Multiple myeloma (MM) is an incurable malignant plasma cell disease. Although the widespread use of targeted therapy and stem cell transplantation has significantly increased the rate of complete remission (CR) and prolonged overall survival in MM, the effects of MM treatment are difficult to maintain in the long term.
Even after effective chemotherapy and stem cell transplantation, patients with primary MM will still relapse and eventually enter the refractory stage. The low remission rate and short median survival of relapsed and refractory MM treatment seriously endanger the health of patients. How to choose the appropriate treatment plan for relapsed and refractory MM patients remains a major challenge. Now we will elaborate on the key points related to the treatment process of relapsed and refractory MM.
1. Definition and mechanism of relapsing and refractory MM
Relapsed and refractory MM can be divided into three categories: (1) relapsed MM refers to patients with disease progression after receiving one or more treatments and requiring salvage therapy; (2) relapsed and refractory MM refers to patients who do not respond to salvage therapy, or whose disease progresses within 60 d after receiving the last treatment to achieve a minor response (MR); (3) primary Refractory MM is defined as patients who do not respond or respond poorly to initial treatment. Patients with relapsed MM are the most common.
Current studies show that residual myeloma stem cells are the root cause of MM relapse, while their biological alterations and the increase of drug-resistant clones are the main causes of MM drug resistance. Also factors such as impaired drug transport, bone marrow microenvironment and clonal plasma cell interactions, and cell adhesion play an important role in MM drug resistance.
Therefore, the key to the treatment of relapsed and refractory MM is to remove myeloma stem cells as much as possible and interfere with the interaction between myeloma cells and bone marrow microenvironment, so as to delay the disease relapse and overcome the drug resistance of MM.
2. Factors related to the choice of treatment options for relapsed and refractory MM
It is crucial to choose the right time for treatment, develop a reasonable treatment plan, and balance the efficacy and toxicity for relapsed and refractory MM patients. Both patient condition and disease characteristics should be fully considered.
Disease characteristics include the extent and duration of remission from previous therapy, aggressiveness of the disease, and cytogenetic abnormalities. Patient characteristics include adverse effects associated with previous treatment, patient age, physical status, and the presence of co-morbidities.
Broadly speaking, patients can be divided into two categories: high-risk and standard-risk. High-risk MM patients have aggressive disease, such as the presence of extensive bone lesions, plasma cell leukemia, extramedullary plasmacytoma, elevated blood β2-microglobulin levels, decreased serum protein levels, cytogenetic abnormalities, short duration of previous treatment effects, and poor current treatment outcomes.
For high-risk patients, chemotherapy remission rates are low and combination therapy with three to four drugs is recommended. For standard-risk patients, l to 2 unused or effective drugs are recommended for treatment.
2. 1. Goals of treatment
CR is now recognized as a predictor of good prognosis in non-transplant patients. Quality of life (QoL) is a key factor in determining the intensity and goals of treatment. For patients in good general condition and able to tolerate intense treatment, high-dose chemotherapy, radiotherapy, and stem cell transplantation are recommended to achieve maximum remission for long-term survival.
For patients with poor general condition and unable to tolerate intense treatment, controlling disease progression, improving QOL and prolonging survival through palliative treatment are the main treatment goals.
2.2, Timing of treatment
For the timing of treatment initiation at relapse, current guidelines mostly recommend that treatment should be started at clinical relapse rather than biochemical relapse. Biochemical relapse is defined as an increase in detectable biochemical parameters without clinical symptoms, specifically, at least one of the following: confirmation of the reappearance of M protein in blood or urine; an increase in blood M protein of ≥ 25% and an absolute value of ≥ 5 g/L compared to baseline values; a 25% increase in 24-h urine M protein and an absolute value of ≥ 200 mg; if blood or urine M protein is not measurable, blood free light chains (FLC) are not available. If blood and urine M protein are not measurable, the difference of free light chains (FLC) is increased by >25% and the absolute value is >1 0 mg/dl.
In contrast, clinical recurrence was defined as the presence of increased tumor load and end-organ insufficiency, such as the appearance of new plasmacytomas or areas of bone destruction, or an increase in pre-existing plasmacytomas or bone damage (length diameter × width diameter ≥ 50%, absolute value increase ≥ 1 cm), hypercalcemia > 11.5 mq/d](2.875 mmol/L), decreased hemoglobin ≥ 20 g/L, blood creatinine ≥ 1 77 μmol /L.
If patients have paraproteins including blood, urine M protein or FLC doubling time < 2 months, treatment and therapy need to be started even if no clinical symptoms are present.
2.3. Cytogenetic factors
MM has significant genetic heterogeneity, with survival ranging from a few months to more than a decade. The individualized treatment of tumor is the current trend of international development. According to cytogenetic examination, MM is divided into 3 groups: high risk, intermediate risk and standard risk.
Patients with hyperdiploidy and t(1 1; 1 4) are the standard-risk group, which are more sensitive to conventional chemotherapy, while patients with subdiploidy, t(4; l4), del(1 7), and del(13) are the high-risk group, which are less effective to conventional chemotherapy; the rest are the intermediate-risk group.
Clinical studies have shown that bortezomib can overcome the adverse prognostic effects of t(4;14) and l3q14 deletion; lenalidomide-based therapy is effective in improving the prognosis of patients with del(17). These data are encouraging, and therefore a bortezomib-based 3-drug combination (bortezomib + dexamethasone + lenalidomide or bendamustine) was recommended for the treatment of relapsed, refractory MM at the American Society of Hematology (ASH) annual meeting in 201 2.
2.4. Order of treatment
There is no uniform conclusion about the best treatment sequence for relapsed, refractory MM. When choosing a treatment plan, the time to relapse is an important indicator to be examined. The National Comprehensive Cancer Collaborative Network (NCCN) guidelines recommend that when the duration of remission is long, 6 months to 1 year, it suggests sensitivity to the original regimen and a repeat of the previous treatment can be considered in case of relapse.
When the remission period is short, <6 months, it suggests possible drug resistance and suggests switching to a new regimen. Also even if resistant to monotherapy and 2-drug therapy, there may be synergy with other drugs in combination, so the guidelines recommend that combination with previously unused drugs or 3-drug or 4-drug therapy may be effective.
However, there are different opinions on this, and European experts believe that regardless of whether prolonged remission is achieved with front-line therapy, the treatment regimen should be changed in case of relapse to reduce the risk of inheritance of drug-resistant clones.
2.5 Impact of co-morbidities on the choice of treatment regimen
MM occurs in elderly patients with multiple underlying diseases that may affect pharmacokinetics and increase the incidence of adverse effects. Therefore, the impact of comorbid diseases should be fully considered in the individualized treatment of MM. Bortezomib is suitable for patients with renal insufficiency because it is not metabolized by the kidney and has a rapid onset of action.
When lenalidomide-based regimens are used, the drug dose needs to be adjusted according to creatinine clearance. Bortezomib-based regimens do not increase the incidence of thrombotic events and are preferred for patients with recent thrombotic events.
In contrast, thalidomide and lenalidomide are prone to vasoembolism in treatment and are generally not recommended for hypercoagulable patients, but can be used with caution in the context of anticoagulation when treatment options are scarce or when drug sensitivity is demonstrated.
Nearly 80% of patients develop varying degrees of neuropathy during MM treatment. Lenalidomide has a lower incidence of neuropathy than thalidomide and bortezomib and is recommended for patients with combined neuropathy.
In patients with pre-existing peripheral neuropathy, clinical adjustments in dose, interval and route of administration are recommended when using potentially neurotoxic drugs such as bortezomib. Lenalidomide is not metabolized by the liver and is indicated for patients with hepatic insufficiency.
3. Treatment options available
There is no unified opinion on the treatment of relapsed, refractory HM, and the previous first-line treatment regimen can be chosen, or an alternative regimen can be tried. At present, there are three main types of treatment options available for relapsed, refractory HM, as follows.
3.1, conventional chemotherapy
In the 20th century, salvage therapy for relapsed, refractory MM was usually based on high-dose and/or multi-drug combination regimens. The common salvage regimens reported at home and abroad include high-dose melphalan, high-dose methylprednisolone (methylprednisol0ne), high-dose dexamethasone, vincristine combined with doxorubicin, and high-dose dexamethasone. VMPC regimen (vincristine, melphalan, cyclophosphamide and methylprednisolone), CEVAD regimen (doxorubicin, vincristine, dexamethasone, etoposide and cyclophosphamide), and DCEP regimen (dexamethasone, cyclophosphamide, etoposide and cisplatin).
Currently, with the in-depth cytogenetic studies, it is clear that relapsed, refractory HM is often combined with genetic alterations of poor prognostic significance, the overall efficacy of traditional drugs is poor, the overall remission rate is low, and it is difficult to obtain high-quality remission, and the median survival is only 6-9 months, so it is now recommended to routinely add new drugs in combination.
3.2. Hematopoietic stem cell transplantation
A large number of literature reports have confirmed that autologous stem cell transplantation has significant advantages over conventional chemotherapy and can improve the CR rate and event-free survival of MM patients. At present, new drugs cannot completely replace autologous stem cell transplantation. Combining autologous stem cell transplantation on the basis of new drug induction can achieve better efficacy.
The overall remission rate of secondary autologous HSCT is 55%-69%, and the mortality rate within 100 d is about less than 10%. the NCCN guidelines recommend secondary autologous stem cell transplantation for patients who are suitable for transplantation with class I recommendation for patients with relapse or progression of disease after induction therapy.
The Mayo Center evaluated the efficacy and safety of secondary transplantation in 98 patients who had previously received primary stem cell transplantation and had a positive outcome after receiving two transplants, and the median progression-free survival (PFS) after two transplants was 1 0.3 months, with a median survival of 33 months. . Treatment-related mortality was 4%.
In multifactorial analysis, a short time to disease progression (TTP) after the first transplantation was significantly correlated with a short survival after the 2nd transplantation. This suggests that 2 autologous stem cell transplantation is an effective treatment for patients with recurrent MM and is suitable for patients with a long TTP (>1 2 months) after the first transplantation.
Allogeneic HSCT is limited by the source of the donor, and only 1% of relapsed, refractory patients can be treated. And a significant percentage of patients develop chronic graft-versus-host disease (GVHD) with other treatment-related toxicities and high transplant-related mortality. Based on these conditions, the NCCN and IMWG recommend allogeneic HSCT only for high-risk patients in well-designed clinical trials.
3.3 Novel Targeted Therapies
3.3.1, Immunomodulators
Thalidomide is an immunomodulatory drug (1mmunom0dulat0rydrugs (IMiD)) that, in addition to directly affecting MM tumor cells, can also target the bone microenvironment and stimulate the body to generate an anti-myeloma immune response.
The efficacy of thalidomide is well established, with current data showing that 30% of patients with relapsed, refractory MM can achieve more than partial remission with a median survival of 14 months with thalidomide monotherapy.
NCCN guidelines recommend treatment with thalidomide for patients who are corticosteroid intolerant. Thalidomide in combination with multiple cytotoxic agents has been successfully used in the treatment of relapsed, refractory H
The combination with dexamethasone has increased remission rates by 50% compared to thalidomide monotherapy. The combination of thalidomide with sustained low doses of cyclophosphamide was also effective, with 64% of patients achieving more than partial remission.
Additional data show that thalidomide in combination with melphalan, melphalan-prednisone, melphalan-dexamethasone, liposomal doxorubicin (PLD)-dexamethasone, DT-PACE, or cyclophosphamide-etoposide-dexamethasone regimens all improve remission rates.
The NCCN guidelines now list thalidomide as a Class 2A regimen with dexamethasone and DT-PACE, respectively. The European Society of Medical Oncology (ESMO) guidelines also recommend the use of thalidomide in combination with dexamethasone for chemotherapy.
Lenalidomide is an amino acid-substituted derivative of thalidomide that maintains or enhances its biological activity while reducing thalidomide toxicity. In vitro experiments have demonstrated that lenalidomide has the ability to stimulate the secretion of tumor necrosis factor alpha (TNFα) 50,000 times more than thalidomide.
In clinical phase I and phase II trials, lenalidomide was effective as monotherapy in 29% to 39% of patients with a median number of relapses of three.
NCCN guidelines recommend lenalidomide monotherapy for patients with relapsed, refractory HM who are steroid hormone intolerant. Further clinical studies comparing the efficacy of lenalidomide monotherapy and with combined dexamethasone therapy showed that lenalidomide combination therapy significantly improved overall remission rates and prolonged survival.
In the two randomized clinical phase III studies MM-009 and MM-010, lenalidomide combined with dexamethasone significantly improved the outcome of relapsed, refractory MM compared with dexamethasone monotherapy, increasing the overall remission rate (60.6% versus 21.9%, P<0.01) and extending median overall survival (38 months versus 31.6 months, P=0.45).
Subgroup analysis showed that patients previously treated with thalidomide had shorter TTP with subsequent lenalidomide treatment than patients not previously treated with thalidomide, with median PFS of 1.4.2 months and 8.5 months, respectively (P<0.001), suggesting the possibility of cross-resistance.
The study also found that lenalidomide. The NCCN and ESMO have recognized lenalidomide and dexamethasone combination therapy as a class I treatment option.
In addition, other lenalidomide combination regimens have been shown to be effective, with lenalidomide and doxorubicin-dexamethasone combination therapy showing partial remission (PR) in more than 73.0% of patients, with low-dose cyclophosphamide-prednisone combination therapy showing a total remission rate of 64.3%, and with cyclophosphamide. The overall remission rate with the combination of cyclophosphamide-prednisone was 75.0%.
There is debate as to whether patients benefit from lenalidomide maintenance therapy. Although the MM-015 study demonstrated an improvement in PFS with lenalidomide maintenance therapy, the findings are not generalizable because the study enrolled elderly patients. Further results will depend on additional clinical trial data in the future.
3.3.2, Proteasome inhibitors
Bortezomib is a first-generation proteasome inhibitor that inhibits proteasome 26S subunit enzyme activity and affects a number of proteins involved in cell cycle arrest and apoptosis, such as NF-K B and cystathionin9.
The proliferation of MM tumor cells is highly dependent on the over-activated NF-KB signaling pathway, so bortezomib, a proteasome inhibitor targeting this signaling pathway, was rapidly transformed from basic research to a clinical drug.
Subgroup analysis of the APEX study confirmed that the lower the number of lines treated prior to bortezomib treatment, the higher the remission rate. Early use of bortezomib after first relapse improved overall survival. Bortezomib is now increasingly being used for induction therapy, and further studies have confirmed that it does not increase the rate of drug resistance at relapse.
Multicenter, retrospective studies conducted in Germany and Switzerland have shown that bortezomib retreatment is a well-tolerated and effective treatment option, especially for patients with a treatment-free interval (TFI) of more than 6 months.
The authors retrospectively analyzed the efficacy and safety of 76 bortezomib retreatment M. The total effective rate was 58%, with CR, very good partial remission (VGPR), PR, and NR rates of 7.9%, 18.4%, 39.5, and 34.0 patients, respectively.
Eighty percent of the patients had new adverse reactions of varying degrees on retreatment, of which only 9 were grade III or higher, mainly centronuclear cytopenia, thrombocytopenia, and diarrhea. Again, bortezomib retreatment was confirmed to be well tolerated and feasible.
Combination therapy with anthracyclines and alkylating agents based on bortezomib significantly improves the efficacy, with remission rates of 50% to 80%. The synergistic effect of bortezomib and PLD combination therapy in the treatment of relapsed, refractory MM patients has attracted the attention of researchers.
In a clinical phase III study of primary bortezomib patients, the combination of bortezomib and PLD significantly improved treatment outcomes relative to bortezomib monotherapy (CR+VGPR: 27% vs. 19%, P=0.01 57) and improved survival at 1.5 months (76% vs. 65%, P=0.03), confirming that PLD combined with bortezomib in relapsed, refractory MM patients treatment was superior to bortezomib monotherapy in patients with relapsed, refractory MM. More importantly, the combination of bortezomib and PLD is safe and effective in elderly patients and does not increase the incidence of grade III or higher adverse events.
The current multidrug combination based on new drugs is the mainstream trend in the treatment of relapsed, refractory MM.201 2 The status of transplantation with new drugs was emphasized in the European expert consensus in 201 2. The choice of treatment options for first relapse HM is based on the following 2 points, (1) suitability for transplantation: for patients in remission >2 years after initial transplantation, 2 transplants should be considered; while for those with high-risk factors, allogeneic transplantation is also a treatment option.
(2) Whether the prior therapy includes new drugs and how effective it is: regimens that include new drugs are recommended for salvage therapy. If the new drug is included in the first-line treatment and the remission period is long, the previous treatment can be repeated; if the remission period is short, a change of treatment regimen will be considered. If the first-line treatment does not include a new drug, a regimen that includes a new drug is recommended for relapse.
According to the types of new drugs, there are mainly 3 categories: (1) treatment regimens based on immunomodulators, such as TD, RD, CTD regimens; (2) treatment regimens based on bortezomib, such as V±D, bortezomib combined with PLD, VTD regimens; (3) treatment regimens based on bortezomib combined with immunomodulators, such as VMPT regimens, etc.
4 .Outlook
The treatment of relapsed and refractory MM is still a challenge. Generally, both disease- and patient-related factors are mainly considered in the development of treatment strategies, such as the degree of remission of previous treatment, duration, disease aggressiveness, patient age, and general status.
The current treatment of relapsed, refractory HM is mainly a multi-drug combination, containing new drugs, treatment regimen. The future progress of relapsed and refractory MM treatment depends on the progress of basic research such as molecular biology and genomics, as well as the continuous research on tumor stem cells.
At the same time, clinical workers should also continue to explore and improve the existing treatment methods and efficacy, and reduce the occurrence of their adverse effects. For example, allogeneic stem cell transplantation has a very attractive clinical application prospect, but the current high transplantation-related mortality rate severely restricts its application. In the future, with the progress of basic research and improvement of clinical technology, it is expected to gradually solve this problem and improve the survival of patients or even cure myeloma.