Holmberg, Leona

Abstract Introduction CAR T cell treatment is the standard of care for patients (pts) with primary refractory and relapsed large B-cell lymphoma (LBCL) within the first 12 months of chemoimmunotherapy, or for those unfit for autologous stem cell transplant (ASCT) regardless of timing of relapse. Consequently, the role of ASCT is limited to pts with late relapse (>12 months) who achieve a complete or partial response (CR or PR) to salvage therapy and are deemed eligible for ASCT based on comorbidities and performance status. In this report, we evaluated post-ASCT outcomes in this population of pts. Methods We conducted a retrospective cohort study using publicly available data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Adult pts (age ≥18 years) with DLBCL, NOS, and high-grade large B-cell lymphomas (HGBL) who relapsed after having responded to initial treatment and who remained on response for at least 12 months since diagnosis were selected. We considered for this analysis only pts who achieved a CR or PR after salvage treatment at the time of relapse, documented on pre-ASCT CT or PET scan (per the 2014 Lugano definition). CIBMTR databases used for this study included pts who received ASCT from 2013 to 2021. We compared baseline characteristics between ASCT in CR vs PR using the Wilcoxon rank sum test for continuous variables and the Pearson's χ2 test for categorical variables after ignoring missing data. Primary endpoints included Progression-free survival (PFS) and overall survival (OS). Non-relapse mortality (NRM) and relapse rate were among the secondary endpoints. Results 182 were included in the analysis: 100 were in CR and 82 in PR before ASCT. The median age at ASCT was 60 years (range, 26-79). Race distribution was similar across CR and PR pts. Advanced-stage disease at diagnosis (stage III–IV) was seen in 61% of CR pts and 55% of PR pts. High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements was similar in the CR and PR groups (7% vs 4%). The median number of lines of treatment before ASCT were identical in CR and PR pts (N=2). BEAM was the most frequently used transplant conditioning regimen in both groups (80%). Median follow-up after ASCT was 34 months (range, 1–95): it was 37 months (range 1-95) in the CR group and 26 months (range 1-79) in the PR group For the entire cohort, OS at 3 years was 67.6% and PFS was 50.6%. NRM was 1.7% at 100 days and 3.4% at 1 year. Cumulative incidence of relapse at 3 years was 43.9%. The NRM analysis showed no statistically significant difference between pts in CR and PR. The 3-year OS for CR pts was 73.9%% compared to 59.4% for PR pts (95% CI, 0.334-0.99; p=.044). The 3-year PFS for CR pts was 59.8%, compared to 38.6% for PR pts (95% CI, 0.321-0.784; p=.001). The median PFS for CR pts was 52.01 months, compared to 14.05 months for PR pts. The cumulative incidence of relapse at 3 years in CR and PR pts was 35.2% vs 55.7%, respectively (95% CI, 0.311-0.811; p=.003.). Higher age (HR 1.03; p=.026) and number of previous lines of treatment (HR 1.43; p=.002) were associated with inferior OS. For PFS, no variables showed any significant impact in univariable analysis. The stepwise multivariable analysis showed that only the number of previous treatments had a significant impact on the OS (p=.009), while undergoing ASCT on a PR was the only factor significantly associated with shorter PFS (HR 1.41; 95% CI, 1.09-1.82; p=.029). Conclusion This dataset supports that ASCT provides high efficacy in pts experiencing late relapses (after 12 months) achieving CR following pre-transplant savage and validates the value of achieving CR. Outcomes for PR are inferior, and this analysis provides a benchmark for future investigations. At this time, until convincing on other non-transplant treatment show superior outcomes in this setting, ASCT remains a standard of care for fit pts with chemo-sensitive late relapsed DLBCL. In this group of patients, who have a better prognosis compared to patients who relapse within a year the major hurdle is achieving a remission pre-ASCT.

The NCCN Guidelines for Multiple Myeloma (MM) provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with MM. These NCCN Guidelines Insights highlight the important updates and changes specific to systemic therapy for patients with newly diagnosed as well as previously treated MM included in Version 1.2025 of the NCCN Guidelines for MM.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.

AbstractBackgroundLenalidomide maintenance after autologous stem cell transplant (ASCT) in multiple myeloma (MM) results in superior progression‐free survival and overall survival. However, patients with high‐risk multiple myeloma (HRMM) do not derive the same survival benefit from lenalidomide maintenance compared with standard‐risk patients. The authors sought to determine the outcomes of bortezomib‐based maintenance compared with lenalidomide maintenance in patients with HRMM undergoing ASCT.MethodsIn total, the authors identified 503 patients with HRMM who were undergoing ASCT within 12 months of diagnosis from January 2013 to December 2018 after receiving triplet novel‐agent induction in the Center for International Blood and Marrow Transplant Research database. HRMM was defined as deletion 17p, t(14;16), t(4;14), t(14;20), or chromosome 1q gain.ResultsThree hundred fifty‐seven patients (67%) received lenalidomide alone, and 146 (33%) received bortezomib‐based maintenance (with bortezomib alone in 58%). Patients in the bortezomib‐based maintenance group were more likely to harbor two or more high‐risk abnormalities and International Staging System stage III disease (30% vs. 22%; p = .01) compared with the lenalidomide group (24% vs. 15%; p < .01). Patients who were receiving lenalidomide maintenance had superior progression‐free survival at 2 years compared with those who were receiving either bortezomib monotherapy or combination therapy (75% vs. 63%; p = .009). Overall survival at 2 years was also superior in the lenalidomide group (93% vs. 84%; p = .001).ConclusionsNo superior outcomes were observed in patients with HRMM who received bortezomib monotherapy or (to a lesser extent) in those who received bortezomib in combination as maintenance compared with lenalidomide alone. Until prospective data from randomized clinical trials are available, post‐transplant therapy should be tailored to each patient with consideration for treating patients in clinical trials that target novel therapeutic strategies for HRMM, and lenalidomide should remain a cornerstone of treatment.

Abstract The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P &lt; .001 and HR 5.01, P &lt; .001, respectively) and OS (HR 3.85, P &lt; .001 and HR 8.13, P &lt; .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post–auto-HSCT.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with various plasma cell neoplasms, including multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates/changes specific to the treatment of patients with multiple myeloma in the 2022 version of the guidelines.

Introduction: Standard of care for patients (pts) with relapsed or refractory (RR) Hodgkin lymphoma (HL) is salvage therapy (tx) followed by autologous hematopoietic cell transplantation (HCT). However, most pts with high-risk RR HL will relapse after HCT. The AETHERA study demonstrated that post-HCT consolidation with brentuximab vedotin (BV) in high-risk HL pts improved progression-free survival (PFS) compared to placebo, particularly in pts with 2+ risk factors (Moskowitz, 2018). Pts with prior BV exposure were excluded from AETHERA, and BV is increasingly used prior to HCT in HL. PD1 blockade is effective in pts with RR HL and PD1 monotherapy as post-HCT consolidation in HL resulted in promising 18 mo PFS (Armand, 2019). Combined BV and nivolumab (Nivo) is a safe and effective salvage tx in HL, therefore we conducted a multicenter phase 2 study to evaluate the safety and efficacy of BV-Nivo post-HCT consolidation in high risk RR HL. Methods: After HCT, adult pts with high-risk HL defined as having ≥ 1 of the following modified AETHERA risk factors were eligible: primary refractory HL, relapse &lt; 1 year of completing initial tx, extranodal disease (dz) at relapse, B symptoms (sx) at relapse, requiring &gt; 1 salvage tx, not in CR at HCT. Prior BV or PD1 blockade were allowed if pts were not refractory. Pts underwent HCT according to institutional standards at the 5 centers. Starting between day 30-75 after HCT, pts received 1.8 mg/kg of BV and 3mg/kg nivo q21 days for a planned 8 cycles. If 1 drug was discontinued due to toxicity, the other could be continued. Investigators assessed response and progressive disease (PD) according to the 2014 Lugano classification. The primary endpoint was 18 mo PFS from study tx initiation. Secondary endpoints were overall survival (OS), safety, and the response rate in pts not in complete response (CR) at baseline. Results: 59 pts were enrolled and treated with at least one dose of study tx. Baseline characteristics are listed in Table 1. 18 (31%) pts were primary refractory, 35 (59%) had early relapse, 23 (39%) had extranodal dz and 14 (24%) had B sx at relapse, 15 (25%) received &gt; 1 salvage tx before HCT, and 48 (81%) were in CR at HCT. 21 (36%) had 1 modified AETHERA risk factor, 23 (40%) had 2 and 14 (24%) had 3+ risk factors. The median follow-up time from study tx initiation was 15.7 months (range, 2.8-35.5). Patients initiated BV-nivo a median 54 days from HCT (range, 34-75) and received a median of 8 cycles (range, 1-8). 29 (49%) pts completed all 8 cycles of BV and nivo and 45 (76%) patients completed 8 cycles of one drug. 14 (24%) pts discontinued both BV and nivo early, including 6 for adverse events (AE), 6 pt withdrawals, 1 pt lost to follow-up, and 1 pt death from PJP pneumonia unrelated to study tx. BV was discontinued in 8 (14%) pts - due to grade (gr) 3 peripheral neuropathy (PN) in 2 pts, gr 2 PN in 2 pts, carpal tunnel syndrome in 1 pt, gastrointestinal AEs in 2 pts, and infusion related reaction in 1 pt. Nivo was discontinued in 7 (12%) pts - due to pneumonitis in 2 pts, and colitis, elevated bilirubin, abnormal transaminases, pneumonia with elevated creatinine, and hypotension with fever in 1 pt each. BV was dose reduced to 1.2mg/kg in 11 (19%) pts, 9 pts for PN, and 1 each for neutropenia and arthralgia. The most common AEs related to BV-Nivo consolidation were PN (51%, 3% gr 3), neutropenia (42%, 31% gr 3-4), fatigue (37%), diarrhea (29%, 3% gr 3), nausea (25%, 2% gr 3), arthralgia (24%), AST elevation (24%, 2% gr 3). The most frequent gr 3-4 AEs were neutropenia (31%), pneumonitis (7%), and ALT elevation (5%). Immune-related (ir) AEs requiring systemic corticosteroids occurred in 18 (31%) patients. Most common Gr 2 or higher irAEs included: pneumonitis (12%), AST or ALT elevation (8%), hypothyroidism (5%), and rash (3%). 6 pts were not in CR at baseline after HCT (all PR). 5 pts converted to CR with study tx and 1 pt remained in PR without PD. There were only 2 PFS events, 1 pt with relapse at 15 months and PJP-related death after prophylaxis was self-discontinued. The estimated 18 mo PFS and OS in all patients were 95% and 98%, respectively. The estimated 18 mo PFS in pts with 2+ and 3+ risk factors were 92% and 89%, respectively. Conclusions: Post-HCT consolidation with BV-Nivo in pts with high-risk RR HL is a promising approach, with only 1 relapse observed in our cohort with short follow-up thus far. Post-HCT BV-Nivo was tolerable, though IrAEs were observed more frequently than in the pre-HCT setting and PN and neutropenia were common. Disclosures Herrera: Pharmacyclics: Research Funding; Karyopharm: Consultancy; AstraZeneca: Research Funding; Gilead Sciences: Consultancy, Research Funding; Immune Design: Research Funding; Seattle Genetics: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding. Nieto:Affimed: Consultancy, Other: Grant Support; Secura Bio: Other: Grant Support; Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support. Holmberg:Sanofi: Research Funding; Seattle Genetics: Research Funding; Millenium-Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; UpToDate: Patents & Royalties: Royalties; Janssen: Research Funding; Merck: Research Funding. Mei:Sanofi: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees. Chen:Autolus Therapeutics: Current Employment. Rosen:Abbvie: Speakers Bureau; Seattle Genetics: Consultancy; NeoGenomics: Consultancy; Aileron Therapeutics: Consultancy; Novartis: Consultancy; Pebromene: Consultancy; Celgene: Speakers Bureau; paradigm Medical Communications: Speakers Bureau. Kwak:CJ Healthcare: Consultancy; Xeme Biopharma/Theratest: Other: equity; Sellas Life Sciences Grp: Consultancy; Enzychem Life Sciences: Membership on an entity's Board of Directors or advisory committees; Antigenics: Other: equity; InnoLifes, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pepromene Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc.: Consultancy. Feldman:Portola: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Trillium: Research Funding; Janssen: Speakers Bureau; Viracta: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; AstraZeneca: Consultancy. OffLabel Disclosure: Nivolumab is not FDA-approved for use as consolidation after autologous stem cell transplantation

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.