The 55th Annual Meeting of the American Society of Hematology (ASH) was held in the United States, where hematologists from around the world gathered for the annual academic event. The Congress held several presentations and poster sessions around the latest advances in the field of hematology, and published the latest results of a large number of relevant studies. Among them, multiple myeloma (MM) remained a hot topic of discussion, mainly concerning the efficacy of the new drug bortezomib (Vanco) in the treatment of MM, exploring the risk factors of MM patients and the treatment of high-risk patients, and discussing some of the remaining challenges in the treatment of MM.
I. Significant progress in the treatment of myeloma
In the past decade, the treatment of MM has been greatly improved by the development of new drugs and their successful use in all stages of the disease. 1998 data showed that the 5-year overall survival (OS) rate of MM patients treated with melphalan + prednisone (MP) was 24%. In 2012, the 5-year OS rate for MM patients treated with Total Treatment Option 3 (TT3) was 73%.
Researchers from Mayo Medical Center (Mayo Clinic), who analyzed 1,056 newly diagnosed MM patients from January 1, 2001 to December 31, 2010, again confirmed that the use of a new drug (Vanco)-based regimen consistently prolonged patient survival (abstract number: 3972). Patients had a median OS period of 5.4 years and the median OS period was significantly longer in patients in the second 5 years (2006-2010) than in patients in the first 5 years (2001-2005) (not reached vs. 4.6 years, P < 0.001). In particular, the latter 5-year OS rate was significantly higher in MM elderly (>65 years) patients than in the first 5-year OS rate (56% versus 31%, P < 0.001).
II. Therapeutic goals of myeloma
Since MM is a disease with recurrent progression and can eventually lead to patient death, whether to pursue a cure or a prolonged remission remains a topic of clinical debate. Italian researcher Prof. Palumbo found that achieving complete remission (CR) was significantly associated with prolonged progression-free survival (PFS) and OS after a long-term follow-up (more than 70 months) and could be an independent predictor of long-term outcome. Thus, CR rates are critical in high-risk MM patients, and the pursuit of high-quality remission has been well established in long-term clinical practice.
Notably, although PFS is a common clinical trial endpoint, studies point out that it is currently poorly suggestive when choosing a treatment modality and does not truly represent clinical benefit (OS or patient quality of life). This is because many clinical studies have shown that there is a PFS benefit but not an OS benefit in patients. Toxicity, patient quality of life, prognosis, and patient economic burden should be more fully considered when selecting a treatment regimen.
III. Reflections on treatment strategies
1 transplant or 2 transplants Studies have shown that patients with 2 transplants have a longer PFS period (31 months vs. 24 months), but no significant difference in OS rates (54% vs. 55%).
2-times tumor incidence The highest rates of 2-times tumor incidence in MM therapy were observed with immunomodulator combined with melphalan regimens. Clinical studies have now confirmed that lenalidomide treatment increases the risk of secondary tumorigenesis and should be considered in a comprehensive manner when selecting a treatment regimen.
Drug selection in special populations Based on a comparison of several different combination regimens, for younger patients, the investigators recommend a proteasome inhibitor (Vanco) based combination regimen. For older patients, a bortezomib (VANCOUVER)-based combination regimen achieved a higher proportion of patients in CR and partial remission (PR) or higher, and had longer PFS and OS periods than a combination regimen without bortezomib (VANCOUVER).
Long-term maintenance therapy A meta-analysis showed that α-interferon maintenance therapy moderately prolonged PFS with little or no OS benefit, while corticosteroid maintenance therapy prolonged remission with no improvement in survival. The effect of long-term maintenance therapy with new drugs on patient OS has not been clarified.
IV. Clinical benefits of Vanco
1. Induction therapy
Several studies have confirmed that bortezomib-based induction therapy regimens are a better option for patients with rapid reduction in tumor load and faster achievement of PR and CR (Figure 1).
Prof. Cavo reported on a study of 1894 European patients carrying high-risk cytogenetic abnormalities in MM treated with autologous hematopoietic stem cell transplantation (ASCT) (abstract number: 749) to compare the benefit of induction therapy. The results showed that the bortezomib (Vanco)-based combination regimen group had a significantly higher CR rate after induction than the control group (14.5% versus 4%, P < 0.001) and a significantly longer median PFS period (41.5 months versus 33 months, P < 0.001). A significant benefit in median PFS duration was also seen in patients with t(4;14) and 17p deletion (36 months versus 24 months, P=0.001) and in patients with 17p deletion only but not t(4;14) (27 months versus 19 months, P=0.014). The study also showed that performing ASCT was also an independent factor in significantly prolonging the PFS period in patients with t(4;14) and 17p deletion, but the benefit on OS needs to be observed for a longer period of time.
2. Consolidation therapy
Previous studies have shown that taking consolidation therapy after ASCT can lead to further remission and improve the remission rate. In Prof. Cavo’s study, for example, 5% of patients went from PR to CR and 40% went from very good partial remission (VGPR) to CR; similar results were obtained in Prof. Ladetto’s study, where 39% of patients with VGPR were treated with VTD regimen (Vanco+Salidomide+Dexamethasone). + dexamethasone) could deepen remission to CR after consolidation therapy.
3.Maintenance therapy
Previous studies have shown that maintenance therapy can be administered at low doses for a longer period of time to maintain the efficacy that patients have achieved. Whether the combination regimen is based on proteasome inhibitors or immunomodulators, or interferon maintenance therapy, it can prolong the PFS period of patients. The benefit of proteasome inhibitors has been confirmed in the literature in terms of prolonging patients’ OS. However, the ability of maintenance therapy, especially immunomodulator-based maintenance therapy, to prolong OS period is still a controversial topic.
An Italian multicenter phase III clinical study (abstract number: 200) included 511 patients with newly diagnosed MM, divided into a bortezomib + melphalan + prednisone + thalidomide (VMPT) induction therapy followed by bortezomib + thalidomide (VT) maintenance therapy (VMPT-VT) group and a bortezomib + melphalan + prednisone (VMP) induction therapy alone group, treated for 9 cycles , with a mean follow-up of 47.2 months. The results showed that patients in the VMPT-VT group had a significantly higher 5-year OS rate than those in the VMP group (59.3% versus 45.9%, P=0.04) and a 26% reduction in the risk of death (Figure 2). The benefit in 5-year OS rate was more significant in patients <75 years of age and in those who achieved CR after induction therapy (67.8% versus 49.9%, P=0.01, Figure 3; 81.4% versus 48.2%, P=0.006, Figure 4).
Further analysis of patients who completed induction therapy showed a significantly higher 4-year OS rate (64.6% versus 49.7%, P=0.02) and a 33% lower risk of death in patients who were subsequently treated with VT (vancomycin + saridomide) maintenance therapy compared with induction therapy with VMP (vancomycin + marfalan + prednisone) alone. In addition, the relapse rate was lower in the VMPT-VT (treatment: Vanco + Marfalan + prednisone + saridomide – follow-up maintenance: Vanco + saridomide) treatment group (49% vs. 70%), but survival after relapse did not differ between the two groups. the median duration of VT maintenance treatment was 23.8 months, and the incidence of adverse events was similar to that of the general population. VMPT-VT was recommended as the new standard of care due to a 37% reduction in the risk of death in the 65 to 75 year old age group.
A randomized phase III clinical study in Spain compared the efficacy of three different maintenance regimens (vanco + thalidomide, thalidomide or interferon-α2b) after patients underwent ASCT (abstract number: 334). The study included 266 patients (≤65 years) with newly diagnosed MM who were given ASCT and then divided into 3 different maintenance treatment groups with a median follow-up of 34.9 months. The results showed that the addition of bortezomib to the maintenance regimen significantly prolonged the PFS period of patients and did not show a significant increase in adverse effects.