Lacy, Martha Q.

AbstractIn this phase 1/2 study, carfilzomib was added to high‐dose melphalan conditioning prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma that had been treated with ≤2 prior lines of therapy. Carfilzomib was escalated at doses of 27, 36, 45, and 56 mg/m2 on days −6, −5, −2, and −1 before ASCT in the phase 1 component of the study. In addition, all the patients received melphalan 100 mg/m2 on days −4 and −3. The primary endpoint of the phase 1 component was to identify the maximum tolerated dose, and the primary endpoint of the phase 2 component was the rates of complete response (≥CR) at 1 year after ASCT. The phase 1 dose escalation cohort included 14 patients, and 35 patients were included in the phase 2 cohort. The maximum tested dose was 56 mg/m2 (MTD). The median time from diagnosis to study enrollment was 5.8 (range 3.4–88.4) months, and 16% of patients had obtained a ≥CR prior to ASCT. The best response within 1 year after ASCT was a ≥ CR rate in 22% for the entire cohort, and 22% for patients treated at the MTD. The ≥VGPR rates improved from 41% before ASCT to 77% by 1 year after ASCT. One patient had a grade 3 renal adverse event, and renal function returned to baseline with supportive care. The rate of grade 3–4 cardiovascular toxicity was 16%. The addition of carfilzomib to melphalan conditioning was safe and resulted in deep responses after ASCT.

e14594 Background: Voyager-V1 (VV1) is an oncolytic vesicular stomatitis virus engineered to express interferon beta (IFNβ) to boost cellular antitumor immunity and sodium iodine symporter (NIS). A phase 1 trial investigating a single infusion of VV1 in patients with relapsed refractory multiple myeloma and T-cell lymphoma (TCL) showed promising and durable clinical activity, primarily in patients with TCL. VV1 infects tumor cells and macrophages in the lymph nodes and spleen, resulting in release of tumor antigens and IFNβ that activates and boost cellular antitumor immunity. We present the preliminary pharmacokinetic analysis in patients given one intravenous (IV) dose of VV1. Methods: Patients received 5e9 to 1.7e11 TCID50 (50% tissue culture infective dose) of VV1 given over 30 minutes. We also explored the impact of infusion duration (0.25, 0.5,1 and 3 hours) in 17 patients with solid tumors. The objectives were to determine the impact of viral dose on pharmacokinetics (PK) of VSV and IFNβ. For VSV and IFNβ PK, whole blood was collected in 30 patients on days 1, 2, 3, and 8. Dose levels were 1.7E10, 5E10, and 1.7E11 TCID50. The plasma concentration-time data were estimated with non-compartmental analysis using WinNonlin 8.3. Results: The half-life of VV1 is comparable (10-12h) between dose levels of 1.7e10, 5e10 and 1.7e11. Ideal infusion rate was found to be 30 minutes and provides the highest Cmax and AUC. Most peak concentrations for viremia and IFNβ were achieved between ‘end of infusion’ and 2.5 hours, 4.5 and 24 hours, respectively. Following infusion, a second concentration peak is found in over half the patients leading to highly variable terminal elimination half-life, specifically where the second peak is at 24 hours. There was no second peak for IFNβ levels. Peak plasma concentration and systemic exposure increased in proportion to increased dose, consistent with linear clearance. Conclusions: The 30 minute infusion rate was considered the best as its PK provides the highest Cmax and AUC with no significant CRS differences among other groups. IL-6 and IFNα markers at hour 4 indicate a likely CRS and hour 24 provides a possible prediction of the grade. Cmax and AUC were also highest at 1.7e11 TCID50. This is the recommended dose that will be used in the expansion arm in patients with TCL. Clinical trial information: NCT03017820 , NCT02923466 . [Table: see text]

Abstract Patients with multiple myeloma (MM) who do not respond to initial therapy have worse outcomes than primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not yet been studied. We reviewed patients with MM treated with triplet/quadruplet therapy at our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. We identified 1127 patients, of whom 1086 were evaluated for hematologic responses after 4 to 6 cycles. Of these, 93.3% (1013) had evidence of response, whereas 6.7% (73) had primary refractory disease. With a median overall survival (OS) of 51.3 months, patients with primary refractory disease had an increased risk of shorter survival in univariable and multivariable analyses (hazard ratio [HR], 3.5 [95% confidence interval (CI), 2.5-4.9]; HR, 4.3 [95% CI, 2.6-6.9], respectively). In the subgroup analysis of patients with primary refractory disease, those who received second-line autologous stem cell transplantation (ASCT) had increased second progression-free survival (20.9 vs 8.1 months; P < .01) and second OS (74.7 vs 31.3 months; P = .02) compared with patients who did not. We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population.

e20032 Background: The introduction of anti-CD38 antibodies (daratumumab) in the treatment landscape of multiple myeloma (MM) has increased the progression-free survival (PFS) in recent years. Still, the ideal combination (Dara-IMiD vs. Dara-PI) of these drugs in patients with relapsed MM is unclear. Methods: We reviewed MM patients treated with daratumumab as second-line therapy at our institution from 2016 to 2022 to assess the outcomes with the different combination therapies. We used the Kaplan-Meier method to estimate PFS from the first relapse. Results: We identified 329 patients with a median age of 63.6 years (range: 27.1 – 90.4). Most of the patients received triplet induction therapy (95%) and upfront transplant (67%) as primary therapy. At the time of Dara initiation, 41% were refractory to IMiDs, 22% to PIs, 18% to both, and 18% to neither drug. Patients treated with Dara-IMiD had significantly better PFS than Dara-PI (28.7 months vs. 18.5 months, p < 0.01, respectively). In a subgroup analysis based on the FISH results, high-risk patients had similar PFS outcomes (24.3 vs. 10.2 months, p = NS, respectively), while standard-risk patients benefited significantly from the Dara-IMiD regimen (48.3 vs. 19.2 months, p < 0.01, respectively). Among patients treated with Dara-IMiD, those already refractory to IMiDs from the first line had significantly shorter PFS than those without IMiD resistance (14.9 vs. 43.3 months, p < 0.01, respectively). In addition, the lenalidomide-based combination resulted in significantly better PFS compared to pomalidomide in our cohort (40.5 vs. 19.2 months, p < 0.01, respectively). However, no difference was found in the IMiD refractory population (12.3 vs. 15.1 months, respectively). Finally, no significant differences were seen between Dara-IMiD and Dara-PI in patients only refractory to IMiDs (16.1 vs. 12.8 months, p = NS, respectively). Conclusions: While further studies are required to adjudicate the best combination, we conclude that Dara-IMiD might be more effective in patients with relapsed MM, especially for patients not refractory to IMiD at first line. [Table: see text]

e20011 Background: Drug refractoriness is an important factor determining choice of next therapy and prognosis in multiple myeloma (MM). It is debatable whether refractoriness to a drug varies among patients (pts) with MM progressing on different administration schedules of the drug. Outcomes of MM pts refractory to different doses of lenalidomide have been previously described, but similar data about proteasome inhibitors (PIs) are limited. In this study, we assessed the impact of refractoriness to different schedules of bortezomib (V) on outcomes with subsequent therapies in MM pts. Methods: We retrospectively reviewed MM pts at our center diagnosed between January 2004 and December 2018, who progressed on/ after receiving first line therapy with V containing regimens. At first relapse, we divided pts into 3 groups- MM progressing on or within 60 days of receiving (1) 1-1.3 mg/m2 V once weekly or more frequently (Standard Dose Refractory), (2) 1-1.3 mg/m2 V once every 2 weeks or less frequently (Low Dose Refractory), and (3) MM progressing at least 60 days after stopping V (Not Refractory). In addition to V, we classified pts as being refractory to cyclophosphamide and immunomodulatory drugs (IMiDs) at first relapse. We classified salvage regimens into daratumumab (Dara), PI, IMiD, PI+IMiD, and VDTPACE like regimens. We then assessed progression free survival (PFS) and overall survival (OS) for next line therapy, and for next V containing therapy using Kaplan Meier and Cox models. Results: A total of 302 pts were included. Median age at diagnosis was 62 years and 60% pts were male. Overall, 23%, 31%, and 27% were International Staging System (ISS) stage I, II, and III respectively; 40% had high risk FISH as per mSMART. Of the 302 pts, 134 (44%) pts received another V containing regimen after the first line therapy at any time during the disease course. Using a multivariable Cox model to adjust for ISS, high risk FISH, refractoriness to other drugs, duration of first line therapy, and treatment received at relapse, the Not Refractory Group had a better PFS for both 2nd line therapy and the next V containing line of therapy, while no significant differences were seen between the Standard Dose Refractory and Low Dose Refractory groups. OS differences followed the same trend but were not statistically significant (Table). Conclusions: On multivariable analysis, the PFS did not differ among standard dose vs low dose refractory pts, and both were significantly inferior to pts not refractory to V. These data suggest that refractoriness to V might not be a dose dependent phenomenon. [Table: see text]

8051 Background: Patients with multiple myeloma (MM) that do not respond to initial therapy have worse outcomes compared to primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not been studied. Methods: From 2007-2019, we reviewed MM patients treated with triplet/quadruplet therapy in our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. Primary refractory disease was defined as either progressive disease or stable disease at 4-6 cycles. The Kaplan-Meier estimates were used for survival probabilities. PFS and OS were calculated from MM diagnosis to progression, escalation/change of treatment, or death, respectively. For the primary refractory group, the second PFS and second OS were measured from the start of second-line therapy. The Cox regression model was used for multivariable analysis with the following variables (age, ISS, induction therapy, FISH, and bone marrow plasma cells at diagnosis). Results: We identified 1127 patients, of which 1086 were evaluated for hematologic response after 4-6 cycles. Of these, 93.3% (1013) had evidence of response, while 6.7% (73) had primary refractory disease. With a median OS of 50.7 months, patients with primary refractory disease had an increased risk for shorter survival in univariable and multivariable analysis (HR: 3.6, 95% CI = 2.61 – 4.96, HR = 3.89, 95% CI = 2.68 – 5.65, respectively). In subgroup analysis of primary refractory patients, the median second PFS and second OS from the first relapse were 11.9 months (95% CI: 8.7 – 17.3 months) and 43.4 (95% CI: 31.4– 75.9 months), respectively. Patients that received 2nd line ASCT had increased second PFS (20.9 vs. 8.1 months, respectively, p < 0.01) and second OS (74.7 vs. 31.3 months, respectively, p = 0.02) compared to patients that did not. Patients that took daratumumab as the second line did not have any significant survival differences compared to those who did not, p = NS. Conclusions: We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population. [Table: see text]

8043 Background: Extramedullary Multiple Myeloma (EMM) has an aggressive clinical course and can present at diagnosis [primary EMM, (pEMM)] or relapse [secondary EMM, (sEMM)]. Here, we report clinical characteristics and outcomes of EMM, and predictive factors for the development of sEMM. Methods: We identified 299 patients with biopsy-proven EMM between 01/01/2000 and 12/31/2021. Patients with solitary plasmacytomas, paraskeletal MM and primary plasma cell leukemia were excluded. A 1:1 matched pair analysis (matched for year of diagnosis of MM for comparable follow-up and treatment eras) was performed to compare clinical characteristics and outcomes for patients with and without sEMM. Results: The median follow-up from the diagnosis of MM was 11.5 years (95%CI: 9.3-14.8). Of 299 patients, 204 (68%) patients had sEMM and 95 (32%) had pEMM, with largely comparable baseline characteristics (Table). The median overall survival (OS) from the diagnosis of sEMM was 0.7 (95% CI: 0.6-0.9) years compared to 3.6 (95%CI: 2.4-5.6) years for pEMM (p<0.0001). For sEMM, mutlvariable analysis (MVA) for OS identified visceral organ involvement (eg. liver, lung/pleura, brain, pancreas, etc.) to be associated with inferior OS [HR 1.6 (95% CI: 1.1-2.4), p=0.01]; high-risk cytogenetics (HR-CTG), ISS-3 stage, and age did not impact OS from sEMM. For pEMM, HR-CTG [HR 2.3 (95% CI 1.1 -4.8), p=0.03] and ISS-3 stage [HR 3.1 (95% CI 1.5-6.7), p=0.003] were associated with inferior OS on MVA whereas visceral EMM or age did not impact OS from pEMM. On univariate analysis, patients with sEMM were younger (median age 58.7 vs 61 years, p=0.006), had a higher proportion of 1q duplication (32% vs 17%, p=0.001), t(4;14) [16% vs 9%, p=0.047] and elevated LDH (30% vs 19%, p=0.04), compared to the matched cohort of patients without sEMM. On MVA, younger age at diagnosis, t(4;14) and 1q duplication at diagnosis of MM were independent predictors of development of sEMM. The median OS from diagnosis of MM was 5.4 years (95%CI: 4.1-6.2) for patients with sEMM versus 7.5 years (95% CI: 6.4-10.1; p <0.001) for the matched cohort. Secondary EMM was an independent poor prognostic marker for OS from the diagnosis of MM [HR 1.6 (95%CI: 1.2-2.1); p=0.004] in addition to age, ISS3 disease and HR-CTG. Conclusions: Outcomes of patients with EMM, especially sEMM, remain dismal. Patients with sEMM have higher rates of 1q duplication and t(4;14) at diagnosis of MM and carried an independent adverse prognosis in a matched cohort. [Table: see text]

8022 Background: Extramedullary Multiple Myeloma (EMM) is an aggressive entity with a dismal prognosis. Immune effector therapies (IETs), including chimeric antigen receptor T-cell (CAR-T) therapies and bispecific T-cell engaging antibodies (BsAb), have demonstrated excellent efficacy in relapsed/refractory MM with limited data for efficacy in EMM. Here, we report the treatment outcomes for patients with EMM. Methods: We identified 299 patients with EMM diagnosed between 01/01/2000 and 12/31/2021 after excluding solitary plasmacytomas, paraskeletal MM and primary plasma cell leukemia. The IMWG criteria were used for response definition. Results: Of the 299 patients, 204 (68%) patients had secondary EMM (sEMM) and 95 (32%) patients had primary EMM (pEMM). For sEMM (n=204), the median progression free survival (PFS) with initial therapy was 2.9 (95% CI: 2.4-3.2) months. Initial treatment strategies for sEMM were heterogenous and demonstrated in the table; 44% patients achieved ≥partial response (PR) with initial treatment for sEMM. The median PFS in patients with ≥PR was 5.8 (95%CI: 4.5-6.9) months vs 1.8 (95%CI: 1.4-2; p <0.0001) months for <PR. For patients with pEMM (n=95), the median PFS was 12.9 (95% CI: 6.7-18) months; the median PFS was 17.4 (95%CI: 12.9-25.4) months for patients with ≥PR versus 1 month (95%CI: 0.8-2) in patients with <PR. Thirty patients (all sEMM and triple class refractory) were treated with IET after development of EMM: 18 with BCMA-directed CAR-T, 10 with BsAbs, and 2 with both CAR-T and BsAbs. In patients receiving CAR-T therapy, 75% (15/20) achieved ≥PR with 40% (n=8) achieving MRD negative (by flowcytometry) complete response. Fifteen (75%) patients receiving CAR-T had progressive disease (PD); 7 with systemic and EMM PD and 4 patients each with isolated EMM or systemic PD. The median PFS for patients treated with CAR-T was 4.9 months [3.1- not reached (NR)]. Among patients achieving a ≥PR with CAR-T, the median PFS was 5.8 (95%CI: 4.7-NR) months vs 1.4 months [(95%CI: 0.8-NR), p<0.001] for <PR. Among patients treated with BsAbs (10-BCMA, 1 each against FcRH5 and GPRC5D), 33% (4/12) achieved a ≥PR. Ten (83%) patients had PD on BsAb; 8 with both EMM and systemic PD and 1 patient each with isolated EMM or PD. The median PFS with BsAb was 2.9 months (95%CI: 2.2-NR). Conclusions: Patients with EMM continue to have dismal outcomes with conventional therapies. High response rates were noted with CAR-T therapy, but these tend to be short-lived. [Table: see text]

7530 Background: Oncolytic virotherapy is a novel immunomodulatory therapeutic approach currently under study for relapsed refractory (R/R) hematologic malignancies. The engineered Vesicular Stomatitis Virus VSV-IFNβ-NIS used in this study encodes interferon beta (IFNβ) and sodium iodine symporter (NIS). Virally-encoded IFNβ serves as an index of viral proliferation and enhances host anti-tumor immunity. Herein, we report the updated results of the phase 1 clinical trial NCT03017820 of a one-time administration of systemic VSV-IFNβ-NIS among patients (pts) with R/R multiple myeloma (MM), T cell Lymphoma (TCL) and Acute myeloid Leukemia (AML) with particular focus on the TCL cohort treated at the highest dose level (DL4) without Ruxolitinib. Methods: VSV-IFNβ-NIS was administered as a single IV dose following a classical 3+3 phase I trial, starting at 5e9 TCID50 DL1 through 1.7e11 TCID50 DL4. A dose expansion cohort of 8 additional R/R TCL pts was added at DL4 in view of an initial signal of activity. The primary objective was to determine the maximum tolerated dose of VSV-IFNβ-NIS as a single agent. Secondary objectives were determination of safety profile and preliminary efficacy of VSV-IFNβ-NIS. Adverse events (AEs) are reported based on CTCAE V4; cytokine release syndrome (CRS) grading was based on Lee (Blood 2014) criteria. Results: To date, a total of 43 pts received VSV-IFNβ-NIS: MM (N=21), TCL (N=21) and AML (N=1). In the TCL cohort: at DL4 Group A (no Ruxolitinib), 12 pts were registered, but only 11 pts were treated (mycosis fungoides (MF) N=3; ALK- ALCL N=1; PTCL-NOS N=2; AITL N=4; Nodal PTCL, TFH N=2; ages 33-79). These pts received a median of 3 lines of therapy (range: 1-5). No dose limiting toxicities were observed. Grades 3 and higher AEs were hematologic with transient lymphopenia (63.6%), neutropenia (36.4%) being the most common. The non-hematologic AEs observed included unique toxicities such as CRS grades 1-2 (81.8%); the transient transaminitis grade 1-2 (36.4%) and grade 3 (27.3%) along with thrombocytopenia grade 1-2 (63.6%) and grade 3 (18.2%) were a reflection IFNβ toxicity. All the AEs observed were short lived. Responses were seen in pts with PTCL. At DL4, in pts with systemic PTCL (N=9), there were 5 responses including 3 complete responses (CR) with two long-lasting at 24 months, an ongoing 15 month CR, and a 5 month CR, and 2 partial responses (PR) lasting 5 months in one pts and 6 months in the other. Conclusions: These updated results of single agent VSV-IFNβ-NIS which include pts with PTCL treated at the highest dose level and a dose expansion cohort demonstrates not only the safety of VSV-IFNβ-NIS but also a strong efficacy signal in pts with PTCL with impressive durable responses. Two expansion cohorts at DL4 have been added (20 additional PTCL, 10 B-cell lymphoma pts) to obtain additional data on tolerability and efficacy and biomarkers of response in these pts. Clinical trial information: NCT03017820 .

AbstractWaldenström macroglobulinemia (WM) is a rare, indolent lymphoma, that predominately affects the elderly. We report the outcomes of young WM patients, evaluated over five decades, compared to their older counterparts, matched for the time of diagnosis. Between January 1, 1960 and October 31, 2013, 140 (11.8%) WM patients were ≤50 years of age at diagnosis in our database, and their estimated 10‐year overall survival (OS) was 74%, with death attributable to WM in a higher proportion of patients compared to their older (≥65 years) counterparts (91% vs. 58%, p = .0001). Young patients were grouped into three cohorts based on the timing of the initiation of therapy: Group 1 (1960–1977, n = 12), Group 2 (1978–1995, n = 48), and Group 3 (1996–2013, n = 74). Among young patients, there was no disease‐specific survival (DSS) difference across the three periods, [median DSS at 13 years (95% CI 5–23), 16 years (95% CI 14–22), and 15 years (95% CI 10‐NR; p = .41), respectively]. However, DSS for the older cohort incrementally improved (Group 1, median 5.2 years, Group 2: 9.6 years, Group 3: 12 years; p = .05) over these periods. The estimated average years‐of‐life lost for the young cohort was 11.2 years from diagnosis, based on the expected survival for a normal age‐ and sex‐matched population. Despite a protracted disease course, nearly all young patients succumb to their disease. In contrast to the improved survival of the elderly patient population, the evolving treatment strategies in WM have not impacted the outcome of young patients; however, the impact of Bruton tyrosine kinase inhibitors on this unique patient population remains to be determined.