CD38 Antibodies Keep Adenosine High in Myeloma Bone Marrow Despite Treatment
New research shows daratumumab and isatuximab paradoxically sustain immunosuppressive adenosine signaling in multiple myeloma patients during therapy.
Summary
Multiple myeloma drugs daratumumab and isatuximab target CD38, a surface enzyme on malignant plasma cells. A new study finds that instead of shutting down adenosine production, these antibodies actually promote NAD+ degradation into ADPR in lab tests, while adenosine levels in bone marrow remain in the immunosuppressive micromolar range throughout treatment. Inosine — adenosine's breakdown product — progressively accumulates, but this fails to fully clear the immunosuppressive signal. The findings suggest that CD38-targeted antibodies leave a tolerogenic bone marrow niche largely intact, potentially explaining treatment resistance and supporting the rationale for combining these drugs with adenosine pathway inhibitors.
Detailed Summary
Multiple myeloma (MM) is an incurable blood cancer in which malignant plasma cells thrive within an immunosuppressive bone marrow (BM) niche. CD38, highly expressed on these cells, is not merely a tumor marker — it is a multifunctional enzyme that degrades NAD+ into ADPR, which is then sequentially processed by CD203a and CD73 to generate adenosine (ADO), a potent immunosuppressive molecule that silences T cells and NK cells via A2A/A2B receptors. Two approved CD38-targeting antibodies, daratumumab (DARA) and isatuximab (ISA), have transformed MM treatment but resistance remains common and poorly understood.
This study investigated three interconnected questions: how CD38 enzymatic activity is altered when these antibodies bind to the receptor; what happens to NAD+ metabolism and its products in MM cell lines and primary MM cells in vitro; and how adenosine and its metabolite inosine (INO) evolve in the bone marrow and peripheral blood of MM patients receiving DARA monotherapy over time.
Surprisingly, in vitro experiments with both DARA and ISA demonstrated that antibody binding actually promoted NAD+ degradation and led to ADPR accumulation rather than suppressing CD38 enzymatic activity. In the in vivo arm, BM adenosine concentrations remained persistently in the micromolar range — well above the activation thresholds for P1 purinergic receptors — throughout DARA treatment, declining only modestly. Meanwhile, inosine progressively increased and the BM-to-peripheral blood gradient for ADO gradually attenuated, consistent with ongoing adenosine deaminase (ADA)-mediated clearance rather than true suppression of production. The authors attribute sustained ADO production to residual CD38 activity on microvesicles released from MM cells and by reduced surface CD38 expression from antibody-driven internalization rather than complete enzymatic silencing.
These findings carry important mechanistic implications: even as DARA depletes CD38-positive tumor cells and immune-regulatory subsets, the adenosinergic metabolic network remains substantially active in the BM. This sustained immunosuppressive ADO milieu may blunt the therapeutic immune response, fostering T cell dysfunction and a tolerogenic niche that promotes immune evasion and eventual resistance. The study provides a biochemical rationale for combining CD38-directed antibodies with adenosine pathway antagonists — such as A2A/A2B receptor blockers, CD73 inhibitors, or ADA inhibitors — to fully mobilize antitumor immunity.
The work is notable for connecting in vitro enzymatic biochemistry with longitudinal in vivo metabolomics in actual MM patients, though the patient cohort is small and the study was not designed to correlate adenosine dynamics directly with clinical response or resistance endpoints.
Key Findings
- Both DARA and ISA promoted NAD+ degradation and ADPR accumulation in MM cells in vitro, not enzymatic inhibition.
- Bone marrow adenosine remained in the immunosuppressive micromolar range throughout daratumumab monotherapy.
- Inosine progressively increased during treatment, reflecting adenosine deaminase activity rather than reduced adenosine production.
- The BM-to-peripheral blood adenosine gradient gradually attenuated but did not normalize during therapy.
- Microvesicles bearing CD38 may sustain adenosinergic activity even as surface CD38 declines on tumor cells.
Methodology
In vitro NAD+ metabolism was assessed by HPLC in primary MM cells and the LP-1 cell line exposed to DARA or ISA. In vivo, paired bone marrow and peripheral blood plasma from relapsed/refractory MM patients on DARA monotherapy (16 mg/kg) were analyzed longitudinally for adenosine and inosine concentrations. Microvesicle phenotyping was performed by differential centrifugation and flow cytometry from BM plasma of seven patients.
Study Limitations
The in vivo patient cohort is small (7 patients for microvesicle analysis) and the study lacks direct correlation between adenosine dynamics and clinical response or progression. The phase 1/2 DARA monotherapy trial was not randomized, limiting causal inference. Additionally, the contribution of non-MM cells in the BM niche to total adenosine production was not fully resolved.
Enjoyed this summary?
Get the latest longevity research delivered to your inbox every week.
Enter your email to subscribe: