Multiple myeloma (MM) is a malignant disease of monoclonal plasma cells. In recent years, the application of new drugs such as the proteasome inhibitor bortezomib and the immunomodulatory agents thalidomide and lenalidomide has not significantly improved the overall survival time compared with the conventional VAD regimen, despite the partial improvement of remission rate and disease-free survival time in MM patients, and the treatment still faces great challenges. In this paper, we intend to give a brief review on the molecular genetic characteristics of MM, induction chemotherapy, consolidation and maintenance therapy, the value of allogeneic hematopoietic stem cell transplantation and the treatment of relapsed refractory MM. 1. Cytomolecular genetics and prognosis One of the pathogenesis of MM is the dysregulation of cyclin D gene expression directly or indirectly caused by genetic or genetic abnormalities. According to the type of chromosomal abnormality, MM is divided into two genetic subtypes: 1) hyperdiploid type characterized by trisomy 3, 5, 7, 9, 11, 15, 19, 21 of the basal chromosome; 2) non-hyperdiploid type characterized by chromosomal translocations t(4;14), t(14;16) , t(14;20), t(6;14), t(11;14), etc. The prognosis of patients was classified into standard-risk, intermediate-risk, and high-risk according to the cytogenetic and molecular biological alterations of the tumor. High risk is defined as del(17p), t(14;16), t(14;20) and GEP high risk gene expression, intermediate risk is defined as t(4;14), del(13) or subdiploid type, and standard risk is defined as hyperdiploid type, t(11;14), t(6;14). Treatment can be scientifically stratified according to the degree of prognostic risk.1 2. Induction therapy VAD has been used for many years as one of the main induction regimens for MM, and does the VAD regimen still have its application in the current era of bortezomib therapy? In a phase III clinical study, Neben K et al. compared the efficacy of VAD and PAD induction therapy before autologous stem cell transplantation and maintenance therapy with thalidomide or bortezomib, respectively, after transplantation. The results showed that for patients with del(17p13), PFS and OS were significantly prolonged in the group receiving bortezomib-based therapy before and after autologous stem cell transplantation compared with the group receiving standard therapy without bortezomib (median PFS: 26,2m vs. 12m; 3-year OS: 69% vs. 17%). For those without del(17p13), PFS and OS did not differ between the two groups, suggesting that the VAD regimen remains one of the first options for those without del(17p13).2 Avet-Loiseau H et al. found that bortezomib combined with dexamethasone induction therapy improved outcomes (EFS, OS benefit) in patients with t(4;14) MM compared with the VAD regimen, whereas for those with del(17 p) showed no difference in EFS, OS, and the same efficacy for both regimens.3 Harousseau JL et al. compared the efficacy of pre-transplant bortezomib and dexamethasone regimens with the VAD regimen in patients with primary MM and found that CR/nCR, VGPR, and RR were significantly higher in the bortezomib and dexamethasone groups than in the VAD group after induction (p<0,05), but that median follow-up of 32,2m, PFS (36m vs. 29,7m ), and 3-year OS (81, 4% vs. 77, 4%) did not differ between the two groups (P>0, 05).4 A randomized phase III study from PETHEMA/GEM enrolling patients ≤ 65 years of age with primary MM compared the differences in efficacy between VTD (n=130), TD (n=127), and the three regimens alternatively (VBMCP/VBAD/B, n=129). The results showed that VTD had higher CR rates (pre- and post-transplant) and significantly longer PFS (56,2m vs. 35,3m vs. 28,2m) than the other 2 regimens, but no statistical difference in 4-year OS.5 These studies suggest that although bortezomib-containing regimens significantly increase efficiency, high efficiency does not necessarily translate into actual survival benefit, and for many patients the preferred option remains VAD induction regimens. In addition, San Miguel JF et al. compared the efficacy of VMP or MP in 682 previously untreated patients with multiple myeloma without indications for transplantation. The results showed a 31% reduction in the risk of death with VMP compared to MP at a median follow-up of 60,1m (P<0,001), 1% vs. 1% for secondary hematologic malignancies, and 5% vs. 3% for secondary solid tumor incidence. Compared with MP, VMP significantly reduced the risk of death without an increase in secondary malignant events (P<0,05), confirming that bortezomib-containing regimens significantly prolonged OS compared with MP regimens in a specific population.6 3. Consolidation and maintenance therapy Two important clinical observations were made: 1) Some MM patients converted to MGUS (monoclonal gammaglobulin of undetermined significance) after treatment, but had similar survival compared with patients who achieved CR patients but with similar survival compared to those who achieved CR. 2) Patients who could not maintain CR had shorter survival compared to those who did not achieve CR. Therefore, it is important to find predictors of non-sustained CR (relapse within 1 year), such as detection of MRD (microresidual lesions), for consolidation and maintenance therapy. The results showed that 12% of patients failed to achieve sustained CR and that high-risk cytogenetic abnormalities and MRD were independent predictors of non-sustained CR.7 Cavo M et al. evaluated the efficacy of consolidation therapy with bortezomib, thalidomide and dexamethasone (VTD) versus thalidomide and dexamethasone (TD) after autologous stem cell transplantation in patients with primary diagnosis of multiple myeloma. Results showed CR/nCR rates of 73, 1%, 60, 9% in the VTD and TD groups, respectively (P=0, 020); median follow-up was 30, 4m, and 3-year PFS was also significantly different (60% vs. 48%, P=0, 043), but OS was not statistically different indicating that increasing the application of vanco did not increase the OS efficacy of consolidation.8 The MRC Myeloma IX study enrolled 820 Patients who had received induction therapy were divided into a thalidomide maintenance group (n=408 ), a non-maintenance group (n=410), and 2 other cases were withdrawn from the study. There was a benefit in PFS in the thalidomide maintenance group compared with no maintenance treatment (23m vs. 15m, P<0.001), but no significant difference in OS (HR=0.91, 95% CI 0.72-1.17, P=0.40). Stratified analysis based on FISH test results showed that those with favorable FISH results had significantly longer PFS than those without maintenance treatment, but no significant difference in OS, however, for those with unfavorable FISH results, PFS was not statistically different in the maintenance or non-maintenance groups, and those with maintenance treatment had shorter OS than those without maintenance treatment (P=0, 009). The authors also performed a Meta-analysis on the value of maintenance therapy with thalidomide and found a benefit in OS with thalidomide maintenance therapy, but mainly in terms of prolonged long-term OS (e.g., 7-year OS rate).9 A study comparing the maintenance efficacy of bortezomib and thalidomide regimen (VT) with bortezomib and prednisone regimen (VP) in elderly patients with multiple myeloma enrolled in the GEM2005MAS65 study The results showed that the CR rates of VP and VT regimens were 39% and 46%, respectively; the VT regimen also prolonged PFS and OS compared with VP, but the differences were not statistically significant. The authors concluded that these two maintenance therapies can achieve high CR rates, long PFS and acceptable toxicity.10 4. Value of allogeneic HSCT in MM High-dose chemotherapy, autologous HSCT and combination with new generation of anti-myeloma drugs have become the standard of care for young MM patients, however, the role of allogeneic HSCT in MM is still controversial. While there is no doubt that anti-graft-host effects have a therapeutic role in myeloma, should this treatment option be offered as first-line therapy to all myeloma patients? A recent study provides the answer. The study compared the efficacy of donor transplantation with that of non-transplantation in patients with primary multiple myeloma included in the HOVON-50 Multiple Myeloma Study. 260 patients who received induction chemotherapy and autologous stem cell transplantation met the inclusion criteria, of whom 122 received maintenance therapy without a sibling donor and 99 of 138 with a sibling donor actually received allogeneic hematopoietic stem cell transplantation. At a median follow-up of 77 months, CR rates, PFS, and OS did not differ between the two groups (donor vs, no donor).11 Therefore, the authors do not recommend allogeneic HSCT for routine use as first-line therapy for MM. MM is a progressive disease, and after remission with chemotherapy, most patients will eventually relapse, and many patients are resistant to the previously sensitive drugs, so increasing the dose does not allow the patient to achieve remission again, but is prone to bone marrow suppression, complicated by infection, or liver function impairment. Therefore, the treatment of relapsed, refractory MM is mainly based on the use of non-cross-resistant regimens and the development of new proteasome inhibitors. 2012 ASCO meeting reported the progress of the second-generation proteasome inhibitor (Carfilzomib, carfilzomib). Carfilzomib is a tetrapeptide epoxyketide that reverses bortezomib resistance and has been shown to be well tolerated in phase I clinical trials and effective alone or in combination in relapsed or refractory MM. The Phase Ib dose-escalation clinical study of carfilzomib, lenalidomide and low-dose dexamethasone regimen for relapsed or progressive multiple myeloma (PX-171-006) included 40 patients with relapsed, refractory MM who had previously received 1-3 different regimens, 75% of whom had previously received bortezomib and 70% of whom had previously received lenalidomide. The results showed significant efficacy of the regimen with an overall efficacy rate of 62,5%, clinical benefit rate of 75%, and median remission time and PFS of 11,8 m and 10,2 m. The most common adverse effects were fatigue (62,5%), neutropenia (55,5%), and diarrhea (52,5%). No grade 3/4 neurotoxicity was seen.12 Another phase II study of carfilzomib monotherapy for relapsed and refractory multiple myeloma (PX-171-003-A1) had 266 patients evaluable for safety and 257 evaluable for efficacy, receiving a median of 5 lines of chemotherapy, with 95% of patients resistant to the last line of therapy and 80% refractory or resistant to bortezomib and lenalidomide. Treatment was carfilzomib 27 mg/m2 (20 mg/m2 in cycle 1) d1, 2, 8, 9, 15, 16, 1 cycle every 28 days for 12 cycles. The results showed an overall remission rate of 23.7%, median remission time of 7.8 m, and median OS of 15.6 m. Adverse effects were manageable, mainly fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). 12.4% of patients had a combination of grade 1/2 neuropathy.13 Thus, carfilzomib not only has good anti-MM activity, but also has low toxicity, especially overcoming the neurotoxicity of bortezomib. the neurotoxicity of bortezomib, allowing patients to tolerate proteasome inhibitors significantly better. A phase I/II dose-escalation clinical study from a bendamustine, lenalidomide, and dexamethasone regimen (BLD) for relapsed or refractory multiple myeloma enrolled 29 patients with refractory or relapsed disease, median age 63 years (38-80 years), and median number of prior regimens 3 (1-6). The treatment regimen was: bendamustine 75 mg/m2 (d1, d2), lenalidomide 10 mg (d1-21), and dexamethasone 40 mg (weekly) for 28 days in a cycle of no more than 8 cycles. The results showed a PR rate of 52%, VGPR of 24%, and minor remission in another 24% of patients. 1-year OS was 93%, with a median PFS of 6,1 m. Grade 3/4 adverse events were mainly neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. Therefore, BLD regimens for relapsed refractory MM are feasible and highly efficacious.14 Ahn JS et al. compared the efficacy of bortezomib, cyclophosphamide, and dexamethasone in combination or not with thalidomide for relapsed or refractory multiple myeloma. In this retrospective study, 67 patients received Vel-CD and 86 patients received Vel-CTD with an efficiency rate of 88% and 90%, respectively. there was no statistical difference in OS and PFS, but Vel-CTD was more toxic, therefore, Vel-CD is recommended for the treatment of relapsed or refractory MM.15 In conclusion, for relapsed or refractory MM, the treatment should be based on patient age, previous chemotherapy regimen, treatment tolerance, and other individualized treatment options. Tumor-related bone disease, especially osteolytic disease, is a major clinical problem for many cancer patients, including MM. Osteolysis is caused by a pathological imbalance between osteoblasts and osteoclasts in the bone marrow microenvironment. Bortezomib and lenalidomide also have effects on the tumor microenvironment and stimulate osteogenesis by targeting tumor cells in the bone marrow nests.16, 17 Thus, drugs that target the bone marrow microenvironment in MM also have anti-MM effects. In the MRC Myeloma IX trial, zoledronic acid not only reduced the incidence of bone-related events but also prolonged OS.18 Another clinical study comparing multiple myeloma patients randomized to zoledronic acid after high-dose chemotherapy and stem cell transplantation showed significant differences in 10-year PFS (66% vs, 52%, P < 0,001) and 10-year OS (67% vs, 48%, P < 0,001).19 Levels of tumor necrosis factor ligand superfamily member 13B (also known as BAFF) were elevated in the bone marrow fluid of MM patients and mediated the osteolytic effect. Preclinical studies have shown that anti-BAFF monoclonal antibodies neutralize this effect, thereby inhibiting tumor cell growth.20 The favorable efficacy has facilitated clinical trials, and phase I trials have demonstrated the efficacy of anti-BAFF monoclonal antibodies in recurrent MM as well. Myeloma cells secrete DKK-1, a soluble Wnt inhibitor, which downregulates osteogenesis. In a murine MM transplantation tumor model, the anti-DKK-1 monoclonal antibody BHQ880 not only promoted new osteogenesis but also inhibited tumor cell growth.21 Clinical phase I trials are ongoing. In conclusion, for young MM patients (<65 years), CR is the goal of treatment, while for older patients or young patients with severe comorbidities, the goal is to prolong OS and improve quality of life, and to balance between efficacy, toxicity, and cost. Further understanding of the biological features of MM, as well as advances in MM genomics and tumor microenvironment studies at the cellular and animal levels will continue to facilitate the application of effective new individualized drugs in MM patients.