Response rates to second-line treatment with daratumumab bortezomib dexamethasone (DVD) in relapsed/refractory light chain amyloidosis (AL) after initial Bortezomib-based regime.

Bortezomib is regularly used as frontline therapy for systemic AL amyloidosis. We assess the efficacy of second-line daratumumab-bortezomib-dexamethasone (DVD) in AL amyloidosis in bortezomib-exposed patients. A total of 116 patients treated with second-line DVD were identified from a prospective observational study of newly diagnosed AL amyloidosis (ALchemy). DVD was initiated in both the relapsed setting or where there was an inadequate response defined as very good partial response (VGPR) or VGPR with organ progression/lack of organ improvement. A complete response (CR)/VGPR to second-line DVD was achieved in 81 (69.8%) patients. A CR/VGPR was achieved in 67 (79.7%) in those who achieved a VGPR/CR to first line versus 14/32 (43.8%) in those who did not. Where DVD was initiated due to an inadequate response to first line (vs. at relapse), the median event-free survival (EFS) was 18 vs. 34 months (p = 0.002). If a CR/VGPR was achieved to DVD, the 2-year EFS was still lower in those with prior inadequate response 54% vs. 66% (p = 0.062). DVD is an efficacious second-line treatment in systemic AL amyloidosis in a bortezomib-exposed population. However, the response to DVD is poorer in those with an inadequate response to first-line bortezomib.

Ethnic diversity in presentation and outcome of Waldenström macroglobulinemia and IgM monoclonal gammopathy of clinical significance in the United Kingdom.

Not available.

Daratumumab monotherapy in refractory warm autoimmune hemolytic anemia and cold agglutinin disease.

ABSTRACT: Autoimmune hemolytic anemia (AIHA) is a rare autoantibody-mediated disease. For steroid and/or rituximab-refractory AIHA, there is no consensus on optimal treatment. Daratumumab, a monoclonal antibody targeting CD38, could be beneficial by suppression of CD38+ plasma cells and thus autoantibody secretion. In addition, because CD38 is also expressed by activated T cells, daratumumab may also act via immunomodulatory effects. We evaluated the efficacy and safety of daratumumab monotherapy in an international retrospective study including 19 adult patients with heavily pretreated refractory AIHA. In warm AIHA (wAIHA, n = 12), overall response was 50% with a median response duration of 5.5 months (range, 2-12), including ongoing response in 2 patients after 6 and 12 months. Of 6 nonresponders, 4 had Evans syndrome. In cold AIHA (cAIHA, n = 7) overall hemoglobin (Hb) response was 57%, with ongoing response in 3 of 7 patients. One additional patient with nonanemic cAIHA was treated for severe acrocyanosis and reached a clinical acrocyanosis response as well as a Hb increase. Of 6 patients with cAIHA with acrocyanosis, 4 had improved symptoms after daratumumab treatment. In 2 patients with wAIHA treated with daratumumab, in whom we prospectively collected blood samples, we found complete CD38+ T-cell depletion after daratumumab, as well as altered T-cell subset differentiation and a severely diminished capacity for cell activation and proliferation. Reappearance of CD38+ T cells coincided with disease relapse in 1 patient. In conclusion, our data show that daratumumab therapy may be a treatment option for refractory AIHA. The observed immunomodulatory effects that may contribute to the clinical response deserve further exploration.

Real-world efficacy of single-agent belantamab mafodotin in relapsed systemic AL amyloidosis.

Systemic light chain (AL) amyloidosis is a relapsing plasma cell disorder. Therapy is limited, particularly for triple-class refractory disease. We report the use of belantamab mafodotin, a BCMA-directed drug-antibody conjugate, for relapsed AL amyloidosis, including patients traditionally excluded from clinical trials. Thirty-one patients were reviewed, with a median of three prior lines of therapy. The median follow-up was 12 months (95% CI 4-19), and a median of five doses were delivered. The best haematological overall response rate was 71%, and the complete/very good partial response was 58%. Sixty-eight percent had keratopathy and improved in all. Belantamab mafodotin has high efficacy and good tolerability in patients with relapsed AL amyloidosis.

Complete responses in AL amyloidosis are unequal: the impact of free light chain mass spectrometry in AL amyloidosis.

ABSTRACT: Amyloidogenic serum free light chains (sFLCs) drive disease progression in AL amyloidosis. Matrix-assisted laser desorption/ionization time of flight mass spectrometry-based FLC assay (FLC-MS) has greater sensitivity than conventional sFLC assays allowing for the detection of serological residual disease. We report the utility of FLC-MS in a large series of patients with AL amyloidosis assessing the impact of FLC-MS negativity after treatment on overall survival (OS) and organ response rates. Serum samples were analyzed using FLC-MS at diagnosis and at 6 and 12 months after treatment. The impact of FLC-MS negativity over standard hematologic responses on survival and organ response was assessed. A total of 487 patients were included; 290 (59%) and 349 (71.5%) had cardiac and renal involvement, respectively. There was 100% concordance between the light chain (LC) fibril type and LC isotype identified by FLC-MS. At 6 and 12 months, 81 (16.6%) and 101 (20.7%) were FLC-MS negative. Of those achieving a conventional hematologic complete response (CR) at 6 and 12 months, 45 (27.7%) and 64 (39%) were FLC-MS negative. At 12 months, median OS for CR + FLC-MS negative was not reached vs 108 months in CR + FLC-MS positive (P = .024). At 12 months, 70% of patients with FLC-MS negativity (vs 50% FLC-MS positive) achieved a cardiac response (P = .015). In a multivariate analysis, FLC-MS negativity at 12 months was an independent predictor of better outcomes. FLC-MS can detect persistent monoclonal light chains in a significant proportion of patients in a conventional hematologic CR. FLC-MS assessment promises to be a new standard for response assessment in AL amyloidosis.

Clinical and clonal characteristics of monoclonal immunoglobulin M-associated type I cryoglobulinaemia.

Monoclonal immunoglobulin M-associated type I cryoglobulinaemia is poorly characterised. We screened 534 patients with monoclonal IgM disorders over a 9-year period and identified 134 patients with IgM type I cryoglobulins. Of these, 76% had Waldenström macroglobulinaemia (WM), 5% had other non-Hodgkin lymphoma (NHL) and 19% had IgM monoclonal gammopathy of undetermined significance (MGUS). Clinically relevant IgM-associated disorders (including cold agglutinin disease [CAD], anti-MAG antibodies, amyloidosis and Schnitzler syndrome) coexisted in 31%, more frequently in MGUS versus WM/NHL (72% vs. 22%/29%, p < 0.001). The majority of those with cryoglobulins and coexistent CAD/syndrome had the molecular characteristics of a CAD clone (wild-type MYD88 in 80%). A half of all patients had active manifestations at cryoglobulin detection: vasomotor (22%), cutaneous (16%), peripheral neuropathy (22%) and hyperviscosity (9%). 16/134 required treatment for cryoglobulin-related symptoms alone at a median of 38 days (range: 6-239) from cryoglobulin detection. At a median follow-up of 3 years (range: 0-10), 3-year cryoglobulinaemia-treatment-free survival was 77% (95% CI: 68%-84%). Age was the only predictor of overall survival. Predictors of cryoglobulinaemia-related treatment/death were hyperviscosity (HR: 73.01; 95% CI: 15.62-341.36, p < 0.0001) and cutaneous involvement (HR: 2.95; 95% CI: 1.13-7.71, p = 0.028). Type I IgM cryoglobulinaemia is more prevalent than previously described in IgM gammopathy and should be actively sought.

Evidence-based management of primary and secondary CNS lymphoma.

Central nervous system (CNS) lymphoma has traditionally had very poor outcomes however advances in management have resulted in dramatic improvements and long-term survival of patients. We describe the evidence for treatment strategies for these aggressive disorders. In primary CNS lymphoma there are randomized trial data to inform treatment decisions but these are lacking to guide management in secondary CNS lymphoma. Dynamic assessment of patient fitness and frailty is key throughout treatment, alongside delivery of CNS-bioavailable therapy and enrolment in clinical trials, at each stage of the disease. Intensive high-dose methotrexate-containing induction followed by consolidation with autologous stem cell transplantation with thiotepa-based conditioning is recommended for patients who are fit. Less intensive chemoimmunotherapy, novel agents (including Bruton tyrosine kinase inhibitors, cereblon targeting immunomodulatory agents, and checkpoint inhibitors in the context of clinical trials), and whole brain radiotherapy may be reserved for less fit patients or disease which is chemoresistant. Data regarding the efficacy of chimeric antigen receptor T-cells therapy is emerging, and concerns regarding greater toxicity have not been realized. Future areas of prospective studies include the identification of those at high risk of developing CNS lymphoma, management in elderly or frail patients as well as incorporating novel agents into regimens, particularly for those with chemoresistant disease.

Management of primary and secondary CNS lymphoma.

Central nervous system (CNS) lymphoma has traditionally had very poor outcomes however advances in management have seen dramatic improvements and long-term survival of patients. In primary CNS lymphoma there are now randomised trial data to inform practice, however secondary CNS lymphoma has a lack of randomised trial data and CNS prophylaxis remains a contentious area. We describe treatment strategies in these aggressive disorders. Dynamic assessment of patient fitness and frailty is key throughout treatment alongside delivery of CNS-bioavailable therapy and enrolment in clinical trials. Intensive high-dose methotrexate-containing induction followed by autologous stem cell transplantation is preferred for patients who are fit. Less intensive chemoimmunotherapy, whole brain radiotherapy and novel therapies may be reserved for patients unfit or chemoresistant. It is essential to better define patients at increased risk of CNS relapse, as well as effective prophylactic strategies to prevent it. Future prospective studies incorporating novel agents are key.

Is there a representative quality-of-life questionnaire for patients with AL amyloidosis?-systematic literature review.

Systemic AL amyloidosis is an incurable condition with various presentations and may cause multiple complications related to organ involvement. As survival has improved, disease and therapy-related quality of life (QoL) is becoming an increasingly important treatment endpoint. We review the literature summarising the utilised QoL questionnaires (QLQs) and assess their validity according to COSMIN (Consensus-based Standards for the Selection of Health Measurement Instruments) standards. Thirteen retrospective observational studies and thirty-two prospective clinical trials were analysed. Most QLQs are generic or only validated in populations with distinct complications of the disease. None meet 'strong evidence' for validation in this context. There is a need to develop a disease-specific QLQ, which could inform treatment choices and facilitate the approval of novel therapies.

Patient reported outcome measures in Waldenström macroglobulinaemia: A real-world data analysis from the WMUK Rory Morrison Registry.

Waldenström macroglobulinaemia (WM) is an incurable chronic B-cell malignancy, but highly responsive to treatment. Treatments include fixed-duration chemotherapy and continuous oral chemoimmunotherapy. In this expanding field, it is important to have reliable information on the impact of the various therapies on patients' quality of life (QoL). Patient reported outcome measures (PROMs) are increasingly recognised as important to understand patient experience of disease beyond traditional clinical outcome measures. Four QoL questionnaires (EORTC QLQ-C30 [European Organisation for Research and Treatment of Cancer quality of life core questionnaire], BIPQ [Brief Illness Perception Questionnaire], HADS [Hospital Anxiety and Depression Scale], EQ-5D-5L [EuroQoL 5-dimensional descriptive system questionnaire]) are embedded in the UK national WM registry, the Rory Morrison Registry. We reviewed the results from a snapshot of PROMs. As of November 2021, 155 patients completed PROM data with 98% completion rate across all 58 questions. Complete clinical information was available for 52 patients. The majority of QoL questions (69%) failed to elicit a notable median response. Only four questions elicited statistically significant responses when comparing groups, and these were exclusively found in the EuroQoL-5D-5L and HADS questionnaires. Our data suggest that widely used questionnaires may not be suitable for patients with WM. We advocate the development of WM-specific outcome measures to overcome this.

The Rory Morrison WMUK Registry for Waldenström macroglobulinaemia: The growth of a national registry for a rare disorder.

National registries are used globally to characterise patient demographics, treatment choices and mortality to inform and improve clinical management. Waldenström macroglobulinaemia (WM) is a rare, treatment-responsive B-cell lymphoproliferative disorder with diverse clinical features and variable outcomes. To prospectively chart changes in the management of WM in the UK, the Rory Morrison Registry (RMR) was developed to systematically collect real-world data. Here we describe the development of the RMR, demonstrate its feasibility and describe preliminary observations. The RMR was devised as a collaborative project between patients and clinicians, under the auspices of the UK Charity for WM in 2016. Patients may be registered after the point of diagnosis and those with historic diagnosis were also eligible. Data collection fields were compiled by focus groups of clinicians, patients, industry and commissioning partners. The RMR launched in November 2017 and as of March 2022, there were 22 participating centres and 1305 patients registered. Median follow-up was 6.4 years, five-year overall survival 90.7% (95% confidence interval [CI] 88.4%-92.5%) and 10-year overall survival 79.3% (95% CI 75.7%-82.4%). There has been a clear evolution in treatments including a rapid growth in the use of Bruton's tyrosine kinase inhibitors in relapsed disease since their availability in the UK.

Prevention and management of secondary central nervous system lymphoma.

Secondary central nervous system (CNS) lymphoma (SCNSL) is defined by the involvement of the CNS, either at the time of initial diagnosis of systemic lymphoma or in the setting of relapse, and can be either isolated or with synchronous systemic disease. The risk of CNS involvement in patients with diffuse large B-cell lymphoma is approximately 5%; however, certain clinical and biological features have been associated with a risk of up to 15%. There has been growing interest in improving the definition of patients at increased risk of CNS relapse, as well as identifying effective prophylactic strategies to prevent it. SCNSL often occurs within months of the initial diagnosis of lymphoma, suggesting the presence of occult disease at diagnosis in many cases. The differing presentations of SCNSL create the therapeutic challenge of controlling both the systemic disease and the CNS disease, which uniquely requires agents that penetrate the blood-brain barrier. Outcomes are generally poor with a median overall survival of approximately 6 months in retrospective series, particularly in those patients presenting with SCNSL after prior therapy. Prospective studies of intensive chemotherapy regimens containing high-dose methotrexate, followed by hematopoietic stem cell transplantation have shown the most favorable outcomes, especially for patients receiving thiotepa-based conditioning regimens. However, a proportion of patients will not respond to induction therapies or will subsequently relapse, indicating the need for more effective treatment strategies. In this review we focus on the identification of high-risk patients, prophylactic strategies and recent treatment approaches for SCNSL. The incorporation of novel agents in immunochemotherapy deserves further study in prospective trials.

Evidence-based medical treatment of POEMS syndrome.

POEMS syndrome is a rare multisystem paraneoplastic disorder due to an underlying low-level plasma cell dyscrasia. Due to its rarity, there are limited data to guide treatment and there are no consensus guidelines. Therapy choices are dictated by patient characteristics, disease factors and local funding arrangements. The goals of therapy are to eradicate the underlying clone in order to improve quality of life and overall survival. Most evidence has been garnered in the front-line setting. Localised disease responds well to radiotherapy, whilst for those with systemic disease, the best outcomes are demonstrated with induction chemotherapy followed up with high-dose melphalan and stem cell rescue if eligible. For transplant-ineligible patients lenalidomide-dexamethasone remains a preferred treatment option. Data in the relapse setting are scarce. Supportive care including management of neuropathy, endocrinopathy, thrombotic risk and anti-infective agents is necessary. Future international collaboration is crucial to define optimal treatment strategies particularly in the relapse setting.

Bortezomib-based therapy is effective and well tolerated in frontline and multiply pre-treated Waldenström macroglobulinaemia including BTKi failures: A real-world analysis.

Waldenström macroglobulinemia (WM) is a rare, incurable low grade lymphoma following a relapsing trajectory. Management strategies have evolved with the introduction of targeted therapy including new classes of Bruton tyrosine kinase inhibitor (BTKi). Treatment may however be limited particularly at relapse by a lack of drug availability and tolerability. We assessed the real-world efficacy and tolerability of bortezomib-containing regimens in patients with WM at frontline and relapse including those with prior BTKi resistance. Forty-one patients were identified with 44 bortezomib-containing regimens administered (n = 12 frontline, n = 32 relapse). Of patients treated at relapse, the median prior lines of therapy was 3 (range 1-7). 24% (10/41) of the cohort were refractory or intolerant to BTKi prior to bortezomib delivery. The median follow-up after bortezomib administration was 34 months (range 0-131). Overall response rate was 88%; 2-year overall survival and progression-free survival were 90% (95% confidence interval [CI] 73-96) and 76% (95% CI 55-87), respectively. Median time-to-next-treatment was 66 months. Neuropathy (grade 1-2) occurred in 24% (8/34) and did not result in treatment cessation in any case. Gastrointestinal disturbance occurred in 7% (3/41). Treatment discontinuations were rare (1/44; 2%), suggesting a manageable safety profile. Major response rate was comparable in those with prior BTKi compared with those without (75% [6/8] vs 84% [27/32], p = 0.61). Bortezomib should be considered as a treatment modality particularly in those who are refractory to BTKi.