McCarthy, Philip L.

Solitary plasmacytomas (SPs) are rare localized tumors of clonal plasma cells, either in the bone (solitary bone plasmacytoma) or in soft tissue/extraosseous (extramedullary) with either no or with minimal bone marrow (BM) infiltration (<10% clonal plasma cells by immunohistochemistry) and no evidence of systemic involvement or myeloma defining events. Approximately 50% of SPs will progress to symptomatic myeloma within 5 years after initial definitive local radiotherapy. Increased availability of improved diagnostic and monitoring tools has increased the sensitivity of detection of additional lesions and marrow involvement and has implications for the follow-up strategy after treatment. Thus, the definitions and requirements for the diagnosis and follow-up of SPs are evolving. The diagnosis of SP requires the careful exclusion of multiple myeloma (MM) that would require systemic therapy, by using all the available methods to detect systemic disease (advanced imaging, sensitive BM assessment methods, blood and urine tests). Local radiotherapy remains the mainstay of therapy, and despite the availability of innovative drugs for MM, the clinical benefit of systemic therapy currently remains poorly defined. The International Myeloma Working Group provides here updated recommendations for the diagnosis, evaluation, treatment, and response assessment of patients with SPs, incorporating recent data and advances in diagnostic tools.

PURPOSE Newly approved drugs and combinations treating multiple myeloma (MM) have resulted in substantial improvements in patients' survival. To deliver rapid access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to evaluate the minimal residual disease–negative complete response (MRD-CR) as an intermediate end point for progression-free survival (PFS) and overall survival (OS) in newly diagnosed (ND) transplant-eligible (NDTE) patients, ND transplant-ineligible (NDTinE) patients, and patients with relapsed/refractory (RR) MM. PATIENTS AND METHODS Individual patient data from 20 randomized multicenter trials were collected. Eleven studies (4,773 patients) with sufficient data were analyzed to evaluate whether 9- or 12-month MRD-CR classified at a 10 –5 threshold could be reasonably likely to predict the clinical benefit of new agents regarding PFS and OS. Global odds ratio (OR) was estimated using the bivariate Plackett Copula model. Supportive evaluation included correlations of the treatment effects on MRD-CR end points and PFS/OS, evaluated by both linear regression ( R 2 weighted least squared ) and Copula ( R 2 Copula ) models. RESULTS The analysis demonstrated that both 9- and 12-month MRD-CR strongly correlated with PFS at patient level in NDTE patients, NDTinE patients, and patients with RRMM. Global ORs ranged from 3.06 to 16.24, all with 95% CIs excluding 1.0. Encouraging trial-level correlations ( R 2 , 0.61-0.70) were observed by pooling three populations and were stronger ( R 2 , 0.67-0.78) in the ND population. Similar results were observed for OS. CONCLUSION Our findings provided the support for use of MRD-CR classified at a 10 –5 threshold at either 9 or 12 months after starting of the treatment, as an intermediate end point to support accelerated approvals, in future trials in NDTE patients, NDTinE patients, and patients with RRMM.

Background: 24-hour urine (24HRU) assessments are a key component of International Myeloma Working Group (IMWG) response criteria for multiple myeloma (MM) and are requested longitudinally in clinical trials even if not routinely used in real-world practice. Several analyses have suggested a limited role for 24HRU if serum immunofixation or free light chain (LC) testing is abnormal (Dejoie Blood 2016, Lahuerta Blood 2023). Adopting urine-free response criteria (with 24HRU removal from every level of IMWG response) may change responses in &lt;5% of patients (Natsuhara et al, Leuk Lymph 2023) but not have been studied in terms of progression-free survival (PFS) in a larger population. Methods: This was a secondary analysis of data from the Phase 3 BMT CTN 0702 (STaMINA) trial (Stadtmauer et al, JCO 2019) studying post-autologous stem cell transplantation (ASCT) strategies. Only patients evaluable for Day +56 response following ASCT were included, and patients with progressive disease (PD, n=8) at this timepoint were excluded. Post-ASCT responses relative to diagnosis were calculated by two sets of criteria. First, traditional responses were calculated per IMWG criteria (Kumar et al, Lancet Onc 2016) as stable disease (SD), partial response (PR), very good PR (VGPR), or complete response (CR, including stringent CR). Second, urine-free response assessments were calculated as follows: negative 24HRU immunofixation no longer required for CR, 24HRU M-protein &lt; 100 milligrams (mg) per day no longer required for VGPR, and no 24HRU M-protein thresholds (e.g., &lt; 200 mg per day or &gt; 90% reduction) required for PR. PFS was estimated (using PD by traditional IMWG criteria or death as events) using proportional hazard models. Results: Of 636 evaluable patients (84% of all BMT CTN 0702 participants), LC-only disease was noted in 18.9% (n=120). Pre-enrollment 24HRU testing at diagnosis was done in 28.9% of patients (n=184). IMWG responses were as follows: CR, 29.4% (n=187) traditional vs 29.7% (n=189) urine-free; VGPR, 37.0% (n=235) traditional vs 36.6% (n=233) urine-free; PR, 30.7% (n=195) for both; SD, 3.0% (n=19) for both. A total of 4 responses (0.6%) changed with urine-free criteria. Three patients were ‘upgraded’ (VGPR to CR, n=2, PR to VGPR, n=1) because 24HRU requirements for CR/VGPR were no longer required. One patient without a measurable serum paraprotein was ‘downgraded’ from a traditional VGPR (with negative 24HRU immunofixation) to a urine-free PR based on LC-only criteria. Among the subset of 184 patients with 24HRU electrophoresis results at diagnosis, there were no differences between traditional and urine-free IMWG responses. Median PFS and 95% confidence intervals (CI) were the same at each depth of both traditional and urine-free criteria: 63.0 months (50.8 - 71.4 months) for CR, 49.6 months (42.6 - 55.1 months) for VGPR, 44.9 months (37.2-54.8 months) for PR, and 34.4 months (14.0-51.5 months) for SD. Urine-free IMWG criteria were highly prognostic for PFS (p = 0.006, 95% CI 1.05-1.36). The achievement of urine-free CR vs urine-free ≤CR was also prognostic (p = 0.005, 95% CI 0.54 - 0.89). Urine-free VGPR vs urine-free ≤VGPR was of borderline significance (p = 0.102, 95% CI 0.66 - 1.04), with median PFS 53.8 months (48.0 - 57.6 months) vs 44.6 months (36.3 - 54.7 months) respectively. Discussion: In this secondary analysis of a Phase 3 trial, omitting 24HRU assessments from IMWG criteria changed &lt;1% of responses and had no impact on PFS prediction at any response depth. 24HRU assessments had been performed for less than a third of patients as standard of care prior to study entry, underscoring its infrequent use outside of trials. Urine-free IMWG assessments would reduce time toxicity and discomfort for patients, particularly for those with limited dexterity. If implemented in trials, they would also simplify study logistics and lower operational costs. Outside of situations such as AL amyloidosis where 24HRU assessments remain critical or for patients with urine as their only measurable MM biomarker, our results support the removal of 24HRU assessments from future iterations of IMWG response criteria. Funding: Grants #U10HL069294 and #U24HL138660 to the BMT CTN from the NHLBI and the NCI; contributions by Celgene Corporation and Millennium Pharmaceuticals, Inc.; funding by The Alliance for Clinical Trials in Oncology, the ECOG-ACRIN Cancer Research Group and SWOG.

8009 Background: Measuring response among patients with multiple myeloma is essential for the care of patients. Deeper responses have been associated with better progression free survival (PFS) and overall survival (OS). Serum (SIFE) and urine immunofixation are the currently used markers for biochemical documentation of CR after which marrow is tested for plasma cell clearance. Next generation flow cytometry and sequencing are used to document the presence of minimal residual disease (MRD). Mass spectrometry of blood by MALDI (Mass-Fix) is a new simple, inexpensive, sensitive, and specific means of detecting monoclonal immunoglobulins. To better test the hypothesis that Mass-Fix is superior to existing methodologies to predict for survival outcomes—especially SIFE-- samples from the STAMINA trial (NCT01109004), a trial comparing 3 transplant approaches among patients who have already received induction, were employed. Methods: Five-hundred and seventy-five patients were included. Samples from enrollment post-induction (post-I) and 1-year post enrollment (1YR) were tested when available. Four response parameters were assessed univariately: Mass-Fix, SIFE, complete response, and MRD by next generation flow cytometry. Mass spectrometry spectra were evaluated in a blinded fashion. Complete response was according to the 2006 International Myeloma Working Group criteria. Multivariate Cox proportional hazard models using stepwise regression were developed to explore the independent effect of the different response parameters on PFS and OS and interactions with other risk factors. Results: Of the 4 response measures, only MRD and Mass-Fix predicted for PFS and OS at multiple testing points on multivariate analyses (Table). Of the 4 post-I measurements, only MRD predicted for PFS; however, Mass-Fix was the only post-I measurement to predict for OS. Of all the 1-year measures, both 1YR Mass-Fix and 1YR MRD positivity predicted for inferior PFS and OS. In models including MRD and Mass-Fix, SIFE and CR were not prognostic for PFS or OS. Conclusions: Mass-Fix is a powerful means to track monoclonal proteins. The full utility of Mass-Fix was not exploited given the absence of a diagnostic sample and the fact that only serum (and not urine) was tested. Despite these limitations, it performed well at pre-induction and at 1 year. Mass-Fix provides a convenient and non-invasive means of predicting for myeloma outcomes. Clinical trial information: NCT01109004. [Table: see text]

Autologous stem cell transplantation (ASCT) has been a backbone of therapy for newly diagnosed patients with multiple myeloma eligible for high-dose therapy for decades. Survival outcomes have continued to improve over time, in part because of the incorporation of highly effective induction regimens prior to ASCT as well as post-ASCT maintenance therapy. Randomized phase III clinical trials have helped establish lenalidomide maintenance as a standard of care. However, as nearly all patients will eventually experience disease relapse, there continues to be significant interest in developing novel maintenance strategies to improve upon lenalidomide maintenance. In this review, we summarize the available evidence for the use of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies as post-ASCT maintenance therapies as well as discuss future directions and unanswered questions in the field.

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for pts with R/R LBCL with ≥ 2 prior systemic therapies. With a median follow-up of 27.1 months in ZUMA-1, the objective response rate (ORR) with axi-cel was 83% (58% complete response rate) in pts with refractory LBCL. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 11% and 32% of pts, respectively (Locke FL, et al. LancetOncol. 2019). Although CRS can be ameliorated with use of the anti-IL-6 receptor antibody tocilizumab, NEs may be unaffected or worsened by tocilizumab (Gust J, et al. Cancer Discov. 2017; Lee DW, et al. Blood. 2014; Santomasso BD, et al. Cancer Discov. 2018; Locke FL, et al. ASH 2017. #1547). Identification of mitigation strategies for NEs is complicated by a significant association between CAR T cell expansion and both ORR and Grade ≥ 3 NEs, suggesting a correlation between efficacy and adverse events (AEs; Neelapu SS, et al. N EnglJ Med. 2017). ZUMA-1 Cohort 4 suggested that earlier utilization of systemic corticosteroids for broad immune system suppression in pts with mild NEs and low-grade CRS may reduce the incidence of Grade ≥ 2 NEs without significant impact on efficacy (Topp MS, et al. ASH 2019. #243). However, this reactive approach has not fully abrogated NEs; as such, proactive strategies to further improve safety management with CAR T cell therapy without negatively impacting efficacy are needed. Upon tumor challenge, CAR T cells produce granulocyte-macrophage colony-stimulating factor (GM-CSF; Giavridis T, et al. Nat Med. 2018), which acts to promote myeloid activation, expansion, and cytokine production (Spath S, et al. Immunity. 2017). GM-CSF was among the cytokines significantly associated with Grade ≥ 3 NEs in ZUMA-1 (Neelapu SS, et al. N Engl J Med. 2017). Notably, peak GM-CSF levels occurred before those of most other cytokines, and no direct association was observed between GMCSF levels and ORR (Rossi JM, et al. EMA Workshop, 2016). These findings suggest that GM-CSF may initiate inflammatory events that cause NEs and that GM-CSF inhibition has the potential to improve the safety of CAR T cells, without impacting efficacy. GM-CSF depletion with lenzilumab, a humanized monoclonal antibody that neutralizes GM-CSF, prevented CRS and NEs in preclinical models of CAR T cell toxicity (Sterner RM, et al. Blood2019). The Phase 1/2 ZUMA19 study is evaluating sequenced therapy with lenzilumab and axi-cel to prevent axi-cel-related CRS and NEs in pts with R/R LBCL. Methods: Eligible pts are adults (≥ 18 y) with LBCL who relapsed after ≥ 2 systemic lines of therapy or are chemorefractory - defined as i) a best response of progressive disease (PD) or stable disease (SD) to ≥ 4 cycles of first-line systemic therapy (SD duration ≤ 6 months); or ii) a best response of PD or SD after ≥ 2 cycles of the most recent second-or-later line of systemic therapy. Prior therapy must have included an anti-CD20 monoclonal antibody and an anthracycline-containing regimen. Pts will undergo leukapheresis and may receive optional corticosteroid bridging therapy. Pts will then receive lymphodepleting chemotherapy on Days ‒3 to ‒5 followed by Day 0 administration of lenzilumab and, 6 hours later, a single infusion of axi-cel (target dose, 2 × 106 CAR T cells/kg). Phase 1 will initially enroll pts in 2 dose-escalation cohorts; each will receive a single infusion of lenzilumab. Safety data will be reviewed after 3 and 6 (if needed) pts in each cohort have been followed for 28 days. The recommended Phase 2 dose (RP2D) of lenzilumab will be based on the dose-limiting toxicity rate (phase 1 primary endpoint), and, if necessary, translational assessment of GM-CSF axis suppression. Phase 2 will assume a Simon 2-stage design. The primary endpoint for phase 2 is the incidence of Grade ≥ 2 NEs within 28 days of axi-cel administration. Efficacy, safety (including CRS and NEs), and blood levels of CAR T cells and cytokines (including GM-CSF) will be evaluated as secondary endpoints. An interim analysis will be performed when 14 subjects have received the RP2D in Phase 1 or 2 and are followed for ≥ 28 days after axi-cel infusion. If futility criteria are not met, enrollment will continue. Primary analysis will be performed after 30 pts are treated with RP2D of lenzilumab and have ≥ 6 months of follow up. ZUMA-19 is open and actively recruiting pts. Disclosures Kenderian: Mettaforge: Patents & Royalties; Humanigen: Consultancy, Patents & Royalties, Research Funding; Lentigen: Research Funding; MorphoSys: Research Funding; Sunesis: Research Funding; Tolero: Research Funding; BMS: Research Funding; Juno: Research Funding; Gilead: Research Funding; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy. Oluwole:Bayer: Consultancy; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy. McCarthy:Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Juno Therapeutics, a Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board , Research Funding is to Roswell Park, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Karyopharm: Consultancy, Honoraria; Magenta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Starton: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board. Reshef:Celgene: Consultancy; Pharmacyclics: Research Funding; Shire: Research Funding; Bluebird: Research Funding; Kiadis: Research Funding; Monsanto: Consultancy; Takeda: Research Funding; Atara: Consultancy, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Research Funding; Immatics: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria; Magenta: Consultancy. Shiraz:Kite, a Gilead Company: Research Funding; ORCA BioSystems: Research Funding. Ahmed:Humanigen, Inc.: Current Employment, Current equity holder in publicly-traded company. Le Gall:Kite, a Gilead Company: Ended employment in the past 24 months; Gilead Sciences: Current equity holder in publicly-traded company. Nahas:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Tang:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Neelapu:Takeda Pharmaceuticals: Patents & Royalties; Cellectis: Research Funding; Calibr: Other; Precision Biosciences: Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Acerta: Research Funding; Karus Therapeutics: Research Funding; Poseida: Research Funding; Cell Medica/Kuur: Other: personal fees; Incyte: Other: personal fees; Unum Therapeutics: Other, Research Funding; N/A: Other; Adicet Bio: Other; Legend Biotech: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees.

Abstract INTRODUCTION: Obesity is increasingly common in the US and is frequently associated with co-morbid medical conditions that may increase the risk of HCT, often the optimal treatment for AML. HCT risk and outcomes for AML on the basis of body mass index (BMI) have not been well-characterized. Using data from the Center for International Blood and Marrow Transplant Research (CIBMTR), we have previously shown no significant difference in outcomes for autologous HCT for lymphoma among normal weight, overweight, and obese patients (pts) but worse outcomes for underweight pts (Navarro et al, BBMT 2006, 12(5): 541–51). Here, we compare outcomes by weight groups for AML patients who underwent autologous, related, or unrelated HCT. METHODS: Our final population included patients age ≥ 18 who underwent myeloablative unpurged autologous or allogeneic HCT for AML in 1st or 2nd complete remission, primary induction failure, or 1st relapse reported to the CIBMTR from 1995 to 2004. Cord blood HCTs were excluded. Four weight groups were defined based on BMI (BMI=weight (kg)/ height (m2)): underweight &lt;18; normal=18–25; overweight &gt;25–30; and obese &gt;30. Treatment-related mortality (TRM), relapse, leukemia-free survival (LFS), and overall survival (OS) were compared using multivariable proportional hazards regression analysis accounting for patient, disease and HCT-related variables. RESULTS: We included 373 autologous, 2041 related, and 1801 unrelated transplant recipients. Patient-, disease-, and transplant characteristics were well-matched across weight groups and transplant types. Multivariable analysis examining risks (95% confidence intervals) relative to the normal weight group are: HCT Type Normal Underweight Overweight Obese -- =not done due to insufficient number of pts; NS=not significant; treatment failure = death or recurrence of disease. Autologous n=164 n=5 n=112 n=81 Death -- NS NS Treatment failure -- NS NS Relapse -- NS NS TRM -- NS NS Related Allogeneic n=1161 n=31 n=543 n=268 Death 1.86 (1.24–2.78) NS 1.23 (1.04–1.47) Treatment failure 2.08 (1.37–3.15) NS 1.19 (1.00–1.42) Relapse 2.02 (1.18–3.47) NS NS TRM 2.22 (1.17–4.22) NS 1.32 (1.02–1.70) Unrelated Allogeneic n=846 n=31 n=523 n=368 Death NS NS NS Treatment failure NS NS NS Relapse NS 0.82 (0.68–0.99) 0.76 (0.60–0.96) TRM NS NS NS CONCLUSIONS: There were no significant differences in risk of TRM, LFS, relapse or OS for normal weight, overweight or obese patient groups who received autologous HCT. Obese recipients of related HCT for AML had increased risk of death, treatment failure, and TRM, though the magnitude was small, an effect was not seen in the unrelated HCT group. Underweight patients who received a related, but not unrelated HCT, fared substantially worse than normal weight patients for all outcomes. It may be that the higher risk of the unrelated HCT procedure masks important but less obvious risks associated with being underweight whereas in the related donor HCT setting, such risks become manifest. Small numbers of patients limit the ability to better characterize this finding in underweight patients. Disproportionately, fewer transplants have been reported in underweight patients which suggest they experience disease and patient-related factors that preclude transplantation. No differences were observed for incidence of acute or chronic GVHD for any weight group. Overweight and obesity should not be a barrier to HCT; however, caution should be exercised in selecting underweight patients for HCT.