/pdf/phase-1-2-study-of-carfilzomib-pomalidomide-dexamethasone-2qh5dgb7.pdf

Phase 1/2 study of carfilzomib, pomalidomide, dexamethasone with and without daratumumab in relapsed multiple myeloma.

mRNA cancer vaccine: A novel and potential immunotherapy for multiple myeloma

Simple Summary Multiple myeloma is an incurable hematologic malignancy arising from terminally differentiated B-cells. Over the last decade, advancements in therapeutics have radically shifted the treatment landscape of MM, significantly improving the survival of patients. In this review, we will discuss the available therapeutic modalities for relapsed–refractory disease, highlighting critical factors that guide the therapy selection process. Abstract Multiple myeloma (MM) is the second most common hematologic malignancy in adults worldwide. Over the past few years, major therapeutic advances have improved progression-free and overall survival, as well as quality of life. Despite this recent progress, MM remains incurable in the vast majority of cases. Patients eventually relapse and become refractory to multiple drug classes, making long-term management challenging. In this review, we will focus on the treatment paradigm of relapsed/refractory MM (RRMM) in the era of advanced therapies emphasizing the available novel modalities that have recently been incorporated into routine practice, such as chimeric antigen receptor T-cell therapy, bispecific antibodies, and other promising approaches. We will also discuss major factors that influence the selection of appropriate drug combinations or cellular therapies, such as relapse characteristics, and other disease and patient related parameters. Our goal is to provide insight into the currently available and experimental therapies for RRMM in an effort to guide the therapeutic decision-making process.

/pdf/management-of-relapsed-refractory-multiple-myeloma-in-the-1smppchq.pdf

Management of Relapsed–Refractory Multiple Myeloma in the Era of Advanced Therapies: Evidence-Based Recommendations for Routine Clinical Practice

8012 Background: Daratumumab (dara), carfilzomib (K), pomalidomide (P), and dexamethasone (d) are established in relapsed multiple myeloma (MM) with activity in 3-drug combinations including: dara Kd; dara Pd; and KPd. The paradigm in relapsed/refractory disease is moving towards more intensive and well-tolerated combinations to achieve deeper and more durable responses while ensuring tolerability. Quadruplet regimens are now becoming standard in newly diagnosed MM, and we explored a 4-drug regimen in relapsed disease. Preliminary results of a phase 2 study of dara KPd with a twice/week schedule of K showed an ORR of 86% in pts with a median of 1 prior line (Jasielec et al., ASH 2020). Here we report an ongoing study of dara with weekly KPd (dara wKPd) to improve the accessibility of this regimen. Methods: This phase 2 study (NCT04176718) will enroll up to 43 pts with relapsed/refractory MM who have received at least 1 prior therapy, including both lenalidomide and a proteasome inhibitor. Prior therapy with dara, K, or P was permitted except for K and P given together as last line of therapy. Dara wKPd was given on a 28-day schedule. Dara was given according to the dara Pd schedule. An initial cohort received dara 16 mg/kg iv (with first dose split over two days); the trial was amended to dara 1800 mg sc. K 56 mg/m2 iv was given weekly on days 1, 8, 15; for C1D1, dose was 20 mg/m2. P 4 mg was given po on days 1-21. Dex 40 mg was given weekly with the dose split over two days. Treatment was until progression or unacceptable toxicity. The primary endpoints are overall response and the safety profile of dara wKPd. Secondary endpoints include PFS. Results: At time of data cutoff, 24 pts were enrolled; median age was 65 (range 42-73), and median number of prior regimens was 2 (range 1-3). All pts were refractory to their last line of therapy and had prior lenalidomide and bortezomib. Additional prior therapies included: pomalidomide (54%), carfilzomib (13%), ixazomib (46%), cyclophosphamide (4%), auto SCT (29%). High risk FISH was present (out of 24 pts): del 17p (13%); t(14;16) (8%); gain of 1q (46%). Median follow up was 8.4 months. 2 pts came off study due to neutropenia leading to delay in treatment. Grade 3-4 hematologic AEs included neutropenia (46%) and thrombocytopenia (25%). There was 1 episode of febrile neutropenia. Common non hematologic AEs (all; grade 3-4) included fatigue (42%; 0%); dyspnea (38%; 4%); increase in ALT/AST (29%; 8%); insomnia (21%; 0%); neuropathy (17%; 0%). 22 pts were evaluable for response, with an overall response rate of 95% (PR 23%, VPGR 68%, CR 5%). Median PFS at 12 months was 86.2% (95% CI, 70%-100%). Conclusions: Dara wKPd shows some of the highest response rates (95%) reported to date in relapsed/refractory MM. This likely reflects the incorporation of 4 active drugs in 1 regimen and builds on the efficacy of dara-based triplet regimens, with manageable toxicity and convenience of weekly K. Clinical trial information: NCT04176718.

A phase II study of daratumumab with weekly carfilzomib, pomalidomide, and dexamethasone in relapsed and refractory multiple myeloma.

Key Points • Although patients with MM and WM generate SARS-CoV-2 antibodies, their antibody-mediated effector functions are significantly imparied.• Administration of at least two SARS-CoV-2 booster doses can overcome ineffective vaccine responses in nearly 90% of patients with MM and WM.

Prospective study of immunogenicity to SARS-CoV-2 booster vaccines in multiple myeloma and Waldenström macroglobulinemia.


 BACKGROUND
 Multiple myeloma (MM) and Waldenström macroglobulinemia (WM) are associated with significant immunoparesis. Based on the ongoing COVID-19 pandemic, there is an urgent need to understand whether patients are able to mount a sufficient response to COVID-19 vaccines.
 
 METHODS
 MM and WM patients are vaccinated with mRNA-1273 (Moderna), BNT162b2 mRNA (Pfizer/BioNTech), or JNJ-78436735 (Johnson & Johnson) in a prospective clinical trial. Primary endpoint is SARS-CoV-2 spike protein (S) antibody (Ab) detection 28 days after final vaccination. Secondary endpoints include functional serologic assessments and T-cell responses at 28 days, 6 months, 9 months, and 12 months following vaccination. S Abs were detected by Elecsys assay (Roche Diagnostics), with ³ 0.80 U/mL defined as positive and titers > 250 U/mL considered stronger correlates of neutralization. SARS-CoV-2 wildtype and variant S-specific Ab isotypes and FcγR binding profiles were quantified by custom Luminex assay. Antibody-dependent neutrophil and cellular phagocytosis (ADNP and ADCP) were assessed using flow cytometry.
 
 RESULTS
 To date 141 patients have been enrolled, 137 (91 MM and 46 WM) of whom had an S Ab assessment. Median Ab titer was 178.0 (IQR, 16.10-1166.0) for MM and 3.92 (IQR, 0-278.9) for WM. S Ab response rate was 91% (83/91) in MM and 56% (27/46) in WM. However, responses achieving S Ab >250 U/mL were 47.3% (43/91) in MM and 26.1% (12/46) in WM. In patients ³75 years, responses >250 u/mL were 13.3% (2/15; p<0.05). Vaccine-specific S Ab responses >250 u/mL following mRNA-1273, BNT162b2, and JNJ-78436735 were 67.6% (23/34; p<0.05), 38.3% (18/47; p=NS), and 20% (2/10; p=NS) in MM and 50.0% (8/16; p<0.05), 14.8% (4/27; p<0.05), and 0% (0/3; p=NS) in WM.
 Among MM patients with progressive disease, S Ab response >250 u/mL occurred in 30% (6/20) as opposed to 55.6% (30/54) for VGPR+ (p<0.05). MM patients having autologous stem cell transplant within 12 months demonstrated 100% (5/5; p<0.05) S Ab responses. For MM patients actively receiving an anti-CD38 monoclonal Ab or an immunomodulatory drug, S Ab response occurred in 38.9% (14/36; p=NS) and 50.9% (28/55; p<0.05).
 Among WM patients, S Ab responses >250 U/mL occurred in 63.6% (7/11; p<0.05) previously untreated; 0% (0/9; p<0.05) who received rituximab within 12 months; 10% (2/20); p<0.05) on an active Bruton Tyrosine Kinase (BTK) inhibitor; and 20% (3/15; p=NS) who received other therapies.
 Functional Ab studies were performed on 14 MM patients, 14 WM, patients, and 14 healthy donors (HD) (Figure 1). All patients were assessed 28 days following their final vaccination and myeloma patients had an additional assessment 28 days following initial vaccination. MM and WM patients demonstrated less IGG1 and IGG3 S Ab production than HD. MM patients showed increased IgA and IgM S Ab production as well as increased FcgR2A binding following a second vaccine in contrast to HD. Both ADNP and ADCP were reduced in MM and WM patients. MM patients demonstrated improved ADCP in SARS-CoV-2 variants B.1.351, B.1.117, and P.1 versus wildtype (p<0.05).
 
 CONCLUSIONS
 We report the first known evidence of impaired functional humoral responses following COVID-19 vaccines in patients with MM and WM. Overall, WM patients showed more severe impairment of COVID-19 S Ab responses. Most previously untreated WM patients achieved S Ab responses, however the most significant reduction in S Ab responses were seen in WM patients who received rituximab within 12 months or active BTK inhibitors. For MM patients, being in disease remission associated with improved S Ab response. Among MM and WM patients, age ³75 years associated with significantly lower rates and vaccination with MRNA-1273 (Moderna) elicited significantly higher S Ab response rates than other vaccines. A defect in ADNP and more profound defect in ADCP suggests overall compromised opsinophagocytic activity among MM and WM patients. Data comparing first and second vaccine responses in MM patients, suggest less efficient class switching to IGG as well as incomplete maturation of their FcgR2A binding profiles but normal maturation of FcgR3A. Interestingly, ADCP was improved in several emerging SARS-CoV-2 variants. T-cell studies are pending and will be updated. Further understanding of the immunological response to COVID19 vaccination is needed to clarify patients risks, and necessity for booster or alternative protective measures against COVID-19.
 
 
 
 Figure 1
 
 
 
 
 
 Disclosures
 
 Branagan: 
 Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; CSL Behring: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Consultancy; Sanofi Genzyme: Consultancy. Lei: 
 AbbVie: Honoraria; Epizyme: Honoraria; Fresenius Kabi: Consultancy; Intervention Insights: Consultancy. Yee: 
 Amgen: Consultancy; Bristol Myer Squibb: Consultancy; Adaptive: Consultancy; GSK: Consultancy; Janssen: Consultancy; Oncopeptides: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. O'Donnell: 
 Adaptive: Consultancy; Bristol Myer Squibb: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Onocopeptide: Consultancy; Takeda: Consultancy. Castillo: 
 Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding. Raje: 
 Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Treon: 
 BeiGene: Consultancy, Research Funding; Eli Lily: Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding. Mo: 
 GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Eli Lilly: Consultancy; Janssen: Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nadeem: 
 Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Richardson: 
 Oncopeptides: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Secura Bio: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Juleg: 
 Leyden Labs: Current Employment; Amsterdam: Current Employment; Netherlands: Current Employment.


COVID-19 Vaccine Responsiveness in Patients with Multiple Myeloma and Waldenström Macroglobulinemia

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Papers

A phase II study of daratumumab with weekly carfilzomib, pomalidomide, and dexamethasone in relapsed and refractory multiple myeloma.

Prospective study of immunogenicity to SARS-CoV-2 booster vaccines in multiple myeloma and Waldenström macroglobulinemia.

COVID-19 Vaccine Responsiveness in Patients with Multiple Myeloma and Waldenström Macroglobulinemia