Bone marrow Ki-67 index is of prognostic value in newly diagnosed multiple myeloma.

BACKGROUND: Ki-67 is an index of proliferative activity and is an established predictive and prognostic marker in multiple malignancies. However, its prognostic relevance in multiple myeloma (MM) is unclear. We investigated the relationship between Ki-67 expression and survival outcomes in MM in the era of novel therapies. METHODS: We interrogated our database to identify patients with MM, newly diagnosed between July 1, 2013 and December 31, 2020, with Ki-67 expression assessed by immunohistochemistry (IHC) on bone marrow biopsies. Using an established threshold of 5% we defined Ki-67low (≤5%) and Ki-67high (>5%) subgroups for association with progression-free survival (PFS) and overall survival (OS). RESULTS: Of 167 patients included: 53 (31.7%) had Ki-67high and 114 had Ki-67low. More patients with R-ISS 3 had Ki-67high (22.2% vs. 9.7%). The gain of 1q21 was overrepresented in the Ki-67high group (28% vs. 8%). Median PFS in the Ki-67low group was 3.1 years, and in the Ki-67high group 1.6 years (log-rank p < .001, HR: 1.9). Median OS was not reached in the Ki-67low vs. 4.8 years in the Ki-67high cohort (HR: 1.9; log-rank test: p = .018). In the multivariable modeling, after adjusting for other risk factors, HR for Ki-67high versus Ki-67low was 2.4 (p < .001) for PFS and 2.1 (p = .026) for OS. CONCLUSIONS: Our results demonstrate that a high Ki-67 index (>5%) is an independent prognostic marker associated with worse OS and PFS in newly diagnosed MM. IHC staining for Ki-67 on bone marrow biopsies could be easily adopted as a prognostic biomarker for MM in economically constrained healthcare settings.

Standardizing Clinical Workflow for Assessing Minimal Residual Disease by Flow Cytometry in Multiple Myeloma.

INTRODUCTION: Minimal residual disease (MRD) status is an established prognostic biomarker for patients with multiple myeloma. Commonly used MRD testing techniques such as next generation sequencing or next generation flow cytometry can detect as little as one or two multiple myeloma plasma cells in 106 normal bone marrow cells. Early pull of bone marrow aspirates (BMA), necessary to achieve such level of sensitivity, can be difficult to secure in routine clinical practice due to the competing need for early pull samples for clinical response assessment, therefore introducing the risk of analytical interference during MRD testing. METHODS: To overcome this challenge, we standardized our workflow for collecting specimens by using a technical first pull after needle repositioning for MRD testing. To capture a comprehensive picture of MRD assay performance and specimen adequacy, we tested for MRD on 556 technical first pull bone marrow aspirates by next generation flow cytometry. Among the specimens, several key multiple myeloma treatment milestones were represented: end of induction therapy, two to three months post-autologous stem cell transplant, early and late stages of maintenance therapy. RESULTS: By using the technical first pull bone marrow aspirate, we achieved an analytical assay input of 10 million nucleated cells for 97.5% of specimens. Our analytical sensitivity reached 10-6; (i.e., 10 multiple myeloma plasma cells in 10 × 106 bone marrow cells). Twenty-four percent of specimens were significantly hemodiluted. Low assay input or hemodilution quantifiably lowered the assay sensitivity. CONCLUSION: Specimen adequacy is, therefore, an important metric to incorporate into MRD status reporting.

Transition from Intravenous to Subcutaneous Daratumumab Formulation in Clinical Practice.

INTRODUCTION: Daratumumab is an anti-CD38 monoclonal antibody widely used for treating patients with newly diagnosed or relapsed/refractory multiple myeloma. The subcutaneous formulation of daratumumab was developed with the purpose of minimizing the treatment burden (to patients and health care system) associated with intravenous daratumumab. Given its recent approval, there is a knowledge gap regarding the best practices that should be instituted for safe administration of subcutaneous daratumumab. METHODS: A retrospective chart review was performed from August 2020 until November 2020 to identify patients either switched to or treated upfront (daratumumab naive) with any subcutaneous daratumumab-based treatment regimen. All patients received appropriate premedications per institutional standards of care. The study end points were to report real-world data regarding administration-related reaction rates (at or following discharge from infusion center), as well as compare their incidence rates to those noted in the COLUMBA study (historical cohort). RESULTS: The study included 58 patients, of whom 38% (n = 22) were daratumumab naive. The majority (84%, n = 49) received subcutaneous daratumumab in combination with various antimyeloma regimens. There were no cases of administration-related reactions at infusion center or after discharge irrespective of previous exposure to intravenous daratumumab. None of the patients included herein required rescue home medications or visited the emergency department within 24 to 48 hours after subcutaneous daratumumab administration. These translated into a significant difference in incidence of administration-related reactions compared with historical cohort (0% vs. 13%, P = .003). CONCLUSION: Subcutaneous daratumumab was extremely well tolerated and could be safely administered without need for monitoring or rescue home medications.

Evaluation of Montelukast for the Prevention of Infusion-related Reactions With Daratumumab.

BACKGROUND: Daratumumab is an anti-CD38 monoclonal antibody indicated for the treatment of multiple myeloma. Infusion-related reactions (IRRs) are among the most common adverse events associated with daratumumab. IRRs are most common with the first infusion of daratumumab. Recommended premedications to be given prior to the daratumumab dose include acetaminophen, diphenhydramine, and a corticosteroid. There is emerging data to suggest that the addition of montelukast to this premedication regimen can lower the incidence of daratumumab-related IRRs. PATIENTS AND METHODS: This was a single-center, retrospective chart review conducted at a large, multistate health system with several different hematology/oncology practice sites. Eligible patients included those with a primary diagnosis of a plasma cell disorder who received at least 1 dose of daratumumab. The primary outcome was the incidence of IRRs with the first daratumumab infusion. RESULTS: A total of 141 patients receiving daratumumab-based therapy were included in this study. All patients received acetaminophen, diphenhydramine, and a corticosteroid as premedications prior to the first infusion of daratumumab. Overall, 46 (33%) patients experienced an IRR with the first infusion of daratumumab. The incidence of IRR was lower in patients that received montelukast as a premedication compared with those that did not (montelukast, n = 25 [27%]; no montelukast, n = 21 [45%]; P = .0371). Patients in each arm experienced similar rates of overall, composite pulmonary, gastrointestinal, and systemic IRR manifestations. CONCLUSION: The use of montelukast prior to the first daratumumab infusion led to a reduction in the incidence of IRRs in our experience.

Ex vivo efficacy of BCMA-bispecific antibody TNB-383B in relapsed/refractory multiple myeloma.

TNB-383B is a fully human BCMA-targeting T-cell engaging bispecific monoclonal antibody (T-BsAb). We assessed ex vivo efficacy of this drug to mediate killing of bone marrow mononuclear cells (BMMCs) freshly isolated from 10 patients with relapsed multiple myeloma (MM). BMMC were treated ex vivo with TNB-383B at doses ranging from 0.001-1 µg. Plasma cell (PC) lysis, viability, BCMA expression, CTL distribution, and degranulation were assessed by flow cytometry. Cytokine response to TNB-383B was quantified by multiplex protein assay. Dose-dependent PC lysis was triggered in all cases by TNB-383B at doses as low as 0.001 µg (P = .0102). Primary MM cells varied in BCMA expression. High BCMA+ PC count correlated with increased PC lysis (P = .005) and significant CTL degranulation specific to TNB-383B treatment (P = .0153 at 1 µg). High E:T ratio in bone marrow specimens led to lower viable and higher apoptotic PC compared with low E:T ratio (P < .001). Three cytokines were significantly modulated by TNB-383B: IL-2/TNFα increased by ∼4 ± 3.5-fold average (P < .005 at 1 µg) and IP10 increased by ∼50 ± 15-fold (P < .001 at 1 µg). We conclude that TNB-383B triggers primary PC lysis and CTL degranulation in a dose-dependent fashion ex vivo with no T cell expansion and mild increase of CRS-associated cytokines.