Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma.

BACKGROUND: The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown. METHODS: We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles. RESULTS: In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively. CONCLUSIONS: Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).

Diagnostic performance of 18 F-FDG-PET/CT compared to standard skeletal survey for detecting bone destruction in smouldering multiple myeloma: time to move forward.

Skeletal survey (SS) continues to be used in the community to detect bone disease in patients with multiple myeloma (MM). While the false-negative rate is high, the specificity of SS is less well characterised. Here, we compare the diagnostic accuracy of SS compared to 18 F-FDG-PET/CT (positron emission tomography/computed tomography) in 79 patients referred to our tertiary centre with a diagnosis of smouldering MM. SS had a specificity of 83·1% (95% confidence interval: 72·0-90·5%). This study reinforces the importance of using more specific imaging techniques to avoid inaccurate diagnosis that could lead to the risks associated with unnecessary therapy in patients with smouldering MM.

Avelumab, a PD-L1 Inhibitor, in Combination with Hypofractionated Radiotherapy and the Abscopal Effect in Relapsed Refractory Multiple Myeloma.

LESSONS LEARNED: Despite the initial optimism for using immune checkpoint inhibition in the treatment of multiple myeloma, subsequent clinical studies have been disappointing. Preclinical studies have suggested that priming the immune system with various modalities in addition to checkpoint inhibition may overcome the relative T-cell exhaustion or senescence; however, in this small data set, radiotherapy with checkpoint inhibition did not appear to activate the antitumor immune response. BACKGROUND: Extramedullary disease (EMD) is recognized as an aggressive subentity of multiple myeloma (MM) with a need for novel therapeutic approaches. We therefore designed a proof-of-principle pilot study to evaluate the synergy between the combination of the anti-PD-L1, avelumab, and concomitant hypofractionated radiotherapy. METHODS: This was a single-arm phase II Simon two-stage single center study that was prematurely terminated because of the COVID-19 pandemic after enrolling four patients. Key eligibility included patients with relapsed/refractory multiple myeloma (RRMM) who had exhausted or were not candidates for standard therapy and had at least one lesion amenable to radiotherapy. Patients received avelumab until progression or intolerable toxicity and hypofractionated radiotherapy to a focal lesion in cycle 2. Radiotherapy was delayed until cycle 2 to allow the avelumab to reach a study state, given the important observation from previous studies that concomitant therapy is needed for the abscopal effect. RESULTS: At a median potential follow-up of 10.5 months, there were no objective responses, one minimal response, and two stable disease as best response. The median progression-free survival (PFS) was 5.3 months (95% confidence interval [CI]: 2.5-7.1 months), and no deaths occurred. There were no grade ≥3 and five grade 1-2 treatment-related adverse events. CONCLUSION: Avelumab in combination with radiotherapy for patients with RRMM and EMD was associated with very modest systemic clinical benefit; however, patients did benefit as usual from local radiotherapy. Furthermore, the combination was very well tolerated compared with historical RRMM treatment regimens.

Practical guidance for new multiple myeloma treatment regimens: A nursing perspective.

As is the case for solid tumors, treatment paradigms have shifted from non-specific chemotherapeutic agents towards novel targeted drugs in the treatment of patients with multiple myeloma (MM). Currently, multiple targeted therapies are available to treat patients augmenting the arsenal of modalities which also includes chemotherapy, immunotherapy, radiation therapy, hematopoietic stem cell transplantation (HSCST) and chimeric antigen T-cell therapy (CAR-T). These novel, targeted agents have dramatically increased optimism for patients, who may now be treated over many years with successive regimens. As fortunate as we are to have these new therapies available for our patients, this advantage is juxtaposed with the challenges involved with delivering them safely. While each class of agents has demonstrated efficacy, in terms of response rates and survival, they also exert class effects which pose risks for toxicity. In addition, newer generation agents within the classes often have slightly different toxicity profiles than did their predecessors. These factors must be addressed, and their risks mitigated by the multidisciplinary team. This review presents a summary of the evolution of drug development for MM. For each targeted agent, the efficacy data from pivotal trials and highlights of the risks that were demonstrated in trials, as well as during post-marketing surveillance, are presented. Specific risks associated with agents within the classes, that are not shared with all new class members, are described. A table presenting these potential risks, with recommended nursing actions to mitigate toxicity, is provided as a quick reference that nurses may use during the planning, and provision, of patient care.

Daratumumab: A review of current indications and future directions.

Daratumumab, a human IgG1 kappa monoclonal antibody targeting CD38 has transformed the treatment paradigm of multiple myeloma (MM). With the identification of CD38 as a crucial receptor involved in immune system function, it became an ideal target for monoclonal antibody (mAb) drug development in MM. Daratumumab's unique multifaceted mechanism of action has led to great success in the treatment of relapsed refractory multiple myeloma (RRMM) as well as newly diagnosed multiple myeloma (NDMM) patients. Along with its efficacy comes a low toxicity profile, improved further with the introduction of subcutaneous daratumumab. With such success within MM, daratumumab is now being explored in other disease states. This article will review daratumumab's drug development, practical use, and future potential indications.

Carfilzomib, Lenalidomide, and Dexamethasone Followed by Lenalidomide Maintenance for Prevention of Symptomatic Multiple Myeloma in Patients With High-risk Smoldering Myeloma: A Phase 2 Nonrandomized Controlled Trial.

IMPORTANCE: High-risk smoldering myeloma has a 5-year risk of progression to symptomatic multiple myeloma of approximately 75%. Treatment with lenalidomide decreases the risk of progression; however, novel triplet regimens are superior, and earlier disease may be more treatment sensitive. OBJECTIVE: To evaluate the use of carfilzomib, lenalidomide, and dexamethasone (KRd) with lenalidomide maintenance therapy as early intervention in high-risk smoldering myeloma and to determine the rates of minimal residual disease (MRD)-negative complete response (CR). DESIGN, SETTING, AND PARTICIPANTS: In this single-arm, single-center, phase 2 nonrandomized controlled trial, responses were evaluated at every cycle during KRd treatment and every 3 cycles subsequently. Bone marrow biopsies and imaging were performed by cycle 8 and then annually. The study enrolled patients from May 29, 2012, to July 23, 2020, at the National Institutes of Health Clinical Center, a highly specialized tertiary cancer center. Patient key eligibility criteria included a diagnosis of high-risk smoldering myeloma based on the Mayo Clinic, Spanish, and/or Rajkumar, Mateos, and Landgren criteria. INTERVENTIONS: Patients received eight 4-week cycles of intravenous carfilzomib 36 mg/m2 (first 2 doses, 20 mg/m2), dexamethasone (20 mg, cycles 1-4; 10 mg, cycles 5-8 twice weekly), and lenalidomide 25 mg (days 1-21) followed by twenty-four 28-day cycles of maintenance lenalidomide 10 mg (days 1-21). Stem cell harvest and storage were optional. MAIN OUTCOMES AND MEASURES: The primary outcome was the MRD-negative CR rate. Key secondary outcomes included duration of MRD-negative CR and progression to multiple myeloma. RESULTS: A total of 54 patients (median age, 59 years [range, 40-79 years]; 30 men [55.6%]; and 2 Asian [3.7%], 15 Black [27.8%], 1 Hispanic [1.9%], and 36 White [66.7%] patients) were enrolled, with a median potential follow-up time of 31.9 months (range, 6.7-102.9 months). The MRD-negative CR rate was 70.4% (95% CI, 56.4%-82.0%), with a median sustained duration of 5.5 years (95% CI, 3.7 years to not estimable). The 8-year probability of being free from progression to multiple myeloma was 91.2% (95% CI, 67.4%-97.9%), and no deaths occurred. Nonhematologic grade 3 adverse events occurred in 21 patients (38.9%) and included thromboembolism, rash, and lung infection, with no grade 4 events. CONCLUSIONS AND RELEVANCE: Results of this phase 2 nonrandomized controlled trial suggest that treatment of high-risk smoldering myeloma with novel triplet regimens, such as KRd and lenalidomide maintenance therapy, may alter the natural history of smoldering myeloma by significantly delaying development of end-organ disease. Randomized clinical trials are needed to confirm this favorable benefit-to-risk profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01572480.

Diagnostic challenges of early Lyme disease: lessons from a community case series.

BACKGROUND: Lyme disease, the most common vector-borne infection in North America, is increasingly reported. When the characteristic rash, erythema migrans, is not recognized and treated, delayed manifestations of disseminated infection may occur. The accuracy of diagnosis and treatment of early Lyme disease in the community is unknown. METHODS: A retrospective, consecutive case series of 165 patients presenting for possible early Lyme disease between August 1, 2002 and August 1, 2007 to a community-based Lyme referral practice in Maryland. All patients had acute symptoms of less than or equal to 12 weeks duration. Patients were categorized according to the Centers for Disease Control and Prevention criteria and data were collected on presenting history, physical findings, laboratory serology, prior diagnoses and prior treatments. RESULTS: The majority (61%) of patients in this case series were diagnosed with early Lyme disease. Of those diagnosed with early Lyme disease, 13% did not present with erythema migrans; of those not presenting with a rash, 54% had been previously misdiagnosed. Among those with a rash, the diagnosis of erythema migrans was initially missed in 23% of patients whose rash was subsequently confirmed. Of all patients previously misdiagnosed, 41% had received initial antibiotics likely to be ineffective against Lyme disease. CONCLUSION: For community physicians practicing in high-risk geographic areas, the diagnosis of Lyme disease remains a challenge. Failure to recognize erythema migrans or alternatively, viral-like presentations without a rash, can lead to missed or delayed diagnosis of Lyme disease, ineffective antibiotic treatment, and the potential for late manifestations.

Baseline mutational patterns and sustained MRD negativity in patients with high-risk smoldering myeloma.

Early results of a prospective phase 2 clinical trial of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide maintenance in high-risk smoldering myeloma showed promising results that were previously published. Here, we provide novel insights into the genetic landscape of high-risk smoldering myeloma and information on sustained minimal residual disease (MRD) negativity with an expanded cohort of patients. Eighteen patients with high-risk smoldering myeloma were enrolled between 29 May 2012, and 14 January 2014. We included patients with newly diagnosed multiple myeloma enrolled in a parallel trial who received the same therapy (reference group). The overall response rate was 100%. With median potential follow-up of 43.3 months, 10 (63%) remain in MRD negativity, and the estimated 4-year progression-free and overall survival rates are 71% and 100%, respectively. Importantly, we report differences in mutational patterns in patients with high-risk smoldering myeloma and newly diagnosed multiple myeloma, reflected in a lower frequency of mutations in significant myeloma genes (6.6% vs 45%) and NFKB pathway genes (6.6% vs 25%). Treatment with carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide maintenance was associated with a 100% response rate and 63% MRD negativity with a safety profile consistent with previous reports for this regimen. This study had a small numbers of participants, but there seemed to be important differences in the genetic landscape of patients with high-risk smoldering myeloma and those with newly diagnosed multiple myeloma, suggestive of a more treatment-responsive biology in early disease.

Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma.

IMPORTANCE: Carfilzomib-lenalidomide-dexamethasone therapy yields deep responses in patients with newly diagnosed multiple myeloma (NDMM). It is important to gain an understanding of this combination's tolerability and impact on minimal residual disease (MRD) negativity because this end point has been associated with improved survival. OBJECTIVE: To assess the safety and efficacy of carfilzomib-lenalidomide-dexamethasone therapy in NDMM and high-risk smoldering multiple myeloma (SMM). DESIGN, SETTING, AND PARTICIPANTS: Clinical and correlative pilot study at the National Institutes of Health Clinical Center. Patients with NDMM or high-risk SMM were enrolled between July 11, 2011, and October 9, 2013. Median follow-up was 17.3 (NDMM) and 15.9 months (SMM). INTERVENTIONS: Eight 28-day cycles were composed of carfilzomib 20/36 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on days 1 through 21; and dexamethasone 20/10 mg (cycles 1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, and 23. Patients who achieved at least stable disease subsequently received 24 cycles of lenalidomide extended dosing. MAIN OUTCOMES AND MEASURES: Primary end points were neuropathy of grade 3 or greater (NDMM) and at least very good partial response rates (SMM). Minimal residual disease was also assessed. RESULTS: Of 45 patients with NDMM, none had neuropathy of grade 3 or greater. Of 12 patients with high-risk SMM, the most common of any-grade adverse events were lymphopenia (12 [100%]) and gastrointestinal disorders (11 [92%]). All patients with SMM achieved at least a very good partial response during the study period. Among the 28 patients with NDMM and the 12 with SMM achieving at least a near-complete response, MRD negativity was found in 28 of 28 (100% [95% CI, 88%-100%]), 11 of 12 (92% [95% CI, 62%-100%]) (multiparametric flow cytometry), 14 of 21 (67% [95% CI, 43%-85%]), and 9 of 12 (75% [95% CI, 43%-94%]) (next-generation sequencing), respectively. In patients with NDMM, 12-month progression-free survival for MRD-negative vs MRD-positive status by flow cytometry and next-generation sequencing was 100% vs 79% (95% CI, 47%-94%; P < .001) and 100% vs 95% (95% CI, 75%-99%; P = .02), respectively. CONCLUSIONS AND RELEVANCE: Carfilzomib-lenalidomide-dexamethasone therapy is tolerable and demonstrates high rates of MRD negativity in NDMM, translating into longer progression-free survival in patients achieving MRD negativity. Carfilzomib-lenalidomide-dexamethasone therapy also demonstrates efficacy in high-risk SMM.

Unusual presentation of Lyme disease: Horner syndrome with negative serology.

Early disseminated Lyme disease can be difficult to diagnose because of atypical symptoms and physical findings. A clinical diagnosis must be made in the absence of confirmatory serologic testing to allow timely therapy. We report a case of a 69-year-old woman who presents with fever, Horner syndrome, and a 12-cm oval-shaped erythematous macular rash with multiple vesiculopustular eruptions. The patient recovered after appropriate intravenous antibiotics, but serologic testing only confirmed the diagnosis 4 weeks later. This case also describes an unusual complication involving the neurologic system. We illustrate the clinical presentation and review the medical literature. Lyme disease should always be considered in patients from endemic regions with viral-like symptoms or a new rash.

High-dose therapy and blood or marrow transplantation for non-Hodgkin lymphoma with central nervous system involvement.

The role of autologous or allogeneic blood or marrow transplantation (BMT) remains undefined in patients with central nervous system (CNS) involvement by lymphoma. The records of all adult and pediatric non-Hodgkin lymphoma patients receiving BMT at Johns Hopkins from 1980 to 2003 were reviewed, and 37 patients were identified who had CNS involvement that was treated into remission by the time of BMT. The chief histologies were diffuse large B-cell lymphoma and T-cell lymphoblastic lymphoma/leukemia. Twenty-four percent received intrathecal chemotherapy alone, and 70% received intrathecal chemotherapy and CNS irradiation before BMT. The main preparative regimens were cyclophosphamide/total body irradiation and busulfan/cyclophosphamide. Forty-one percent received an allogeneic transplant. Lymphoma relapsed after BMT in 14 patients (38%), and at least 5 had documented or suspected CNS relapse. In multivariate models, age > or =18 years at diagnosis, resistant systemic disease, busulfan/cyclophosphamide conditioning, and lack of intrathecal consolidation after BMT were statistically significant predictors of inferior survival. The 5-year actuarial event-free survival was 36%, and overall survival was 39%. After BMT, long-term survival is thus achievable in a subset of patients with a history of treated CNS involvement by non-Hodgkin lymphoma. The survival rates are not dissimilar to those typically seen in other high-risk lymphoma patients undergoing BMT. These data suggest that patients with lymphomatous involvement of the CNS who achieve CNS remission should be offered BMT if it is otherwise indicated.

Identification and management of delirium in the critically ill patient with cancer.

Rather than a specific entity, delirium is at the midpoint on a spectrum of potential mental status changes that ranges from full consciousness to deep coma. The extremes are relatively easy to recognize, but other points along the spectrum may go unrecognized or be misdiagnosed. If recognized and treated expeditiously, delirium may be reversed in some patients. It is imperative that those caring for critically ill patients with cancer have the knowledge and tools necessary to identify and manage delirium appropriately. Although all critically ill patients are at risk for delirium, cancer presents additional assaults to the central nervous system via direct tumor invasion or iatrogenic provocations. This article describes delirium in cancer, and addresses diagnostic and management issues across the course of the disease.

ANNA-2: an antibody associated with paraneoplastic opsoclonus in a patient with large-cell carcinoma of the lung with neuroendocrine features--correlation of clinical improvement with tumor response.

This report describes a case of large-cell lung carcinoma with neuroendocrine features, presenting with the full clinical picture of paraneoplastic opsoclonus-myoclonus syndrome. The patient had an unexpectedly dramatic resolution of the neurologic dysfunction after receiving antineoplastic treatment. Symptom improvement paralleled a progressive decline of serum ANNA-2 antibody titers to undetectable levels.