1. Introduction
Multiple myeloma (MM) is the second most common hematologic malignancy worldwide, with an estimated annual incidence of 7.1 per 100,000 people [
1]. Treatment options have expanded widely over the past several years, significantly improving outcomes [
2]. For newly diagnosed (ND) eligible patients, the three-drug induction regimens with immunomodulatory (IMiDs), proteasome inhibitors, and dexamethasone followed by autologous stem cell transplantation (auto-SCT) and maintenance treatment have shown significantly improved progression-free survival (PFS) and overall survival (OS) [
3]. Two decades ago, the median survival was approximately three years, and now it is eight to ten years and can be even longer for many patients.
The advent of four-drug regimens has raised the question of whether certain patients would benefit from the addition of another drug. Daratumumab (DARA) is a human IgG monoclonal antibody targeting CD38 on clonal plasma cells with direct on-tumor and immunomodulatory mechanisms of action [
4]. DARA-based combination induction therapy’s clinical efficacy and safety for transplant-eligible NDMM patients was first investigated in the phase II Griffin trial [
5]. The addition of DARA to lenalidomide (R), bortezomib (V), and dexamethasone (d) (D-RVd) improved the depth of response and PFS in this setting of patients. DARA plus V, thalidomide, and d (D-VTd) were validated in the phase III CASSIOPEIA trial, which compared VTd for induction and post-transplant consolidation without or with the anti-CD38 antibody DARA [
6,
7]. The stringent complete response (sCR) rates, measurable residual disease (MRD) negativity, and PFS improved when DARA was added to pre-transplant induction and post-transplant consolidation therapy. Currently, D-VTd represents the standard of care in Europe for transplant-eligible NDMM patients. DARA could be involved in CD38 expression on CD34+ cells, possibly to affect mobilization kinetics and lineage-specific progenitor proliferative capacity, and recent studies have reported a potential reduction in stem cell yields in patients who were exposed to DARA before stem cell mobilization [
8,
9]. This regimen also increased the use of the hematopoietic stem cell mobilizer plerixafor in this population [
10,
11]. Moreover, some recently published studies have reported slower hematopoietic reconstitution after auto-SCT in patients treated with DARA, without an excess of infectious complications, with the limitation that the criteria for defining platelet and neutrophil engraftment were not uniform [
8,
10,
12,
13,
14,
15,
16,
17,
18,
19]. This real-life single-center study aimed to investigate the possible impact of D-VTd induction therapy on hematopoietic engraftment after auto-SCT.
3. Results
The study population included 140 patients. Among these, 60 (43%) were treated with D-VTd (
Table 1). Patients treated with D-VTd significantly differed from those treated with VTd in the number of basal CD34+ infused, either as a continuous variable or as categorized in binary terms (<4 and ≥4 × 10
6/kg). Indeed, the median number of basal CD34+ infused was significantly lower (and the proportion of patients with CD34 <4 × 10
6/kg was higher) in patients treated with D-VTd than those treated with VTd. No differences were found for the remaining variables listed in
Table 1, including disease status.
3.1. Analysis of Outcome Variables by Treatment
The median days to reach neutrophil and platelet engraftment significantly differed between patients in the D-VTd arm (11 and 13 days, respectively) compared with the VTd arm (10 and 12 days, respectively) (
Table 2). In
Figure 1, the number of patients reaching neutrophil engraftment is plotted as a function of days to neutrophil engraftment (ANC ≥ 0.5 × 10
9/L) in the overall group and separately in D-VTd and VTd groups. The highest number of patients achieving neutrophil engraftment was observed on day 11 (
n = 20) in the D-VTd arm and on day 10 (
n = 28) in the VTd arm.
Remarkably, univariable Cox analyses (
Table 3a) show that patients treated with D-VTd had a hazard ratio of neutrophil engraftment that was 42% lower than those treated with VTd (HR: 0.58, 95% CI: 0.41–0.82,
p = 0.002), and these results did not change in multivariable age- and sex-adjusted analysis (
Table 3b). Univariable Cox analyses (
Table 4a) indicate that patients receiving D-VTd treatment and those with micromolecular characteristics displayed significantly longer times to platelet engraftment (HR: 0.62, 95% CI: 0.43–0.89 for therapy, HR 0.46, 95% CI: 0.25–0.83 for myeloma type). Multivariable analysis fully confirmed these results (
Table 4b). The hazard to engraftment for patients affected by the micromolecular type was 57% lower than those with the IgG subtype (HR 0.43, 95% CI: 0.23–0.79) and 37% lower in patients treated with D-VTd compared to those who received VTd (HR 0.63, 95% CI: 0.44–0.92).
3.2. FN, Mucositis, and Diarrhea
Patients treated with D-VTd developed FN more frequently than those in the VTd group. Notably, patients on D-VTd had a lower incidence of a WHO fever > 2 and a higher incidence of WHO diarrhea> 2. The incidence of mucositis tended to be higher in the D-VTd arm (
p = 0.094). Remarkably, patients with FN more frequently had WHO diarrhea > 2 grade (
Table 5). Univariable and multivariable logistic regression analyses confirmed the strong association between D-VTd and FN (
Table 6a and b, respectively). Specifically, the likelihood of developing febrile neutropenia in patients receiving D-VTd was more than twice as high as those treated with VTd (OR 2.24, 95% CI: 1.12–4.47).
A higher WHO diarrhea grade was associated with D-VTd treatment (
Table 2), but unrelated to the remaining baseline characteristics. Univariable and multivariable logistic models confirmed the link between WHO diarrhea grade and D-VTd treatment. Patients receiving D-VTd were eight times more likely to develop grade 2 or higher diarrhea compared to those who did not receive treatment (
Table 7).
No associations were found between D-VTd treatment, mucositis, and the other baseline characteristics.
3.3. Transfusions
The proportion of patients who underwent RBC did not differ between the treatment groups, while patients treated with D-VTd underwent PT more frequently than those treated with VTd. There was no difference in the median number of platelet-transfused patients (
Table 2).
3.4. Discharge
The median number of days to discharge was unaffected by treatment (13 days for both groups;
Table 2), and Kaplan–Meier analysis of time to discharge confirmed this result (median: 13 days, 95% CI: 12.5–13.5 in VTd group; median: 13 days, 95% CI: 12.4–13.6, in D-VTd group) (Log-Rank test
p = 0.99). No patients experienced unexpected side effects during transplantation. In particular, no cardiac, renal, or hepatic toxicities were reported.
During the first 100 days after transplantation, we observed four COVID-19 infections, two in both arms. Patients developed a symptomatology with fever and cough and without respiratory failure, and were treated with specific symptomatic and antiviral drugs, with rapid resolution of the clinical picture. Between 100 and 180 days post-transplant, three patients developed radiologically proven pneumonia with FUO, two in the D-VTd arm. Patients were managed as outpatients with rapid resolution of the picture.No patients died during the first six months of follow-up.
4. Discussion
Eliminating auto-SCT is a topic of discussion among opinion leaders in MM. However, it is not currently advised, and transplant remains a standard of care for eligible MM patients, as recommended by the most recent guidelines [
23]. In 2022, 27,132 auto-SCTs were reported by 689 European centers [
24]. The main indications for auto-SCT were lymphoid malignancies, with MM comprising 57.1% of all auto-SCT indications. Auto-SCT activities for lymphoproliferative disorders increased by +2.4% for MM (+4.8% in 2021) and declined for non-Hodgkin lymphoma by −10.5% (+4.3% in 2021).
Auto-SCT in MM continues to survive and thrive, even in the context of new treatments. This is because every trial comparing transplant to no transplant, even with new drugs, has shown that transplant deepens the response and offers significant benefits [
25,
26,
27,
28,
29]. Auto-SCT was also considered in the trials of DARA-based quadruplets as induction therapy in MM [
5,
6,
7] and in studies investigating other anti-CD38 MoAb-based therapies in the same setting [
30,
31,
32].
While no direct effect on stem cells was observed in vitro, emerging evidence suggests possible dysregulation of CD34+ cell adhesion after DARA treatment. Overall, anti-CD38 monoclonal antibodies appear to interfere with CD34+ cell mobilization, with no apparent clinical consequences during the transplantation phase.
A comparison between the various studies in terms of post-transplant engraftment is difficult because of the different definitions used for platelet and neutrophil recovery. In several studies, platelet engraftment was significantly slower in the DARA group, while no significant differences were reported in other trials [
12,
13,
14,
15,
16,
17]. Similarly, neutrophil recovery was significantly slower in patients treated with DARA in different studies [
8,
10,
18,
19,
20], but not significantly different in others [
13,
18,
33]. The delay in hematopoietic engraftment was typically 1 or 2 days, but all patients achieved hematopoietic recovery. Regarding transfusion requirements, study results are conflicting, showing in some cases the need for increased PT in those who had received DARA [
15]. Additionally, in some trials, DARA-treated patients received more RBC transfusions [
24], while in other studies, transfusion rates were similar between the DARA and control groups [
13,
17].
The rates of neutropenic fever were comparable between DARA and control patients across all studies. No significant differences in severe infections, antibiotic therapy duration, or hospitalization length were observed [
9,
16,
17,
19,
33]. However, Papaiakovou et al. reported longer durations and the need for more lines of antibiotic therapy, higher incidence of septic shock, and prolonged hospitalization in the patients treated with DARA [
15]. This did not translate into higher transplant-related mortality rates. The authors suggested that this excess risk was unlikely to be solely explained by the slight delay in neutrophil recovery, and they hypothesized that DARA might worsen immunosuppression through hypogammaglobulinemia and lymphodepletion.
Our findings indicate that patients treated with D-VTd experienced longer neutrophil and platelet engraftment times than those treated with VTd. Additionally, D-VTd treatment was associated with a higher incidence of febrile neutropenia and grade 2 or higher diarrhea. However, no significant differences were observed in the median number of days to discharge or the incidence of mucositis between the two treatment groups. Despite the study’s limitations and observational design, these results provide valuable insights into the differential effects of D-VTd and VTd treatments. It is important to note that, although the median number of CD34+ cells infused was significantly lower in the D-VTd group compared to the VTd group, the magnitude of this difference was very small from a clinical perspective (D-VTd: 4.6 versus VTd: 4.9). Therefore, it does not explain the differential outcomes observed between patients treated with D-VTd and those treated with VTd. In any case, the number of CD34+ cells infused was considered in all multivariable models as a potential confounder, thus excluding the possibility that this variable could influence the study results.
Although not a goal of this study, we evaluated infectious events that occurred after engraftment for neutrophils and within six months post-transplantation, showing no difference in incidence between the two study groups. We follow the current indications of the European Society for Blood and Marrow Transplantation (EBMT), which recommend revaccination starting between 6 and 12 months after transplant [
34]. To reduce the risk of SARS-CoV-2 infection, the primary immunization schedule consisted of three vaccine doses starting from 3 to 6 months after transplant, followed by a booster dose after 3–4 months from the primary vaccine schedule.
Our study was not aimed at assessing survival, so we did not consider data related to patients’ cytogenetic risk in the statistical analysis. With more mature follow-up, it will be interesting to consider data in terms of PFS and OS, stratifying patients according to cytogenetic features at disease onset.