Disease Treatment
Smoldering MM is not indicated for treatment, but disease progression needs to be monitored because there is no clinical benefit to initiating treatment early. The risk of disease progression is greatest in the first 5 years and then decreases, with an overall risk of disease progression of 10% per year for the first 5 years, 3% per year for the next 5 years, and only about 1% per year for the next 10 years. For high-risk smoldering MM, enrollment in clinical trials is recommended.
End-organ damage is primarily based on CRAB criteria, namely hypercalcemia, renal failure, anemia, and bone destruction, which are associated with plasma cell proliferative disease and cannot be explained by the associated disease.
In addition, treatment of renal insufficiency induced by aggressive myeloma should be initiated before creatinine reaches 177 μmol/L. Renal failure due to MM can be reversed if treated early. When tubulointerstitial nephropathy is identified, appropriate therapeutic measures need to be initiated as soon as possible. Once a patient has achieved remission of renal impairment, the prognosis is similar to that of a patient without renal impairment.
Local disease control and systemic therapy
For isolated bone and extraosseous plasmacytomas, radical radiation therapy is given to achieve a cumulative local dose of 45Gy
and above. Surgical resection of extraosseous damage can be performed if needed. Although cure is the primary goal of treatment for isolated plasmacytoma, the rate of progression to systemic MM is still 30-60% and therefore regular follow-up is required.
In patients with systemic, active MM with end-organ damage, systemic chemotherapy is given to prevent progression and reduce disease-induced symptoms. Patients who achieve very good partial remission (VGPR) and complete remission (CR) after systemic therapy have better long-term survival. Therefore the goal of the new treatment measures is to increase the response rate in all patients. In elderly patients, side effects and quality of life also need to be taken into account, as better remission rates do not necessarily correspond to survival benefits. Surgery and radiation therapy may be considered if bone-related complications arise.
Autologous stem cell transplantation
High-dose myeloablative chemotherapy combined with autologous stem cell transplantation can significantly prolong patient survival compared to conventional cytostatic therapy and has become an important component of MM treatment. Due to its toxic side effects and the older age of most MM patients, a thorough assessment of the patient’s suitability for transplantation is essential.
The most common criteria for considering a patient suitable for transplantation are: patient preference for transplantation, age between 65-70 years, absence of organic cardiopulmonary disease, renal disease, liver function abnormalities, and other uncontrolled complications such as diabetes mellitus.
Eligible patients received marrow clearance after standard first-line induction therapy to achieve remission, and pretreatment with reduced doses of marfalan for elderly patients or patients with substantial organ impairment.
A randomized trial in France found that tandem transplantation was superior to single transplantation, however, this benefit was limited to patients who did not achieve VGPR after initial transplantation.
in patients who did not achieve VGPR after the first transplant. Results from a systematic review showed no significant difference in OS between tandem and single-transplant patients, but the former had higher event-free survival (EFS) and overall response rates.
One reason why most clinical centers are now starting with only single autografts is that the use of current new therapeutic agents in induction therapy can more than double the rate of complete remission after chemotherapy. In addition multiple non-randomized trials have shown that stem cell transplantation can work again in relapsed patients.
Autologous stem cell transplantation has been controversial for many years as high-dose therapy has been shown to be beneficial prior to the application of new therapeutic agents and has been shown to improve EFS in Meta-analyses. However, early results of these randomized trials incorporating new drugs have shown that high-dose therapy has an important role in sustained progression-free survival.
Although autologous transplantation as soon as possible is a current standard of care option, retrospective analyses suggest that in the current era of new drugs, autologous transplantation should be delayed until relapse and the patient has no adverse prognostic factors.
First-line treatment for patients unsuitable for transplantation
Many patients with MM are not suitable for high-dose therapy due to their age, and in these patients, emphasis should be placed on patient tolerance of therapy to reduce excessive treatment-related mortality. Patients should be given multiple cycles of therapy, as the degree of treatment response increases over time.
Quality of life is an issue of particular emphasis in the treatment of current diseases, especially for MM
a disease that is not curable. To avoid possible toxic effects of overtreatment and to improve patient tolerance, we need to take into account dose reduction according to age, modification of treatment regimens and provision of adequate supportive therapy.
Standard treatment options include traditional drugs such as marfalan and prednisone and emerging therapeutic agents such as immunomodulators and proteasome inhibitors. Results from several clinical trials have shown that the addition of thalidomide to the MP regimen (mafran + prednisone) increases response rates and progression-free survival, and may improve overall survival.
Results from a large international clinical trial showed that the addition of the proteasome inhibitor bortezomib to the MP regimen was more effective than the MP regimen and significantly improved survival prognosis. However, no randomized trials comparing MP with thalidomide and MP with bortezomib have been reported.
However, a recent Meta-analysis showed no significant difference in PFS and OS between MP combined with bortezomib and thalidomide, despite a higher response rate. Another indirect Meta-analysis comparing the two showed that MP combined with bortezomib significantly benefited patients in terms of complete response rate and grade 3/4 adverse events, but otherwise all treatment outcomes were not statistically different between the two regimens.
Because of the survival benefit of combination therapy, MP combined with bortezomib and MP combined with thalidomide are preferred if tolerated by patients.
Lenalidomide combined with dexamethasone is an effective treatment option for older patients with MM. Preliminary results from a large randomized controlled trial suggest a higher response rate and similar PFS after multiple cycles of lenalidomide combined with low-dose dexamethasone compared to the MP combined with thalidomide regimen.
Prophylactic antithrombotic measures are required when thalidomide and lenalidomide are given; prophylactic acyclovir is recommended to prevent herpes zoster activation when bortezomib treatment is applied. Careful clinical monitoring and dose adjustment during treatment are required to reduce the toxic effects of therapy and to ensure patient adherence to therapy to maximize the chances of achieving a higher response rate and providing long-term remission.
To reduce the toxic effects of MM therapy, treatment with thalidomide and lenalidomide may require a reduced therapeutic dose; however, patients receiving thalidomide may also require light laxatives. For bortezomib-induced polyneuropathy, there are 3 major prophylactic measures that can be taken: extending the interval between doses in each cycle by changing the use of doses on days 1, 4, 8, and 11 to days 1, 8, 15, and 22; using subcutaneous injections rather than intravenous use; and reducing the dose.
First-line therapy for transplant patients
Patients who are suitable are more likely to be young and fit than those who are not suitable for high-dose therapy for MM. Since patient survival is positively correlated with the depth of treatment response, the goal of induction therapy is to achieve a maximal response before high-dose therapy, which translates into a higher remission rate after autologous transplantation.
Therefore, there are many effective, intensive measures to improve treatment outcomes, similar to those for patients unsuitable for transplantation, and newer drugs such as thalidomide, lenalidomide and bortezomib, in combination with standard drugs, have higher response rates than the previous standard VAD regimen (vincristine + adriamycin + dexamethasone). Therefore, regimens combining these new drugs need to be used as induction therapy when the appropriate drugs are available and not medically contraindicated.
Three-drug combinations containing one or two new drugs have higher response rates than two-drug combinations, such as bortezomib + dexamethasone in combination with cyclophosphamide, adriamycin, or thalidomide. However, the addition of a fourth drug for induction therapy was not found to further increase response rates.
Based on these studies, experts and guidelines preferentially recommend a three-drug combination regimen for 3 to 6 cycles of induction therapy in patients suitable for transplantation.
In the presence of contraindications, a two-drug combination regimen may be chosen. However, there is still a need for randomized controlled trials comparing different first-line, two- and three-drug regimens that take into account not only disease progression but also overall survival.
Consolidation and maintenance therapy
To further reduce the tumor load in patients after autologous transplantation, a few additional cycles of treatment after transplantation, called consolidation therapy, may be used to improve the depth of response.
The concept of continuous or maintenance therapy has been resurrected with the introduction of newer drugs with less toxic side effects than traditional anti-MM drugs. The previous maintenance drugs, such as hormones and interferons, had weak therapeutic effects and were severely limited by long-term side effects and poor tolerability.
Thalidomide is the first new drug and a large number of patients have already received thalidomide for continuous treatment. Meta
Meta-analysis of randomized trials of transplant-eligible patients showed that maintenance therapy with thalidomide significantly improved PFS and OS compared to non-maintenance patients.
These positive results need to be considered for possible long-term toxicities, most notably peripheral neuropathy, which can lead to shorter treatment duration. In a large clinical trial of thalidomide maintenance therapy, patients with high-risk cytogenetic abnormalities had a significantly shorter OS after thalidomide maintenance therapy compared to the non-maintenance group, a difference that was attributed to a higher incidence of drug-resistant disease in the thalidomide maintenance group, which responded less well to salvage therapy.
Of four clinical trials of thalidomide maintenance therapy in elderly patients following MPT regimen chemotherapy, only one study showed a prolongation of OS.
Lenalidomide, the second new agent, has been extensively studied in three large clinical trials. Compared to thalidomide, its long-term use is feasible because of its fewer and mainly hematologic side effects.
IFM-2005 and CALGB-100104 are two randomized trials evaluating the efficacy of maintenance treatment with lenalidomide after high-dose therapy; IFM-2005 showed that lenalidomide significantly prolonged PFS compared to placebo at a median follow-up of 45 months; CALGB-100104 showed that patients had significantly longer time to disease progression compared to placebo at a median follow-up of 34 months; while IFM-2005 showed that lenalidomide did not benefit OS, CALGB-100104 showed that Although the IFM-2005 trial showed no OS benefit from lenalidomide, the CALGB-100104 trial showed a significant increase in 3-year OS in the lenalidomide group compared to placebo.
Another study examined the role of lenalidomide maintenance therapy in elderly patients who were not candidates for high-dose therapy. The results showed that the PFS in the MP combined with lenalidomide group was 14 months, which was extended to 31 months when lenalidomide maintenance therapy was added after the combination therapy; there was no significant difference in OS between the two groups at a median follow-up of 30 months.
In three trials, patients receiving lenalidomide maintenance therapy had an increase in second primary malignancies compared to the non-maintenance group. preliminary results from the FIRST clinical trial showed that in patients with MM, PFS and OS were significantly prolonged with continued first-line lenalidomide in combination with dexamethasone until disease progression, rather than with a fixed number of cycles.
Although the third new drug, bortezomib, was administered non-orally, maintenance treatment with bortezomib was shown to be feasible in the Dutch-Germa randomized trial, which compared induction therapy followed by maintenance treatment with bortezomib in a bortezomib-based regimen with maintenance treatment with thalidomide followed by a VAD regimen, in which the main adverse effects were infection, neuropathy, and gastrointestinal symptoms.
After a median follow-up of 41 months, PFS was significantly longer in the bortezomib group than in the thalidomide group; the 5-year OS was 61% and 55% in the two groups, respectively, and the difference was statistically significant in the Cox regression model only after correction for unbalanced risk factors. The risk of second primary malignancy was not increased in the bortezomib group.
Another study was conducted to evaluate the difference in efficacy of consolidation therapy with 6 cycles of bortezomib after autologous stem cell transplantation in MM patients compared to non-consolidation therapy. At a median follow-up of 38 months, PFS was 27 and 20 months in the two groups (P=0.05), while the 3-year OS
was 80% in both groups. The tolerability was acceptable, with a higher incidence of severe neuropathy in the bortezomib consolidation group.
Overall, the concept of maintenance therapy remains a controversial issue. Proponents emphasize its ability to prolong PFS and potentially lead to OS
benefits, its moderate tolerability and manageable side effects. Opponents are more concerned about chemotherapy-free remission periods, which are an important factor in the treatment of patients’ lives, and emphasize the uncertain outcomes of OS, side effects, risk of second primary malignancies, and the high cost of treatment.
To date, no drug has been approved for maintenance therapy, and experts believe that treatment decisions for individual patients need to carefully balance potential risks and benefits, as no widely agreed-upon standard has been reached to date.
Allogeneic Stem Cell Transplantation
Allogeneic stem cell transplantation for patients with MM has been performed for decades. Despite improvements in pretreatment tolerability, supportive care, and donor selection, the potent antitumor effects of allogeneic stem cell transplantation have been somewhat offset by transplant-related complications, most notably graft-versus-host disease (GVHD). To date, most studies have not reported high survival in allogeneic transplant patients, and therefore allogeneic stem cell transplantation is still not a definitive cure for most MM patients.
Overall, the routine use of allogeneic transplantation as a pre-treatment for unselected MM patients is not supported. However, only a minority of MM patients aged 30-40 years prefer allogeneic stem cell transplantation after clear-cut therapy, as it is difficult to achieve 5-10 years of survival with conventional therapy in these patients.
Treatment of Relapsed and Progressive Patients
Treatment decisions for relapsed and progressive patients require a careful weighing of efficacy, risk, and patient quality of life. The decision is not only about which treatment option to choose, but also about when to initiate treatment.
When clinical relapses characterized by CRAB symptoms occur, immediate treatment is required; however, in patients with biochemical relapses, such as those with only increased protein markers in blood or urine without symptoms, even if formal criteria for relapse and progression are met, kinetics need to be observed first, and proliferative relapses need to be initiated more quickly than slow relapses.
Patients with MM need to initiate treatment more quickly. If the time to monoclonal protein doubling is ≤2 months, treatment needs to be initiated even if the CRAB criteria are not met.
For patients with recurrent MM, there are several treatment options, including traditional cytostatic agents such as marfalan, cyclophosphamide and bendamustine, liposomal adriamycin and hormones, as well as newer agents such as thalidomide and bortezomib. Most recommended treatment regimens include a combination of these drugs.
Pomalidomide, a new immunomodulatory agent, has been approved by the U.S. Food and Drug Administration and the European Medicines Agency for patients who have received at least 2 prior courses of treatment with lenalidomide and bortezomib and who have experienced disease progression within 60 days of the end of their last treatment.
Patients who have experienced disease progression within 60 days of the end of their last treatment. Pomalidomide remains effective even in patients who are resistant to lenalidomide and bortezomib. In randomized controlled trials, its higher dose of dexamethasone, had higher response rates, PFS and
OS, with statistically significant differences. Its most frequently reported side effects are hematologic toxicity and febrile hypogranulocytosis.
Carfilzomib, another approved drug, is a new proteasome inhibitor that demonstrates viability in patients previously treated with high doses and has lower neurotoxicity than bortezomib. Carfilzomib has been approved by the U.S. Food and Drug Administration for patients who have received at least 2 prior courses of bortezomib- and immunomodulator-containing regimens and whose disease progressed within 60 days of the end of the last treatment. The most common side effects in early trials were fatigue, anemia, nausea, and thrombocytopenia.
The choice of a specific regimen depends on patient-related factors such as age, behavioral status, comorbidities and pre-existing toxicities, disease characteristics and disease aggressiveness.
Drugs such as thalidomide, lenalidomide and bortezomib need to be used with caution and given with appropriate prophylaxis in patients with previous recurrent and severe thromboembolic events. Bortezomib and thalidomide should be avoided or reduced in patients with neuropathy and gastrointestinal disorders.
Doses of marfalan, cyclophosphamide, doxorubicin, and lenalidomide need to be limited in patients with renal insufficiency. Hormones can be a useful monotherapy as a component of most relapse regimens, especially in patients whose other medications need to be reduced or cannot be used due to hematologic abnormalities.
If relapse and progression occur after a prolonged period of chemotherapy-free remission, reapplication of the previous specific agent is usually feasible. This is defined as 6 months in the United States and 12 months is recommended in Europe. Numerous prospective and retrospective studies have shown that reintroduction of bortezomib at a later stage is feasible and results in remission in most patients.
For patients who remain resistant to new drugs, complex drug combinations and participation in clinical trials with experimental agents may be considered. In young patients <50 years of age with an HLA-compatible sibling donor, allogeneic stem cell transplantation can be performed with reduced dose pretreatment, particularly in patients within two years of diagnosis.
Supportive therapy
The most important supportive therapy for patients with MM is the use of bisphosphonates in patients with bone destruction, as they reduce pathological vertebral fractures, skeletal-related events, and bone pain. According to the guidelines, bisphosphonates should be used for at least 2 years after the initial diagnosis.
2 years after initial diagnosis.
Bisphosphonates can be used in conjunction with vitamin D3 and calcium. Because of the risk of osteonecrosis of the jaw, all patients should undergo a dental examination prior to treatment with bisphosphonates and be cautious about invasive dental procedures.
Future perspectives
Increased understanding of the pathogenesis of MM, the development of many new, effective targeted therapeutic agents for MM cells and microenvironment, and more effective support strategies have led to a prolongation of the median OS in MM over the past 20 years, largely due to the introduction of autologous stem cell transplants, new drugs, and bisphosphonates. However, for most patients, MM is still considered an incurable disease.
There is a debate on whether MM should be treated aggressively with a multidrug regimen to achieve complete remission or with a sequential approach to disease control, which places more emphasis on quality of life and overall survival.
Although there are multiple aggressive regimens that appear to be appropriate for young patients with a poor prognosis, we need to keep in mind the treatment-related complications, the fact that only a minority of patients achieve long-term remission, and the fact that this group of patients has so far shown only a short survival. Furthermore, it is still not clear whether the persistent complete remission is due to the less aggressive nature of the disease or to the effect of the treatment.
Since achieving a cure and durable remission after intensive therapy is rare or even impossible, emphasis should be placed on disease control, such as achieving a stable plateau of non-transfusion dependence, stable renal function, non-progression of bone disease, high life treatment and improved survival, rather than achieving complete remission in patients of frail age or non-high risk.
A big challenge in the short-term future is to establish a rational dosing and combination regimen for MM patients with well-defined biology but different subgroups in order to avoid overtreatment of low-risk patients and those who cannot tolerate more aggressive chemotherapy regimens. However, more aggressive regimens may be used in younger, fitter patients, who are more likely to achieve long-term benefit from them.
Such stratified regimens are more difficult to test in prospective trials and require the coordinated collaboration of large research institutions and international molecular diagnostic networks. As our understanding of when to choose a particular drug in the disease process increases, and with a variety of promising new drugs in clinical development, we believe that the prognosis for MM patients will continue to improve in the future.