Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma

Richardson, Paul G.; Jacobus, Susanna; Weller, Edie; Hassoun, Hani; Lonial, Sagar; Raje, Noopur; Medvedova, Eva; McCarthy, Philip L.; Libby, Edward N.; Voorhees, Peter M.; Orłowski, Robert Z.; Anderson, Larry D.; Zonder, Jeffrey A.; Milner, Carter P.; Gasparetto, Cristina; Agha, Mounzer; Khan, Abdullah; Hurd, David D.; Gowin, Krisstina; Kamble, Rammurti T.; Jagannath, Sundar; Nathwani, Nitya; Alsina, Melissa; Cornell, Robert F.; Hashmi, Hamza; Campagnaro, Erica; Andreescu, Astrid C.; Gentile, Teresa; Liedtke, Michaela; Godby, Kelly N.; Cohen, Adam D.; Openshaw, Thomas H.; Pasquini, Marcelo C.; Giralt, Sergío; Kaufman, Jonathan; Yee, Andrew J.; Scott, Emma C.; Torka, Pallawi; Foley, Amy; Fulciniti, Mariateresa; Hebert, Kyle; Samur, Mehmet K.; Masone, Kelly; Maglio, Michelle E.; Zeytoonjian, Andrea A.; Nadeem, Omar; Schlossman, Robert; Laubach, Jacob P.; Paba‐Prada, Claudia; Ghobrial, Irène M.; Perrot, Aurore; Moreau, Philippe; Avet‐Loiseau, Hervé; Attal, Michel; Anderson, Kenneth C.; Munshi, Nikhil C.

doi:10.1056/nejmoa2204925

Cited by 242 publications

(226 citation statements)

References 38 publications

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“…Patients in Phase B were randomized to receive either CART-BCMA alone or CART-BCMA + huCART19. Phase B patients who were eligible for autologous stem cell transplant (ASCT) elected to defer ASCT to a future line of therapy, a practice which previous phase-three trials indicate is associated with similar overall survival (13,14), but underwent hematopoietic stem cell collection prior to CAR T cell infusion to preserve ASCT as a future treatment option. All subjects were required to be responding to their current therapy, defined as at least a minimal response by IMWG criteria, but have some persistent detectable disease by serologic markers, bone marrow biopsy, or imaging.…”

Section: Methodsmentioning

confidence: 99%

Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy

Garfall

Cohen

Susanibar-Adaniya

et al. 2022

Blood Cancer Discovery

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We conducted a phase 1 clinical trial of anti-BCMA CAR T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third- or later- line therapy (Phase A, N=10) or high-risk patients responding to first-line therapy (Phase B, N=20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade CRS and only one instance of low-grade neurologic toxicity. Among 15 subjects with measurable disease, 10 exhibited PR or better; among 26 subjects responding to prior therapy, 9 improved their response category and 4 converted to MRD-negative CR/sCR. Early maintenance therapy was safe, feasible, and coincided in some patients with CAR T cell re-expansion and late-onset, durable clinical response. Outcomes with CART-BCMA + huCART19 were similar to CART-BCMA alone. Collectively, our results demonstrate favorable safety, pharmacokinetics, and antimyeloma activity of dual-target CAR T cell therapy in early lines of multiple myeloma treatment.

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Section: Methodsmentioning

confidence: 99%

Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy

Garfall

Cohen

Susanibar-Adaniya

et al. 2022

Blood Cancer Discovery

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Section: Tam-targeted Therapeutic Strategiesmentioning

confidence: 99%

“…In mouse MM models, lenalidomide was proven to promote M2 macrophage depletion and affected the Th1/Th2 balance (129). The effect of adding ASCT to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]) in patients with multiple myeloma was associated with longer progression-free survival than RVD alone in a phase 3 clinical trial (NCT01208662) (130). Martino et al reported a retrospective multicenter analysis of 600 RRMM patients treated with the combination of lenalidomide and dexamethasone (KRd) with a 79.9% overall response rate after a median of 11 KRd cycles (131).…”

Section: Tam-targeted Therapeutic Strategiesmentioning

confidence: 99%

Role and Mechanisms of Tumor-Associated Macrophages in Hematological Malignancies

Yang

et al. 2022

Front. Oncol.

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Mounting evidence has revealed that many nontumor cells in the tumor microenvironment, such as fibroblasts, endothelial cells, mesenchymal stem cells, and leukocytes, are strongly involved in tumor progression. In hematological malignancies, tumor-associated macrophages (TAMs) are considered to be an important component that promotes tumor growth and can be polarized into different phenotypes with protumor or antitumor roles. This Review emphasizes research related to the role and mechanisms of TAMs in hematological malignancies. TAMs lead to poor prognosis by influencing tumor progression at the molecular level, including nurturing cancer stem cells and laying the foundation for metastasis. Although detailed molecular mechanisms have not been clarified, TAMs may be a new therapeutic target in hematological disease treatment.

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“…In the FORTE trial, patients who received KRD induction followed by ASCT had a slightly higher MRD negativity rate compared to patients treated with 12 cycles of KRD without ASCT [14]. In the DETERMINATION trial, which also compared RVD vs. RVD followed by ASCT, the PFS was similar in patients who achieved MRD negativity in both groups [61]. Additionally, as three-and four-drug induction therapies are becoming increasingly effective and resulting in high MRD-negative rates (Figure 2), it is important to continue discussing and further personalizing upfront ASCT to avoid overtreatment and possible toxicities especially in the non-high-risk patient population.…”

Section: Mrd-driven Therapymentioning

confidence: 99%

Minimal Residual Disease in Multiple Myeloma—Current Approaches and Future Clinical Implications

Akhlaghi

Firestone

Hultcrantz

2022

Hemato

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The prognosis and clinical outcomes for patients with multiple myeloma have improved significantly over the past two decades. A substantial number of patients now achieve complete remission after induction therapy, and more sensitive methods are needed to assess response. Minimal or measurable residual disease (MRD) has been incorporated in many clinical trials as well as in clinical practice. The importance of MRD assessment and correlation between MRD negativity and prolonged progression-free and overall survival has been confirmed in numerous clinical trials and several meta-analyses. Recent studies have even suggested that MRD negativity can partly overcome the impact of the negative prognostic factors such as high-risk cytogenetics or adverse revised international scoring system (R-ISS) stage. MRD can be measured in the bone marrow via imaging and via emerging blood-based techniques. The most common methods are multicolor flow cytometry and next-generation sequencing of bone marrow samples. Using these methods in optimal settings, MRD negativity with a sensitivity level of 10−6 can be detected. In this review, we discuss the benefits and limitations of these techniques as well as the clinical implications.

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Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma

Cited by 242 publications

References 38 publications

Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy

Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy

Role and Mechanisms of Tumor-Associated Macrophages in Hematological Malignancies

Minimal Residual Disease in Multiple Myeloma—Current Approaches and Future Clinical Implications

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