Phase I study of once weekly treatment with bortezomib in combination with lenalidomide and dexamethasone for relapsed or refractory multiple myeloma

Abstract

Proteasome inhibitors (PIs) in combination with immunomodulatory drugs (IMiDs) have been shown to be effective against relapsed/refractory multiple myeloma (RRMM). To determine the optimal dosing schedule of once weekly bortezomib (BTZ) combined with lenalidomide (LEN) and dexamethasone (DEX), especially in the outpatient setting, we conducted a phase I dose escalation study. A 21-day cycle of BTZ 1.3 mg/m(2) on days 1 and 8, LEN 10 mg/day (cohort 1) or 15 mg/day (cohort 2) on days 1-14, and DEX 20 mg/day on days 1, 2, 8, and 9 was administered. Three patients were enrolled in each cohort. No dose-limiting toxicity was observed in either cohort. Although hematological toxicities estimated as >grade 3 were common, non-hematological toxicities of grade 3 or higher were rare. Two cases of newly diagnosed peripheral neuropathy (PN) were observed, while no grade 3/4 PN was observed. Two patients achieved partial response and two achieved stable disease. The recommended doses of BTZ and LEN were determined to be 1.3 mg/m(2) and 15 mg, respectively. Combination therapy of once weekly BTZ with LEN and DEX was well tolerated and shows promise as a regimen for patients with RRMM previously treated with both PIs and IMiDs.

Patient‐reported outcomes of multiple myeloma patients treated with panobinostat after ≥2 lines of therapy based on the international phase 3, randomized, double‐blind, placebo‐controlled PANORAMA‐1 trial

“…Whether the impact of side effects, such as neurotoxicity (which ranks among the most worrisome toxicities for patients with MM [Burnette et al , ]), is offset by improvements in disease‐related symptoms and prolonged progression‐free and overall survival requires further studies with prolonged patient follow‐up over a period of several years. Additionally, accumulating evidence also points toward the ability to improve on the tolerability of established combination regimens for MM, such as by extending the dosing interval for BTZ to once‐weekly administration (Bringhen et al , ; Girnius et al , ; Totani et al , ). PAN, dosed at 10 mg, is being explored with lenalidomide + BTZ + DEX (RVD regimen) based on phase I/II data in the induction setting (Shah et al , ), as promising efficacy and tolerability data for combining PAN with the selective proteasome inhibitor carfilzomib also emerge (Berdeja et al , ).…”

Natural killer-like signature observed post therapy in locally advanced rectal cancer is a determinant of pathological response and improved survival

“…Both of these agents are already established in routine clinical practice in the treatment of hematological malignancies. 15,16 The heatmap shows the relative contribution (or Contribution Fraction) of each individual probes input to the overall score and we can conclude from this that the cancer testis antigen families SPANX and GAGE were the most significant contributors to the connection scores and hence are potential targets for the mechanism of action of the two drugs ( Supplementary Figure 1a). This result prompted us to cluster resection specimens based on the expression of a list of cancer testis antigens genes.…”

“…12 Based on the expression of immune checkpoints such as PDL1, there is rationale for the use of immune checkpoint inhibitors in MSI-H colorectal cancers and although most immune checkpoint inhibitors execute their effects through CD8+ cytotoxic lymphocytes, therapeutic modulation of other immune cell types such as macrophages, myeloid-derived suppressor cells and natural killer cells could have similar effects in the rectal paradigm. [13][14][15] Natural killer cells are cytotoxic lymphocytes of the innate immune system and act as the body's first line of defence against tumor cells. Natural killer cells have been observed to be critical for response to gemcitabine in pancreatic mouse models.…”

“…Lenalidomide and proteosomal inhibitors (bortezomib and carfilzomib) are already in clinical use for the treatment of hematological malignancies and have demonstrated the ability regulate natural killer-cell function. 15,16,[29][30][31][32][33] By analyzing the connections further using the Contribution Fraction capabilities of QUADrATiC, both compounds were shown to have an association with the increased expression of cancer testis/ antigens which are potentially activators of T cell receptor-mediated cytotoxicity, and thus may have a role in therapy-related immunomodulation. 4,5 We hypothesize that using immune-modulating compounds such as lenalidomide and low-dose bortezomib (or the second-generation proteosomal inhibitor Carfilzomib) as single agents or even in combination could prime the natural killer-cellrelated immune system, improving the efficacy of standard chemoradiotherapy.…”

Histone deacetylase inhibitors in plasma cell leukemia treatment: effect of bone marrow microenvironment

“…PCL can arise de novo (primary PCL) or as a leukemic transformation of existing MM (secondary PCL). Despite the progressive treatment approaches comprising novel drugs like proteasome inhibitors (PI) and/ or immunomodulatory drugs (IMIDs) as well as combination chemotherapy [3,4,5] and stem cell transplantation, the disease still remains incurable [6,7,8]. Histone deacetylase inhibitors (HDACi) are promising therapeutic agents for cancer treatment including multiple myeloma [9].…”