Lenalidomide Maintenance Therapy Research Articles

Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

BackgroundDaratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed.MethodsIn this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)–negative status.ResultsAt a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P=0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group.ConclusionsThe addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.)

Outcomes Analysis of Lenalidomide-Induced Rashes in Myeloma Patients

CONCLUSIONS Lenalidomide is an immunomodulatory drug fundamental in treating and managing patients with multiple myeloma (MM). It works through various pathways to induce T-cell proliferation and activation of natural killer (NK) cells. This mechanism of T-cell activation is hypothesized to be one of the mechanisms that cause lenalidomide-related skin reactions. Skin reactions are a well-known adverse effect of lenalidomide treatment, with some studies showing that 44% of patients developed a rash while receiving treatment. Rash development has been associated with improved outcomes with other chemotherapy agents in patients with solid tumors. Initial investigation demonstrated that lenalidomide-induced rashes in myeloma patients were associated with improved survival. Other immune-mediated adverse reactions, such as lenalidomide-related diarrhea (LRD), have also been associated with improved patient outcomes. Lenalidomide-related diarrhea and rash likely stem from the same pathways involving the activation of Th2 and NK cells. This single-site retrospective study analyzed charts from patients with multiple myeloma whose treatment course included lenalidomide single therapy or lenalidomide plus dexamethasone therapy. Patients who were only treated with lenalidomide in combination with other chemotherapies were excluded from the study. The development of a rash while receiving lenalidomide single therapy was recorded. We also recorded the number of patients who developed severe diarrhea requiring hospitalization or a change in therapy regimen. Other adverse reactions that altered lenalidomide treatment were also recorded. Outcomes were assessed using 5-year survival (5YS), overall survival (OS), and time to next treatment (TTNT). We analyzed the charts of 100 patients who met the criteria for the study and found that 25 (25%) patients developed rashes compared to 75 (75%) that did not. There was not a significant difference in OS or 5YS between the rash group compared to the non-rash groups [(OS: 40.0%, 38.7%, p = 0.90); (5YS: 68%, 52%, p = 0.196) respectively]. There was a statistically significant difference in TTNT between the rash group and the non-rash group (43.0 months, 21.2 months, p = 0.035). We compared 31 (31%) patients who displayed immune-related adverse effects (diarrhea and/or rash) to the 69 (69%) patients who developed no rashes or diarrhea. In these groups, there was a significant difference in TNTT and 5YS ( p = 0.035; p = 0.017 respectively) but not in OS ( p = 0.857). TTNT was measured in this study and is similar to progression-free survival, as patients whose diseases progressed initiated another treatment. We observed similar results to previous studies showing that patients who developed rashes on lenalidomide exhibited longer TTNT. We observed that patients who developed rashes or LRD exhibited longer TTNT and had significantly higher 5-year survival. These reactions may be manifestations of an increased immune response contributing to their improved response to lenalidomide. Many patients with multiple myeloma undergo complex treatment regimens involving multiple therapies. We observed occasions when patients developed drug rashes on bortezomib, lenalidomide, and dexamethasone triple therapy but didn't develop a rash later on lenalidomide maintenance therapy. To isolate the rash to lenalidomide, these rashes were not counted in our study, skewing the number of patients counted as developing rashes.

Primary Endpoint Analysis from a Response Adaptive Phase II Clinical Trial of Carfilzomib, Lenalidomide, Dexamethasone Plus Daratumumab (KRd-Dara) in Patients with Newly Diagnosed Multiple Myeloma (NDMM)

Background Minimal residual disease (MRD) status has prognostic significance for progression-free survival (PFS) and overall survival (OS) in NDMM, but its value in guiding therapy remains unclear. We conducted a 2-stage, phase II trial evaluating the quadruplet regimen of KRd-Dara as induction therapy followed by MRD adapted KRd consolidation +/- autologous stem cell transplantation (ASCT) and maintenance versus observation. We previously reported the results of our stage I analysis at ASH 2022 (n=23; Blood 2022;140:4440-4441). Here we provide an updated analysis of the primary endpoint after completed enrollment of stage 2. Methods Eligible patients had NDMM with measurable disease. The induction phase allowed 8 cycles of KRd-Dara. Post-induction treatment assignment was informed by ASCT eligibility and MRD status by next generation sequencing (NGS at 10 -5), and included Group A (MRD negative, transplant-eligible and -ineligible, optional lenalidomide maintenance), Group B (MRD positive, transplant eligible, ASCT) and Group C (MRD positive, transplant ineligible, KRd consolidation for up to 12 cycles). Patients in Group B could receive up to 12 cycles of KRd consolidation therapy after ASCT if MRD positive. All groups could receive optional lenalidomide maintenance therapy after achievement of MRD negativity after induction ± consolidation. The primary endpoint was ≥complete response (CR) rate at the end of induction. The secondary endpoints were safety, MRD status, stem cell mobilization failure, and survival outcomes. Efficacy endpoints including MRD were evaluated with the intent to treat principle. Results Thirty-nine patients were enrolled: 23 in stage 1 and 16 in stage 2. Median age was 62 (range 34-78), 31% were female and 31% were African American. R-ISS stage 3 was present in 4 (10%), high-risk cytogenetics (including 1q21 gain) in 15 (39%). At the end of induction, ≥CR was achieved in 22/39 (56%, 90% CI: 42%-70%) patients including stringent CR (sCR) in 17 (44%), VGPR in 14 (36%) and PR in 1(3%). Of note, 2 patients did not complete induction therapy; one died during cycle 2, while another was withdrawn from study after an SAE during cycle 1. Evaluating by NGS, 62% achieved MRD negativity at 10 -5 and 41% MRD negativity at 10 -6 post-induction. MRD negativity by next generation flow cytometry (NGF) was 74% at 10 -5 and 31% at 10 -6. Concordance of MRD by NGS/ NGF at 10 -5 was 26/34 (76% in agreement and 24% disagreement, Cohen's kappa: 0.436), and by NGS/ NGF at 10 -6 was 17/25 (68% in agreement and 32% disagreement, Cohen's kappa: 0.351). 39 patients (100%) experienced treatment emergent AE, with grade ≥ 3 AE in 31 (80%). The most common (≥ 25%) any grade treatment related AE (TRAE) were diarrhea (39%), fatigue (36%), neutropenia (28%), and constipation (26%). Grade 3-4 TRAE (≥10% of patients) included neutropenia (21%) and hypophosphatemia (13%). Covid infection occurred in 10 (26%); only one patient needed hospitalization. Other infections (any grade) were seen in 20 (51%) patients. Fourteen (36%) patients experienced at least one SAE, of which 8 patients had a treatment-related SAE, including one death. Thromboembolic events were observed in 3 (8%) patients. Of 23 patients who collected stem cells upon completion of induction (7-8 cycles of KRD-Dara), 7 (30%) failed to collect an optimal target (3 million CD34+ cells/kg) on first attempt. Comparatively, 0 of 11 patients who collected after 3-5 cycles experienced stem cell collection failure (Fisher's exact: p=0.07). Post-induction, 24 patients were assigned to Group A, 8 to Group B, and 5 to Group C. After a median follow up of 26 months (95% CI: 17 - 27; data cut off 7/6/2023), 28 remain on treatment, 9 are in follow up, and 2 are off study. The 2-year PFS is 85.3% (95% CI: 71.6% - 99.1%); median PFS is not reached. Updated data on the best MRD/ CR/ sCR responses achieved post-induction will be presented at the meeting. Conclusions Our data confirm high rates of sCR and MRD negativity of the quadruplet regimen of KRd-Dara in NDMM. The safety data was in alignment with known safety profile of investigational products. With modification of the protocol to allow earlier stem cell collection, we were able to reduce the rate of stem cell mobilization failure from 30% to 0%. Based on our results, we recommend further testing of this MRD-based platform in randomized studies with stem cell collection after 3-4 cycles of KRd-Dara. Clinical trial: NCT04113018

Autologous Hematopoietic Stem Cell Transplantation Combined with High-Dose Chemotherapy As First-Line Treatment for HIV-Associated Lymphoma: A Retrospective Analysis

BACKRGOUND At present, lymphoma is one of the three most common malignant tumors in AIDS patients. With the popularization of cART treatment, the incidence of AIDS-associated lymphoma has decreased, but it is still higher than that in the general population with poor prognosis. The Central and Western China AIDS Lymphoma League (CALL) is committed to investigate the efficacy and related factors of autologous hematopoietic stem cell transplantation (auto-HSCT) as consolidation therapy for newly diagnosed HIV-associated lymphoma. METHODS From 2018 to 2023, 11 newly diagnosed patients with AIDS-associated lymphoma in our center were collected, including 10 males and 1 female, 2 of whom received double ASCT, with a median age of 38 years (range 25-64 years). One case (11.1%) had bone marrow involvement, 3 cases (27.3%) had low/low-intermediate risk according to IPI, and 2 cases (63.6%) had high/intermediate risk according to IPI. Ten patients (90.9%) achieved complete remission (CR) and 1 patient (9.1%) achieved partial remission (PR) before transplantation. RESULTS Among the 11 patients, 2 patients (1 with high-risk diffuse large B cell lymphoma and 1 with plasmablastic lymphoma) received double transplantation within 6 months, and the remaining patients received single transplantation. The median CD34 collection before transplantation was 4.67 (2.5-12.52) *10^6/kg. 3 patients received BeEAC regimen, 7 patients received BeEAM regimen, and 1 patient received IAC regimen for the second transplantation. Five patients (45%) developed various degrees of infection during transplantation, which was improved after anti-infection treatment. All patients achieved hematopoietic reconstitution. The median time of neutrophil and platelet engraftment was 11.9 ± 2.23 days and 12.1 ± 2.96 days, respectively. At a median follow-up of 12 (3-14) months after transplantation, 1 patient died within 100 days after transplantation, 1 patient died of Covid-19 virus infection, 1patient achieved PR, other 8 patients remained CR.. Patient no. 1 died from bacteremia 1 months after ASCT. Patient no. 8 relapsed 6 months after ASCT and died from Covid-19 virus infection when 5 months after ASCT. Patient no. 9 relapsed 6 months after ASCT, but is still alive in second CR and is receiving lenalidomide maintenance therapy. Other 8 patients in CR post-ASCT are receiving lenalidomide/Interferon/rituximab maintenance therapies. Therefore, overall survival for the 11 transplanted patients is 81% at 12 months, with a median follow-up of 12 months (range 5-60 months). Furthermore, eight patients remained in CR, for an progression-free survival of 72% at 12 months, with a median follow-up of 19 months (range 9-60 months).It is worth mentioning that active HIV replication was not monitored with the continuous use of cART agents during lymphoma chemotherapy and ASCT; cART administration did not affect the number of harvested stem cells or the time to engraftment after transplantation.

Health-Related Quality of Life in Multiple Myeloma Patients Treated with High- or Low-Dose Lenalidomide Maintenance Therapy after Autologous Stem Cell Transplantation-Results from the LenaMain Trial (NCT00891384).

The LenaMain trial (NCT00891384) reported increased progression-free survival with 25 mg of lenalidomide maintenance compared to 5 mg. Here, we report the patient-reported outcomes. Scores obtained from the EORTC Quality of Life Questionnaire C30 were analyzed for longitudinal changes from baseline within the groups as well as cross-sectional scores. Compliance rates were high, with 95.7% at baseline and 70% during maintenance. At study entry, scores were high for functioning and low for symptoms. During maintenance, the median global health status/quality of life (GHS/QoL) was constant, without significant differences over time (median GHS/QoL: 68 at baseline and 58 for Len high and 68 for Len low at 2 years) and between treatment arms (mean change < 2). Similarly, most functional scale domains were constant. Notably, diarrhea increased consistently for both treatment arms (baseline: -1.905 (range: -5.78-1.97); end of year 2: 16.071 (range: 5.72-26.42); p < 0.05). The subgroup analysis showed that neither disease activity, duration of treatment, nor adverse events affected the health-related quality of life (HR-QoL) or utility. High baseline scores were maintained throughout the trial without significant differences between the Len dosages, which supports continuous treatment with a dose tailored to patients' HR-QoL.

Immunophenotypic correlates of sustained MRD negativity in patients with multiple myeloma

The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor β sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure. We compare patients achieving sustained minimal residual disease (MRD) negativity to patients who never achieved or were unable to maintain MRD negativity. We observe that the composition of the immune microenvironment in both the blood and the marrow varied substantially according to both MRD negative status and history of autologous stem cell transplant, supporting the hypothesis that the immune microenvironment influences the depth and duration of treatment response.

Lenalidomide-based monotherapy versus augmented therapy for maintenance in standard risk multiple myeloma patients with no complete response post autologous hematopoietic cell transplantation.

8055 Background: Standard risk (SR) multiple myeloma (MM) is typically characterized by the absence of poor prognostic cytogenetic aberrations, and better outcomes. However, outcomes in SR MM remain far from homogeneous, especially in patients undergoing autologous hematopoietic cell transplant (AHCT). While many patients do well initially, relapse is inevitable. Here, we studied the role of lenalidomide (R) maintenance therapy in determining outcomes in SR MM with no complete response (non-CR) post-AHCT. Methods: We retrospectively reviewed all MM patients who underwent AHCT at the Cleveland Clinic between January 1, 2011 and January 15, 2021. Electronic medical charts were accessed to retrieve data on demographic characteristics, comorbidities, International Scoring System (ISS) staging, cytogenetic risk categorization, serum and bone marrow studies, as well as maintenance therapy. SR MM was considered in patients who did not have t(4;14), t(14;16), t(14;20), del(17p), or gain(1q). Remission status was determined by serum studies at 3 months post-AHCT. The primary endpoint was median time to either progression or death, reported as time to event (TTE) determined by Kaplan Meier analysis. Results: A total of 517 patients were reviewed, of whom 279 were determined as SR MM. Further stratification yielded 100 non-CR SR patients on lenalidomide-based maintenance, of whom 87 were on R monotherapy and 13 on R combination. Comparison between the R-monotherapy and combination groups showed similar age at AHCT (60.5 vs 56 years, P=0.07), time to transplant (23.5 vs 30.8%, P=0.7), albumin levels (&lt;3.5 g/dL 25 vs 25%, P=1), Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score (≥3 43.5 vs 30.8%, P=0.5), Male preponderance (58.8 vs 69.2%, P=0.6), ethnicity (White 82.4 vs 76.9%, P=0.7), ISS stages (I 41 vs 45.5%, II 41 vs 36.4%, III 17.9 vs 18.2%, P=0.9), pre-AHCT lines of therapy (≥2 31.8 vs 38.5%, P=0.8), and pre-AHCT bone marrow plasma cells (≥10%:9.5 vs 7.7%, P=1), respectively. The only significant difference between the two groups was in the MM immunoglobulin subtype (IgG 80 vs 50%, P=0.02). Kaplan-Meier analysis for median TTE revealed that the R monotherapy group had a significantly shorter median TTE at 38.1 months versus 68.6 months (P=0.03) for the R combination group. Conclusions: SR MM patients who do not achieve a CR post-AHCT have better outcomes with R-combination rather than monotherapy.

Impact of bortezomib-based versus lenalidomide maintenance therapy on outcomes of patients with high-risk multiple myeloma.

Lenalidomide 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. In total, the authors identified 503 patients with HRMM who were undergoing ASCT within 12months 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. Three 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 2years compared with those who were receiving either bortezomib monotherapy or combination therapy (75% vs. 63%; p=.009). Overall survival at 2years was also superior in the lenalidomide group (93% vs. 84%; p=.001). No 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.

Real-world data for lenalidomide maintenance in responding patients of diffuse large B-cell lymphoma.

Approximately 40% patients of diffuse large B-cell lymphoma (DLBCL) would develop disease recurrence/progression after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) induction therapy, with highly poor prognosis. An effective strategy to prolong the survival of this patient population is the additional single-drug maintenance therapy. lenalidomide, an immunomodulatory drug with oral activity, has direct anti-tumor activity and indirect effects mediated by multiple immune cells in the tumor microenvironment, such as B, T, natural killer (NK), and dendritic cells. Combining its controllable toxicity, it is promising in long-term maintenance therapy. This study aims at evaluating the clinical effect of lenalidomide maintenance therapy in responding DLBCL patients with R-CHOP treatment. This retrospective study was devised in DLBCL cases who obtained complete response (CR) or partial response (PR) following 6-8cycles of R-CHOP treatment between January 1, 2015 and July 31, 2019. Patients (n=141) included were respectively assigned to receive lenalidomide maintenance treatment (lenalidomide, n=50) and drug-free maintenance treatment (control, n=91) after CR/PR. lenalidomide was provided orally at 25 mg/day for 10 days, with a cycle of 21 days and a treatment course of 2 years. Progression-free survival (PFS) was taken as the primary outcome. Of the total 141 subjects, the median follow-up time was 30.9months (range, 5.7-68.9months). The 2-year PFS was 84% (95% CI: 74%-94%) in the lenalidomide group and 53% (95% CI: 43%-63%) in the control group. The median PFS of the lenalidomide group was not reached, and that of the control group was 42.9months (HR=0.32; 95% CI: 0.16-0.63; p=0.001). No remarkable difference in overall survival (OS) between the two groups was indicated (HR=0.42; 95% CI: 0.16-1.12; p=0.08). Central nervous system (CNS) recurrence happened in 5 patients (5.5%) of the control group, while none of the patients with lenalidomide had CNS recurrence. Additionally, neutropenia and cutaneous reactions were the most common Grade 1-2 adverse reactions after lenalidomide treatment, and neutropenia was the most frequent Grade 3-4 adverse reaction. Two-year lenalidomide maintenance treatment can significantly prolong the PFS of DLBCL patients who obtained CR/PR to first-line R-CHOP treatment.

Revisiting checkpoint inhibitors for myeloma: maintenance after stem cell transplant.

Multiple myeloma is a hematologic malignancy of plasma cells that manifests with bone marrow tumors causing lytic bone lesions. Autologous stem cell transplantation (ASCT) after high-dose chemotherapy and followed by prolonged maintenance therapy with lenalidomide (LEN) is an effective standard-of-care therapy for multiple myeloma. However, most patients ultimately relapse. Rational combination strategies that address immune dysfunction may prolong the durability of ASCT. In this issue of the JCI, Minnie and colleagues investigated the addition of a checkpoint inhibitor to LEN maintenance therapy after ASCT. They found that the immune checkpoint TIGIT was an optimal target in patient samples. In a syngeneic, immunocompetent multiple myeloma mouse model, blockade of TIGIT synergized with LEN maintenance by inducing immune protection, characterized in part by the expansion of polyfunctional T cells in the bone marrow. The treatment enhanced durable antimyeloma efficacy and has translatable implications.

Isolated relapse of plasma cell leukemia in the central nervous systems: a case report and literature review

Plasma cell leukemia is a rare yet aggressive form of multiple myeloma characterized by high levels of plasma cells circulating in the peripheral blood. We recently experienced a case of plasma cell leukemia that had been in stringent complete remission for nine years after autologous stem cell transplantations with subsequent courses of lenalidomide maintenance therapy, and then relapsed as an extramedullary plasmacytoma in the central nervous system. Assessment of the bone marrow did not prove proliferation of plasma cells at relapse, but imbalanced elevation of serum levels of free light chains was observed without changes in other clinical biomarkers including immunoglobulin levels. Salvage chemotherapy with isatuximab, pomalidomide, and dexamethasone (IsaPD) was promptly initiated. After two courses of IsaPD, significant remission was achieved and the neuronal symptoms completely resolved. When excessive serum levels of clonotypic free light chains are noted, their significance should be carefully assessed even when plasma cell propagation in the bone marrow is not observed. In such cases, hematologists should search for extramedullary proliferation of plasma cells, including in the immune-privileged central nervous system.

Development of Epstein-Barr virus-associated lymphoproliferative disorder and hemophagocytic lymphohistiocytosis during long-term lenalidomide maintenance therapy in multiple myeloma.

Reactivation of Epstein-Barr virus (EBV) has been considered a very rare event among patients on immunomodulatory drugs (IMiDs) such as lenalidomide, and an association between the two has not well been recognized. We have recently experienced a rare case of multiple myeloma in which the patient had suffered EBV reactivation during long-term lenalidomide maintenance therapy. The patient subsequently developed EBV-associated lymphoproliferative disease (LPD) as well as EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), which was fatal despite intensive treatment. Although rare, clinicians should be aware that such fatal EBV reactivation could occur as a minor yet critical complication of long-term maintenance therapy with IMiDs in multiple myeloma patients. Regular monitoring and early detection of EBV reactivation would be beneficial for these patients, so that proper diagnostic examinations can be initiated without delay.

The Determination Trial Impact on Upfront (vs Delayed) Autologous Stem Cell Transplantation for Transplant-Eligible Newly Diagnosed Multiple Myeloma

Background: Following the completion of induction therapy for newly diagnosed multiple myeloma (NDMM) patients who are transplant-eligible, autologous stem cell transplantation (ASCT) consolidation with high-dose melphalan followed by lenalidomide maintenance therapy is considered standard of care. However, accumulated evidence of significant benefit and deep responses to newer induction therapies that contain combinations of immunomodulatory drugs and proteasome inhibitors have raised questions about the role as well as timing (upfront vs delayed) of ASCT consolidation in the initial treatment of ASCT-eligible NDMM. DETERMINATION is a phase III clinical trial (NCT01208662) that randomly assigned transplant-eligible NDMM patient to treatment with lenalidomide, bortezomib, and dexamethasone with and without an ASCT consolidation, followed by lenalidomide maintenance until progression. The present study surveyed oncologists and hematologists to evaluate their perceptions of the DETERMINATION trial and the benefits and barriers of integrating ASCT into 1L therapy for transplant-eligible NDMM. Methods: In July 2022, U.S.-based oncologists were invited to attend a live meeting to discuss abstracts presented at ASCO 2022. Demographics data were collected in a premeeting survey. The perceptions and reactions of these providers to abstract data, including an abstract detailing the findings from the DETERMINATION trial, were captured via audience response system (ARS) technology. Not all participants answered every question. Responses were aggregated and analyzed using descriptive statistics. Results: Among the 52 participants who attended the live meeting, 79% (n=41) identified as community providers; these providers reported that they see an average of 20 patients on clinic days. Ninety percent (n=45) of the participants who were responders to the DETERMINATION trial data (n=50) indicated that they treat NDMM. After reviewing the trial data, slightly less than half of providers (42%) reported that the data were compelling enough to increase the use of ASCT in the 1L for patients with transplant-eligible NDMM. Of those respondents who treat NDMM, three-quarters were likely to give lenalidomide maintenance therapy until disease progression as opposed to a fixed duration of maintenance therapy. We also found that a lack of overall survival (OS) benefit was a major drawback in DETERMINATION results for most respondents; specifically, when queried on the top limitation of the trial, 73% of respondents (n=33) chose lack of significant OS data. Finally, when making decisions on triplet regimens in multiple myeloma, OS and progression-free survival (PFS) benefits were reported as treatment decision drivers by 44% and 23% of respondents who treat NDMM, respectively. Conclusions: Overall, our data show that OS (which was not a primary endpoint in DETERMINATION) is viewed as the most significant factor when considering 1L treatment decisions in NDMM, and less than half respondents indicated that PFS (a primary endpoint in DETERMINATION) persuaded them to increase their use of upfront, vs delayed, ASCT in their patients with transplant-eligible NDMM. Future research by the Cardinal Health Specialty Solutions will aim to clarify various aspect of novel therapies for NDMM including quadruplet 1L therapy, other anti-CD38 antibody upfront usage, minimal residual disease, and their respective impacts on the choice of upfront (vs delayed) ASCT consolidation in the 1L setting.

Interim Report of Bendamustine Plus Rituximab As First-Line Induction Therapy with or without Lenalidomide Maintenance Therapy in Chinese Patients with Indolent Non-Hodgkin's Lymphoma or Elderly Mantle Cell Lymphoma: Data from a Multi-Center Prospective Trial

Background: Bendamustine plus rituximab (BR) was established as a preferred first line therapy for patients with previously untreated indolent non-Hodgkin's lymphoma (iNHL) and elderly MCL (eMCL) based on the BRIGHT and STiL trials. But the data is rare from Chinese patients because the unavailability of bendamustine. Furthermore, the safety and efficacy of maintenance therapy with rituximab remained contradictory after BR induction therapy, due partly to the durable immuno-supression of bendumustine. On the other hand, lenalidomide, as a proven effective agent for iNHL and MCL, have immune modulatory function. So, as maintenance therapy after BR induction, lenalidomide may increase response rate and prolong progression free survival (PFS) for iNHL and eMCL. Aims: To assess the efficacy and safety of BR regimen for Chinese patients with iNHL and eMCL. And more importantly, to assess the efficacy and tolerability of lenalidomide as maintenance therapy after BR. Methods: We conducted a multi-institutional, prospective, non-randomized clinical trial for patients with iNHL and eMCL. The patients received standard six cycles of BR regimen as induction therapy, and then received lenalidomide (10 mg, qd) maintenance vs. no maintenance, from December 2020 to July 2022. Patients with iNHL and elderly MCL who received at least two cycles of BR were evaluated. The primary endpoint of the study was progression-free survival (PFS). Results: Overall, 72 patients enrolled in the study, baseline characteristics of cohort were shown in Table 1. Median age at BR initiation was 55 years (range 24-74), 76.4% had ECOG 0-1, and 23.6% ECOG 2. Follicular lymphoma (FL) (55.6%) and marginalzone lymphoma (MZL) (30.6%) were the main subtypes of iNHL. The proportion of elderly MCL was 9.7%. Most patients were in stage 3 (16.7%) and stage 4 (65.3%). All patients have indication for systemic therapy. Till the date of July 10, 2022, a total of 91.7% completed 4 cycles induction therapy. Overall response was 98.6%, with 84.7% complete response (CR) and 13.9% partial remission (PR), (Figure 1). Progression during induction occurred only in one MCL patient. And another two patients with FL was suspected progressive disease during observation. After 4 cycles induction therapy, PET/CT detected in 59 patients (81.9%), while CT or MRI detected in 13 patients (18.1%). Among the 39 patients with complete remission assessed by PET-CT, 10 patients (25.6%) of them had residual lymph nodes with diameter > 1cm. So the CRR by CT is 69.4%, which is much higher than that reported in STiL study and BRIGHT study. The safety profile of BR regimen was shown in Table 2. Hematological toxicities was the main adverse events, with grade 3-4 neutropenia was recorded in 27.8%, febrile neutropenia in 8.3%, grade 3-4 anemia in 5.6%, and grade 3-4 thrombocytopenia in 4.2% of patients. The rate of fatigue, nausea/vomiting, skin rash and infections were less than 20%. A total of 52.1% patients proceeded to lenalidomide maintenance. However, 11% patients discontinued because of rash or other adverse reaction to lenalidomide. Conclusion:BR regimen was feasible, safety and got high CRR for Chines iNHL and eMCL patients by our clinical trial. The efficacy and safety of maintenance lenalidomide after BR induction are still under follow-up. This trial was registered at http://www.chictr.org.cn. Clinical trial information: ChiCTR2200056288. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Analysis of Transplant-Eligible Patients (Pts) Who Received Frontline Daratumumab (DARA)-Based Quadruplet Therapy for the Treatment of Newly Diagnosed Multiple Myeloma (NDMM) with High-Risk Cytogenetic Abnormalities (HRCA) in the Griffin and Master Studies

Introduction: DARA as monotherapy and combination therapy is approved across lines of treatment for multiple myeloma. The single-arm phase 2 MASTER study (NCT03224507) evaluated DARA + carfilzomib/lenalidomide/dexamethasone (D-KRd), which demonstrated promising clinical efficacy in transplant-eligible NDMM. The primary endpoint analysis (median follow-up, 25.1 mo) showed that minimal residual disease (MRD) negativity at the 10-5 threshold was achieved by 80% of D-KRd pts(Costa, et al. JCO. 2021). The randomized phase 2 GRIFFIN study (NCT02874742) evaluated DARA + lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible NDMM; the primary endpoint analysis (median follow-up, 13.5 mo) showed that the rate of stringent complete response by the end of consolidation was significantly higher for D-RVd versus RVd (42.4% vs 32.0%; 1-sided P = 0.068, meeting the prespecified 1-sided α of 0.1) (Voorhees, et al. Blood. 2020). Here, we present an analysis of pts with HRCA, defined as having ≥1 genetic abnormality: del17p, t(4;14), t(14;16), t(14;20), and/or gain/amp1q (≥3 copies of chromosome 1q21) from MASTER (median follow-up, 31.1 mo) and GRIFFIN (median follow-up, 49.6 mo). Methods: In MASTER, enrolled pts (no age limit with enrichment for high-risk disease) received 4 D-KRd induction cycles, autologous stem cell transplant (ASCT), and 0, 4 or 8 D-KRd consolidation cycles with treatment cessation upon achievement of 2 consecutive MRD-negative assessments, or lenalidomide (R) maintenance therapy if 2 consecutive MRD-negative assessments were not achieved. Pts received 28-day cycles of K (20/56 mg/m2 IV Days [D] 1, 8, 15), R (25 mg PO D1-21), d (40 mg PO or IV D1, 8, 15, and 22), and DARA (16 mg/kg IV: D1, 8, 15, and 22 for Cycles 1-2; D1 and 15 for Cycles 3-6; and D1 for Cycles 7+). In GRIFFIN, enrolled pts (age ≤70 years) were randomized 1:1 to receive 4 D-RVd/RVd induction cycles, ASCT, 2 D-RVd/RVd consolidation cycles, and up to 2 years of maintenance with R ± DARA. For induction/consolidation (21-day cycles), pts received R (25 mg PO on Days 1-14), V (1.3 mg/m2 SC on Days 1, 4, 8, and 11), and d (40 mg PO QW) ± DARA (16 mg/kg IV QW in Cycles 1-4 and D1 of Cycles 5-6). During maintenance (28-day cycles), pts received R (10 mg PO D1-21; if tolerated, 15 mg Cycles 10+) ± DARA (16 mg/kg IV Q8W or Q4W, or 1800 mg SC Q4W per protocol amendments). Following completion of study therapy, pts could continue R maintenance per local standard of care. Before the randomized phase, a safety run-in was conducted to assess D-RVd dose-limiting toxicities. Results: Among pts in MASTER (D-KRd, n = 123), 43% (n = 53) had standard risk (0 HRCA), 37% (n = 46) had high risk (1 HRCA), and 20% (n = 24) had ultra-high risk (≥2 HRCA) NDMM. Among 120 pts in GRIFFIN who received D-RVd (n = 104 randomized phase pts and n = 16 safety run-in pts), 56% (n = 67) had NDMM with 0 HRCA, 28% (n = 34) had 1 HRCA, 11% (n = 13) had ≥2 HRCA, and 5% (n = 6) were not evaluable. In an analysis of best response on study, rates of complete response or better (≥CR) for pts with 0, 1, and ≥2 HRCA were 91%, 89%, and 71% for D-KRd pts in MASTER, respectively, and 91%, 79%, and 62% for D-RVd pts in GRIFFIN. MRD-negativity rates at the 10-5 threshold were 80%, 86%, and 83% for D-KRd for pts with 0, 1, and ≥2 HRCA, respectively, and MRD-negativity rates at the 10-6 threshold were 68%, 80%, and 67%. For D-RVd pts, MRD-negativity rates at the 10-5 threshold were 76%, 56%, and 62% for pts with 0, 1, and ≥2 HRCA, respectively, and MRD-negativity rates at 10-6 were 45%, 26%, and 15%. MRD negativity (10‒5) with ≥CR occurred in 76%, 79%, and 67% of D-KRd pts with 0, 1, and ≥2 HRCA, respectively, and 75%, 53%, and 54% of D-RVd pts. In MASTER, 24-month progression-free survival (PFS) rates were 92%, 96%, and 66% for D-KRd pts with 0, 1, and ≥2 HRCA, respectively (Figure A). In GRIFFIN, 24-month PFS rates were 97%, 94%, and 64% for D-RVd pts with 0, 1, ≥2 HRCA, respectively, and 48-month PFS rates were 94%, 91%, and 54% (Figure B). Conclusions: In MASTER and GRIFFIN, pts with NDMM and 0 HRCA or 1 HRCA who received DARA-based quadruplet therapy achieved high rates of ≥CR, MRD negativity, and 2-year PFS rates. These data support use of DARA-based quadruplet therapy as frontline treatment among pts with high cytogenetic risk. However, among pts with NDMM and ≥2 HRCA, results were not similar, and the subgroup was small suggesting that more research is needed for pts with the poor prognosis of ultra-high-risk disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interim Results of a Risk-Adaptive Phase II Study: Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab (KRD-Dara) in Newly Diagnosed Multiple Myeloma (NDMM) at the Levine Cancer Institute (LCI)

Background: The combination of carfilzomib, lenalidomide and dexamethasone (KRd) has previously demonstrated deep and durable responses in patients with NDMM. A quadruplet regimen incorporating daratumumab (KRd-Dara) may further improve results. We report an interim analysis from stage 1 (Simon's optimal 2-stage design) of an ongoing minimal residual disease (MRD)-driven, single center phase 2 trial of KRd-Dara. Methods: The study design has been previously published (Bhutani et al, Blood 2020 Abstr 1388). Briefly, patients with NDMM (both transplant eligible and ineligible) were allowed one cycle of non-protocol therapy (if deemed necessary) and then 7 or 8 cycles of induction therapy with KRd-Dara (total induction cycles: 8). MRD assessment was performed by both next generation sequencing (NGS) and next generation flow cytometry (NGF) at the end of 8 cycles of induction, post- autologous stem cell transplantation (ASCT), and every 4 cycles of consolidation (maximum of 12 cycles). Post-induction treatment was dictated by an MRD-driven algorithm, using MRD (NGS, 10-5) to assign patients to one of the 3 study groups. The primary endpoint is complete response (CR) + stringent CR (sCR) at the completion of KRd-Dara induction therapy. Group A (MRD negative post-induction) proceeded directly to lenalidomide maintenance therapy deferring ASCT, if transplant eligible. Group B (MRD positive, transplant eligible) received upfront ASCT, KRd consolidation (maximum 12 cycles), and then lenalidomide maintenance. Group C (MRD positive after 8 cycles of induction, transplant ineligible) received KRd consolidation (maximum 12 cycles) followed by lenalidomide maintenance. Conversion to MRD negative status at any protocol specified time point allowed the patients to proceed to lenalidomide maintenance. Results: Stage 1 futility analysis criteria were met in November 2021 and stage 2 enrollment is actively ongoing. As of a data cutoff of 4/8/22, 30/39 patients have been enrolled. Twenty-three patients were enrolled in Stage 1. The median age of stage I patients was 60 (range 34- 76) years, 74% were male and 35% were Black. R-ISS stage 3 was present in 2 (8.7%), high-risk cytogenetics in 1 (4.4%) and gain 1q21 in 7 (30.4%). Fifteen patients (65.2%) received one cycle of pre-study treatment. All patients completed 8 total cycles of induction therapy. At the end of induction, CR + sCR was achieved in 15/23 (65.2%) patients with sCR in 52.2%, and very good partial response (VGPR) in 7 (30.4%). The MRD negativity rate was 69.6% (NGS, 10-5) and 43.5% (NGS, 10-6). The MRD negativity rate by NGF was 82.6% at 10-5and 47.4% at 10-6 sensitivity level in 23 and 19 evaluable patients, respectively; 43% of bone marrow specimen tested by NGF were hemodiluted. Concordance of MRD by NGS/ NGF at 10-5 was 16/23 (69.6% in agreement and 30.4% disagreement, Cohen's kappa: 0.183). Concordance of MRD by NGS/ NGF at 10-6 was 12/19 (63.2% in agreement and 36.8% disagreement, Cohen's kappa: 0.257). Grade 3-4 treatment related adverse events (>10% of patients) included hypophosphatemia (30%), hypertension (13%), and neutropenia (13%). Covid infection occurred in 7 (30.4%) patients; only one needed hospitalization. Other Infections (any grade) were seen in 15 (65.2%) patients. At least one dose reduction of carfilzomib was required in 5 (21.7%) patients, dexamethasone in 3 patients, and lenalidomide in 4 patients. Systemic injection reactions to subcutaneous daratumumab occurred in 5 (21.7%). Thromboembolic events happened in 3 patients. No patient discontinued treatment because of toxicity. There was no treatment-related mortality during stage 1. Post-induction, 16 patients (MRD negative) transitioned to lenalidomide maintenance, 5 patients (MRD positive) underwent ASCT, and 2 patients (MRD positive) proceeded to consolidation phase. Stem cell collection for eligible patients (n=22) was performed upon completion of induction; 5 patients failed to collect optimal target (3 million CD34+ cells/kg) during their first mobilization attempt. Survival results will be updated after stage 2 enrollment is completed, but as of data cutoff, no subjects in the Stage 1 cohort have progressed. Conclusions: The quadruplet regimen KRd-Dara as induction in NDMM leads to deep responses reflected in high rates of sCR and MRD negativity with an acceptable and well-tolerated safety profile. The stage 2 enrollment is ongoing.

A Phase I Study of Safety, Tolerability and Immunological Effects of SVN53-67/M57-KLH in Patients with Multiple Myeloma Receiving Lenalidomide Maintenance Therapy

A Phase I Study of Safety, Tolerability and Immunological Effects of SVN53-67/M57-KLH in Patients with Multiple Myeloma Receiving Lenalidomide Maintenance Therapy

Phase Ib/II Study of Rituximab, Lenalidomide and Methotrexate Followed By Lenalidomide Maintenance in Patients with Newly Diagnosed Primary CNS Lymphoma: The Remla Trial

Purpose: We evaluated the tolerability and efficacy of adding lenalidomide to a rituximab and methotrexate combination (R2-MTX) regimen, followed by lenalidomide maintenance as a first-line treatment of patients with primary central nervous system lymphoma (PCNSL). Patients and methods: This multicenter prospective phase Ib/II study, enrolled immunocompetent patients aged 18-75 years with untreated PCNSL. The phase I study increased lenalidomide dose from 15 to 20 to 25 mg. Patients were treated with rituximab 375 mg/m2 and methotrexate 3.5 g/m2 on day 1 and lenalidomide daily for 14 days every 3-week cycle. After 6 cycles of the R2-MTX regimen, responsive patients received lenalidomide maintenance therapy(lenalidomide 25 mg daily for 21 days every 4-week cycle for 2 years).ASCT was optional in eligible patients before lenalidomide maintenance. The primary phase I endpoint was the maximum tolerated dose of lenalidomide. The primary phase II endpoint was the 2-year progression-free survival (PFS). Results: Eleven patients were enrolled in phase Ib of the study. No Dose-limiting toxicities were observed, and the recommend phase II dose of lenalidomide was 25mg. In phase II, 23 patients were treated. The median follow-up period was 14.2 months (range, 8.0-33.4), the estimated 2-year PFS and OS were 61.5%(95% CI 50.7-91.8 ) and 81.7%(95% CI 57.4-92.9), respectively. In the PR2D group, the objective response rate was 92.%, and estimated 2-year PFS and OS were 78.5%(95% CI 50.7-91.8) and 90.4%(95% CI 66.8-97.5). Compared with historical controls in our center, 2-year PFS were significantly improved (P = 0.0088). Hematological toxicities, GI symptoms and infection were the most frequent adverse events, and grade 3/4 toxicities were seen in 62.5% of patients. Quality of life was stabilized during the lenalidomide maintenance phase. Conclusion: R2-MTX regimen supported the integration of lenalidomide to HD-MTX in induction therapy and maintenance as front-line treatment PCNSL patients with good safety, response rate and 2-year PFS. More importantly, the REMLA trial suggested lenalidomide maintenance could be an option instead of WBRT/ASCT consolidation even in younger patients. Randomized trials that incorporate this regimen are needed to determine its efficacy compared with other strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 2 Trial of Colesevelam for Lenalidomide-Associated Diarrhea

Introduction Lenalidomide maintenance therapy is associated with a significantly improved progression-free survival in patients with newly diagnosed multiple myeloma; a meta-analysis additionally reported significantly prolonged overall survival. Lenalidomide maintenance is overall well-tolerated; however, fatigue and diarrhea are common side effects. Indeed, the incidence of lenalidomide-associated diarrhea has been documented in up to 25-40% of patients in treated with lenalidomide in clinical trials. The stool microbiome has been linked to sustained responses in patients on lenalidomide maintenance but has not been studied in the setting of lenalidomide-associated diarrhea. Based on a clinical case series with 12 patients (Pawlyn et al, Blood 2014), bile acid malabsorption has been implicated in lenalidomide-associated diarrhea, and, consequently, bile acid binders such as colesevelam have been used in clinical practice. Colesevelam is not taken up systemically and is assumed to not effect lenalidomide pharmacokinetics (PK). To evaluate the safety and efficacy of a bile acid binder systematically, we conducted a phase 2 investigator-initiated trial of colesevelam for patients with lenalidomide-associated diarrhea. In this trial, stool microbiome studies as well as lenalidomide PK studies of were included to evaluate any potential effect of colesevelam on lenalidomide concentration. Methods This was a phase 2 single arm open label trial of colesevelam for patients on with lenalidomide-associated diarrhea. Patients with multiple myeloma who were treated with single agent lenalidomide maintenance, and who had grade 1 or more diarrhea per the CTCAE v5 criteria were eligible. Infectious diarrhea was an exclusion criterion and was ruled out in all patients before starting colesevelam. This was a Simon 2-stage pilot study including up to 25 patients. If 5 or more (30%) of the first 16 patients had a clinical response, defined as a decrease in diarrhea by at least 1 grade per CTCAE within the first 4 weeks of treatment, the remaining 9 patients were to be enrolled. Patients were treated with colesevelam daily starting at 1250 mg (2 tablets 625 mg) for a total of 12 weeks. There was a dose adjustment schedule for colesevelam, up to maximum 6 tablets (3750mg) per day and minimum 1 tablet (625 mg) per day, based on grade of diarrhea on initial weekly clinical assessment. Patients were instructed to take colesevelam in the morning and lenalidomide in the evening (at least 4 hours apart). For a subset of 15 patients, pharmacokinetic evaluation of lenalidomide was performed on day 1 and day 8 after starting colesevelam. Stool microbiota was collected at baseline and at the end of trial. Results The study met the endpoint per the Simon stage 2 criteria, and a total of 25 patients were enrolled. There were 15 women and 10 men with a median age at inclusion of 60 years. At baseline, 1 patient had grade 3 diarrhea, 14 patients had grade 2, and 10 patients had grade 1 diarrhea, respectively. In total, 22 (88%) of the 25 patients responded with improvement with complete resolution (N=17, 68%) or improvement by 1 grade (N=5, 20%) of diarrhea. Three patients (12%) patients did not respond after treatment with colesevelam, 2 with had ongoing grade 1 and 1 with grade 2 diarrhea (Figure). Five patients (20%) had a dose reduction to colesevelam 625 mg daily and 3 (12%) patients required dose increase to 1875-2500mg (3-4 pills) per day for control of the diarrhea. Side effects from colesevelam included constipation in 2 patients, flatulence in 1 patient, and acid reflux in 1 patient. Pharmacokinetic laboratory studies and stool microbiome analyses are ongoing. Conclusion In this prospective, single arm clinical trial, colesevelam was safe and highly effective for the control of lenalidomide-associated diarrhea in multiple myeloma patients receiving single agent lenalidomide maintenance. Lenalidomide PK and stool microbiome studies are ongoing and will be reported at the ASH Annual Meeting 2022. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Refractory postherpetic neuralgia in a multiple myeloma patient with lenalidomide maintenance therapy: a case report

Herpes zoster is not common in multiple myeloma (MM) patients treated with lenalidomide-based regimens. We report an MM patient in his late 60s who received lenalidomide as maintenance treatment and whose condition was complicated with refractory postherpetic neuralgia. The patient received antiviral treatment and analgesia immediately after the diagnosis of herpes zoster. Two months later, the patient received acupuncture, radiofrequency treatment, and even spinal cord stimulation, which failed to relieve the pain. Consequently, we performed high-resolution magnetic resonance imaging of the cervical and thoracic nerves. Then, stellate ganglion block, left C5/C6/C7/C8 nerve root block, and left thoracic 1, 2 paravertebral nerve block were performed with the assistance of real-time ultrasound. The pain was immediately relieved after treatment; however, the symptoms reappeared 2 days later. At 5 months after treatment, the patient still experienced severe pain. We suggest that MM patients complicated with postherpetic neuralgia are refractory to treatment. Starting nerve block therapy, pulsed radiofrequency, and other interventional therapies as early as possible could be a more optimal treatment plan for these patients.