Beyond protein degradation, the diverse biological activities of thalidomide are discussed, including modulation of cytokines, angiogenesis, and immune signaling pathways. Collectively, thalidomide exemplifies how mechanistic insight, synthetic innovation and careful risk-benefit evaluation can transform a once-discarded molecule into a cornerstone of contemporary drug design.

Post-ASCT2 maintenance, particularly with lenalidomide or carfilzomib-based regimens, significantly prolonged disease control in randomized and real-world studies. In the modern treatment landscape, second or salvage autologous transplantation remains a valid, safe, and effective strategy for carefully selected patients with relapsed multiple myeloma, particularly those with chemosensitive disease and prolonged initial remissions. ASCT2 should be integrated in a risk-adapted manner alongside maintenance therapy and emerging immunotherapies, serving as a durable consolidation or bridging approach rather than routine therapy for all relapsed patients.

Co-treatment of BoHV-1 with either bortezomib or lenalidomide increased anti-MM cytotoxicity. Finally, BoHV-1 upregulated CD38 on both MM cells and immune effectors, thereby increasing sensitivity to the anti-CD38 daratumumab. These findings establish BoHV-1 as a promising immunovirotherapy agent, effective as a single agent and in combination strategies, by coupling direct oncolysis with broad immune remodeling of the BM microenvironment.

Immunomodulatory imide drugs (IMiDs) like lenalidomide and pomalidomide are effective in treating multiple myeloma (MM) but pose hematotoxicity risks by degrading neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3). Moreover, we have identified a CRBN ligand that mitigates these safety liabilities and can be effectively incorporated into PROTACs. This advancement provides a promising path toward safer preclinical development of PROTACs, especially as the field expands into chronic disease treatments beyond oncology.

Competitive inhibition experiments using excess MA or lenalidomide, along with MLN4924 treatment, validated the requirement for ternary complex formation and cullin-RING E3 ligase pathway dependence. P4 effectively downregulates the IL-6/JAK2/STAT3 signaling axis and simultaneously activates dual apoptotic pathways: intrinsic mitochondrial apoptosis (decreased Bcl-2, XIAP, survivin; increased Bax, cytochrome c, cleaved caspases) and ER stress-mediated apoptosis (elevated IRE1, BIP, ATF4, CHOP, p-JNK1, cleaved caspase-12). This work establishes P4 as a promising JAK2-targeting degrader whose anticancer efficacy derives from coordinated target elimination, oncogenic pathway suppression, and dual apoptotic pathway activation, validating natural product PROTACylation as a viable strategy for developing multifunctional anticancer therapeutics.

Subsequent genetic or epigenetic alterations render leukemogenesis independent of ongoing lenalidomide exposure. Altogether, these data define IDH2mt B-ALL as a distinct molecular subtype that is markedly overrepresented after lenalidomide treatment and highlight clonal hematopoiesis as a key contributing factor in the development of LenB-ALL.

These data provide a rationale for the combination of lenalidomide with IL-2 family of cytokines to enhance the effectiveness of NK cells.

P1/2, N=55, Completed, University of Chicago | Active, not recruiting --> Completed

Potential therapeutic agents (e.g. capivasertib, lenalidomide) were predicted, and lenalidomide may represent a feasible initial treatment option for PTCL, with an objective response rate (ORR) of 40.0% and a maximum survival duration exceeding 50 months. NET-RGs play crucial roles in diagnosis, prognosis, and TME regulation, and lenalidomide, a putative TNF-targeting agent, may represent a feasible initial treatment option in PTCL.

P3, N=180, Active, not recruiting, University of Chicago | Trial completion date: Nov 2026 --> Nov 2027 | Trial primary completion date: Nov 2025 --> Nov 2027

Herein, we report the synthesis of lenalidomide (63% overall yield) and pomalidomide (62% overall yield) using an integrated continuous flow platform with residence times of 42 minutes and 52 minutes, respectively. The products are obtained without the need for column chromatography, and both immunomodulatory imide drugs (IMiDs) can be accessed from a common intermediate through our developed route. Furthermore, we explore the synthesis of CRBN ligand-linkers under continuous flow, affording a series of derivatives with diverse properties in yields exceeding 90%.