compared to thalidomide maintenance. Completion rate of Bort-maintenance was higher compared to thalidomide, 48% vs. 28%, respectively. In this trial, the poor prognostic-impact of del-17p3 AN mutation was abrogated due to prolonged Bort-exposure but the adverse impact of other high-risk cytogenetics such as t(4:14) and gain of 1q21 (≥3 copies) was not neutralized. Bortezomib-based arm M had improved OS among patients who had elevated creatinine or del-17p3. Recently, the role of subclones in malignant plasma cells apart from major high-risk clones has been reviewed in a single D patient. This means that in addition to major high-risk clones such del-17p3, gain 1q21 and t(4:14), the presence of certain subclones such as deletion or gain of MYC-locus or extra chromosomes may be TE responsible for a variable response to bortezomib. Merz et al. explored such subclones in the GMMGHD4 part of this trial and found that the negative influence of high-risk clones was abrogated only if EP subclones were absent in these patients [43]. Therefore, both malignant plasma cells clones and subclones may influence a therapeutic response to bortezomib in HRMM given cytogenetic aberration C heterogeneity. AC The GEM05MENOS65 trial compared Bort-Thal maintenance with thalidomide or IFN-α after ASCT. BortThal combination was more effective in achieving a CR, i.e., 21% vs. 11% for Thal and 17% for IFN-α, and lengthening the PFS compared to other comparators, 50.6-mo for Bort-Thal vs. 40.3-mo for Thal vs 32.5mo for IFN-α, p: 0.03. OS did not differ among these groups. The incidence of neurotoxicity was higher in Thal-Bort combination than Thal alone [6]. Solovev et al. evaluated the efficacy of Bort-maintenance after single or tandem-ASCT in MRD-pos and MRD-neg patients (Stringent (s) CR) who had a CR. They randomized both MRD-pos and MRD-neg patients to either Bort-maintenance or no-MT. Bortmaintenance did not improve RFS in MRD-neg patients but prolonged RFS in MRD-pos patients, 43% vs. Information Classification: General 35%, p: 0.076. Among MRD-pos patients, 52% of patients who received Bort-maintenance converted to MRD-neg status (sCR) whereas the rest of them who could not achieve a sCR showed a better antitumor response [44]. Ixazomib (Ixaz) is a newer oral PI that has shown promising efficacy when used as maintenance in two IP T clinical trials (Moreau et al. and Morgan et al.) [45, 46]. Moreau et al. in a phase-II trial by IFM group reported an increment of CR from 36% to 48% after ixazomib maintenance. Ixazomib maintenance (4 mg on days 1, 8 and 15, 28-day cycle) was given after ixazomib-based induction and consolidation in R HDM/ASCT patients. Two-year PFS and OS were 83% and 95% with this regimen. Ixazomib was welltolerated as maintenance with completion of 13 planned cycles in 84% of participants [45]. Morgan et SC al. used the same regimen of ixazomib (vs. placebo) for two years after ASCT in phase-III TourmalineMM3 trial and reported promising results with 54% of PFS, 28% of reduction in death or progression U (HR: 0.72, CI: 0.582-0.890, p: 0.002), and 12% conversion from MRD-pos to MRD-neg at median follow- AN up of 31 months. The rates of maintenance interruption due to AEs were low and ixazomib benefitted all subgroups, including patients with stage-III, high-risk cytogenetics, PI-exposed, and PI-naïve. With the limitation of a shorter follow-up, SPM rates were equal in both Ixaz and placebo groups. Discontinuation M rates were similar, 7% in Ixaz vs. 5% in placebo. Grade-3/4 AEs (infections, gastrointestinal, neutropenia, TE D thrombocytopenia) were higher in Ixaz than placebo, but SPM rates were equal, 3% each [46]. 5. Combination Therapies EP Various combination (triplet) therapies have been studied in different clinical trials and have shown promising efficacy but preliminary results (Table 4). In 45 HRMM patients (42% del-17p, 20% del-1p and 11% t(14:16)), Nooka et al. studied RVD (lenalidomide-bortezomib-dexamethasone) in 2014 both as C consolidation and maintenance following ASCT. RVD was given for three years as maintenance followed AC by lenalidomide as single agent. With this maintenance strategy, 100% of patients had at least a PR or more and 96% had ≥VGPR. Stringent CR was considerably high, 51%. Median-PFS was 32-mo and 3-Yr OS 93%; m-PFS (28-mo for del-17p vs 32-mo, p: 0.86), and 3-Yr OS (94% for del-17p vs. 93%, p: 0.51) were not significantly different for del-17p vs. other HRMM groups. There were no discontinuations due to AEs, but the authors recorded 15 events of progression [47]. Nadiminti et al. used intensive sequential bortezomib-based maintenance (VDT followed by VCD) in a phase-II trial after early ASCT in elderly patients (HRMM in 40% cases) and showed encouraging early Information Classification: General findings of higher deepened and sustained response rates without increasing mortality, hospitalizations or ICU admissions. Three-year PFS and OS were 82% and 90%, respectively. Most common G-3/G-4 nonhematologic-AEs were infections, diarrhea, and mucositis [48]. Major studies on combination maintenance therapies are given in Table 4. IP T 6. Future Maintenance trials: The Forte trial compared three cohorts, 1) KRd (carfilzomib-lenalidomide-dexamethasone) as induction and consolidation before and after ASCT, 2) KCd (carfilzomib-cyclophosphamide-dexamethasone) as R induction and consolidation before and after ASCT and 3) KRd as ongoing therapy without ASCT. KRd SC inductions with or without ASCT had similar response rates and MRD-neg status but was better than the KCd cohort. This trial aims to evaluate the role of KR (carfilzomib-lenalidomide) compared to lenalidomide maintenance and results are not published yet [49]. The CASSIOPEIA trial is also evaluating U the role of daratumumab as maintenance in NDMM due to its proven benefit as induction and AN consolidation [50]. AURIGA (MMY3021), an ongoing trial, also aims to evaluate MRD conversion rates with lenalidomide-daratumumab maintenance compared to lenalidomide alone in NDMM [51]. Other M clinical trials evaluating the role of maintenance therapy in NDMM are given in Table 5 [52]. D 7. Conclusion: TE In this review, we summarized the evidence that maintenance therapy given after ASCT improves PFS, but the evidence regarding the improvement in OS is not consistent. Thalidomide (+/- dexamethasone EP or prednisone) given for 1-4 years or until disease progression or unacceptable toxicity, showed improved PFS but no OS benefit and its use caused significant neurotoxicity [17-20,22]. Thalidomide use C adversely impacted the survival of patients with adverse cytogenetics [18]. Thalidomide-bortezomib combination was more effective in achieving a longer PFS at the expense of more neurotoxicity [6]. Bort- AC based maintenance proved to be better than Thal-based-maintenance, especially in HRMM and its use was associated with a survival benefit [42]. There is some evidence that Lena-MT improves OS in addition to consistent PFS-benefit [12]. Lenalidomide MT use is linked with myelosuppression; especially neutropenia that requires frequents dose reductions or interruptions [11,12,28,32,33]. SPM rates (hematologic and non-hematologic) are higher in Lena compared with placebo and SPM rate was not higher for thalidomide-MT vs. placebo or observation [28,33]. Even reduced doses of Lena-MT conferred a benefit to show improved PFS [34]. The combination of IMiD with steroids is beneficial but the Information Classification: General combination has more side effects. Lenalidomide-based novel combinations with newer drugs are feasible, but the data is limited and still emerging from clinical trials [6,8,36,37,47,48]. Ixazomib has shown promising efficacy as MT [45,46]. Relapse-free survival is lower in MRD-pos patients compared to MRD-neg patients, and MRD-neg status is associated with better PFS [44]. Further exploration of the IP T interaction of MRD-status and maintenance therapy is required. R 8. Expert opinion The use of MT after HDCT/ASCT is the current standard of care with the intent to delay progression SC measured by PFS and improve survival while ensuring the quality of life (Figure 1 shows the summary of maintenance therapy options in NDMM after HDM/ASCT). Among IMiDs, lenalidomide is preferred over U thalidomide due to less incidence of neurotoxicity, better PFS, and some evidence to suggest OS benefit (HR: 0.75, CI: 0.63-0.90, p: 0.001, 25% lower hazards of deaths compared to placebo or observation) AN [12]. Lenalidomide has established a role as maintenance in standard-risk multiple myeloma but lacks similar benefit in HRMM when used alone [12]. Thalidomide use is particularly discouraged in NDMM M with adverse cytogenetics due to a shorter survival recorded when thalidomide was given in MRC Myeloma-IX-study, p: 0.009 [18]. Lenalidomide can be started at 10 mg daily and the dose later D escalated to 15 mg daily after 3 months, barring unacceptable toxicity. Lenalidomide maintenance TE should be preferably continued until disease progression, relapse, or profound toxicity. As data is still evolving for the role of MRD status and its practical role in the clinical management of patients, we postulate that the detection of MRD status may help in the future to tailor the duration of lenalidomide EP use as MT, i.e., fixed duration use vs. continuous use until disease progression. MRD-pos status may affirm the decision of a long-term recommendation of lenalidomide use until progression or C unacceptable toxicity. Lenalidomide can help convert MRD-pos state to MRD-neg state (32% vs. 4% for observation, p: 0.0045) and therefore improve PFS and OS as MRD-negativity does correlate with AC survival outcomes [8]. Moreover, shortened duration of lenalidomide may weaken the OS impact of maintenance [27]. In case of toxicity, the dose of lenalidomide may be reduced. Even at smaller doses it may confer a PFS benefit [12,34]. Though lenalidomide is associated with myelosuppression and SPMs, myelosuppression is manageable, and the benefit of maintenance outweighs the risk of SPMs. Patients on long term lenalidomide MT, therefore, need to be carefully screened with age-appropriate cancer screening procedures. Lenalidomide is successfully combined with agents such as steroids, proteasome inhibitors and monoclonal antibodies etc. that have paved the way for future novel combinations [37- Information Classification: General 39, 47]. Such combinations may further improve outcomes especially in HRMM due to their synergistic activity. Bortezomib is beneficial as maintenance in NDMM with renal failure and HRMM (del-17p3) as reported by the HOVON-65/GMMG-HD4 trial [40-42]. Appropriate maintenance dosing and schedule of bortezomib need to be further evaluated. Future trials should evaluate a convenient but effective maintenance schedule involving bortezomib. Ixazomib is more convenient to use as maintenance due to IP T its oral formulation. Moreover, it has shown promising efficacy without increasing toxicity or SPM rates in the TOURMALINE-MM3 trial [46]. R In HRMM, MT with Bort or combination such as RVD lite may improve PFS and OS. Patients with high risk cytogenetics (42% with del-17p, 20% with del-1p, 11% with t(4:14), 75% more than cytogenetic SC aberration) who received RVD combination therapy showed Median-PFS of 32-mo and 3-Yr OS of 93% [47]. The TOURMALINE-MM3 trial also showed evidence of PFS benefit with the use of ixazomib in the U presence of high-risk cytogenetics, HR: 0.625 with about a 37% lower risk of progression in ixazomib AN group vs. placebo [46]. MT use is associated with a higher proportion of negative MRD-status [8]. Prognosis correlates better M with negative MRD status compared to a traditional CR. MT is relatively more beneficial in MRD-pos patients after ASCT when compared to MRD-neg patients in this setting. The relationship between MRD and MT warrants further exploration in prospective randomized trials. The relationships between D individual maintenance agents or regimens and MRD-negative status also need further clinical trials. TE Research is needed to establish the role of subclones as predictors of prognosis [43]. Many clinical trials on MT have focused on PFS and OS, side effects may be undermining the influence of maintenance on EP quality of life, which needs to be further studied. Patients with HRMM in particular should be enrolled in RCTs using novel combinations for MT, especially those that involve newer agents such as ixazomib, carfilzomib, daratumumab, elotuzumab and isatuximab. Many clinical trials (e.g., NCT02389517, C NCT03901963, NCT03617731 and NCT04071457) are evaluating the role of combinations of these AC agents with lenalidomide due to inconsistent OS benefit of lenalidomide alone, especially in HRMM. Investigators need to conduct further trials in a risk-adapted manner to identify the subgroups or subpopulations that would get the most benefit from various combinations. Information Classification: General Author contributions A Wahab and F Anwer designed the study. All authors performed the study, contributed to data extraction, literature review, analyzed the data, and wrote the paper. Acknowledgments IP T Authors thank Ms. Marsha Halajian for providing her English language editing services and proofreading. Funding R This paper was not funded. SC Declaration of interest F Anwar has a consulting or advisory role for Seattle Genetics, Incyte Corporation Speakers' Bureau, U Company: Incyte Corporatio; receives travel and accommodations expenses from Seattle Genetics, AN Incyte; receives honoraria from Incyte, Company: Seattle Genetics; and received research funding from Seattle Genetics, Company: Celgene, Acetylon Pharmaceuticals, Millennium, Astellas Pharma and AbbVie. The authors have no other relevant affiliations or financial involvement with any organization or M entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. D Reviewer Disclosures 1. EP References: TE Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Attal M, Harousseau J-L, Stoppa A-M, et al. A prospective, randomized trial of autologous bone C marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335(2):91- AC 97. 2. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348(19):1875-1883. 3. Gay F, Oliva S, Petrucci MT, et al. 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Prognostic significance of cytogenetic heterogeneity in D 43. patients with newly diagnosed multiple myeloma. Blood Adv. 2018;2(1):1-9. Solovev MV, Mendeleeva LP, Pokrovskaya OS, et al. Maintenance Therapy after Autologous TE 44. Haematopoietic Stem Cell Transplantation (auto-HSCT) in Multiple Myeloma Patients with and 45. EP without Minimal Residual Disease (MRD). Blood. 2016;128 (22): 2260. Moreau P, Hulin C, Caillot D, et al. Ixazomib-lenalidomide-dexamethasone (IRd) combination C before and after autologous stem cell transplantation (ASCT) followed by ixazomib maintenance in patients with newly diagnosed multiple myeloma (NDMM): a phase 2 study from the AC Intergroupe Francophone Du MyéLome (IFM). Blood. 2016;128 (22): 674. 46. Morgan G, Dimopoulos M, Gay F, et al. Maintenance Therapy with the Oral Proteasome Inhibitor (PI) Ixazomib Significantly Prolongs Progression-Free Survival (PFS) Following Autologous Stem Cell Transplantation (ASCT) in Patients with Newly Diagnosed Multiple Myeloma (NDMM): Phase 3 Tourmaline-MM3 Trial. Biol Blood Marrow Transplant. 2019;25(3):S19-S20. Information Classification: General 47. Nooka AK, Kaufman JL, Muppidi S, et al. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014;28(3):690-693. doi: 10.1038/leu.2013.335. 48. Nadiminti K, Strouse C, Vikas P, et al. A Single Autologous Stem Cell Transplant (ASCT) Followed By Two Years of Post-Transplant Therapy in Recently Diagnosed Elderly Multiple Myeloma (MM) 2018;132(Supplement 1):2153-2153. doi: 10.1182/blood-2018-99-118443. 49. IP T Patients. Safety and Response Results from the Prospective Phase II Trial (NCT01849783). Blood. Gay F, Cerrato C, Rota Scalabrini D, et al. Carfilzomib-lenalidomide-dexamethasone (KRd) R induction-autologous transplant (ASCT)-Krd consolidation vs KRd 12 cycles vs carfilzomib- randomized Forte trial in newly diagnosed SC cyclophosphamide-dexamethasone (KCd) induction-ASCT-KCd consolidation: analysis of the multiple 50. (NDMM). Blood. U 2018;132(Supplement 1):121-121. myeloma Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without AN daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 51. M 2019;394(10192):29-38. Lin T, Hampras S, Krey R, et al. Daratumumab Plus Lenalidomide Versus Lenalidomide Alone as D Maintenance Treatment in Patients With Newly Diagnosed Multiple Myeloma After Frontline Transplant: A Multicenter, Randomized, Phase 3 Study (AURIGA). Clin Lymphoma Myeloma ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US); [cited 2020 Sep EP 52. TE Leuk. 2019;19(10):e199. AC C 12]. Available from: https://clinicaltrials.gov/ct2/home. Information Classification: General Table 1: Summary of data from studies using thalidomide maintenance therapy after ASCT. No of Pts Treatmen Maintenance Efficacy of maintenance Safety (N), t regimens therapy maintenance therapy median maintena age in Yrs. nce (MA) therapy Maiolino et al., N= 213 IT: VAD Arm-A: m-PFS: Thal stopped (n: 13) 2012 MA= 55 Dexa 40 mg qd 36-mo (Arm-B) vs. 19-mo for 4/28 days. (Arm-A) HDM+AS SC 2-Yr-PFS: Dexa as above + 64% (Arm-B) vs. 30% Thal 200 mg qd (Arm-A), p: 0.002 U Arm-B: 2-Yr-OS: AN PD 33% (Arm-B) vs. 8% (ArmA), p: 0.001. M (Arm-A), p: 0.27 21% PN in Arm-B Thal 50 mg qd m-PFS: AEs (Thal): e: CTD or vs. no-Thal 23-mo (Thal) vs. 15-mo Paresthesia-26.6% (no-Thal), Drowsiness-6.8% [HR: 1.45, Rash-4.1% CI: 1.22-1.73, p: 0.001] Constipation-4.1% and TE D: till PD HDM+ Infection-1.0% Non- same, [HR: 0.91, CI: 0.72- Thrombosis-1.0% intensiv 1.17, p: 0.40] EP m-OS: SPM: e: MP SPM rates similar or (n: 12). CTDa Stewart et al., N= 332 IT+ 200 mg of Thal 4-Yr-PFS: TE: 2013 MA= 58 HDM+ qd + 50 mg of 35% (Thal-Pred) vs. 14% 7.3%(Thal-Pred) ASCT Pred (Obs), [HR: 0.56, vs. 0%(Obs), CI: 0.43-0.73, p: 0.0004 qod vs. Obs. p: 0.001]. D: 4 Yrs. or till PD Information Classification: General [18] Hematologic-1.4% ASCT C G3-4 AEs: Intensiv CVAD AC neuropathy) 85% (Arm-B) vs. 70% D N= 820 [17] n: 3 (DVT, skin rash, D: 1-Yr or till Morgan et al., Reference Thal discontinued, CT 2012 of IP T before concerns R Author, Yr. 4-Yr-OS: SPM: [19] 68% (Thal-Pred) vs. 60% Thal-Pred (n: 9) vs. (Obs), [HR: 0.77, Obs (n: 6) CI: 0.53-1.14, p: 0.18] IT+ ASCT Thal 100 mg qd 1-Yr-EFS: 60.47% Discontinuation: for [CI: 44.34-73.26%] 34.9% Pts due to AEs and 28 days PD. +Dexa 40 mg qd PFS: for 4 days. D: 1-Yr 86.05% (1-Yr) [CI: 71.55- Dose reduced/delayed in 93.48%] vs. 72.09% (2- 23.3% Pts/cycle. Yr) [CI: 56.12-83.08%] [21] IP T N= 43 R Kim et al., 2017 SC AEs: G-3/4 hematologic OS: 90.7% (1-Yr) U [CI: 77.09-96.41%] vs. MA= 56 M Arm-A: Arm-A: VAD (ctrl) IFN-α 3x106 IU/ thrice/wk TE Arm-B: Serious AE: 94.99%] Fulminant hepatitis Arm-B: (Thal) Thal 50 mg qd EP C AC DVT m-EFS: AEs (Thal)- 42%: 33-mo (Thal) vs. 22-mo Neuropathy-75% (ctrl), Skin reaction-6% [HR: 0·66, CI: 0·54–0·81, Fatigue-3% HDM/AS D: PD, CT relapse, or AE AEs (IFN-α)-27%: 10-Yr-EFS: Psychiatric-21% 20% (Thal) vs. 9% (ctrl) Flu-like symptoms-21% Hematologic-17% m-PFS: Skin reaction-13% 34-mo (Thal) vs. 23-mo (ctrl), SPM: [HR: 0·64, CI: 0·52–0·79, Thal (n: 29) vs. p <0·0001]. ctrl (n: 23), [HR: 1·08, CI: 10-Yr-PFS: 21% (Thal) vs. 9% (ctrl) m-OS: 75-mo (Thal) vs. 61-mo (ctrl), Information Classification: General Pneumonia p <0·0001]. TAD till PN- 44.2% 88.37%(2-Yr) [CI: 74.29- AN al. 2018 N= 536 D Van de Donk et URI- 46.5% 0·58–2·03; p: 0·80] [20] [HR: 0·81, CI: 0·65–1·02, Deaths: p: 0·075]. Thal (n: 16) vs. ctrl (n: 19) 10-Yr-OS: IP T 36% (Thal) vs. 26% (ctrl) R Abbreviations: AE: adverse effects; CI: 95% confidence intervals; CR: complete response; ctrl: control; CTD: cyclophosphamidethalidomide-dexamethasone; CTDa: attenuated-CTD; CVAD: cyclophosphamide-vincristine-Adriamycin-dexamethasone; D: duration; SC DVT: deep venous thrombosis; EFS: event-free survival; G: Grade; HDM: high-dose melphalan; HR: hazard ratio; IT: induction therapy; MA: median age; m-OS: median overall survival; m-PFS: median progression-free survival; MP: melphalan-prednisone; N: number; Obs: observation; PN: peripheral neuropathy; PD: progressive-disease; PFS: progression-free survival; Pts: patients; qd: once daily AN respiratory infection; VAD: vincristine-Adriamycin-dexamethasone. U dosing; qod: every other day dosing; SPM: second primary malignancy; TAD: thalidomide-Adriamycin-dexamethasone; URI: upper Notes: Confidence intervals (CI) are 95% unless specified otherwise. M P values less than 0.05 show significant results. AC C EP TE D Studies are described chronologically according to the year of publication. Information Classification: General Table 2: Summary of data from studies using lenalidomide maintenance therapy after ASCT. No of Pts (N), Treatment Maintenance Efficacy of maintenance Safety median age in before regimens therapy maintenance therapy Yrs. (MA) maintenance vs. Lena 10-15 mg m-PFS: G-3/4 Heme AE: vs. qd vs. Pbo 41-mo (Lena) vs. 23-mo 58% (Lena) vs. 23% (Pbo) N= 614 IT (VAD Bort-Dexa 2012-13 others) + ASCT (Pbo), [HR: 0.50, p: D: till relapse 0.001]. SC Attal et al., 5-Yr-PFS: U 42% (Lena) vs. 18% or AC younger HDM/ASCT vs. General-68% 5-Yr-OS: Vascular-17% 68% (Lena) vs. 67% Rash-20% (Pbo), [HR: 1] Nervous-51% PN-23% SPM: Lena (n: 44) vs. Pbo (n: 28) Lena 10 mg qd vs. no-MT m-PFS: 41.9-mo AES (Lena): (Lena) vs. 21.6-mo (no-MT), [HR: MPR D: till PD or AEs 0.47, CI: 0.33-0.65, p <0.001] 3-Yr-OS: 88% (Lena) vs. 79.2% Information Classification: General Infections-82% p <0.0001 AN M 65 [11,23] Hematologic-69% Gastrointestinal-72% D MA= Reference AEs: (Pbo), TE IT, N= 273 C 2014 EP Palumbo et al., of R Therapy concerns IP T Author, Yr. Neutropenia-23.3% Infections-6% Thrombocytopenia/rash 4.3% Anemia/vascular-1.7%. (no-MT), [HR: 0.64, SPM: CI: 0.36-1.15, p: 0.14] 4.3% in Lena vs. no-MT [33] Sborov et al., 2015 N= 16 IT, ASCT+ HDM MA= 58 vorinostat Median 200 mg, 300 38.4-mo mg, and 400 mg follow-up: Neutropenia-14.4% m-PFS/m-OS: NR Thrombocytopenia-11.9% Improved response: n: 7 10-25 Fatigue-13.5% Diarrhea-9.3% IP T Lena [37] AEs: mg qd Hypokalemia-7.6% Rash-5.9% + single/tandem ASCT MT (n:82) vs. no-MT (n: 44) MT: Lena-84% Thal-13% 51.5-mo, CI: 35.9-61.8 56% stopped MT due to PD [25] [8] OS (Lena): NR m-OS (post- relapse): 9.2-mo (MT) vs. 19.9- AN Lena-Bort-2% m-PFS (Lena): R CyBorD SC N= 136 U Cote et al., 2016 de Tute et al., N= 389 2017 IT:CTD vs. RCD Bort-based IT if response. 9.5% 55.8% conversion rate, post-MT vorinostat vs. no-MT vs. p <0.0001] EP MA= 61 (MRD-pos), [HR: 0.2, CI: 0.11-0.37, MRD-neg conversion: 32% (MT) vs. 4% (no- C AC N= 119 MT), p: 0.0045 ASCT Lena 10 mg qd m-PFS: AEs: D: 41.7-mo (CI: 30.1-NR) Neutropenia(G-3/G-4 33.2-mo (CI: 26.1-NR) OS: NR heme)-31% Infections-66% Fatigue-58% Diarrhea-29% Information Classification: General positive PFS: 20-mo no- ASCT Yang et al., 2017 MRD 50-mo (MRD-neg) vs. TE ASCT MRD-negativity: D suboptimal Lena vs. Lena- M mo (no-MT), p: 0.006. [34] Rash-23% Muscle cramps-18% PN-15% SPM: n: 4 N=280 RVD + ASCT 2017 Lena vs. no- Progression to 2nd- MT line: 22.1% (Lena) vs. 34.1% (no-MT), (HR: 5.466, TTNT: (Lena) U 52.24-mo SC p < .001] [26] R CI: 3.34-8.946, Not reported. IP T Fonseca et al., vs. 21.32-mo (no-MT), p: Cherniawsky et N= 198 al., 2017 AN <.001 Bort-based IT+ Lena-MT ASCT (+/Bort if M high-risk) vs. TE D no-MT NR (Lena) vs. 89-mo AEs: 3-Yrs-OS: Cytopenia -29.8% 88.4% (Lena) vs. 80.5% Rash-10.7% Infection-9.1% m-PFS: Fatigue-5.8% 55-mo (Lena) vs. 32.9mo (no-MT), p: 0.002 Thromboembolism-3.3%. SPM: 1.7% [27] IT: PAD/VCD Arms-A: m-PFS: AEs: HDM/ASCT A1: PAD+ 2- A1: 43.2-mo 77.6% (Arms-A) vs. A2: 40.9-mo 58.2% (Arms-B), p<0.001 Consolidation: Lena 25 mg qd. Yr-Lena. A2: VCD+ 2Yr-Lena. Arms-B: B1: PAD+ B1: 35.9-mo B2: 35.7-mo (p: 0.60) Infections: 36-mo-PFS: 52.7% A1+A2: Information Classification: General reduction in 60% (no-MT), p:0.01 (no-MT) EP N = 502 AC al., 2017 C Goldschmidt et [24] Discontinuation/dose m-OS: 56.1% vs. (Arms-A) vs. 32.3%(Arms-B), p<0.001 Lena till CR. B2: VCD+ Lena till CR. Lena 10-15 mg qd B1+B2: 49.4% [HR : 1.15, CI: 0.93- 1.44, p: 0.20] 36-mo-OS: A1: 82.9% IP T A2: 85.2% B1: 75.1% R B2: 77.1% SC (p: 0.02) 36-mo-OS: A1+A2: vs. 76.1%, U B1+B2: 84.1% AN [HR : 1.42, CI: 1.04–1.93, p: 0.030] N=2042 2017 IT CRD vs. CTD +/- PI if 2017 MA= 60 0.60] CRD-R: 50.2% CTD-R: 39.1% CTD-Obs: 23.4% CRD-Obs: 18.5% IT+ ASCT MT vs. no-MT m-PFS: MT: 50.3-mo Lena-80%, 30.8-mo [30] (Lena) vs. (no-MT), [HR: 0.62, CI: 0.46- Bort-11% 0.82, p: .0009] Lena-Bort-6% m-OS:NR for both. 3-Yr-OS: Information Classification: General [29] vs. Obs, 60-mo-PFS: EP C N= 432 AC Jagganath et al., m-PFS longer in Lena [HR: 0.47, CI: 0.38- TE response. D suboptimal Lena vs. Obs M Jackson et al., 85% (Lena) vs. 70% N= 460 2017 2 IT at maximum, ASCT Lena 10 mg qd vs. Pbo Neutropenia: m-TTP: 57.3-mo D: till PD (Lena) vs. 28.9-mo (Pbo), [HR: 0.0001] U m-OS: SC 057, CI: 0.46-0.71, p: AN 113.8-mo (Lena) vs. 84.1-mo (Pbo), [HR: 0.61, CI: 0.46-0.80, p: N= 84 TE D M 0.0004]. Thomas et al., ≤2 lines of IT ASCT AC C EP 2018 Information Classification: General [28] 50% (Lena) vs. 18% (Pbo) R Holstein et al., IP T (no-MT) Thrombocytopenia: 15% (Lena) vs. 5% (Pbo) SPM: Hematologic: 8%(Lena) vs. 1% (Pbo) Solid: 6% (Lena) vs. 4% (Pbo) 5-Yr-OS: 76% (Lena) vs. 64%(Pbo) ELO 10-20 3-Yrs-PFS: 81% AEs: mg/kg At 23-mo, 96% alive Neutropenia-32% Lena 10-15 mg Respiratory infections-17% qd Febrile neutropenia-15% D: until PD Diarrhea-14% Fatigue-13% Thrombocytopenia-8% Infections-8% Anemia/PN-7% SPM: n: 6 [38] Abbreviations: AE: adverse effects; CR: complete response; ctrl: control; 95%CI: Confidence interval; CTD: cyclophosphamidethalidomide,-dexamethasone; CyBorD: cyclophosphamide-bortezomib-dexamethasone; CRD: cyclophosphamide-lenalidomidedexamethasone; CVAD: cyclophosphamide-vincristine-Adriamycin-dexamethasone; D: duration; EFS: event-free survival; ELO: elotuzumab; HR: hazard ratio; MA: median age; mo: month or months; m-OS: median overall survival; m-PFS: median progression-free survival; MRD: Minimal residual disease; m-EFS: median event-free survival; m-TTP: median time to progression; MP: melphalan-prednisone; N: number; IP T NR: not reached; Obs: observation; PAD: bortezomib-doxorubicin-dexamethasone; Pbo: placebo; PN: peripheral neuropathy; PD: progressive-disease; PFS: progression-free survival; PI: proteasome inhibitor; qd: once daily dosing; SPM: second primary malignancy; TAD: thalidomide-Adriamycin-dexamethasone; TTNT: Time-to-next-line of therapy; IT: induction therapy; URI: upper respiratory infection; VAD: R vincristine-Adriamycin-dexamethasone; VCD: bortezomib-cyclophosphamide-dexamethasone. Notes: SC Confidence intervals (CI) are 95% unless specified otherwise. P values less than 0.05 show significant results. AC C EP TE D M AN U Studies are described chronologically according to the year of publication. Information Classification: General Table 3: Summary of data from studies using proteasome inhibitors maintenance therapy after ASCT. Maintenance Efficacy median age in maintenance regimens maintenance maintenance Yrs. (MA) therapy therapy therapy N= 52 Bort-containing MA= 52 regimens +/- IMiD or bendamustine. of 2-Yr-RFS: Bort (n: 14) vs. no- 49% (MRD-pos) vs. MT (n: 11) 60% CI: MRD-neg: Single/Tandem ASCT Not reported. MRD-pos: (MRD-neg), [HR: 1.7, 1.3−3.4, Safety concerns of IP T 2016 Treatment before Reference [44] R Solovev et al., No of Pts (N), p: SC Author, Yr. 0.056) Bort (n: 19) vs. no- MRD-neg: U MT (n: 8) 2-Yr-RFS 84% for Bort vs. no-MT, p: AN Bort-regimen: 1.3 mg/m2 SC q2wks for 1-Yr 0.46 M MRD-pos: 2-Yr RFS 43% (Bort) Rosinol et al., N= 283 2017 0.076 IT: TD vs. VTD Thal 100 mg qd + CR: Dose reduction: vs. IV Bort 1.3 mg/m2 Thal-Bort: 21% Thal-Bort: 33.7% VBMCP/VBAD/B on D1, 4, 8, 11 IFN-α: 17% Thal: 27.5% every 3-mo Thal: 11% IFN-α:11.1% vs. Thal 100 mg qd PFS: vs. 50.6-mo (Thal-Bort) Discontinuation: vs. 40.3-mo (Thal) Thal: 39.7% vs. 32.5-mo (IFN-α), Thal-Bort: 21.9% p: 0.03. IFN-α: 20% EP Age= 65-year- TE D vs. 35% (no-MT), p: old or younger. C ASCT+ HDM IFN-α 1.5-3 SC 3 MU AC times/wk. [6] OS: not different. G3-PN highest in Thal-Bort group. Moreau et al., 2017 N= 42 MA= 60 IT: Ixaz-Lena- Dexa (IRd) HDM/ASCT Information Classification: General Ixaz: CR: AEs (Ixaz-MT): 4 mg on D1, 8, 15 IT: 12% Rash (n: 1) ASCT: 19% Infection (n: 1) on 28 days cycle [45] Early (IRd) and D: 12-mo late (IR) cons Early cons: 32% Late cons: 36% MT: 48% 2-Yr-PFS: 83% Total relapses: n:7 al., 2018 VAD arm (ctrl): m-PFS: qd 34-mo (Bort) vs. 28mo (ctrl), [HR: 0.7, CI: VAD+ Bort-based: Bort HDM/ASCT 1.3 mg/m2 q2wks Bort-based D: 2-Yrs PAD+ Median duration: HDM/ASCT 14-mo (Thal) vs. 0.65-0.90, p <0.001] 91-mo (Bort) vs. 82mo (ctrl) M D IT, HDM/ASCT vs. Bort-11% (Bort) 33% (Thal) vs. 36% PD/relapse: 96-mo-OS: 75% (ctrl) vs. 70% (Bort) (ctrl), [HR: 0.89, CI: 0.74-1.08, p: 0.24] SPM: 7% in both Ixaz (D1, 8, 15 of 28-day cycle) vs. Pbo PFS at 31-mo: Discontinuation: 26.5-mo (Ixaz) vs. 7% (Ixaz) vs. 5% 21.3-mo (Pbo), [HR: (Pbo) 0.72, D: 2-Yrs, till PD or toxicity CI: 0.582- 0.890, p: 0.002] MRD-neg status: 12% (Ixaz) vs. 7% (Pbo) Information Classification: General (Thal) (Bort) 48% (Bort) vs. 45% TE EP C MA= 58 AC 2019 N= 656 31% discontinuations: 23-mo (Bort) Morgan et al., discontinuations: PD-related m-OS: AN arm: [40] Toxicity-related Ctrl: Thal 50 mg SC N= 827 U Goldschmidt et R MT: n:2. IP T OS: 95% G3 or above AEs: 42% (Ixaz) vs. 26% (Pbo). SPM: 3% in both. [46] Deaths: Ixaz (n: 1) vs. Pbo (n: 0) Abbreviations: Cons: consolidation; CR: complete response; CI: 95% confidence interval; D: duration or days; G: grade; MRD: minimal-residual disease; MA: median age; HDM: high-dose melphalan; HR: hazard ratio; Pbo: placebo; Ixaz: ixazomib; IRd: IP T ixazomib-lenalidomide-dexamethasone; IR: Ixazomib-lenalidomide; PAD: bortezomib-Adriamycin-dexamethasone; Pbo: placebo; Pts: patients; PD: progressive-disease; RFS: relapse-free survival; SC: subcutaneous; SPM: second primary malignancy; VAD: vincristineAdriamycin-dexamethasone wk: week or weeks. R Notes: SC Confidence intervals (CI) are 95% unless specified otherwise. P values less than 0.05 show significant results. AC C EP TE D M AN U Studies are described chronologically according to the year of publication. Information Classification: General Table 4: Summary of data from studies using combination maintenance therapy after ASCT. (N), median before regimens maintenance therapy maintenance therapy age in Yrs. maintenance (MA) therapy N= 45 IT+ RVD(1st-3rd Yrs.: m-PFS: 32-mo Discontinuation al., 2014 HDM/ASCT IV/SC 3-Yr-OS: 93% Bort 1.3 M/ASCT MA= 68 1st-Yr: VDT AN et al., 2018 VDT- neuropathy: 0% modification: U 4th-Yr: Lena IT+ [47] 40% 40 mg/wk N= 41 G-3/4 Dose mg/m2/wk., Pred Nadiminti of Reference MT due to AE: 0% Lena 10 mg qd for 21/28 days, IP T et of Efficacy Pts R Nooka concerns Maintenance of of Safety Treatment No SC Author, Yr. Median follow-up: 27-mo 2nd-Yr: VCD M m-PFS/OS: NR D D: 2 Yrs. 3-Yr-PFS (82%) vs. 3Yr-OS (90%) [48] AEs: Infection (25%) Diarrhea (16%) Mucositis (11%) TE sCR (n: 16) CR (n: 2) Abbreviations: B: bortezomib; CTD: cyclophosphamide-thalidomide-dexamethasone; CRD: cyclophosphamide-lenalidomide, EP dexamethasone; G: Grade; HDM: high-dose melphalan; m-PFS: median progression-free survival; MPR: melphalan-prednisonelenalidomide; MT: maintenance therapy; NR: not-reached; OS: overall survival; RCD: lenalidomide-cyclophosphamidedexamethasone; sCR: Stringent complete response; TD: thalidomide-dexamethasone; VTD: bortezomib-thalidomide- C dexamethasone; VDT: bortezomib-dexamethasone-thalidomide; VCD: bortezomib-cyclophosphamide-dexamethasone; VBMCP: AC vincristine-BCNU-melphalan-cyclophosphamide-prednisone; VBAD: vincristine-BCNU-doxorubicin-dexamethasone. Information Classification: General Table 5: Ongoing clinical trials on novel combinations of maintenance therapy. NCT number Phase Number of Start date Maintenance regimens Completion date participants, N I 18 SVN53-67/M57-KLH Peptide Vaccine+ 03/2016 Sargramostim+ Lena II 50 05/2020 II 50 Dara-carfilzomib-Dexa SC Bort-Lena NCT03004287 09/2022 R NCT03641456 11/2022 IP T NCT02334865 07/2017 01/2021 alternating with Dara-Lena- II 52 Ixaz-Lena vs. Ixaz 03/2019 02/2024 NCT03942224 II 76 Dara-Dexa-Ixaz M 07/2019 07/2024 NCT02389517 II Ixaz-Lena-Dexa vs. Lena 03/2015 03/2022 400 Ixaz vs. Ixaz-Dara 04/2019 02/2025 III 214 Dara-Lena vs. Lena 04/2019 05/2021 NCT03617731 III 662 Isatuximab-Lena vs. Lena 10/2018 12/2025 NCT03948035 III 576 ELO-Lena vs. Lena 08/2018 08/2029 AC NCT03901963 86 EP NCT03896737 TE D NCT03733691 C AN U Dexa. II Information Classification: General NCT04071457 III 1100 Dara-Lena vs. Lena 06/2019 07/2040 NCT04217967 IV 180 Ixaz vs. Lena vs. Ixaz-Lena 01/2020 10/2022 IP T Abbreviations: Bort: bortezomib; Dara: daratumumab; Dexa: dexamethasone; ELO: elotuzumab; Lena: AC C EP TE D M AN U SC R lenalidomide; NCT: national clinical trial; Ixaz: ixazomib. Information Classification: General IP T R SC U AN Figure 1. Summary of maintenance therapy options after HDM/ASCT in newly diagnosed multiple M myeloma (Abbreviations: ASCT: Autologous stem cell transplantation, HDM: high-dose melphalan, HRMM: high-risk multiple myeloma, MM: multiple myeloma, MRD: minimal-residual disease, OS: overall AC C EP TE D survival, PFS: progression-free survival, SPM: second primary malignancies). Information Classification: General