Therapy Post Autologous Stem Cell Transplantation Research Articles

Disease Characteristics and Outcomes of 493 Young Myeloma Patients Treated With Modern Therapies: A Canadian Myeloma Research Group Database Study.

Young patients ≤ 50 years old with multiple myeloma (MM) account for about 10% of cases and are underrepresented in the literature. We explored disease characteristics, treatments, and outcomes following modern therapies of young MM patients using the Canadian Myeloma Research Group (CMRG) database. We included 493 patients ≤ 50 years old diagnosed with MM or plasma cell leukemia without concurrent amyloidosis or POEMS syndrome from January 1, 2010, to July 1, 2022. The median age was 46 years old (range: 25.6-50). Most patients fell into the R-ISS II category (72.7%), and 24.1% had high-risk cytogenetics. The majority of patients (89.9%) received a proteasome inhibitor-based first-line treatment, 92.1% received a stem cell transplant, and 65.6% had maintenance therapy post-autologous stem cell transplant (ASCT). Median follow-up from initial treatment to patients' last follow-up was 48.5 (range: 0-155) months. Median progression-free survival (PFS) was 45.0 months (95% CI: 40.2-50.0). Maintenance therapy post-ASCT improved median PFS to 52.3 months (95% CI: 43.1-68.2), compared to 23.6 months (95% CI: 20.0-34.8) without maintenance[p < 0.001]. Although the overall survival has not yet been reached in this young population, our reported median PFS of only 45 months highlights the urgent need to develop innovative treatments to induce more profound and durable responses.

Final results of a phase II study of lenalidomide-elotuzumab as maintenance therapy post-autologous stem cell transplant (AuSCT) in patients (Pts) with multiple myeloma (MM).

7509 Background: Randomized controlled trials oflenalidomide (LEN) maintenance after AuSCT have shown a progression free survival (PFS) benefit in pts with MM. We report final results of a phase 2 trial evaluating the efficacy and safety of adding elotuzumab (ELO) to LEN as maintenance therapy post- AuSCT. Methods: On 28-day cycles, patients received ELO 10mg/kg iv weekly for cycles 1-2.Between 4/15/2015-1/27/2016, 27 pts received ELO 10mg/kg q2 weeks for cycles 3-6 and 20mg/kg monthly for cycles 7+. From 1/28/2016 forward, 74 pts received ELO 20 mg/kg monthly from cycle 3+. LEN was dosed at 10 mg/day for cycles 1-3 and increased to 15 mg/day at physician discretion starting with cycle 4 in the absence of non-hematologic (HEME) toxicity &gt; grade 1, ANC &lt; 1000/mL and platelet count &lt; 100K/ml. For the 1st 8 weeks, pts &lt;75 yrs received 28 mg of dexamethasone (DEX) 3-24 hours pre-infusion and pts ≥75yrs received 8 mg; pts received 4-10 mg iv DEX pre-infusion for all cycles. Zoster and thromboembolic prophylaxis were prescribed as per standard recommendations. The primary endpoint was PFS, defined as time from AuSCT to progressive disease (PD) or death (whichever occurred first), or censored at last contact date. Secondary objectives were best response, overall survival (OS), incidence of second primary malignancies (SPMs) and adverse event (AE) profile. Enrollment was completed on 6/5/2019. Eligible pts received ≤2 induction lines of therapy (LOT) and were 60-210 days post-AuSCT. Results: Pts (n=100) were treated for a median of 40 cycles (2-109). With a median follow up of 74.3 mos, 78% of pts (n=79) remain alive. Median PFS was 75.4 months. Median OS has not been reached; 5-year OS rate was 86.7%. At study entry, rate of ≥VGPR was 77.3% and ≥CR was 37.7%. On study, this improved to 91.1% ≥VGPR and 69.3% ≥CR. Of pts in ≥VGPR and tested for minimal residual disease (10-5 sensitivity by flow cytometry), 37/44 were negative. High-risk cytogenetics (n=44; p&lt;0.0001), International Staging System (ISS) Stage III (n=10/95, p=0.049) and Revised-ISS Stage III (n = 3/89; p= 0.026) predicted shorter median PFS (39.2, 53.2 and 32.2 mos. respectively). Median PFS on next LOT was 21.8 mos. Grade 3-4 HEME AEs (n=102) were: neutropenia 35%, thrombocytopenia 7%, and anemia 10% . Grade 3-4 non-HEME AEs in &gt;3 pts were: respiratory infections 23%, hypophosphatemia 19%, diarrhea 13% , fatigue 11% , peripheral neuropathy 7%, other infections 6%, myalgias 4%, and high ALT 4%. Incidence of HEME, non-invasive and solid tumor SPMs was 8%, 8% and 7%. Median time to HEME SPM diagnosis was 45.5 mos. Conclusions: ELO-LEN is a well-tolerated maintenance therapy on which 53% of patients had improved quality of response. Median PFS and 5-year OS compare favorably with results from CALGB 100104 and IFM 2005-02 trials of lenalidomide alone. SPM incidence is similar to rates reported in these trials. Clinical trial information: NCT02420860 .

Planned Interim Safety Analysis of the Phase 3 Randomized Trial of Selinexor and Lenalidomide Versus Lenalidomide Maintenance Post Autologous Stem Cell Transplant for Patients with Newly Diagnosed Multiple Myeloma (ALLG MM23; Sealand)

Introduction: Upregulation of Exportin 1(XPO1), a molecule that mediates nuclear export of tumor suppressor proteins, is associated with poor prognosis and resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors in myeloma (MM). Selinexor (S) is an oral selective XPO1 inhibitor, that is approved in combination with bortezomib and dexamethasone to treat adult patients with MM who have received at least one prior therapy. We hypothesize that low dose S when combined with low dose lenalidomide (R) will be synergistic and will improve progression free survival (PFS) compared to R maintenance post autologous stem cell transplant (ASCT) in patients (pts) with transplant eligible (TE) newly diagnosed (NDMM). We report here the results of the planned futility analysis, after at least 30 patients had completed a minimum of 6 months follow-up in the phase III randomized SeaLAND (ALLG MM23) study (ANZCTR12620000291987). Method: Eligible pts were TE NDMM who have had 3 to 6 cycles of induction containing bortezomib (V), dexamethasone ± R. Registration occurred pre-ASCT; screening and randomization occurred from day 75 to 115 post-ASCT. Twenty pts in the lead in safety phase were given low-dose S [40mg (increased to 60mg from C2 if well tolerated) po D1,8,15,22] with R (15mg D1 to 21; 10mg in C1 to 3) in a 28-day cycle. Upon review by the independent safety committee in May 2023, after the first twenty pts had completed 2 cycles of SR, a starting dose of S of 40mg/week was deemed generally safe with no escalation recommended. Subsequent patients were randomized 1:1 to either SR (S capped at 40mg/week) or R. Primary objective was to determine 3-year-PFS; secondary objectives included safety/tolerability and additional efficacy measurements. Results: As of 30 May 2023, 117 pts (70% male) received maintenance (69 pts SR; 48pts R). 103 patients (61 SR and 42 R) had clean data at a cut-off date and were included in this analysis. Median (med) age was 60 (range 34-75). 27.4% of patients had high risk cytogenetics; ISS stage 1,2,3 occurred in 31.5%, 47% and 26.5%, respectively. Med follow-up for the overall group was 11.9 (0.3-28) months, with a med 10 (1-27) cycles [10 (1-27) SR; 9.5 (2-21) R] and 86.1% of patients continued treatment (83.1% SR; 90.7% R). All patients (n=103) had ≥ 1 treatment-emergent adverse event (TEAE); 64% grade (Gr) 3-4 (84% SR, 36% R); SAE occurred in 21% (28% SR, 12% R). Hematologic Gr 3-4 TEAEs were anemia (1.6% SR; 4.8% R), neutropenia (60.7 SR; 28.6% R) and thrombocytopenia (24.6% SR; 0% R). Gastrointestinal TEAE occurred in 50.4% of all patients (67.5% SR, 26.2% R). Diarrhea, nausea and vomiting in the SR (Gd 3-4)/R (Gd 3-4) group occurred in 26.3% (3.3%)/23.8% (2.4%), 57.1% (9.8%)/7.1% (0%), and 8.2% (1.6%)/0% (0%), respectively. The incidence of gastrointestinal TEAE in the SR group decreased from C3 onwards. Infections occurred in 41% of all patients (49% SR, 29% R); Gd 3-4 infections in 9 % (15% SR, 0% R). COVID-19 infections occurred in 16% (13% SR; 19% R), and all but one was Gd 1-2. 1 patient died (SR arm) due to progressive disease. In the SR group, the med RDI (relative dose intensity) of S was 66.7% (20.8-150%), and in the R group; the med RDI of R was 100% (33.3-100%). Most patients in the SR arm (n=61) tolerated S dose between 80mg (20mg per week) to 160mg (40mg per week), which remained consistent with time (figure 1). Conclusion: A dose of S 40mg weekly was generally tolerable when combined with R 10-15mg days 1-21 in a 28-day cycle, as maintenance therapy post ASCT. The safety profile was consistent with each of S and R individually. Recruitment in the ALLG MM23 (SeaLAND) study is ongoing and updated safety and treatment data will be presented at the meeting. Acknowledgement: Patients, their families, and participating ALLG members and member sites. ALLG acknowledges the support of Karyopharm for funding and Selinexor supply.

Immunogenicity of Covid-19 Vaccine Among Multiple Myeloma Patients Post Autologous Stem Cell Transplant

Background: mRNA vaccines against SARS-CoV-2 have proven to be safe and effective and have been widely administered. Multiple myeloma (MM) is a disease of plasma cells and is known to weaken the host immunity leading to ineffective vaccine response there by increasing the risk of contracting severe disease. Anti-MM therapy can further suppress the immune system and consequently worsen vaccine response. Autologous stem cell transplant (ASCT) is the standard of care for fit MM patients and leads to prolonged immunosuppression. The effect of ASCT on vaccine response has not been well studied. In an effort to elucidate optimal timing and number of vaccines post ASCT we investigated the seroconversion rate among MM patients who received at least one vaccination post ASCT Methods: We conducted a single center retrospective analysis in patients at the University of Arkansas Medical Center (UAMS) who underwent ASCT for MM and subsequently received at least one dose of either available mRNA vaccine (Pfizer or Moderna). Antibody titers against SARS-CoV-2 spike glycoprotein were checked at various timelines post vaccination. Testing was performed using Roche Elecsys Anti SARS CoV-2 reagent assay from Roche diagnostics. We categorized the patients into two groups: complete responders with titers levels more than 250 U/ml and partial responders/non-responders with titers levels less than 250 U/ml. Covariates used were age, sex, race, MM isotypes, vaccine count, time from last transplant to first dose of vaccine and maintenance therapy post ASCT. Welch's t-test and Wilcoxon rank-sum test were used for continuous variables, while Fisher's exact test was used for categorical variables. Results: A total of 64 patients were analyzed. The mean age was 62.5 years (Range:35-81), with 39.1% (25/69) being female. The most common isotype was IgG and the most common free light chain was kappa, comprising 73.1% (38/53) and 68.8% (44/64) respectively. All patients initiated maintenance after ASCT consisting of daratumumab (30/64, 47.6%), proteosome inhibitors (47/64, 74.6%), immunomodulators (50/64, 78.7%) and steroids (58/64, 92.1%). The first vaccine dose was given at a minimum of 70 days after ASCT and for vaccinations that were given during the maintenance period, treatments were held one week prior and after each vaccine dose. The median follow up duration in days from 1st transplant to last follow-up was [Median, Inter quartile range (IQR)]: 152.0 (68.8, 254.3). At time point of data collection 25/64 (39.1%) had received at least 3 vaccines prior to titer assessment. Of those, 18/25 (72%) were complete responders compared to 7/25 (18%) partial/non-responders, p=0.02. In total, we observed 53.1% of subjects in the entire cohort mounted a complete response (>250 U/ml). Within the complete responders, there were significantly more patients who had received at least 3 vaccines post ASCT having higher chances of a complete response compared to those who received less vaccines, regardless of how many vaccines were given prior to ASCT, 76.5% vs 23.5%, p=0.03. There was a trend towards more time from transplant to first vaccine being associated with a complete antibody response (median days of 171 for complete responders vs 128 days for non/partial responders), albeit that was not significant, p=0.3. Factors that adversely impacted antibody response were higher age (>65), p=0.02 and daratumumab containing maintenance, p=0.04. Intriguingly, we observed significantly better antibody response in patients with IgA MM isotype compared to IgG Isotype, p=0.03, albeit the numbers were small for this analysis (IgA n=14/65). No significant difference was noted between complete and partial/non responders in regard to sex, race, light chain type, IVIG administration and other maintenance regimens. At the time point of data collection, a total of three patients developed symptomatic Covid infections, all of which were in the non-responders/partial responders' group; none of them required hospitalization. Conclusion: The administration of at least 3 mRNA Covid vaccines post ASCT leads to significantly improved antibody titers and should be the minimum standard in this patient population. Higher age (>65 years), IgG subtype and daratumumab based maintenance were associated with suboptimal response to Covid vaccine among post ASCT and those MM patients should have high priority to receive additional prophylactic measures.

Retrospective study of treatment patterns and outcomes post-lenalidomide for multiple myeloma in Canada.

Lenalidomide is an important component of initial therapy in newly diagnosed multiple myeloma, either as maintenance therapy post-autologous stem cell transplantation (ASCT) or as first-line therapy with dexamethasone for patients' ineligible for ASCT (non-ASCT). This retrospective study investigated treatment patterns and outcomes for ASCT-eligible and -ineligible patients who relapsed after lenalidomide as part of first-line therapy, based on data from the Canadian Myeloma Research Group Database for patients treated between January 2007 and April 2019. Among 256 patients who progressed on lenalidomide maintenance therapy, 28.5% received further immunomodulatory derivative-based (IMiD-based) therapy (lenalidomide/pomalidomide) without a proteasome inhibitor (PI) (bortezomib/carfilzomib/ixazomib), 26.2% received PI-based therapy without an IMiD, 19.5% received both an IMiD plus PI, 13.5% received daratumumab-based regimens, and 12.1% underwent salvage ASCT. Median progression-free survival (PFS) was longest for daratumumab-based therapy (22.7months) and salvage ASCT (23.4months) and ranged from 6.6 to 7.3months for the other treatments (P<.0001). Median overall survival (OS) was also longest for daratumumab and salvage ASCT. A total of 87 non-ASCT patients received subsequent therapy, with 66.7% receiving bortezomib-based therapy and 13.8% receiving other PI-based therapy. Median PFS was 15.4 and 24.8months for bortezomib-based and other PI-based therapy, respectively (P=.404). During most of the study period, daratumumab was not funded; in this setting, switching to a different therapeutic class following relapse on lenalidomide produced the longest remissions for non-ASCT patients. Further prospective studies are warranted to determine optimum treatment following relapse on lenalidomide, especially in the light of increased access to daratumumab.

Assessing Outcomes, Healthcare Resource Utilisation and Costs across Europe in Newly Diagnosed Multiple Myeloma (NDMM) Patients Post Autologous Stem Cell Transplant (ASCT)

BACKGROUNDRecently introduced treatment options, including the introduction of maintenance therapy (MT) post ASCT, have significantly improved outcomes and life expectancy of MM patients. To date, the impact these treatment options have on healthcare resource utilisation (HCRU) has not been assessed.AIMSThe aim of the analysis was to determine current management of post-ASCT NDMM patients in terms of outcomes, HCRU and the associated costs in Europe for patients receiving either MT or no MT.METHODSA retrospective chart review was conducted in France, Germany, Italy, Spain and the UK in Q1 2017. Physicians provided data on consecutive patients with MM who had undergone an ASCT as part of first-line (1L) treatment on or after 1st January 2014; HCRU data was collected post initial ASCT until the end of follow-up. Mean follow-up time for patients was 18.2 months (21.2 vs 18.0 months for patients receiving and not receiving MT post initial ASCT, respectively).Data collected pertained to patient characteristics, treatment patterns, duration of treatment and outcomes (including time to progression [TTP] estimated based on Kaplan-Meier method), HCRU post initial ASCT including: supportive drugs, other supportive treatments (blood transfusions and dialysis), hospitalisations, healthcare professional (HCP) visits and monitoring tests conducted, but excluded cancer drug costs.Costs were applied to the relevant resources consumed. Tariffs from a single-country health service (the United Kingdom) were applied; an exchange rate of £1 to €1.1365 was used (correct as of 1st July 2017). Cost for hospitalisations, HCP visits, supportive treatments and monitoring tests were obtained from the NHS Schedule of Reference Costs (2015-2016), and supportive drug costs were obtained from MIMS 2017. The costs have been applied to data collected from the healthcare system perspective, thus allowing for a broad overview to assess the impact of MT on HCRU across treatment lines post 1L ASCT. Monthly resource use was calculated for the duration of the follow-up time for patients.RESULTSFifty-one physicians completed record forms for 337 patients. Fifty-seven percent of patients were male; mean age at diagnosis was 58.7 years (± 7.7 SD). Mean duration from diagnosis to receiving an ASCT was 9.8 months (± 13.2 SD). Of the patients included in the study, 61%, 27% and 9% had received up to 1L, second-line (2L) and third-line (3L) therapy, respectively; 3% of patients also went onto receive ≥ 4 lines. In the 1L setting, 93% of patients did not receive any MT post ASCT; 7% received MT. Of the patients who did not receive MT, 40% and 12% went on to receive 2L and 3L therapy respectively, whereas only 20% of patients who received MT went on to 2L and none on to 3L. The most frequently prescribed regimens at 1L MT were lenalidomide (88%), bortezomib (8%), and thalidomide (4%).The mean TTP from start of 1L therapy was 30.0 months (95% CI: 27-32 months; n = 312) for patients not receiving MT and 39.0 months (95% CI: 31- months; n = 24) for patients receiving MT.Of the 337 patients, 91 had complete resource use data across their treatment pathway. The total cost of HCRU post 1L ASCT per patient was €945.80 per month; patients receiving MT (n = 14) had an associated HCRU cost of €638.14 per month, whereas patients not receiving MT (n = 77) cost €1001.74 per patient per month. Over the course of the treatment pathway, the level of HCRU consumption varied depending on the type of resource (Table 1). Patients receiving MT required a higher level of supportive drugs (€442.52 vs €250.15 per patient, respectively) and other supportive treatments (€55.12 vs €22.18, respectively). However, the utilisation of other resource data captured was higher for no-MT patients vs MT patients (hospitalisations: €243.12 vs €59.78; HCP visits: €498.58 vs €181.11; monitoring tests: €198.48 vs €84.20 per patient, respectively).CONCLUSIONThe patient sample observed within this real-world study is reflective of the patient demographics data reported in Raab et al. 2016. The TTP data for patients not receiving MT post ASCT at 1L is comparable to recently published pooled PFS data from large RCTs. The data presented indicates that the use of MT therapy at 1L defers future treatment lines, therefore reducing the overall monthly HCRU cost relating to hospitalisations, HCP visits and monitoring over a patient's MM treatment pathway. [Display omitted] DisclosuresAshcroft:Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Dhanasiri:Celgene Corporation: Employment, Equity Ownership.

In the Era of Chemoimmunotherapy, Relapse Post Autologous Stem Cell Transplantation for Follicular Lymphoma Is Associated with Prolonged Overall Survival. an Analysis By the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

In the Era of Chemoimmunotherapy, Relapse Post Autologous Stem Cell Transplantation for Follicular Lymphoma Is Associated with Prolonged Overall Survival. an Analysis By the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Update on a Phase II Study of Ixazomib with Lenalidomide As Maintenance Therapy Following Autologous Stem Cell Transplant in Patients with Multiple Myeloma

Update on a Phase II Study of Ixazomib with Lenalidomide As Maintenance Therapy Following Autologous Stem Cell Transplant in Patients with Multiple Myeloma

Phase II Trial of Bortezomib Plus Rituximab As Maintenance Therapy Post ASCT for Patients with Mantle Cell Lymphoma

Background:The standard of care for younger patients with mantle cell lymphoma is induction chemotherapy followed by autologous stem cell transplantation (ASCT). Rituximab (R) maintenance therapy post induction has been shown to improve overall survival (OS) (Kluin-Nelemans et al. NEJM 2012), and R maintenance post ASCT has been shown to improve progression free survival (PFS) (Graf SA et al. Ann Oncol 2015) and OS (Le Gouill S et al. ASH 2016). Bortezomib as consolidation has been shown to be feasible and tolerable in patients with MCL post ASCT (Kaplan L et al, ASH 2015). We hypothesize that the combination of bortezomib plus R as maintenance therapy post ASCT in patients with MCL may increase the disease free survival (DFS). We report our final results including quantitative CCND1 mRNA monitoring for minimal residual disease.Methods:This is a multicenter phase II maintenance study in patients with MCL post ASCT. Bortezomib was given at 1.3 mg/m2SQ once a week for 4 weeks every 3 month for 2 years. Rwas given at 375 mg/m2 IV once a week for 4 weeks every 6 months for 2 years. CT and/or FDG-PETwere performed at every 6 months. The primary endpoint was to reach a 2 year DFS of > 80%. Secondary endpoints included toxicity, relapse rate, OS, and CCND1 mRNA as MRD monitoring. Peripheral Blood was collected at baselineand on day 1 of each cycle (3 month interval), and CCND1 mRNA was assessed using droplet digital PCR technology (ddPCR) on RNA extracted from peripheral blood mononuclear cells. JVM2 (MCL cell line), normal healthy patient, and an untreated patient with MCL involvement served as controls. Absolute transcript concentrations were normalized to HPRT1 (housekeeping gene) followed by a normalization to the positive control, JVM2 (100%).Results:Twenty three patients were accrued, with 23 eligible for analysis. Majority of the patients were male (96%), received ASCT and maintenance therapy in CR1/PR1 (91%), had advanced stage at diagnosis (70% stage IV), and considered young with a median age of 59 (45-66). About half had low risk disease by MIPI and half with intermediate to high risk disease. The median follow- up was 29.8 months. The 2 year DFS is 89.7% (95% CI: 64.8-97.3) and 2 year OS is 94.7% (95% CI: 68.1-99.2) for the whole cohort (Figure 1). The 2 year DFS is 94.4% (95% CI: 66.6-99.2) and 2 year OS is 100% (95% CI: NA) for the 21 patients who received induction therapy followed by ASCT and R maintenance in CR1/PR1. Two patients who entered trial had relapsed/refractory MCL.Treatment was well tolerated. The median number of completed cycle was 8/8 (1-8) with a median duration of therapy of 19.9 month. Grade 3/4 toxicities possiblyattributable to study drug included neutropenia (n=17), lymphopenia (8), pneumonia (2), anemia (2), skin infection (1), hyperglycemia (1), and thrombocytopenia (1). Grade 2 possibly related toxicities that occurred in > 10% included upper respiratory tract infection (5), hypertension (5), diarrhea (3), fatigue (3), neutropenia (1), and thrombocytopenia (3). With regard to the specific adverse event of peripheral sensory neuropathy, Grade 1 event occurred in 10 patients and Grade 2 in 2 patients. There were no treatment discontinuations due to neutropenia or neuropathy. There were 2 death on study, 1 from relapsed MCL and 1 from alloHCT for MDS.MRD monitoring was performed on 18 patients seen at COH. Twelve out of 18 patients had at least 36 months analysis while 6/18 had less than 12 months for analysis. High CCND1 mRNA was detected in an untreated patient (control) with MCL involvement and JVM2 cell line. Low CCND1 mRNA was detected in normal healthy control, all samples while on maintenance R, and all patients without radiographic progression of disease (Figure 1). . Unfortunately, no samples were obtained on the two patients who developed progressive disease (1 due to withdraw of consent prior to relapse, the other due to urgency of treatment).Conclusions: The combination of bortezomib with R as maintenance therapy for MCL is well tolerated post ASCT and has met the primary endpoint of prolonging 2 year DFS. Quantitative CCND1 mRNA monitoring by ddPCR is feasible and appears to correlate with clinical remission status. The combination therapy of bortezoimb and R maintenance therapy post ASCT and CCND1 mRNA MRD monitoring method warrants further investigations. [Display omitted] DisclosuresChen:Pfizer: Consultancy; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Speakers Bureau; Affimed: Research Funding. Nademanee:seattle Genetics: Speakers Bureau. Siddiqi:Juno: Other: Steering committee for JCAR017; Seattle Genetics: Speakers Bureau; Pharmacyclics, an AbbVie Company: Other: Steering committee for ibrutinib, Speakers Bureau. Kwak:Pepromene Bio: Consultancy, Equity Ownership; Celltrion, Inc: Consultancy; InnoLifes: Consultancy, Equity Ownership. Holmberg:Seattle Genetics: Research Funding; Sanofi: Research Funding; Merck: Research Funding; Millennium: Research Funding; JAZZ: Consultancy; Up To Date: Patents & Royalties.

AL Amyloidosis: The Effect of Maintenance Therapy on Autologous Stem Cell Transplantation Outcomes.

Background: Autologous stem cell transplantation (ASCT) remains an effective treatment option for many patients with systemic light chain (AL) amyloidosis. While maintenance post ASCT in multiple myeloma is now standard, the decision to utilize maintenance in AL amyloidosis remains largely unexplored. The present study aims to determine the prognostic significance of utilizing maintenance therapy following ASCT and assess the impact of fluorescent in situ hybridization (FISH) abnormalities, bone marrow plasma cell burden (BMPC), and degree of organ involvement on this decision. Methods and results: This is a retrospective analysis of fifty AL amyloidosis patients who underwent ASCT at The Ohio State University. Twenty-eight patients received maintenance and twenty-two did not. Kaplan–Meier survival analysis was used to compare the effect of maintenance therapy with no significant difference in PFS (p = 0.66) and OS (p = 0.32) between the two groups. There was no difference in survival based on maintenance when further categorized by FISH, PFS (p = 0.15), and OS (p = 0.65); BMPC ≥ 10%, PFS (p = 0.49), and OS (p = 0.32); or with 2 or more organs involved, PFS (p = 0.34) and OS (p = 0.80). Conclusion: Maintenance therapy post ASCT did not impact PFS or OS when categorized by FISH abnormalities, increasing BMPC, or ≥2 organs involved in AL amyloidosis patients.

Update of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant (AuSCT) in Patients (Pts) with Multiple Myeloma (MM)

Update of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant (AuSCT) in Patients (Pts) with Multiple Myeloma (MM)

AL Amyloidosis: The Prognostic Impact of Maintenance Therapy Following ASCT

Introduction Autologous stem cell transplantation (ASCT) remains an effective treatment option for many patients with systemic AL amyloidosis (AL). However, the decision to utilize maintenance therapy following ASCT remains controversial and largely unexplored. Furthermore, the growing relevance of cytogenetics in AL may help dictate this maintenance decision as well. It is also relevant to note the emergence of novel targeted therapy options for AL patients, including the plasma cell monoclonal antibody daratumumab, that offer an exciting option in combination therapies with ASCT. As such, the present study aims to a) determine the prognostic significance of utilizing maintenance therapy following ASCT b) assess the potential impact of cytogenetics on this decision, and c) present novel data on the survival benefits of daratumumab-treated patients who have undergone ASCT. Methods A retrospective chart review was performed on 50 consecutive AL patients who underwent ASCT at The Ohio State University. Patients received high dose Melphalan (140 or 200 mg/m2) prior to ASCT. Patients were divided into subgroups based on FISH, and whether or not they had received maintenance therapy following transplant. Primary endpoints were progression free survival (PFS) and overall survival (OS), both estimated via the Kaplan-Meier survival function. The log-rank test was used to test the equality of survivor functions between different groups of patients. Results Twenty-eight patients (56%) received maintenance and 22 (44%) did not. There was no difference in age, dose of melphalan used, disease stage and number of organs involved between the two groups. There was no statistically significant difference in OS (p=0.32) and PFS (p=0.66) between patients who received maintenance versus those patients who did not receive maintenance (Figure 1A). Among patients with abnormal FISH, there was no difference in survival between the two groups (OS-p=0.65; PFS-p=0.15) (Figure 1B). Patients with three or more organs with AL involvement had worse OS/PFS versus those with 2 or less (OS-p=0.001; PFS-p=0.015). However, among these patients with 2 or more organs involved, the decision to utilize maintenance vs not showed no difference in PFS/OS. Lastly, further evaluation of a subset of patients treated with daratumumab showed no difference in outcome whether or not they underwent ASCT or consolidation. Conclusion In this small retrospective analysis, maintenance therapy post ASCT had no impact on the PFS or OS of patients with AL, even when further stratified based on degree of organ involvement. Survival was also not affected by cytogenetic abnormalities or with addition of novel monoclonal-targeted therapies. It is clear that a larger prospective study is needed to assess the benefit of maintenance post ASCT in AL amyloid patients.

Phase 2 Trial of LDE225 and Lenalidomide Maintenance Post Autologous Stem Cell Transplant for Multiple Myeloma

Background: Lenalidomide maintenance therapy post-autologous stem cell transplantation (ASCT) is associated with improved progression-free survival (PFS) and possibly overall survival in multiple myeloma (MM). However, almost all patients do relapse as a result of residual multiple myeloma cells that remain after the high-dose chemotherapy. In the myeloma setting it has been found that the hedgehog (Hh) pathway is essential for maintaining a subset of tumor causing stem cells. LDE 225 (Sonidegib) is a potent selective oral bioavailable antagonist of Smoothened (SMO), a component of the Hh signaling pathway. In in vitro experiments, LDE225 treatment of myeloma cell lines resulted in a modest inhibition of cell proliferation at increasing doses. When LDE225 was combined with lenalidomide, a more than additive effect was observed in terms of cell proliferation, an effect that was more pronounced in the context of myeloma cell lines growing in co-culture with marrow derived stromal cells. These findings form the basis of evaluation of LDE 225 as a strategy to enhance the activity of lenalidomide in the post-transplant maintenance setting. The minimal residual state post SCT provides the most optimal situation for evaluation of a drug that is likely to work by inhibiting the tumor cells that escaped high dose therapy. Methods: Multiple myeloma patients without evidence of progression, who were 60 - 120 days after a single autologous stem cell transplant (SCT), performed within 1 year of diagnosis were eligible for the study. Maintenance therapy was started approximately 3 months after SCT. Treatment consisted of lenalidomide 10 mg days 1-21 and LDE225 400 mg days 1-28 in 28-day cycles for a total of 18 cycles. The goal of the study was to assess toxicity of this combination, complete response rate (CR) progression free survival (PFS) at 1 and 2 year and overall survival (OS). CR and PFS were estimated using an exact binomial distribution and Kaplan Meier curves respectively. Results: A total of 28 patients were accrued from Jan 2014 to Aug 2016, 1 patient canceled prior to treatment and 1 patient was deemed ineligible resulting in 26 evaluable pts for CR and PFS. The median age of all pts (n=26) was 60 years (range 43-69) and 50% were males. Seventy-three percent of patients reported one treatment regimen prior to SCT, while 27% reported 2 or more prior regimens. The other characteristics of the patient are summarized in Table 1. Twenty seven pts received at least one cycle of treatment and are evaluable for toxicities (AE). Patients were treated for a median of 12.5 (range 1-18) cycles. While 10 pts (38.5%) completed protocol treatment (18 cycles), the remaining 16 pts went off treatment due to AEs (6, 23%), disease progression (3, 11.5%), refusal of further treatment (3, 11.5%) and other reasons (4, 15.4%). A grade 3 or higher AE at least possibly attributed to either drug was seen in 63%. Grade 3+ hematologic toxicities were noted in 30%, with 7% neutropenia and 4% thrombocytopenia. Notable grade 2+ non-hematologic toxicities with more than 5% incidence were dysgeusia 22%, alopecia 11%, and anorexia 7%. Grade 3+ non-hematologic toxicities were fatigue, myalgia and arthralgia each at 7%. The CR rate in evaluable patients was 46% (5 CRs and 7 sCRs) with a 95% CI of 27% - 66%. CR rate improved from 31% to 46%. VGPR or better improved from 42% to 85%. The 24-month PFS (time from SCT to progression or death due to any cause) was 73% (95% CI: 57.9 - 92.3%) with a median time to censoring of 38 months. Conclusion: Lenalidomide in combination with LDE225 as posttransplant maintenance therapy was associated with some toxicity but manageable. The combination improved the depth of response after autologous stem cell transplant. Long-term follow-up is needed to determine overall survival. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Spectrum: Honoraria, Research Funding; Janssen: Honoraria. Kapoor:Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Celgene: Honoraria; Sanofi: Consultancy, Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Russell:Imanis: Equity Ownership. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. OffLabel Disclosure: Sonidegib (LDE 225) is a selective oral bioavailable antagonist of Smoothened (SMO), a component of the hedgehog signaling pathway.

AL Amyloidosis: The Effects of Maintenance Therapy on Autologous Stem Cell Transplantation Outcomes

Introduction: Autologous stem cell transplantation (ASCT) remains an effective treatment option for many patients with systemic AL amyloidosis (AL). However, the decision to utilize maintenance therapy following ASCT remains controversial and largely unexplored. Studies have shown the benefit of post-ASCT maintenance therapy in multiple myeloma (MM) with lenalidomide, but to date, no study has evaluated maintenance in AL patients following ASCT. Furthermore, the growing relevance of cytogenetics in AL may help dictate the incorporation of maintenance therapy as well. It is also relevant to note the emergence of novel targeted therapy options for AL patients, including the plasma cell monoclonal antibody daratumumab, that could be a valuable addition to combination therapies. As such, the present study aims to a) determine the prognostic significance of utilizing maintenance therapy following ASCT b) assess the potential role of cytogenetics on the efficacy of maintenance treatment, and c) investigate the outcomes of daratumumab-treated patients who have undergone ASCT. Methods: A retrospective chart review was performed on 50 consecutive AL patients treated at The Ohio State University who underwent ASCT. Patients received high dose Melphalan (140 or 200 mg/m2) prior to ASCT. Patients were divided into subgroups based on FISH data obtained within 90 days of diagnosis, as well as whether or not they had received maintenance therapy following transplant, which was defined as therapy greater than six months following ASCT. Patients' characteristics were summarized using medians and ranges, or frequencies and percentages, and compared using Mann-Whitney rank sum test or fisher exact test. Primary endpoints were progression free survival (PFS) and overall survival (OS), per updated NCCN guidelines, including both organ and hematologic criteria. PFS was defined as the time from date of transplant to day of progression or death from any cause. OS was defined as the time from date of transplant to death from any cause, with censoring those who were still alive at the last follow up. Kaplan-Meier survival function was used to estimate the PFS and OS. The log-rank test was used to test the equality of survivor functions between different groups of patients. Results: Twenty-eight patients (56%) received maintenance and 22 (44%) did not. Majority of patients received lenalidomide maintenance. The median age at transplant was 58 (range 33-71) years, with 66% male. There was no difference in age, dose of melphalan used, disease stage and number of organs involved between the two groups. There was no statistically significant difference in OS (p=0.32) and PFS (p=0.66) between patients who received maintenance versus those patients who did not receive maintenance (Figure 1A). Among patients with abnormal FISH, there was no difference in survival between these two groups as well (OS: p=0.65; PFS: p=0.15) (Figure 1B). Finally, we tested the efficacy of daratumumab in combination therapy with ASCT in a small patient subset. There was no difference in OS or PFS among patients who underwent ASCT for consolidation, whether or not they received daratumumab. Conclusion: In this small retrospective analysis, maintenance therapy post ASCT had no impact on the PFS or OS of patients with AL. Furthermore, survival was not affected by maintenance in patients with cytogenetic abnormalities or addition of novel monoclonal antibodies. A larger prospective study is needed to assess the benefit of maintenance post ASCT and daratumumab in AL amyloid patients. Disclosures Rosko: Vyxeos: Other: Travel support. Efebera:Janssen: Speakers Bureau; Akcea: Other: Advisory board, Speakers Bureau; Takeda: Honoraria.

Ixazomib-Lenalidomide-Dexamethasone (IRd) Consolidation Following Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma: A Large Multi-Center Phase II Trial

Ixazomib-Lenalidomide-Dexamethasone (IRd) Consolidation Following Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma: A Large Multi-Center Phase II Trial

Updated Results of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant (AuSCT) in Patients (Pts) with Multiple Myeloma (MM)

Background: Lenalidomide (LEN) monotherapy has been effective in extending progression free survival (PFS) after myeloablative AuSCT in pts with MM. Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against signaling lymphocytic activation molecule F7 (SLAM F7), is FDA approved in combination with LEN and dexamethasone (DEX) for treatment of MM pts who have received 1-3 prior therapies. The objective of this phase 2 trial is to evaluate the efficacy and safety of adding ELO to LEN as maintenance therapy post-myeloablative AuSCT. We report updated results of the primary (PFS) and secondary (overall survival [OS] and toxicity) endpoints. Patients and Methods: Between 4/15/2015-1/27/2016, 27 evaluable pts were treated on 28 day cycles with ELO, 10 mg/kg iv weekly for cycles 1-2, q2weeks for cycles 3-6, then 20 mg/kg once monthly for cycles 7+. Pts enrolled after 1/28/2016 (n=57 pts) have received ELO, 10 mg/kg IV weekly for cycles 1-2, and 20 mg/kg on day 1 from cycle 3 until disease progression (PD). LEN has been dosed at 10 mg/day for cycles 1-3, with a dose increase to 15 mg/day at physician discretion starting with cycle 4, in the absence of non-hematologic toxicity > grade 1 and significant cytopenias (ANC The study9s primary endpoint is PFS, defined as time from AuSCT to PD or death (whichever occurs first), or time of last contact. Secondary objectives are best response, OS, incidence of second primary malignancies (SPMs) and adverse event (AE) profile. Total enrollment of 100 pts is planned. Patients are followed until death, withdrawal of consent or removal from study. Eligible pts received ≤2 lines of induction therapy, and are 60-210 days post-AuSCT. Results: Pts (n=84) have been treated for a median of 16 cycles (2-43). At study entry, 27 (32%) had complete response (CR), 36 (43%) had very good partial remission (VGPR), 20 (24%) had partial remission (PR) and 1 (2%) had minor remission (MR). Best response achieved to date on study is CR in 44 pts (52%), VGPR in 31 pts (37%) and PR in 9 pts (11%). For those who have converted to CR on study, median time to CR was 2 months. Of 22 pts in CR who have been tested for minimal residual disease (MRD) to date, 20 are negative by flow cytometry (minimum of 2 million cells evaluated). Three of 20 have converted from VGPR to MRD negativity while on study. With a median follow up of 23 months, 96% of pts (n=81) remain alive. Ten pts have had PD; of these, 6 had high risk cytogenetics. Two died of PD while receiving salvage therapy. One additional pt died on study in VGPR, after developing acute cerebral encephalopathy with refractory status epilepticus of unclear etiology. Four pts withdrew for personal reasons, 4 were removed at physician discretion (prolonged cytopenias [1], drug rash [1], worsening memory impairment [1], therapy related myelodysplastic syndrome (t-MDS) [1]), and 2 lost insurance coverage. Estimated 3 year PFS is 81%. High risk cytogenetics adversely affected PFS (p=0.02). Grade 3-4 Hematologic AEs (no. of pts) were: neutropenia 32% (27), febrile neutropenia 15% (13), thrombocytopenia 8% (7), and anemia 7% (6). Grade 3-4 non-Hematologic AEs (no. of pts): respiratory infections 17% (15), diarrhea 14% (12), fatigue 13% (11), other infections 8% (7), peripheral neuropathy 7% (6), myalgias 6% (5), nausea/vomiting 4% (3), dizziness 2% (2), memory impairment 2% (2), maculopapular rash 2% (2), edema 1% (1). SPMs include intra-epidermal adenocarcinoma of the neck (1), mucinous appendiceal neoplasm (1), t-MDS (1), prostate cancer (1), and melanoma (1). Renal cell carcinoma was diagnosed in 1 pt, 15 months after removal from study for PD. Conclusions: Lenalidomide-elotuzumab is a well-tolerated maintenance therapy during which 33% of 84 pts had improvement in quality of response while on therapy, including 20% who converted to CR. The number of pts experiencing improvement may be underestimated due to ELO interference with paraprotein measurement on electrophoretic studies. Additional follow up is required to determine if the improved quality of responses translate into improvements in PFS and OS. Available data supports conduct of a Phase 3 trial. Disclosures Thomas:Array Pharma: Research Funding; Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding. Shah:Karyopharm Therapeutics: Employment. Lee:Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Patel:Abbvie: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding.

The Role of Clonal Hematopoiesis of Indeterminate Potential (CHIP) in Multiple Myeloma: Immunomodulator Maintenance Post Autologous Stem Cell Transplant (ASCT) Predicts Better Outcome

▪Introduction: Multiple Myeloma (MM) is a clonal plasma cell malignancy, accounting for 10% of all hematological malignancies. Genetic analyses of large populations revealed that blood-specific somatic mutations in hematopoietic stem cells (HSCs) are commonly acquired during aging, a new entity labeled: clonal hematopoiesis of indeterminate potential (CHIP). We sought to determine the role of CHIP on survival of MM patients, specifically those receiving immunomodulator (IMiD) maintenance (Lenalidomide or Thalidomide) post autologous stem cell transplant (ASCT).Methods: We collected the cryopreserved, growth factor mobilized peripheral blood of 629 MM patients who underwent ASCT between 2003 and 2011 at the Dana-Farber Cancer Institute (DFCI). Then, we performed targeted next-generation sequencing using a 224-gene panel at a mean depth of coverage of 978X and ultra-low pass whole-genome sequencing at 0.1X to account for tumor contamination. We downloaded (dbGAP # phs000748.v6.p4) the whole-exome sequencing (WES) data of a cohort of 1144 newly diagnosed, untreated MM patients from the Multiple Myeloma Research Foundation (MMRF) Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass, NCT0145429) study (MMRC) and the WES data of a cohort of 205 newly diagnosed, untreated MM patients from the Broad Institute dataset. We analyzed their peripheral blood (average coverage of 108X) and tumor (average coverage of 107X) data separately, looking for the same CHIP genes included in our target bait panel.Results: The DFCI cohort had a median age of 58 years [range, 24-83] at time of ASCT and median follow up post ASCT of 8 years [range, 0.1-14.5]. 204 patients (32%) in the DFCI cohort had CHIP at time of ASCT. The most commonly detected mutated genes were DNMT3A, TET2, TP53, ASXL1 and PPM1D. 24 patients (3.8%) developed a second hematological malignancy at a median of 4 years [range, 1-10] post ASCT, half of whom had CHIP. Around 48% of the DFCI cohort received IMiDs as part of induction therapy. Different induction regimens had no effect on CHIP prevalence at time of ASCT. Around 56% of the DFCI cohort received IMiD maintenance, 22% of which received maintenance for at least 3 years [range, 0.06-12.8]. Among those who did not receive IMiD maintenance, patients with CHIP had worse progression free survival (PFS) (p-value < 0.001) and overall survival (OS) (p-value = 0.005). In patients receiving IMiD maintenance, having CHIP had no effect on PFS or OS. On the other hand, the MMRF cohort had a median age of 63 years [range, 27-93] and median follow up of 3.03 years [range, 0-5.9] from time of diagnosis. Around 52% of that cohort underwent ASCT and around 76% of those received IMiD maintenance with a median follow up of 2.7 years [range, 0-5.5] from time of ASCT. Furthermore, 200 patients of the MMRF cohort have follow-up samples of both tumor and peripheral blood that had targeted sequencing done by a 562-gene panel that included our genes of interest. Similarly, when studying the genomic results of 139 out of 1144 MMRF patients, as well as the 205 patients from the Broad Institute dataset, we detected CHIP in 25.6% of them and the top 5 most commonly mutated genes were similar to those of our cohort.Conclusion: CHIP is a common entity among MM patients, reaching a prevalence of up to 32%, that predicts a worse PFS and OS in those who do not receive IMiD maintenance therapy post ASCT. As expected, IMiD maintenance improves outcome in MM patients, with and without CHIP. In patients with CHIP, the use of IMiDs abrogated the deleterious effect imposed by CHIP to a point that outcome is identical to that of patients without CHIP. DisclosuresBustoros:Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; OncoPep: Equity Ownership, Other: Scientific founder; Celgene: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; Bristol Myers Squibb: Consultancy; Millennium Takeda: Consultancy. Richardson:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Celgene: Consultancy; Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy.

Abstract 2954: Immunomodulator maintenance post autologous stem cell transplant predicts better outcome in multiple myeloma patients with clonal hematopoiesis of indeterminate potential

Abstract Introduction: Multiple Myeloma (MM) is a clonal plasma cell malignancy, accounting for 10% of all hematological malignancies. Genetic analyses of large populations revealed that blood-specific somatic mutations in hematopoietic stem cells (HSCs) are commonly acquired during aging, a new entity labeled: clonal hematopoiesis of indeterminate potential (CHIP). We sought to determine the role of CHIP on survival of MM patients, specifically those receiving immunomodulators (IMiDs) maintenance (Lenalidomide or Thalidomide) post autologous stem cell transplant (ASCT). Methods: We tested cryopreserved HSCs of 629 MM patients who underwent ASCT between 2003 and 2011 at the Dana-Farber Cancer Institute. We used a target bait panel of 224 genes and performed deep-targeted sequencing at 978x coverage and ultra-low pass whole-genome sequencing at 0.1x to account for tumor contamination. Sequencing data was analyzed using ichorCNA, MuTect, and Strelka and mutation annotations were based on reported mutations in the literature and databases (ClinVar, COSMIC, cBioPortal, TCGA, and ExAC). Results: Our cohort had a median age of 58 years [24-83] at time of ASCT and median follow up post ASCT of 8 years [0.1-14.5]. 24% of patients had CHIP at time of ASCT, which is statistically similar to the 30% reported in non-Hodgkin's lymphoma (NHL), (Gibson et. al, JCO, 2017). The most commonly detected mutated genes were DNMT3A, TET2, TP53 and ASXL1. Acquiring mutations positively correlated with age (p=0.004). In contrast to NHL, PPM1D was not significantly mutated in MM (40% vs. 3.3%). 27 patients (4.3%) developed a second hematological malignancy at median of 4 years [1-10] post ASCT, of which 10 had CHIP. 22% received at least 3 years [0.06-12.8] of IMiD maintenance. Among those who did not receive IMiD maintenance, CHIP was associated with worse progression free survival (PFS) (p=0.047) where PFS at 3 years post ASCT was 31% (95%CI: 25-38) for those without CHIP vs. 15% with CHIP (95%CI: 7-25). In patients with IMiD maintenance, CHIP had no effect on PFS or overall survival (OS) (p=0.9). In patients with CHIP, receiving IMiD was associated with a better OS and PFS below the age of 58 and better PFS only in those above 58. In the overall cohort, CHIP was not associated with more adverse outcomes, which could be attributed to low OS and PFS in MM or the use of IMiD in 56% of this cohort. IMiD maintenance was associated with better OS (p&amp;lt;0.001) and PFS (p&amp;lt;0.001), consistent with prior studies, even in the presence of CHIP mutations. Conclusion: CHIP is a common entity among MM patients that predicts a worse PFS in those who do not receive IMiD maintenance therapy post ASCT. The use of IMiDs abrogated the deleterious effect imposed by CHIP in this cohort. Larger cohorts with longer follow up are needed, especially in the era of novel agents and long-term use of Lenalidomide maintenance. Citation Format: Tarek H. Mouhieddine, Jihye Park, Robert Redd, Christopher J. Gibson, Salomon Manier, Amin Nassar, Kalvis Hornburg, Marzia Capelletti, Daisy Huynh, Romanos Sklavenitits Pistofidis, Mark W. Bustoros, Saud H. AlDubayan, Brendan Reardon, Cody J. Boehner, Henry Dumke, Chia-Jen Lui, Darlys Schott, Eliezer M. Van Allen, Robert L. Schlossman, Nikhil C. Munshi, Kenneth C. Anderson, David P. Steensma, Jacob P. Laubach, Paul G. Richardson, Jerome Ritz, Benjamin L. Ebert, Robert J. Soiffer, Donna Neuberg, Irene M. Ghobrial. Immunomodulator maintenance post autologous stem cell transplant predicts better outcome in multiple myeloma patients with clonal hematopoiesis of indeterminate potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2954.

The evolution of stem-cell transplantation in multiple myeloma.

Autologous stem-cell transplantation (ASCT) remains an integral part of treatment for previously untreated, and may have value in the treatment of relapsed patients with, multiple myeloma (MM). The addition of novel agents like immunomodulators and proteasome inhibitors as induction therapy before and as consolidation/maintenance therapy after ASCT has led to an improvement in complete response (CR) rates, progression-free survival (PFS) and overall survival (OS). With advances in supportive care, older patients and patients with renal insufficiency are now able to safely undergo the procedure. The data concerning the timing of ASCT (early in the disease course or at first relapse), single versus tandem (double) ASCT and the role and duration of consolidation and maintenance therapy post ASCT remain conflicting. This review aims to discuss the evolution of stem-cell transplant over the past 3 decades and its current role in the context of newer, safer and more effective therapeutic agents.

Preliminary Results of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant in Patients with Multiple Myeloma

Background: Lenalidomide (LEN) monotherapy has been effective in extending progression free survival (PFS) and after myeloablative AuSCT in patients (pts) with multiple myeloma (MM) (Attal et al. NEJM 2012, McCarthy et al. NEJM 2012,). Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against signaling lymphocytic activation molecule F7 (SLAMF7), is FDA approved in combination with LEN and dexamethasone (DEX) for treatment of pts with MM who have received 1-3 prior therapies. The objective of this phase 2 trial is to evaluate the efficacy and safety of adding ELO to LEN as maintenance therapy post-myeloablative AuSCT. We report preliminary results of the primary (PFS) and secondary (overall survival and toxicity) endpoints. Patients and Methods: Between 4/15/2015-1/27/2016, 28 evaluable pts were treated on 28 day cycles with ELO, 10 mg/kg iv weekly for cycles 1-2 and q2weeks for cycles 3-6, then 20 mg/kg once monthly for cycles 7+. Pts enrolled after 1/28/2016 (n=27 pts) have received ELO, 10 mg/kg IV weekly for cycles 1-2, and 20 mg/kg on day 1 from cycle 3 until progression. LEN has been dosed at 10 mg/day for cycles 1-3, with a dose increase to 15 mg/day at physician discretion starting with cycle 4, in the absence of non-hematologic toxicity > grade 1 and significant cytopenias (ANC The primary endpoint of the study is PFS, defined as the time from AuSCT to clinical progression or death (whichever occurs first), or the time of last contact. Secondary objectives include best response, overall survival, incidence of second primary malignancies and adverse event (AE) profile. Total enrollment of 100 pts is planned. Pts will be followed for 48 months after the last patient is enrolled in the trial. Eligible pts had received no more than 2 lines of induction therapy, and were between 60-210 days post-AuSCT. Results: Patients (n=55) have been treated for a median of 14 cycles (2-30). At study entry, 13 pts (24%) had complete response (CR), 27 (49%) had very good partial remission (VGPR), 14 (25%) had partial remission (PR) and 1 (2%) had minor remission (MR). Best response achieved to date on study is CR in 28 pts (51%), VGPR in 23 pts (42%) and PR in 4 pts (7%). For those who have converted to CR on study, median time to CR has been 5 months. Of 14 pts in CR who have been tested for MRD while on study, 13 are negative by flow cytometry (minimum of 2 million cells evaluated; sensitivity 10 -4-10-5). Two of these 13 have converted from VGPR to MRD negativity at 4 and 14 months on study, respectively. With a median follow up of 21 months, 95% of pts (n=52) remain alive. Three pts (all with high risk disease) had disease progression at 4 (del 17p), 9 (t [4;14]), and 13 (gain 1q) months; of these, 2 have died of progressive disease while receiving salvage therapy. One patient, in VGPR, died on study after developing acute cerebral encephalopathy with refractory status epilepticus of unclear etiology. Two pts withdrew for logistical reasons; 2 have been taken off study per physician discretion (prolonged cytopenias (1), drug rash (1)). Grade 3-4 Hematologic AEs (no. of pts) were: neutropenia 35% (16), thrombocytopenia 9% (4), febrile neutropenia 7% (3), and anemia 7% (3). Grade 3-4 non-Hematologic AEs (no. of pts): diarrhea 17% (8), fatigue 17% (8), pneumonia 15% (7), other infections 15% (7), peripheral neuropathy 11% (5), myalgias 9% (4), nausea/vomiting 7% (3), maculopapular rash 4% (2), dizziness 4% (2), edema 2% (1), memory impairment 2% (1). Renal cell carcinoma was diagnosed in 1 patient, 15 months after removal from study for disease progression. Conclusions: Lenalidomide-elotuzumab is a well-tolerated maintenance therapy on which 44% of 55 pts have had improvement in quality of response while on therapy, including 28% who have converted to CR and 24% who have tested MRD negative. The number of pts who have experienced improvement on study may, in fact, be underestimated in this analysis due to elotuzumab interference with measurement on electrophoretic studies. Additional follow up is required to determine if the improved quality of responses translate into improvements in PFS and OS. Disclosures Thomas: Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Shah: Kayopharm: Employment. Lee: Pimera Inc: Consultancy; Eutropics Pharmaceuticals: Research Funding; Adaptive: Membership on an entity9s Board of Directors or advisory committees; Daiichi Sankyo: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Manasanch: merck: Research Funding; adaptive biotechnologies: Consultancy; sanofi: Research Funding; celgene: Consultancy; takeda: Consultancy; quest diagnostics: Research Funding. Patel: Juno: Consultancy; Celgene: Consultancy; Pfizer: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Orlowski: BioTheryX: Consultancy, Membership on an entity9s Board of Directors or advisory committees.