The changing landscape of relapsed and/or refractory multiple myeloma (MM): fundamentals and controversies

The increase in the number of therapeutic alternatives for both newly diagnosed and relapsed/refractory multiple myeloma (RRMM) patients has widened the clinical scenario, leading to a level of complexity that no algorithm has been able to cover up to date. At present, this complexity increases due to the wide variety of clinical situations found in MM patients before they reach the status of relapsed/refractory disease. These different backgrounds may include primary refractoriness, early relapse after completion of first-line therapy with latest-generation agents, or very late relapse after chemotherapy or autologous transplantation. It is also important to bear in mind that many patient profiles are not fully represented in the main randomized clinical trials (RCT), and this further complicates treatment decision-making. In RRMM patients, the choice of previously unused drugs and the number and duration of previous therapeutic regimens until progression has a greater impact on treatment efficacy than the adverse biological characteristics of MM itself. In addition to proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies and corticosteroids, a new generation of drugs such as XPO inhibitors, BCL-2 inhibitors, new alkylators and, above all, immunotherapy based on conjugated anti-BCMA antibodies and CAR-T cells, have been developed to fight RRMM. This comprehensive review addresses the fundamentals and controversies regarding RRMM, and discusses the main aspects of management and treatment. The basis for the clinical management of RRMM (complexity of clinical scenarios, key factors to consider before choosing an appropriate treatment, or when to treat), the arsenal of new drugs with no cross resistance with previously administered standard first line regimens (main phase 3 clinical trials), the future outlook including the usefulness of abandoned resources, together with the controversies surrounding the clinical management of RRMM patients will be reviewed in detail.

Solitary Fibrous Tumors Arising from Bilateral Ovaries: A Case Report and Review of the literature

Background: A solitary fibrous tumor (SFT) is a distinct mesenchymal neoplasm. It was originally described as a tumor localized to the pleura but was later reported in several other anatomic sites and exhibited a wide spectrum of histological features. Owing to its rarity, the diagnosis of extrapleural SFT is challenging and requires an integrated approach comprising specific clinical, imaging, histological, and immunohistochemical findings. Case presentation: Herein, we report the imaging findings of a rare case of SFT arising from bilateral ovaries confirmed by surgical excision and histological examination. No adjuvant radiotherapy or chemotherapy was given to the patient, and she was disease-free with no evidence of recurrence or metastasis at the 96-month postoperative follow-up. Although it mostly follows a favorable course, SFT is notoriously difficult for prognostication because of its propensity for late relapse or even metastases in 10–39% of cases. Conclusion: Close follow-up is recommended because of the limited information on its long-term behavior.

Early and late relapses of multiple myeloma after autologous haematopoietic stem cell transplantation

Introduction. Autologous haematopoietic stem cell transplantation (auto-HSCT) is a highly effective treatment for multiple myeloma (MM). Auto-HSCT allows a signifi cant improvement of haematological response leading to higher overall survival and quality of life in MM patients. Nonetheless, the majority of patients develop relapse.Aim — a comparison of clinical MM relapses developing at variant terms after auto-HSCT.Patients and methods. A retrospective study enrolled 65 MM patients aged between 39 and 64 years. All patients had auto-HSCT during 2009–2019, all had achieved complete response (CR) or very good partial response (VGPR) and all since developed immunochemical MM relapse in laboratory evidence. Patients were divided in two cohorts by relapse term, the early (within 12 months of auto-HSCT) and late relapse.Results. Early immunochemical relapse was diagnosed in 13 (20 %), late relapse — in 52 (80 %) patients. The dependence between relapse term and depth of post-auto-HSCT antitumour response has been determined. The proportion of CR patients was signifi cantly higher in late than in early relapse (55.8 vs. 23 %). In follow-up, 60 patients (92.3 %) were initiated on antirelapse therapy, all early relapse and 90.3 % late relapse patients. On day +100 of auto-HSCT, CR patients had later relapse vs. VGPR individuals (median 24 vs. 19.9 months, p = 0.08) with signifi cantly weaker paraprotein secretion resembling the clinical course of monoclonal gammopathy of unclear signifi cance (MGUS).Conclusion. Auto-HSCT allows long-term control of the disease. A signifi cant prognostic factor is antitumour response on +100 day of auto-HSCT. Patients attaining CR have later relapse progressing in a MGUS-like manner. Patients with late indolent relapse can be managed long-term without antitumour therapy.

GNAO1 as a Novel Predictive Biomarker for Late Relapse in Hepatocellular Carcinoma

GNAO1, the alpha O1 subunit of G protein, was reported to be significantly downregulated in hepatocellular carcinoma (HCC), as well as being implicated in a variety of intracellular biological events; findings suggest that it may act as a tumor suppressor. Our goal was to further explore the expression of GNAO1 in HCC patients and its potential clinical significance. Oncomine and Kaplan–Meier plotter databases were used to assess the mRNA expression of GNAO1 in HCC tissues and patient survival time. Subsequently, immunohistochemistry (IHC) was used to measure GNAO1 protein level in tissue from 79 cases of HCC and paired adjacent tissues. The Kaplan–Meier survival analysis, Cox regression model, and prognostic nomogram were used to evaluate the prognostic role of GNAO1 in HCC. Results demonstrated that mRNA and protein expressions of GNAO1 were both lower in HCC tissues than in adjacent tissues (all p < 0.01 ). HCC patients with high expression of GNAO1 had better relapse-free survival (RFS) than those with low GNAO1 expression (all p < 0.05 ). A high expression of GNAO1, meanwhile, functioned as a good predictor of late relapse for HCC ( p < 0.05 ). The nomogram consisting of GNAO1 expression and the tumor-node-metastasis (TNM) model presented good ability in predicting the 3-year relapse for HCC (C-index = 0.614). In conclusion, GNAO1 was a reliable biomarker of relapse prediction for HCC.

Exploring the Impact of Diffuse Large B-Cell Lymphoma (International Prognostic Index [IPI] 2-5) on Clinical and Patient-Relevant Outcomes in the Context of a Clinical Trial

Background: Most patients (pts) with diffuse large B-cell lymphoma (DLBCL) receiving first-line (1L) rituximab plus CHOP (R-CHOP) have similar mortality to the general population (gen popn) if they are progression-free at 24 months (PFS24; Maurer et al. Ann Oncol 2018). Characterization of quality of life (QoL) and clinical outcomes may enable more patient-relevant treatment decisions. Using GOYA trial data (NCT01287741) comparing obinutuzumab (G) + CHOP (G-CHOP) with R-CHOP, we present an exploratory analysis of 1L DLBCL pts with IPI 2-5 and assess overall survival (OS) and QoL relative to the gen popn. GOYA was not included in the previous PFS24 analysis by Maurer et al. Methods: We used data from both GOYA treatment arms to identify pts with IPI 2-5 DLBCL (n=1132 pts, intent-to-treat popn). Post-progression survival (PPS) in DLBCL is independent of prior treatment (Coiffier et al. Blood 2010) and as PFS was similar between treatment arms in GOYA, we assumed similar mortality after PFS24. Clinical outcomes were PFS24 (progression-free ≥24 months [m] from treatment start); early relapse (disease progression [PD]&lt;24m from treatment start); late relapse (PD after PFS24). Outcomes for study pts vs gen popn were evaluated using standardized mortality ratios (SMR; deaths in study pts relative to expected deaths in gen popn matched by age, sex, country, and calendar time-at-risk). Expected deaths were derived using the Human Mortality Database, which provides detailed mortality and population data by country and can be used to estimate the background mortality during the observation period. Post-relapse survival in pts with early vs late relapse was assessed using Kaplan-Meier (KM) estimates and Cox regression. QoL was assessed using EQ-5D-3L and UK-based tariffs (Dolan. Med Care 1997); association between QoL and clinical outcomes used a linear mixed-effects model. The proportion of pts with PFS24 reporting QoL problems at baseline and after 24m was compared with age- and country-matched values in the gen popn (Janssen et al. Springer 2014). Data cut-off was Jan 2018 (GOYA final data cut); overall median follow-up was 48m. Results: In the overall IPI 2-5 population, mean age at treatment initiation was 61 yrs. 711 pts reached PFS24, of whom 64 experienced a late relapse (Table 1). Early relapse was experienced by 261 pts, of whom 164 were &lt;6 months from end of treatment (EOT). OS following PFS24 was 98.6% at 2 years (including patients who later relapsed). 2-year PPS was 35.7% for pts with early relapse vs 74.8% for patients with late relapse (Figure 1.) Mortality following PFS24 was 72% of the matched gen popn (SMR 0.72; not significant: 95% CI 0.44-1.11). Mortality following relapse in pts who experienced early relapse was over 33 times higher than expected in the matched gen popn (SMR 33.57, 95% CI 27.69-40.33). However, risk of death following late relapse was reduced by 78% compared with risk following early relapse (HR 0.22 95 CI% 0.12-0.40), and mortality following late relapse was significantly higher than in the matched gen popn (SMR 6.7, 95% CI 3.05-12.67). Mean QoL utility score at baseline was 0.69 for all pts. After pts reached PFS24, estimated mean utility score was 0.86 (95% CI 0.84-0.87) and worsened by -0.07 (95% CI -0.14 to -0.01) at time of subsequent relapse. For early-relapsing pts, the worsening in utility was -0.15 (95% CI -0.20 to -0.10) compared with those still progression-free (Table 2). Among all PFS24 pts at baseline, problems were reported with mobility (28.1%), self-care (12.6%), usual activities (41.8%), pain/discomfort (62.7%), and anxiety/depression (48.8%); these rates were 2.2-4.7 times higher than the gen popn based on age- and country-standardized values. Compared with the gen popn, after pts reached PFS24, pain/discomfort was 10% lower, whereas anxiety/depression was 34% higher and other QoL items were approximately 20% higher. Conclusions: Most of the clinical course of 1L DLBCL occurred ≤2 years after start of treatment. In DLBCL pts with IPI 2-5 achieving PFS24, mortality was similar to the gen popn, and with the exception of mental health metrics, QoL scores were also similar to the gen popn. Late relapse (≥2 yrs) was associated with better post-relapse survival than early relapse (&lt;2 yrs); however, this was inferior to the gen popn. Health state utilities improved whilst patients were relapse-free but the decline in QoL after early relapse was worse than after late relapse. Figure 1 Figure 1. Disclosures Launonen: F. Hoffmann-La Roche Ltd: Current Employment. Ho: F. Hoffmann-La Roche Ltd: Current Employment. Knapp: F. Hoffmann-La Roche Ltd: Current Employment. Canales Ruiz: Clinical Project Manager in Clinica Universidad de Navarra: Current Employment. Simonella: F. Hoffmann-La Roche Ltd: Current Employment. Thuresson: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company.

Prognostic Relevance of Protocol Deviations in Children with Relapsed ALL Treated in the ALL-REZ BFM 2002 Trial

Introduction: Acute lymphoblastic leukemia (ALL) is the most common cancer affecting children and its cure rates are close to 90%. Nevertheless, relapsed ALL is still a major cause of cancer-associated deaths in children. Therefore, the multicenter trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 2002 was designed to improve the prognosis of children with relapsed ALL by introducing new chemotherapy elements. Little is known though about the prognostic relevance of deviations from the ALL protocols. This study aimed to investigate the characteristics of such protocol deviations and to determine their prognostic relevance for the relapsed disease. Methods: We performed a retrospective analysis of 686 children and adolescents up to 18 years of age with first relapse of ALL who were enrolled between 2002 and 2012 in the ALL-REZ BFM 2002 Study. Deviations were identified in terms of time and type. In order to investigate the prognostic importance of the time delay, the 90th percentile of delays between defined treatment elements (i.e. 15.5 days) was used as a cut-off point. Furthermore, deviations were categorized as avoidable (logistics, family/PI decisions) and non-avoidable (clear medical indication). The protocol deviation occurred during the course of therapy was therefore considered as a time-dependent variable. Disease-free survival, (DFS, induction failures excluded) and OS were analyzed using Kaplan-Meier estimate, log-rank test, Mantel-Byar test and Cox/logistic regression (univariate and multivariate analyses). Results: A total of 587 patients (86%) received the protocol therapy, whereas 99 patients (14%) underwent deviations during their treatment. Baseline characteristics were compared in both groups (Table 1). Deviations were categorized as: change of chemotherapy in 48% of the patients (n=47/99), stop of chemotherapy in 10 % (n=10/99), non-protocol compliant reaction to MRD findings in 28% (n=28/99) and change of radiation treatment in 14% (n=14/99). The cumulative incidence of protocol deviation was 6% and 15.5% at 3 and 9 months, respectively (Figure 1). The remission rate of patients with protocol deviation during induction was slightly lower compared to patients without such deviation (24/29, 83% vs. 579/657, 88%; P=0.38). The estimated 5-year probabilities of DFS and OS between the patients treated according to protocol therapy and those with deviations were significantly different (pDFS, Protocol therapy: 0.61 ± 0.02 vs. Deviation: 0.38 ± 0.05, P &lt; 0.001; pOS, Protocol: 0.70 ± 0.02 vs. Deviation: 0.57 ± 0.05, P &lt; 0.001; Figure 2, 3). In multivariate analyses protocol deviation, time point of relapse and immunophenotype turned out to be independent prognostic factors of the DFS (Table2). The hazard ratio of the protocol deviation was significant only in patients with the late relapse, whereas in patients with early/very early relapse no significant prognostic effect could be found [late (n=40): HR=2.53, 95%CI 1.53-4.21, P&lt;0.001; early (n=29): HR=1.49, 95%CI 0.88-2.51, P=0.13; very early (n=25): HR=1.50, 95%CI 0.84-2.66, P=0.17]. Moreover, DFS probabilities were comparable for avoidable (n=63) and non-avoidable (n=31) deviations (0.43 ± 0.07 vs. 0.40 ± 0.09, P=0.9; Non avoidable: HR=1.19, 95%CI=0.68-2.10, P= 0.53). In terms of the time-related deviations, the extent of the delays between induction and beginning of consolidation therapy was not significantly associated with the DFS [≤90th percentile (n=319/603); pDFS: =0.60 ± 0.02 vs. &gt;90th percentile (n=36/603); pDFS: 0.56 ± 0.08, P=0.3]. Treatment delays during other phases of the protocol were also not related to the outcome. Conclusion: While protocol deviations did not significantly affect remission rates in this study, they were significantly related to inferior DFS. Since a relevant part of the protocol deviations could be classified as avoidable, strict protocol compliance should lead to improved outcomes. The prognostic impact of protocol deviations was in particular relevant in patients with late relapse with generally rather chemosensitive diseases and better prognosis. In this analysis, treatment delays did not influence the outcome. Figure 1 Figure 1. Disclosures von Stackelberg: Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Miltenyi: Consultancy, Honoraria.

Diffuse Large B-Cell Lymphoma (DLBCL) Patients with Late Relapses Who Are Transplant-Eligible Have Excellent Outcomes and May Represent Unique Biology

Introduction Approximately 30-40% of patients (pts) with DLBCL have refractory disease or relapse following R-CHOP. The majority of pts will experience disease progression or relapse early (within 1-2 years), although ~20% experience late relapse &gt;24 months (m) from time of initial diagnosis. Salvage therapy followed by autologous stem cell transplantation (ASCT) has been standard therapy for transplant-eligible pts, regardless of timing of documented relapsed/refractory (rel/refr) disease. Recent studies exploring the use of CAR T-cell therapy in primary refractory and early relapsed pts is challenging this paradigm. However, pts with late relapses were omitted from these studies. Interestingly, emerging molecular data suggest tumors of pts with late relapses exhibit significant genetic diversity from the initial diagnostic tumor, and may in fact represent unique biology (Hilton et al, ICML 2021). We aimed to evaluate outcomes in transplant-eligible pts with rel/refr DLBCL according to timing of documented rel/refr disease in a population-based setting to further explore biological and treatment implications. Method We identified all pts within the BC Cancer Centre for Lymphoid Cancer Database, age 18 to 75y, diagnosed with biopsy-confirmed DLBCL treated with curative-intent R-CHOP-like immunochemotherapy between 2001-2020 with documented rel/refr disease. Only transplant-eligible pts treated with standard salvage immunochemotherapy with intention for hematopoeitic stem cell transolantation (HSCT) were included. Patients with incidental discordant bone marrow involvement with low grade B-cell lymphoma were included, but transformed pts and those with isolated central nervous system relapse were excluded. Pts were divided into three cohorts based on timing of documented rel/refr disease from time of initial diagnosis: (1) rel/refr &lt; 12m; (2) relapse between 12 to 24 m; (3) late relapse &gt;24 m. Overall survival (OS) was calculated from time of documented rel/refr disease and from the time of HSCT in pts undergoing SCT. Results 225 pts meeting the stated eligibily criteria were identified. Clinical characteristics at initial diagnosis were as follows: median age 58y (range 19-72y); 70% male; 46 % IPI score 3-5. Timing of rel/refr disease from initial diagnosis was: rel/refr &lt;12m, n= 145, 64%; rel 12-24m, n=32, 14%; late relapse &gt;24m, n= 48, 21%. 92% of pts with late relapse had biopsy-proven relapsed DLBCL. Approximately 95% of pts received a platinum-based salvage regimen, most commonly GDP (gemcitabine, dexamethasone, cisplatin) +/- rituximab (n= 200 (89%). The overall response rate (ORR) to initial salvage therapy was 54% (14% CR, 40% PR). Response rate to salvage therapy according to timing of rel/refr disease was as follows: rel/refr &lt;12m 41%; rel 12-24m 71%; relapse &gt;24m 82%, with patients with later relapses having higher liklihood of response (p &lt; 0.01). In total, 122 pts (54%) underwent HSCT; 118 ASCT; 4 allo-SCT. The likelihood of proceeding to HSCT based on timing of rel/refr disease was significantly lower in pts with refr/rel &lt;12m (p &lt; 0.01): rel/refr &lt;12m, 43%; rel 12-24m 72%; rel &gt;24m 75%. Pts who did not proceed to HSCT were treated according to the discretion of their treating physicians, with 9 pts proceeding to CAR T-cell therapy. 8 additional patients received CAR T-cell therapy post-SCT failure. The medium follow-up time from documented rel/refr disease was 5.8y (range 0.1-14.5y). The 5-y OS was strongly correlated with timing of rel/refr disease (p&lt;0.001): rel/refr &lt;12m 15.8%, rel 12-24m 33%, rel &gt;24m 58.5%. (Fig. A) The 5-y OS from HSCT in pts undergoing SCT was similarly correlated with timing of rel/refr disease (P&lt;0.001): rel/refr &lt; 12m 31.4%, rel 12-24m 46.5%; rel &lt;24m 65.4%. (Fig. B) Conclusion In pts with transplant-eligible rel/refr DLBCL, response to salvage therapy, likelihood of proceeding to HSCT and OS are strongly correlated with timing of documented rel/refr disease. Pts with late relapses &gt;24m after diagnosis have notably favorable outcomes, compared with pts who experience earlier relapse (rel/refr &lt;12m and rel 12-24m), supporting emerging evidence that these patients represent a subgroup with distinct biology with greater chemo-sensitivity. These data support the early use of alternative therapies (such as CAR T-cell therapy) in pts with earlier relapse. Correlative studies to delineate the biological diversity of rel/refr DLBCL are underway. Figure 1 Figure 1. Disclosures Villa: Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; NanoString Technologies: Honoraria. Gerrie: Sandoz: Honoraria; Roche: Research Funding; Astrazeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Song: Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Takeda: Consultancy, Honoraria; Kite, a Gilead Company: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria. Slack: Seagen: Consultancy, Honoraria. Savage: Servier: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Research Funding; Takeda: Other: Institutional clinical trial funding; Seattle Genetics: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; Astra-Zeneca: Consultancy, Honoraria; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Scott: Abbvie: Consultancy; AstraZeneca: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Research Funding; Rich/Genentech: Research Funding; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. ; NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; Celgene: Consultancy. Sehn: Novartis: Consultancy; Genmab: Consultancy; Debiopharm: Consultancy.

Maneuvering the Complex Web of Treatment Options for Relapsed/Refractory Multiple Myeloma

Numerous treatment options are available for patients with early relapsed multiple myeloma. Clinicians should consider using a monoclonal antibody for patients who have not yet received one, or changing either the immunomodulatory drug, the proteasome inhibitor, or both. Clinical trials are another option, or clinicians can refer transplant-naïve patients for autologous stem cell transplantation (ASCT). For patients with late relapse, a clinical trial is recommended, if possible, but many patients are ineligible due to poor blood cell counts or other factors. Additional treatment options include selinexor combinations, belantamab mafodotin-blmf, melflufen, or CAR T-cell therapy. Salvage ASCT should also be considered for this challenging population.

Breast cancer dormancy is associated with a 4NG1 state and not senescence

Reactivation of dormant cancer cells can lead to cancer relapse, metastasis, and patient death. Dormancy is a nonproliferative state and is linked to late relapse and death. No targeted therapy is currently available to eliminate dormant cells, highlighting the need for a deeper understanding and reliable models. Here, we thoroughly characterize the dormant D2.OR and ZR-75-1, and proliferative D2A1 breast cancer cell line models in vivo and/or in vitro, and assess if there is overlap between a dormant and a senescent phenotype. We show that D2.OR but not D2A1 cells become dormant in the liver of an immunocompetent model. In vitro, we show that D2.OR and ZR-75-1 cells in response to a 3D environment or serum-free conditions are growth-arrested in G1, of which a subpopulation resides in a 4NG1 state. The dormancy state is reversible and not associated with a senescence phenotype. This will aid future research on breast cancer dormancy.

Evaluation of NAB2-STAT6 Fusion Variants and Other Molecular Alterations as Prognostic Biomarkers in a Case Series of 83 Solitary Fibrous Tumors

Risk stratification of solitary fibrous tumor (SFT) patients based on clinicopathological features has limited efficacy, especially in predicting late relapse or metastasis. The hallmark alteration of SFT is the gene fusion NAB2-STAT6, whose prognostic value remains controversial. As biological knowledge of this entity has increased in recent years, new molecular alterations have emerged that could be helpful to refine current risk models. Here, we evaluated NAB2-STAT6 fusion variants and other molecular alterations in a series of 83 SFTs that are enriched in progressing cases. Gene fusion variants were identified by targeted RNA-seq in the whole series, whereas TERT promoter (pTERT) mutations were inspected by Sanger sequencing in a subset of 18 cases. Immunohistochemical assays were performed to assess BCOR and NTRK expression as well as P53 mutation status in 45, 44, and 44 cases, respectively. While confirming the associations of gene fusion variants with clinicopathological parameters, our results do not prove their prognostic value. Pan-TRK immunoexpresion correlated with recurrence/progression, P53 staining associated with higher mitotic counts, and pTERT mutations were enriched in cases with fatal outcome. An intriguing correlation was found for BCOR protein expression with gene fusion variants, size, and tumor location.