To the Editor:

The introduction of high-dose melphalan followed by autologous stem cell transplantation (ASCT) for patients with newly diagnosed multiple myeloma (NDMM) improved overall responses and their depth, prolonged progression-free survival (PFS), and increased overall survival (OS). ASCT has become the therapy mainstay in transplant-eligible MM patients. In the late 1990s, tandem ASCT (T-ASCT) was proposed for NDMM management [1], albeit the results of these studies were inconclusive [2,3,4].

The arrival of novel agents, including proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies, has dramatically improved patient outcomes. However, while ASCT performed following induction with a combination of lenalidomide, bortezomib, and dexamethasone was shown to delay MM progression, this did not prolong OS [5].

Since ASCT is still considered one of highly effective anti-myeloma therapies and T-ASCT has become rarely used these days, the current retrospective study (IRB approval #0110-13RMB) assessed T-ASCT efficacy at an over 20-year follow-up in consecutive NDMM patients who underwent this procedure at a tertiary-care centre in the pre-novel agent era (1998–2006).

During the evaluated period, 68 [57%; median age 55 years (33–66)] out of 119 autografted patients received T-ASCT and were included in the analysis. According to the international staging system (ISS), 23 (33.8%) patients had MM stage I, 15 (22%)—stage II, 8 (11.8%)—stage III, and 22 (32.4%)—unknown stage. Thirteen patients (22%) had haemoglobin levels <10 g/dl, 7 patients (11.7%) had creatinine levels >2 mg/dl and 5 patients (8.6%) had calcium levels >11.5 mg/dl.

All patients received induction therapy with vincristine, doxorubicin and dexamethasone (VAD) (mean 3.3 cycles) prior to the first ASCT. Twenty-two (32%) patients additionally underwent radiation therapy. Eight patients (11.7%) did not respond to the first-line VAD therapy and received salvage treatment pre-ASCT.

Post-induction SC collection was performed with high-dose cyclophosphamide in combination with G-CSF. Patients underwent the first ASCT after a median of 6 months (3.1–38.2) from diagnosis; none of them progressed or received further myeloma treatments before the second ASCT. The median period between two transplantations was 4.5 months (3.1–9.4). Administration of high-dose melphalan (140–200 mg/m2 depending on the renal function) was followed by reinfusion of a median of 12.9 × 106/kg of CD34+cells/kg in the first transplant and 11.3 × 106/kg in the second transplant.

Hematopoietic reconstitution was comparable in both transplants, with no significant differences in the median time to engraftment of either neutrophils (10 vs. 10 days) or platelets (13 vs. 12 days). The same pattern was revealed in hospitalization duration [14.5 (10–27) vs. 14 (9–48) days; p = 0.73]. Grade 3–4 treatment-related toxicity was observed in three patients after the first transplant and in nine patients after the second one (p = 0.32). Two therapy-related deaths occurred 6 and 8 weeks after the second ASCT due to acute respiratory failure.

Overall response rate (ORR) to induction was 71.6%; 18.3% of patients demonstrated a very good partial response or better (≥VGPR). ORR improved after the first ASCT (93.4%; 54.1% ≥VGPR) and further increased after the second transplant (98.6%; 76.2% ≥VGPR) (Fig. 1a). Notably, since bortezomib was approved for the use in MM progression on prior therapy only in 2003, most of our patients were exposed to novel agents years after the second transplant, which emphasizes the impact of T-ASCT on survival.

Fig. 1
figure 1

a Overall response rate after induction therapy, first and second ASCT. SD stable disease, MR minimal response, PR partial response, VGPR very good partial response, CR complete response. b Kaplan–Meier curve presenting overall survival. c Kaplan–Meier curve presenting progression-free survival

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The current study with a very long observational period [median 17.2 (11.7–22) years], demonstrated the median OS of 7.7 years (1.0–20.2), with 5-year, 7-year and 10-year rates of 63%, 51% and 39%, respectively (Fig. 1b). The median PFS in the entire cohort was 4.1 years, whereas 25% of patients remained progression-free at 10 years from diagnosis (Fig. 1c). Maintenance treatment with interferon alpha, given to 30 patients (44%) following the second ASCT, had no impact on either PFS or OS. As of the latest follow-up, 18 (26%) patients are alive at a median of 17.5 years (15.2–20.2) and 8 of them (11.7%) have not relapsed. While the majority of patients (60%) died from MM, other causes of death were: secondary malignancies (n = 3; 6%), infections (n = 4; 8%), ASCT complications (n = 2; 4%), allo-SCT complications (n = 3; 6%), amyloidosis (n = 1; 2%) and unknown (n = 7; 14%).

Both uni- and multivariate analyses identified the normal haemoglobin level (≥13.2 g/dl) at diagnosis as the parameter predicting who would survive after a median follow-up of 17.2 years. In univariate analysis, ISS I was also found to predict this result. Patients exhibiting these parameters at diagnosis were defined as having a “low-burden” disease. Age, immunoglobulin type, calcium and creatinine levels as well as response depth post-induction and post-transplant (first or second) did not predict a long-term survival.

The place of T-ASCT in the era of novel agents and continuous anti-myeloma treatment remains debatable [6,7,8]. The Phase III STaMINA trial, comparing single ASCT followed by RVD (lenalidomide–bortezomib–dexamethasone) consolidation with T-ASCT in front-line treatment of MM [6] demonstrated no differences in either PFS or OS between treatment arms. On the other hand, a 10-year follow-up in Phase III trials including bortezomib-based induction showed a T-ASCT advantage in terms of PFS and OS, particularly for high-risk patients with advanced ISS stage, poor cytogenetics and failure to achieve CR [7, 8]. It is unclear whether differences between results of these trials originate from different efficacy of the induction therapy. And if so, can a very effective novel combination induction offset the benefit of T-ASCT for all MM patients?

Our important observation is related to the ability of the second transplant to deepen response to therapy, which is of particular significance given that minimal residual disease (MRD) has emerged as a key treatment target in myeloma [5]. Possibly, in the current era of intensive therapeutic approaches, T-ASCT should be reserved for patients failing to achieve MRD negativity after the first transplant.

In the current treatment paradigm, short-term therapy is replaced by longer-term or even continuous regimens. This increasing complexity of myeloma treatment warrants rigorous efforts to preserve patient quality of life which requires management of side effects of newer regimens. Our results demonstrate that short-term induction followed by T-ASCT could provide long PFS and OS, mainly in MM patients with low-burden disease. A similar observation has been lately reported in an international study [9]. MRD evaluation following T-ASCT could provide more precise identification of low-burden MM patients who might benefit from less toxic, shorter maintenance therapy.

While increased life expectancy of MM patients raises concerns about a long-term risk of second primary malignancies (SPMs), in our study, SPM-related death rate was low (4%) [10].

The current study, with a very long-term follow-up, demonstrates that low-burden MM patients at presentation may benefit most from T-ASCT, as reflected by their prolonged survival. Our findings suggest that a short-term first-line treatment, including induction followed by T-ASCT, for low-risk MM patients could be an alternative to a continuous anti-myeloma therapy, with its potential toxicity.