1. Introduction
Multiple myeloma (MM) has become the second-most common hematological malignancy, accounting for 10% of all hematological malignancies ( 1 ). MM can be identified by serum immunofixation electrophoresis and the features of MM are the buildup of clonal proliferative malignant plasma cells in the bone marrow as well as the release of monoclonal immunoglobulin (M protein). Anemia, hypercalcemia, osteolytic lesions and renal insufficiency are some of its clinical manifestations (which are commonly referred to as ‘CRAB’ symptoms, denoting hypercalcemia, renal failure, anemia, and bone destruction) ( 2 ). In the past two decades, a notable development has been made in the treatment of MM. MM treatment has been linked to extremely positive outcomes owing to the rapid uptake of autologous hematopoietic stem cell transplantation, the advent of immunomodulatory medications (IMids), and proteasome inhibitors (PIs), with small molecule antitumor medications, such as dexamethasone and other glucocorticoids ( 3 , 4 ). However, MM is considered a fatal illness ( 5 ). The most important concerns include improving patient prognoses, decreasing adverse drug reactions, extending the lives of patients, and enhancing their quality of life. Myeloma cells may die directly or indirectly with the use of an immunomodulator ( 6 ), and MM cells may be indirectly affected by changes to the bone marrow microenvironment. Thalidomide was the first novel medication to be authorized by the US Food and Drug Administration (FDA) for the management of MM in 1999. It has been reported to inhibit tumor necrosis factor production, MM cell growth, and anti-angiogenesis, albeit its therapeutic efficacy is significantly hampered by the neurological side effects of thalidomide, which include drowsiness and peripheral neuropathy ( 7 ). Lenalidomide and pomalidomide are two new IMiDs that were created and used as the result of preclinical studies and subsequent clinical trials. Both could be utilized in MM therapy regimens. Lenalidomide was the first thalidomide analog to be marketed, and it was more potent than its parent drug despite only two differences at the molecular level: The addition of an amino group at position four of the phthaloyl ring and the removal of a carbonyl group from the phthaloyl ring ( 8 ). Lenalidomide was developed by Celgene Corporation (now part of Bristol Myers Squibb) in the U.S. and was approved by the FDA on December 17, 2005 for fast-track marketing for the treatment of anemia caused by myelodysplastic syndromes associated with deletions of chromosome 5q, and has since been approved for a variety of indications, including MM ( 9 ). Lenalidomide, which is a structural and functional analog of thalidomide, can enhance the immunomodulatory, anticancer, and tolerability properties of thalidomide ( 10 ). Lenalidomide has been a global bestseller for numerous years since its introduction to the market, but with the entry of generics into the market, there has been a significant decrease in the price of lenalidomide, rendering it available to a wider range of patients.
2. Pharmacological mechanism
Lenalidomide, a second-generation imine medication, is relatively less toxic and with a higher potency when compared with thalidomide ( 11 ). Lenalidomide has been demonstrated to exhibit an array of effects and mechanisms of action that can contribute to its antitumor properties ( 12 ) ( Fig. 1 ).
Non-immune regulation
Vascular endothelial growth factor (VEGF) is inhibited by lenalidomide, which makes it challenging for tumor cells to form blood vessels. It blocks VEGF and can prevent the production of interleukin-6 (IL-6) ( 13 ). As per a previous study, IL-6 is a cytokine with a wide range of inflammatory and immune regulatory properties ( 14 ). In addition, IL-6 can promote the progression of MM. Lenalidomide has also been linked to the growth arrest of myeloma cells in the G1 phase ( 15 , 16 ), and this direct cytotoxicity is associated with a decrease in IL-6 production. However, the precise mechanism underlying this effect is unknown.
A well-known mitochondrial protein, cytochrome c , can maintain life by transporting electrons to the respiratory chain and allowing continued ATP production. Cell survival and apoptosis significantly depend on cytochrome c ( 17 ). By influencing the release of cytochrome c , lenalidomide can impact the apoptosis of MM cells ( 18 ). In addition, by altering caspase-8, lenalidomide can also affect the apoptosis of MM cells ( 19 , 20 ).
Lenalidomide can directly induce MM cell apoptosis and cell cycle arrest. Previous studies have demonstrated several downstream changes after lenalidomide treatment, which may be associated with the direct anti-myeloma activities of the drug, in addition to the previously mentioned mechanism. These changes include the upregulation of P21 expression ( 21 ), nuclear factor-κB (NF-κB) deactivation ( 22 ), CCAAT/enhancer binding protein-β (C/EBP-β) downregulation ( 23 ), and caspase-8 inhibition or genetic depletion ( 20 ).
By suppressing the production of surface-adhesion molecules on both MM cells and bone marrow stromal cells (BMSCs), lenalidomide prevents contact between them ( 24 ). Lenalidomide can prevent MM-related bone damage by either directly preventing osteoporosis development or by indirectly decreasing the tumor load. The effect of lenalidomide on osteoclasts can slow the development of MM, as osteoclasts have been demonstrated to increase MM growth and medication resistance ( 25 ).
Immune regulation
In contrast to other anti-MM medications, lenalidomide possesses immunoregulatory effects. First, it can improve the co-stimulation of CD4 + and CD8 + T cells ( 26 ). When compared to the first-generation IMiD thalidomide, lenalidomide increases T-cell proliferation and the production of IL-2 and γ-interferon ( 27 ). Lenalidomide can also inhibit regulatory T cells, which are a subset of immunosuppressive T cells, that are important for self-tolerance and the reaction of the the immune system to tumor cells ( 28 ). With the natural killer (NK) cell-surface markers, lenalidomide increases the activity of NK and T lymphocytes (NKT) ( 29 ). In patients with MM who have received suitable treatment, NK cell proliferation is promoted, an important pharmacological effect of lenalidomide. It has also been demonstrated that the ability of human peripheral blood mononuclear cells (PBMC) to produce the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), IL-1, IL-6, and IL-12 is inhibited by the effect of lenalidomide ( 30 ). Lenalidomide reduces the immune checkpoint inhibitor programmed death-1 (PD-1) expression on both T and NK cells in patients with MM; it also reduces the expression of PD-1 and programmed death ligand-1 (PD-L1) on MM cells ( 31-33 ).
3. Pharmacokinetics
Oral lenalidomide is promptly and effectively absorbed (>90% of the dose) under fasting conditions as per the results of a control study conducted on healthy volunteers ( 34 ). Drug oral absorption effectiveness can be affected by food type. The maximum concentration (C max ) and the area under the concentration-time curve (AUC) both decreased by 20-50%, respectively, when combined with a high-fat diet. The increase in AUC and C max was dose-dependent, with minimal to moderate inter-individual variability in plasma exposure. After 24 h, ~80% ( 34 , 35 ) of the oral dose was eliminated in the urine. Lenalidomide has a very brief (3-4 h) half-life and it does not build up in plasma when administered repeatedly.
Renal function is the only significant factor affecting lenalidomide plasma exposure as per a study that assessed the dose range of patients with MM ( 36 ). These researchers also confirmed that plasma AUC and C max were proportional to the dose used in the treatment of patients with MM, without exhibiting any differences when compared with the healthy volunteers.
4. Clinical research and application
The application of lenalidomide for the treatment of MM was approved by the FDA in March 2006. Since then, clinical trials and real-world studies ( 37-61 ) on the single-drug (R) treatment of lenalidomide and the combination of lenalidomide and dexamethasone (RD) as well as various treatment schemes based on the combination of RD have been widely conducted. These studies aimed to confirm the therapeutic efficacy of lenalidomide in patients with newly diagnosed MM (NDMM) or relapsed refractory MM (RRMM) ( Table I ).
Application of lenalidomide alone and with dexamethasone in MM
The conventional course of treatment for young patients with NDMM is autologous-hematopoietic stem cell transplantation (ASCT) after effective induction therapy ( 62 ). Lenalidomide was authorized by the FDA in 2017 for use as a maintenance therapy for patients with MM following ASCT ( 63 ).
A clinical study ( NCT02215980 ) ( 37 ) showed the effectiveness and viability of continuing 10 mg lenalidomide monotherapy (RD-R) daily in comparison with continuous RD after receiving dose/schedule-adjusted RD in elderly, moderately healthy individuals with NDMM who did not undergo ASCT. Additionally, the data revealed that low-dose lenalidomide may be used without dexamethasone after nine cycles of RD, and the outcomes were comparable with those of continuous RD.
According to a randomized controlled trial by Lund et al ( 38 ), a single medication, lenalidomide, may be useful for the prolonged treatment of RRMM once patients exhibit preliminary responsiveness to the induction of the RD regimen. In a subsequent phase 2 clinical trial ( NCT01450215 ), patients with RRMM who responded to first-line RD in an observational study ( NCT01430546 ) received up to 24 cycles of R or RD as extended treatment. The median reaction time in the observational study was 1.7 months, with a range of 0.6-9.6 months. In these two investigations, 11% of the patients experienced a complete response (CR) to all treatments received. Very good partial response (VGPR) and partial response (PR) were observed in 31 and 38% of the patients, respectively. In the subset of patients who were not enrolled in the second phase of the experiment, the equivalent remission rates were 3, 18, and 39%, respectively. RD did not develop within the median time to progress (TTP) during a median follow-up of 36 months for the surviving patients; RD-R was 24.9 months (95% CI, 12.5-not calculable; P<0.001).
Application of lenalidomide combined with bortezomib and dexamethasone in MM
The first PI to receive FDA approval was bortezomib (V) ( 64 ). It can connect to the amino acid residues of the 26S proteasome and block the ubiquitin-proteasome system pathway, thereby preventing the breakdown of protein products involved in fighting tumors ( 65 ). Bortezomib is indispensable in the management of MM. In a phase 3 study and real world research data ( 39 , 66 ), the combination of bortezomib and RD (VRD) was established to be associated with an excellent response rate, manageable toxicity, and therapeutic advantages.
A phase 3 study (S0777) ( 39 ) revealed that when VRD was used instead of RD alone, progression-free survival (PFS) and overall survival (OS) were significantly improved in newly diagnosed patients without immediate ASCT. Additionally, a study by Medhekar et al ( 66 ) which analyzed patient characteristics and treatment outcomes, revealed a median PFS of 26.5 months that was shorter than the pivotal median PFS of 43 months achieved in the SWOG S0777 study ( 39 ). According to a meta-analysis ( 41 ), PFS was continually increased with lenalidomide treatment compared with conventional therapy alone.
In previous research ( 42 , 43 ), sequential ASCT was administered to 751 of the 1,000 consecutive patients receiving VRD induction therapy. The median PFS and OS for this population were 63 and 123.4 months, respectively. The most recent data from the Griffin trial and German-Speaking Myeloma Multicenter Group (GMMG-HD7) trial ( 44 , 45 , 67 ) investigations indicated that in patients deemed eligible for ASCT, the reaction rate of adding CD38 monoclonal antibody, isatuximab to VRD, and the negative rate of measurable residual disease (MRD) were both improved. Although the Griffin trial recently showed that the combination of these four medications offers considerable benefits in terms of PFS ( 45 ), neither research included data on PFS or OS. Therefore, the CD38 monoclonal antibody and VRD quadruple induction procedure may become the norm for patients with MM who are deemed ASCT candidates. The pursuit of negative MRD may also be advantageous for patients who have reached VGPR. Specifically, an analysis of patients who participated in the PETHEMA/GEM 2012 trial ( 68 ) established that negative MRD can improve the prognosis of high-risk patients with cytogenetics. However, the use of the VRD scheme for consolidation treatment after ASCT is still debatable. The published ASCT investigations on consolidation therapy with the VRD scheme ( 46 ), however, were performed throughout two cycles, which revealed improved VGPR and CR after consolidation.
The median age of the study participants was 73 years (range 65-91 years) in a phase 2 study of lenalidomide combined with bortezomib and dexamethasone for treating transplant-ineligible patients with MM ( 47 ). The total effective rate was 86 and 66% of the patients achieved VGPR or improved remission. The median OS was not attained, the mean PFS was 35.1 months (95% CI, 30.9-not reached), and the mean follow-up period was 30 months. Additionally, a phase 2 study (JCOG0904) ( 48 ) revealed that patients with RRMM undergoing VRD treatment exhibited satisfactory 1-year PFS (45.5%) and 3-year OS (70%) outcomes.
Application of lenalidomide combined with ixazomib and dexamethasone in MM
A reversible PI called ixazomib (I) with oral bioavailability was produced by Millenium Pharmaceuticals, Inc. (now Takeda Oncology) ( 69 ). The drug functions by binding to and inhibiting the subunits of the 20S proteasome. The FDA approved its use in combination with lenalidomide and dexamethasone (IRD) in November 2015 for treating patients with MM who have already undergone at least a single therapy. Globally, however, clinical trials involving ixazomib for NDMM and real-world research applications are still ongoing.
In a previous study, a total of 25 patients with NDMM receiving weekly IRD, as well as 18 other patients receiving twice-weekly IRD, then received ≥1 dose of ixazomib maintenance ( 49 ). The median PFS for the weekly IRD group was 25.8 months (95% CI, 9.2-34.8), and for twice-weekly IRD group, it was 26.3 months (95% CI, 5.7-not reached). Patients in the two groups showed a 3-year OS of 96 and 77%, respectively. A study by Kumar et al ( 50 ) treated patients with NDMM using ixazomib for maintenance after examining the long-term effectiveness and safety of the weekly complete oral combination of IRD. In the study, induction was halted in 23 patients and ASCT was performed. The remaining 42 patients showed an overall response rate (ORR) of 80%, of which 63% had VGPR and 32% had CR. This finding reveals that the IRD procedure can be administered for a considerable amount of time without any signs of cumulative toxicity. Furthermore, a double-blind, placebo-controlled TOURMALINE-MM2 clinical trial ( NCT01850524 ) ( 51 ) was conducted, which involved patients with NDMM who were not candidates for or were unable to undergo ASCT. The median PFS of the IRD group was 35.3 months and the median follow-up duration was 53.3 months; 63% had VGPR and 26% had CR.
The response rates of the patients following ASCT increased over time, which was partly due to the advantages of lenalidomide maintenance that were noted in the previous trial. This finding led the researchers to add ixazomib to 64 patients with NDMM after ASCT, to compare the effects of R and IR ( 52 ). The median survival time was not attained, the CR/strict CR (sCR) was 43%, and the median follow-up period was 62 months (25-82 months). The median PFS of the patients was 73 months. The addition of lenalidomide to the maintenance of the drug resulted in a superior PFS than anticipated, and it was safe and was well tolerated when compared with the historical usage of lenalidomide alone.
A double-blind, placebo-controlled TOURMALINE- MM1 phase 3 clinical trial ( 53 ) for treating patients with relapsed and refractory MM revealed that there were no new or worse safety concerns. Moreover, among patients with RRMM, the OS rate of those taking IRD was statistically improved compared with those taking placebo-RD. According to a multicenter real-world study conducted by Japanese researchers using the Kansai Myeloma Forum database ( https://myeloma.jp/ ), IRD treatment exhibited stronger efficacy than other types of treatments in patients with IgG-type RRMM in actual clinical practice ( 54 ), but no additional clinical trials and studies are available to support these findings.
Application of lenalidomide combined with carfilzomib, dexamethasone and CD38 monoclonal antibody, daratumumab (Dara), in MM
In 2012, the FDA authorized carfilzomib (K) for the treatment of MM. The drug, which is a tetrapeptide epoxy ketone, specifically targets and permanently inhibits the proteasome ( 70 ). The FDA originally authorized the single medication therapy for patients with MM who had received at least two treatments in 2012. Later, the FDA approved the use of lenalidomide with dexamethasone or carfilzomib in conjunction with dexamethasone to treat RRMM ( 71 ). Furthermore, several clinical studies on carfilzomib are concurrently being performed on patients with NDMM.
The effectiveness of Dara in combination with carfilzomib, lenalidomide, and dexamethasone (Dara-KRD) in treating patients with NDMM was explored in an open phase 1b research ( 55 ). Regardless of fulfilling the transplantation requirements, 22 patients received Dara-KRD treatment for up to 13 cycles that lasted 28 days or until ASCT. An ORR of 95% was achieved, of which 86% was PR and 67% was CR. Hence, Dara-KRD appears to be well tolerated. In another multicenter, open-label, phase 3 randomized controlled trial ( 56 ), patients with NDMM who did not immediately receive ASCT were compared in terms of VRD and KRD data. The median PFS was 34.4 months [95% CI, 30.1-not estimable (NE)] for VRD and 34.6 months (95% CI, 28.8-37.8) for KRD; KRD did not increase the PFS in patients with NDMM in this randomized phase 3 study.
Patients with NDMM who were eligible for transplantation underwent four cycles of KRD induction, ASCT, four cycles of KRD consolidation, and ten cycles of KRD maintenance in a phase 2 multicenter investigation that evaluated the use of KRD and ASCT in the treatment of NDMM ( 57 ); sCR was the major endpoint after eight cycles of KRD. In total, 76 patients were enrolled in the study, their median age ranged from 40 to 76 years. Furthermore, the sCR rate after eight cycles was 60%. The sCR rate was 76% in the intention to treat (ITT) population. The 5-year PFS and OS rates of ITT were 72 and 84% after a median follow-up of 56 months. In patients with NDMM treated with KRD and ASCT, there was a significant incidence of negative sCR and MRD at the end of the consolidation of KRD. PFS and OS may be extended by prolonging the consolidation treatment for KRD, and safety and tolerance can be effectively managed. Another phase 2 study on KRD and ASCT ( 58 ) involved eight KRD treatments, ASCT for all patients, and a year-long course of lenalidomide, with the primary objective of sCR. Poor cytogenetics affected 21% of the 46 individuals. Of the 42 patients assessed following consolidation, 26 patients (61.9%) and 27 patients (64.3%) had sCR and CR, respectively. In conclusion, eight cycles of KRD resulted in a quick and favorable response in patients with NDMM who qualified for transplantation, however, of note cardiovascular side effects need to be constantly monitored.
Eligible patients were randomly assigned in a ratio of 1:1 to receive KRD or RD treatment for 28 days in a randomized controlled study on RRMM ( 59 ). In patients who had previously received a single therapy, the median OS was extended by 11.4 months for KRD compared with RD, and in patients who had previously received two therapies, the median OS was extended by 6.5 months for KRD compared with RD. Hence, it can be surmised that in RRMM, KRD has a markedly lower risk of mortality and a higher survival rate compared with RD. The therapeutic benefit of KRD is, however, most apparent during the initial recurrence. Similar findings were obtained by Japanese researchers conducting a multicenter real-world investigation using the Kansai Myeloma Forum database ( 60 ). They identified that 107 patients had received KRD therapy. The ORR was 68.2% and the median PFS and OS were 8.8 and 29 months, respectively. The results of 44 patients who had salvage high-dose chemotherapy (HDCT) plus ASCT following KRD reinduction were examined in a study on the use of KRD reinduction and salvage ASCT after first-line transplantation for RRMM ( 61 ). All patients had first-line high-dose chemotherapy plus ASCT (HDCT/ASCT), with a median progression time of 2.9 (1.2-13.5) years. After reinduction and before the salvage transplantation, 25/44 patients (57%) achieved VGPR; however, after salvage HDCT/ASCT, the percentage increased to 34/44 (77%). Given that the median PFS following rescue HDCT/ASCT was 23.3 months, KRD considerably prolonged PFS following rescue HDCT/ASCT and was enhanced by maintenance treatment.
5. Safety and tolerability
Neutropenia, thrombocytopenia and anemia
The Myeloma XI experiment was conducted at 110 National Health Service hospitals in England, Wales, and Scotland. It was an open-label, randomised, phase 3 adaptive design trial with three selection steps ( 72 ). Hematological adverse effects (AEs), such as neutropenia [362 (33%) patients], thrombocytopenia [72 (7%) patients], and anemia [42 (4%) patients], were the most frequent grade 3 or 4 AEs among lenalidomide users. Compared with 150 (17%) of the 874 individuals under observation, 494 (45%) of the 1,097 patients receiving lenalidomide experienced serious AEs. Therefore, complete blood counts, including white blood cells and their counts, platelet counts, hemoglobin, and hematocrit, should be checked weekly at baseline and during the first 8 weeks of lenalidomide treatment, and monthly thereafter. If neutropenia is present, physicians should consider treating the patient with growth factors (G-CSF). Dose adjustments in the event of grade 3 or 4 thrombocytopenia or neutropenia should be made by an experienced physician with reference to the medication package insert. Following the development of hematologic toxicity, if continued lenalidomide therapy results in improved bone marrow function (no hematologic toxicity for at least two consecutive cycles and an absolute neutrophil count ≥1.5x10 9 /l and platelet count ≥100x10 9 /l at the start of a new cycle using the current dose level), and the lenalidomide dose can be reinstated to the original level.
Thyroid dysfunction
Cases of hypothyroidism and hyperthyroidism have been reported in patients taking lenalidomide ( 73 ). Effective management of comorbidities affecting thyroid function should be achieved prior to treatment with lenalidomide. The authors recommend continuous monitoring of thyroid function at baseline and during treatment.
Peripheral neuropathy
One of the main reasons that has caused numerous physicians to abandon the use of thalidomide is peripheral neuropathy ( 74 ). No worsening of peripheral neuropathy was observed in patients with NDMM treated with long-term lenalidomide ( 37 ). In a prospective clinical and neurophysiological study of long-term neurotoxicity of lenalidomide applications, investigators confirmed that the neuropathy induced by lenalidomide is usually subclinical or mild. Neurotoxicity was independent of cumulative lenalidomide dose and hematologic response ( 75 ).
Tumor lysis syndrome
Due to the antitumor activity of lenalidomide, the complication of tumor lysis syndrome (TLS) may occur. However, there have been rare reports of TLS in patients with MM treated with lenalidomide. Nonetheless, caution should be exercised when administering lenalidomide to patients with a high pre-treatment tumor load, and these patients should be closely monitored, with particular attention to the first cycle, and appropriate precautions taken.
Severe skin reactions (including allergic reactions)
Angioedema, hypersensitivity, and severe skin reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS), have been reported with the use of lenalidomide ( 76-78 ). DRESS may be associated with skin reactions (for example, rash or epidermal exfoliative dermatitis), eosinophilia, fever, and/or systemic complications of lymphadenopathy, such as hepatitis, nephritis, pneumonia, myocarditis, and/or pericarditis ( 78 ). These events can have fatal consequences. In addition, lenalidomide should be avoided in patients who have experienced a grade 4 rash with prior thalidomide use. If a grade 2-3 rash occurs, suspending or discontinuing the drug should be considered. If angioedema, hypersensitivity, grade 4 rash, exfoliative or maculopapular rash, or suspected SJS, TEN, and DRESS occur, the drug must be discontinued and must not be restarted after these reactions have resolved.
Second primary tumor
In a retrospective pooled analysis of 11 clinical trials of lenalidomide for RRMM, the overall incidence rate (IR, events per 100 patient-years) of second primary malignancies (SPM) was 3.62. The IR for aggressive SPM (hematologic and solid tumors) was 2.08, which was in line with background cancer incidence. Non-invasive second primary tumors include basal cell or squamous cell skin cancers. In another analysis, pooled data from pivotal phase 3 trials of relapsed or refractory MM (N=703) showed an IR of 3.98 (95% CI, 2.51-6.31) for SPM with lenalidomide/dexamethasone and 1.38 (95% CI, 0.44-4.27) for placebo/dexamethasone ( 79 ). When considering treatment with lenalidomide, the physician should weigh both the potential benefit of lenalidomide and the risk of a second primary malignancy.
Hepatotoxicity
Liver failure, including death, has been reported in patients treated with lenalidomide in combination with other drugs ( 80 , 81 ). The mechanism of drug-induced severe hepatotoxicity is not known, but in some cases, preexisting viral liver disease, elevated baseline liver enzymes and treatment with antibiotics may also be a risk factor. Commonly, abnormal liver function test values were reported, which were generally asymptomatic and reversible with suspension of dosing. Once parameters return to baseline values, treatment at a lower dose may be considered. Lenalidomide is excreted through the kidneys ( 36 ). Dose adjustment in patients with renal insufficiency is particularly important to avoid higher hematological adverse effects or hepatotoxicity that may result from elevated blood levels. Hepatic function monitoring may be indicated by the clinician, particularly if there has been a history of viral liver infection or concurrent viral liver infection, or if lenalidomide is used in combination with medications known to cause abnormalities in liver function.
Infections
Patients with MM are more likely to develop infections, including pneumonia ( 72 ). For patients with NDMM, treatment with lenalidomide in combination with dexamethasone was associated with a higher incidence of infection in the former compared with treatment with melphalan, prednisone, and thalidomide (MPT) ( 82 , 83 ). For patients with NDMM previously treated with ASCT, maintenance therapy with lenalidomide was associated with a higher incidence of infection in the former compared with placebo ( 84 ). All patients should seek immediate medical attention at the first sign of infection (for example, cough and fever) for empirical anti-infective treatment by a hematologist. Cases of viral reactivation, including severe cases of re-inactivation of herpes zoster ( 85 ) or hepatitis B virus (HBV) ( 86 ), have been reported in patients treated with lenalidomide. Some cases of herpes zoster turn into disseminated herpes zoster, herpes zoster meningitis, or ocular herpes zoster, requiring suspension or permanent discontinuation of lenalidomide therapy and adequate antiviral therapy. Patients with prior HBV infection and treated with lenalidomide have progressed to acute liver failure in some cases, leading to discontinuation of lenalidomide and adequate antiviral therapy. HBV status should be clarified prior to initiating lenalidomide therapy. For patients who have tested positive for HBV infection, it is recommended to consult a specialist experienced in the treatment of hepatitis B. Lenalidomide should be used with caution in patients with a history of HBV infection, including those who are anti-HBc antibody-positive but HBsAg-negative. These patients should be closely monitored for signs and symptoms of active HBV infection throughout the course of treatment.
Venous and arterial thromboembolism
Lenalidomide combined with dexamethasone for the treatment of patients with MM increases the risk of venous thrombosis (especially the risk of deep vein thrombosis and pulmonary embolism) ( 87 ). Clinicians routinely apply aspirin or rivaroxaban to prevent thrombosis ( 88 ). Lenalidomide in combination with dexamethasone for the treatment of patients with MM increases the risk of arterial thrombosis (especially myocardial infarction and cerebrovascular events), and the risk of arterial thrombosis is lower when lenalidomide is combined with melphalan and prednisone. Lenalidomide monotherapy is associated with a lower risk of arterial thrombosis than lenalidomide in combination with other drugs for the treatment of MM ( 89 ).
Teratogenicity
Thalidomide, the first-generation IMiD, was once recommended as a sedative antiemetic for pregnant women to reduce their pregnancy reactions before being used as a therapeutic agent for MM ( 90 ), which was withdrawn due to its teratogenicity ( 91 ). Lenalidomide has been shown to be teratogenic, as its predecessor, thalidomide ( 92 ). Hui et al used pregnant cynomolgus monkeys to study the teratogenic potential of lenalidomide ( 93 ). All of the fetuses of the lenalidomide-treated group had deformities upon external fetal inspection, including anomalies of the upper and lower limbs. Therefore, lenalidomide is contraindicated in pregnant women and women who are likely to become pregnant if all contraceptive requirements have not been met.
Tolerability
Cereblon (CRBN) is the central target molecule for lenalidomide. It is suggested that the emergence of lenalidomide resistance is influenced by low CRBN expression, CRBN mutations, and genes encoding downstream proteins ( 94 ). In addition, in a prospective multicenter, single-arm clinical trial, researchers combined longitudinal single-cell RNA sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. This study revealed new MM molecular resistance pathways including hypoxia tolerance, protein folding and mitochondrial respiration, and it was identified that peptidyl prolyl isomerase A (PPIA), a central enzyme in the protein folding reaction pathway, may be a new target for drug-resistant MM. CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small-molecule inhibitor (cyclosporine) markedly sensitized MM tumor cells to proteasome inhibitors ( 95 ). Hematological grade 4 or nonhematological grade 3/4 AEs and drug resistance are the main factors that lead to lenalidomide discontinuation in clinical research and in clinical practice ( 37 , 96 ).
6. Dosage in special populations
Medications for patients with renal insufficiency
No dose adjustment is required for patients with creatinine clearance (CLcr) ≥60 ml/min. Dose adjustments should be made for patients with CLcr <60 ml/min at the start of treatment. Lenalidomide can be administered at a full dose of 25 mg per day 21/28 (daily on days 1-21 of each repetitive 28-day cycle) in patients with a CLcr >30 and can be given daily to patients with a CLcr <30, even on dialysis, at a dose of at least 15 mg per day ( 97 ).
Elderly patients
In a multicenter, open-label, phase 3 FIRST trial (MM-020/IFM07-01), of the 1,623 patients receiving medication in the present study, 94% (1,521/1,623) were 65 years or older and 35% (561/1,623) were 75 years or older. The 1,623 were randomly assigned to the following three groups: Rd in 28-day cycles until disease progression (Rd pers), to the same combination for 18 cycles (Rd18), or to MPT for 72 weeks. The proportion of patients >75 years of age was similar across study groups (Rd pers, 33%; Rd18, 34%; MPT, 33%). The incidence of most adverse reaction categories (for example, all adverse reactions, grade 3/4 AEs, serious adverse reactions) was higher in older subjects (>75 years of age) than in younger subjects (≤75 years of age) in all treatment groups. Grade 3/4 AEs were consistently reported at higher rates for systemic disease and site-of-administration status body systems in older subjects than in younger subjects in all groups (difference of at least 5%). The incidence of grade 3 or 4 AEs for infections and contagions, cardiac diseases (including heart failure and congestive heart failure), skin and subcutaneous tissue diseases, and renal and urologic diseases (including renal failure) was consistently slightly higher in older subjects than in younger subjects in all groups (<5% difference). These trends were not clear with respect to the incidence of grade 3/4 adverse reactions in other body systems (for example, blood and lymphatic system disorders, infections and infectious heart disease, and vascular disease). The incidence of serious adverse reactions was generally higher in older subjects than in younger subjects in all groups ( 83 ). In another study, the population pharmacokinetic analysis included patients of advanced age, and the results of the analysis showed no effect of age on the clearance (plasma exposure) of lenalidomide ( 98 ). Because elderly patients are more likely to have decreased renal function, caution should be exercised in dose selection and renal function should be monitored.
Pregnant and lactating women
As already mentioned, lenalidomide should be contraindicated during pregnancy. Women who are at risk of becoming pregnant should use effective contraception. If a female patient becomes pregnant while using lenalidomide, treatment must be discontinued and she is asked to seek evaluation and advice from a physician with expertise or experience in teratology. It is uncertain whether lenalidomide is secreted through human milk; therefore, it is recommended that breastfeeding women discontinue breastfeeding during treatment with lenalidomide.
7. Conclusion
Lenalidomide, a second-generation IMiD, is highly regarded in the treatment of patients with NDMM and RRMM owing to its several advantages over thalidomide, which is a first-generation immunosuppressant. Lenalidomide kills MM cells in diverse ways, including through direct induction and immune modulation. Lenalidomide is an oral medication that is quickly and well absorbed; however, the renal function of the patient taking it is affected in terms of the plasma exposure concentration. Lenalidomide has a variety of uses in the treatment of MM, including induction therapy and maintenance therapy. It can also be used in combination with other medications such as dexamethasone, PIs, and CD38 monoclonal antibodies. Although several clinical trials have revealed positive outcomes with lenalidomide, there is less real-world research evidence for NDMM relative to RRMM. Despite the fact that the neurological side-effects of lenalidomide, particularly those affecting the peripheral nerves, are markedly reduced compared with those of thalidomide, the clinical application of lenalidomide should be cautious, especially in relation to its performance in the blood system, infections, thrombosis, teratogenic potential and other unpleasant responses.
Acknowledgements
Not applicable.
Availability of data and materials
Not applicable.
Authors' contributions
CWZ was responsible for the conception and writing of the article. YNW collected information and XLG approved the articles and performed modifications with regard to language editing. All authors read and approved the final version of the manuscript. Data authentication is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
1 Bird SA Boyd K 9. Multiple myeloma: An overview of management Palliat Care Soc Pract 13 1178224219868235 2019 10.1177/1178224219868235 32215370 PMC7065505
2 Nijhof IS van de Donk NWCJ Zweegman S Lokhorst HM Current and new therapeutic strategies for relapsed and refractory multiple myeloma: An update Drugs 78 19 37 2018 10.1007/s40265-017-0841-y 29188449 PMC5756574
3 Shah UA Mailankody S Emerging immunotherapies in multiple myeloma BMJ 370 m3176 2020 10.1136/bmj.m3176 32958461
4 Pinto V Bergantim R Caires HR Seca H Guimarães JE Vasconcelos MH Multiple Myeloma: Available therapies and causes of drug resistance Cancers (Basel) 12 407 2020 10.3390/cancers12020407 32050631 PMC7072128
5 Cowan AJ Green DJ Kwok M Lee S Coffey DG Holmberg LA Tuazon S Gopal AK Libby EN Diagnosis and management of multiple myeloma: A review JAMA 327 464 477 2022 10.1001/jama.2022.0003 35103762
6 Delforge M Vlayen S Kint N Immunomodulators in newly diagnosed multiple myeloma: Current and future concepts Expert Rev Hematol 14 365 376 2021 10.1080/17474086.2021.1905513 33733978
7 Burgess J Ferdousi M Gosal D Boon C Matsumoto K Marshall A Mak T Marshall A Frank B Malik RA Alam U Chemotherapy-Induced peripheral neuropathy: Epidemiology, pathomechanisms and treatment Oncol Ther 9 385 450 2021 10.1007/s40487-021-00168-y 34655433 PMC8593126
8 Tageja N Lenalidomide-current understanding of mechanistic properties Anticancer Agents Med Chem 11 315 326 2011 10.2174/187152011795347487 21426296
9 Cives M Simone V Brunetti O Longo V Silvestris F Novel lenalidomide-based combinations for treatment of multiple myeloma Crit Rev Oncol Hematol 85 9 20 2013 10.1016/j.critrevonc.2012.06.008 22809697
10 Quach H Kalff A Spencer A Lenalidomide in multiple myeloma: Current status and future potential Am J Hematol 87 1089 1095 2012 10.1002/ajh.23234 22641420
11 Jabbour E Thomas D Kantarjian H Zhou L Pierce S Cortes J Verstovsek S Comparison of thalidomide and lenalidomide as therapy for myelofibrosis Blood 118 899 902 2011 10.1182/blood-2010-12-325589 21622644 PMC4186644
12 Kotla V Goel S Nischal S Heuck C Vivek K Das B Verma A Mechanism of action of lenalidomide in hematological malignancies J Hematol Oncol 2 36 2009 10.1186/1756-8722-2-36 19674465 PMC2736171
13 Tawara K Scott H Emathinger J Ide A Fox R Greiner D LaJoie D Hedeen D Nandakumar M Oler AJ Co- Expression of VEGF and IL-6 Family Cytokines is Associated with Decreased Survival in HER2 Negative Breast Cancer Patients: Subtype-Specific IL-6 Family Cytokine-Mediated VEGF Secretion Transl Oncol 12 245 255 2019 10.1016/j.tranon.2018.10.004 30439625 PMC6234768
14 Matthes T Manfroi B Huard B Revisiting IL-6 antagonism in multiple myeloma Crit Rev Oncol Hematol 105 1 4 2016 10.1016/j.critrevonc.2016.07.006 27497026
15 Zhou J Shen Q Lin H Hu L Li G Zhang X Decitabine shows potent anti-myeloma activity by depleting monocytic myeloid-derived suppressor cells in the myeloma microenvironment J Cancer Res Clin Oncol 145 329 336 2019 10.1007/s00432-018-2790-6 30426212 PMC11810327
16 Díaz T Rodríguez V Lozano E Mena MP Calderón M Rosiñol L Martínez A Tovar N Pérez-Galán P Bladé J The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling Haematologica 102 1776 1784 2017 10.3324/haematol.2017.164632 28751557 PMC5622862
17 Kulikov AV Shilov ES Mufazalov IA Gogvadze V Nedospasov SA Zhivotovsky B Cytochrome c: The Achilles' heel in apoptosis Cell Mol Life Sci 69 1787 1797 2012 10.1007/s00018-011-0895-z 22179840 PMC11114681
18 Li L Hua Y Dong M Li Q Smith DT Yuan M Jones KR Ren J Short-term lenalidomide (Revlimid) administration ameliorates cardiomyocyte contractile dysfunction in ob/ob obese mice Obesity (Silver Spring) 20 2174 2185 2012 10.1038/oby.2012.106 22522886
19 Zhou L Huang X Niesvizky R Pu Z Xu G Caspase-8 regulates the antimyeloma activity of bortezomib and lenalidomide J Pharmacol Exp Ther 379 303 309 2021 10.1124/jpet.121.000818 34588172
20 Zhou L Caspase-8: Friend or Foe in bortezomib/lenalidomide-based therapy for myeloma Front Oncol 12 861709 2022 10.3389/fonc.2022.861709 35321428 PMC8936587
21 Felici C Passarelli A Cafforio P Racanelli V Leone P Tucci M Lenalidomide arrests cell cycle and modulates PD1-dependent downstream mTOR intracellular signals in melanoma cells Melanoma Res 33 357 363 2023 10.1097/CMR.0000000000000913 37451673
22 Wong AH Shin EM Tergaonkar V Chng WJ Targeting NF-κB signaling for multiple myeloma Cancers (Basel) 12 2203 2020 10.3390/cancers12082203 32781681 PMC7463546
23 Li S Pal R Monaghan SA Schafer P Ouyang H Mapara M Galson DL Lentzsch S IMiD immunomodulatory compounds block C/EBP{beta} translation through eIF4E down-regulation resulting in inhibition of MM Blood 117 5157 5165 2011 10.1182/blood-2010-10-314278 21389327 PMC3357942
24 Bou Zerdan M Nasr L Kassab J Saba L Ghossein M Yaghi M Dominguez B Chaulagain CP Adhesion molecules in multiple myeloma oncogenesis and targeted therapy Int J Hematol Oncol 11 IJH39 2022 10.2217/ijh-2021-0017 35663420 PMC9136637
25 Qu X Mei J Yu Z Zhai Z Qiao H Dai K Lenalidomide regulates osteocytes fate and related osteoclastogenesis via IL-1β/NF-κB/RANKL signaling Biochem Biophys Res Commun 501 547 555 2018 10.1016/j.bbrc.2018.05.035 29746861
26 Cho SF Lin L Xing L Li Y Wen K Yu T Hsieh PA Munshi N Wahl J Matthes K The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models Blood Adv 4 4195 4207 2020 10.1182/bloodadvances.2020002524 32898244 PMC7479960
27 Castelli R Cassin R Cannavò A Cugno M Immunomodulatory drugs: new options for the treatment of myelodysplastic syndromes Clin Lymphoma Myeloma Leuk 13 1 7 2013 10.1016/j.clml.2012.09.016 23153925
28 Neuber B Dai J Waraich WA Awwad MHS Engelhardt M Schmitt M Medenhoff S Witzens-Harig M Ho AD Goldschmidt H Hundemer M Lenalidomide overcomes the immunosuppression of regulatory CD8(+)CD28(-) T-cells Oncotarget 8 98200 98214 2017 10.18632/oncotarget.21516 29228683 PMC5716723
29 Richardson K Keam SP Zhu JJ Meyran D D'Souza C Macdonald S Campbell K Robbins M Bezman NA Todd K The efficacy of combination treatment with elotuzumab and lenalidomide is dependent on crosstalk between natural killer cells, monocytes and myeloma cells Haematologica 108 83 97 2023 10.3324/haematol.2021.279930 35770527 PMC9827168
30 Bodera P Stankiewicz W Immunomodulatory properties of thalidomide analogs: Pomalidomide and lenalidomide, experimental and therapeutic applications Recent Pat Endocr Metab Immune Drug Discov 5 192 196 2011 10.2174/187221411797265890 21913886
31 Benson DM Jr Bakan CE Mishra A Hofmeister CC Efebera Y Becknell B Baiocchi RA Zhang J Yu J Smith MK The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody Blood 116 2286 2294 2010 10.1182/blood-2010-02-271874 20460501 PMC3490105
32 Hallett WH Jing W Drobyski WR Johnson BD Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade Biol Blood Marrow Transplant 17 1133 1145 2011 10.1016/j.bbmt.2011.03.011 21536144
33 Tamura H Ishibashi M Yamashita T Tanosaki S Okuyama N Kondo A Hyodo H Shinya E Takahashi H Dong H Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma Leukemia 27 464 472 2013 10.1038/leu.2012.213 22828443
34 Chen N Kasserra C Reyes J Liu L Lau H Single-dose pharmacokinetics of lenalidomide in healthy volunteers: Dose proportionality, food effect, and racial sensitivity Cancer Chemother Pharmacol 70 717 725 2012 10.1007/s00280-012-1966-z 22955172
35 Chen N Weiss D Reyes J Liu L Kasserra C Wang X Zhou S Kumar G Weiss L Palmisano M No clinically significant drug interactions between lenalidomide and P-glycoprotein substrates and inhibitors: results from controlled phase I studies in healthy volunteers Cancer Chemother Pharmacol 73 1031 1039 2014 10.1007/s00280-014-2438-4 24659021 PMC4000408
36 Chen N Ye Y Liu L Reyes J Assaf MS Kasserra C Zhou S Palmisano M Lenalidomide at therapeutic and supratherapeutic doses does not prolong QTc intervals in the thorough QTc study conducted in healthy men Basic Clin Pharmacol Toxicol 113 179 186 2013 10.1111/bcpt.12081 23639045 PMC3884770
37 Larocca A Bonello F Gaidano G D'Agostino M Offidani M Cascavilla N Capra A Benevolo G Tosi P Galli M Dose/schedule-adjusted Rd-R vs continuous Rd for elderly, intermediate-fit patients with newly diagnosed multiple myeloma Blood 137 3027 3036 2021 10.1182/blood.2020009507 33739404
38 Lund J Gruber A Lauri B Duru AD Blimark C Swedin A Hansson M Forsberg K Ahlberg L Carlsson C Lenalidomide versus lenalidomide + dexamethasone prolonged treatment after second-line lenalidomide + dexamethasone induction in multiple myeloma Cancer Med 7 2256 2268 2018 10.1002/cam4.1422 29673108 PMC6010717
39 Durie BGM Hoering A Abidi MH Rajkumar SV Epstein J Kahanic SP Thakuri M Reu F Reynolds CM Sexton R Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial Lancet 389 519 527 2017 10.1016/S0140-6736(16)31594-X 28017406 PMC5546834
40 Mohammad NS Nazli R Zafar H Fatima S Effects of lipid based Multiple Micronutrients Supplement on the birth outcome of underweight pre-eclamptic women: A randomized clinical trial Pak J Med Sci 38 219 226 2022 10.12669/pjms.38.1.4396 35035429 PMC8713215
41 Zou Y Lin M Sheng Z Niu S Bortezomib and lenalidomide as front-line therapy for multiple myeloma Leuk Lymphoma 55 2024 2031 2014 10.3109/10428194.2013.847935 24067138
42 Joseph NS Kaufman JL Dhodapkar MV Hofmeister CC Almaula DK Heffner LT Gupta VA Boise LH Lonial S Nooka AK Long-Term follow-up results of lenalidomide, bortezomib, and dexamethasone induction therapy and risk-adapted maintenance approach in newly diagnosed multiple myeloma J Clin Oncol 38 1928 1937 2020 10.1200/JCO.19.02515 32298201 PMC7587409
43 McCaughan GJ Gandolfi S Moore JJ Richardson PG Lenalidomide, bortezomib and dexamethasone induction therapy for the treatment of newly diagnosed multiple myeloma: A practical review Br J Haematol 199 190 204 2022 10.1111/bjh.18295 35796524 PMC9796722
44 Goldschmidt H Mai EK Bertsch U Fenk R Nievergall E Tichy D Besemer B Dürig J Schroers R von Metzler I Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma (GMMG-HD7): Part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial Lancet Haematol 9 e810 e821 2022 10.1016/S2352-3026(22)00263-0 36328040
45 Voorhees PM Kaufman JL Laubach J Sborov DW Reeves B Rodriguez C Chari A Silbermann R Costa LJ Anderson LD Jr Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial Blood 136 936 945 2020 10.1182/blood.2020005288 32325490 PMC7441167
46 Attal M Lauwers-Cances V Hulin C Leleu X Caillot D Escoffre M Arnulf B Macro M Belhadj K Garderet L Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma N Engl J Med 376 1311 1320 2017 10.1056/NEJMoa1611750 28379796 PMC6201242
47 O'Donnell EK Laubach JP Yee AJ Chen T Huff CA Basile FG Wade PM Paba-Prada CE Ghobrial IM Schlossman RL A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma Br J Haematol 182 222 230 2018 10.1111/bjh.15261 29740809 PMC6074026
48 Iida S Wakabayashi M Tsukasaki K Miyamoto K Maruyama D Yamamoto K Takatsuka Y Kusumoto S Kuroda J Ando K Bortezomib plus dexamethasone vs thalidomide plus dexamethasone for relapsed or refractory multiple myeloma Cancer Sci 109 1552 1561 2018 10.1111/cas.13550 29478257 PMC5980148
49 Dimopoulos MA Laubach JP Echeveste Gutierrez MA Grzasko N Hofmeister CC San-Miguel JF Kumar S Labotka R Lu V Berg D Ixazomib maintenance therapy in newly diagnosed multiple myeloma: An integrated analysis of four phase I/II studies Eur J Haematol 102 494 503 2019 10.1111/ejh.13231 30943323
50 Kumar SK Berdeja JG Niesvizky R Lonial S Laubach JP Hamadani M Stewart AK Hari P Roy V Vescio R Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: Long-term follow-up including ixazomib maintenance Leukemia 33 1736 1746 2019 10.1038/s41375-019-0384-1 30696949 PMC6755968
51 Facon T Venner CP Bahlis NJ Offner F White DJ Karlin L Benboubker L Rigaudeau S Rodon P Voog E Oral ixazomib, lenalidomide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma Blood 137 3616 3628 2021 10.1182/blood.2020008787 33763699 PMC8462404
52 Patel KK Shah JJ Feng L Lee HC Manasanch EM Olsem J Morphey A Huo XJ Thomas SK Bashir Q Safety and efficacy of combination maintenance therapy with ixazomib and lenalidomide in patients with posttransplant myeloma Clin Cancer Res 28 1277 1284 2022 10.1158/1078-0432.CCR-21-3420 34992070 PMC9365361
53 Richardson PG Kumar SK Masszi T Grzasko N Bahlis NJ Hansson M Pour L Sandhu I Ganly P Baker BW Final overall survival analysis of the TOURMALINE-MM1 phase III trial of ixazomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma J Clin Oncol 39 2430 2442 2021 10.1200/JCO.21.00972 34111952
54 Takakuwa T Yamamura R Ohta K Kaneko H Imada K Nakaya A Fuchida SI Shibayama H Matsuda M Shimazu Y Outcomes of ixazomib/lenalidomide/dexamethasone for multiple myeloma: A multicenter retrospective analysis Eur J Haematol 106 555 562 2021 10.1111/ejh.13586 33476404
55 Jakubowiak A Usmani SZ Krishnan A Lonial S Comenzo RL Wang J de Boer C Deraedt W Weiss BM Schecter JM Chari A Daratumumab plus carfilzomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma Clin Lymphoma Myeloma Leuk 21 701 710 2021 10.1016/j.clml.2021.05.017 34274290
56 Kumar SK Jacobus SJ Cohen AD Weiss M Callander N Singh AK Parker TL Menter A Yang X Parsons B Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): A multicentre, open-label, phase 3, randomised, controlled trial Lancet Oncol 21 1317 1330 2020 10.1016/S1470-2045(20)30452-6 32866432 PMC7591827
57 Jasielec JK Kubicki T Raje N Vij R Reece D Berdeja J Derman BA Rosenbaum CA Richardson P Gurbuxani S Carfilzomib, lenalidomide, and dexamethasone plus transplant in newly diagnosed multiple myeloma Blood 136 2513 2523 2020 10.1182/blood.2020007522 32735641 PMC7714092
58 Roussel M Lauwers-Cances V Wuilleme S Belhadj K Manier S Garderet L Escoffre-Barbe M Mariette C Benboubker L Caillot D Up-front carfilzomib, lenalidomide, and dexamethasone with transplant for patients with multiple myeloma: the IFM KRd final results Blood 138 113 121 2021 10.1182/blood.2021010744 33827114
59 Siegel DS Dimopoulos MA Ludwig H Facon T Goldschmidt H Jakubowiak A San-Miguel J Obreja M Blaedel J Stewart AK Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma J Clin Oncol 36 728 734 2018 10.1200/JCO.2017.76.5032 29341834
60 Onda Y Kanda J Kaneko H Shimura Y Fuchida SI Nakaya A Itou T Yamamura R Tanaka H Shibayama H Real-world effectiveness and safety analysis of carfilzomib-lenalidomide-dexamethasone and carfilzomib-dexamethasone in relapsed/refractory multiple myeloma: a multicenter retrospective analysis Ther Adv Hematol 13 20406207221104584 2022 10.1177/20406207221104584 35785245 PMC9240591
61 Baertsch MA Fougereau M Hielscher T Sauer S Breitkreutz I Jordan K Müller-Tidow C Goldschmidt H Raab MS Hillengass J Giesen N Carfilzomib, lenalidomide, and dexamethasone followed by salvage autologous stem cell transplant with or without maintenance for relapsed or refractory multiple myeloma Cancers (Basel) 13 4706 2021 10.3390/cancers13184706 34572934 PMC8472377
62 Bazarbachi AH Al Hamed R Malard F Bazarbachi A Harousseau JL Mohty M Induction therapy prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma: An update Blood Cancer J 12 47 2022 10.1038/s41408-022-00645-1 35347107 PMC8960754
63 Pulte ED Dmytrijuk A Nie L Goldberg KB McKee AE Farrell AT Pazdur R FDA approval summary: Lenalidomide as maintenance therapy after autologous stem cell transplant in newly diagnosed multiple myeloma Oncologist 23 734 739 2018 10.1634/theoncologist.2017-0440 29438096 PMC6067941
64 Liu J Zhao R Jiang X Li Z Zhang B Progress on the application of bortezomib and bortezomib-based nanoformulations Biomolecules 12 51 2021 10.3390/biom12010051 35053199 PMC8773474
65 Yang MH Jung SH Chinnathambi A Alahmadi TA Alharbi SA Sethi G Ahn KS Attenuation of STAT3 signaling cascade by daidzin can enhance the apoptotic potential of bortezomib against multiple myeloma Biomolecules 10 23 2019 10.3390/biom10010023 31878046 PMC7022648
66 Medhekar R Ran T Fu AZ Patel S Kaila S Real-world patient characteristics and treatment outcomes among nontransplanted multiple myeloma patients who received Bortezomib in combination with Lenalidomide and Dexamethasone as first line of therapy in the United States BMC Cancer 22 901 2022 10.1186/s12885-022-09980-9 35982416 PMC9386920
67 Harousseau JL Mohty M Daratumumab in transplant regimens for myeloma? Blood 136 917 918 2020 10.1182/blood.2020006298 32818244
68 Goicoechea I Puig N Cedena MT Burgos L Cordón L Vidriales MB Flores-Montero J Gutierrez NC Calasanz MJ Ramos MM Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard- and high-risk myeloma Blood 137 49 60 2021 10.1182/blood.2020006731 32693406
69 Shirley M Ixazomib: First global approval Drugs 76 405 411 2016 10.1007/s40265-016-0548-5 26846321
70 Arastu-Kapur S Anderl JL Kraus M Parlati F Shenk KD Lee SJ Muchamuel T Bennett MK Driessen C Ball AJ Kirk CJ Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: A link to clinical adverse events Clin Cancer Res 17 2734 2743 2011 10.1158/1078-0432.CCR-10-1950 21364033
71 Jayaweera SPE Wanigasinghe Kanakanamge SP Rajalingam D Silva GN Carfilzomib: A promising proteasome inhibitor for the treatment of relapsed and refractory multiple myeloma Front Oncol 11 740796 2021 10.3389/fonc.2021.740796 34858819 PMC8631731
72 Jackson GH Davies FE Pawlyn C Cairns DA Striha A Collett C Hockaday A Jones JR Kishore B Garg M Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): A multicentre, open-label, randomised, phase 3 trial Lancet Oncol 20 57 73 2019 10.1016/S1470-2045(18)30687-9 30559051 PMC6318225
73 Hamnvik OP Larsen PR Marqusee E Thyroid dysfunction from antineoplastic agents J Natl Cancer Inst 103 1572 1587 2011 10.1093/jnci/djr373 22010182 PMC3206040
74 Koeppen S Treatment of multiple myeloma: Thalidomide-, bortezomib-, and lenalidomide-induced peripheral neuropathy Oncol Res Treat 37 506 513 2014 10.1159/000365534 25231692
75 Dalla Torre C Zambello R Cacciavillani M Campagnolo M Berno T Salvalaggio A De March E Barilà G Lico A Lucchetta M Lenalidomide long-term neurotoxicity: Clinical and neurophysiologic prospective study Neurology 87 1161 1166 2016 10.1212/WNL.0000000000003093 27534712
76 Patrizi A Venturi M Dika E Maibach H Tacchetti P Brandi G Cutaneous adverse reactions linked to targeted anticancer therapies bortezomib and lenalidomide for multiple myeloma: new drugs, old side effects Cutan Ocul Toxicol 33 1 6 2014 10.3109/15569527.2013.787086 23638756
77 Tinsley SM Kurtin SE Ridgeway JA Practical management of lenalidomide-related rash Clin Lymphoma Myeloma Leuk 15 (Suppl) S64 S69 2015 10.1016/j.clml.2015.02.008 26297281
78 Shanbhag A Pritchard ER Chatterjee K Hammond DA highly probable drug reaction with eosinophilia and systemic symptoms syndrome associated with lenalidomide Hosp Pharm 52 408 411 2017 10.1177/0018578717717394 29276264 PMC5735696
79 Dimopoulos MA Richardson PG Brandenburg N Yu Z Weber DM Niesvizky R Morgan GJ A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide Blood 119 2764 2767 2012 10.1182/blood-2011-08-373514 22323483
80 Nojkov B Signori C Konda A Fontana RJ Lenalidomide-associated hepatotoxicity-a case report and literature review Anticancer Res 32 4117 4119 2012 22993370
81 Hussain S Browne R Chen J Parekh S Lenalidomide-induced severe hepatotoxicity Blood 110 3814 2007 10.1182/blood-2007-06-097758 17984315
82 Facon T Dimopoulos MA Dispenzieri A Catalano JV Belch A Cavo M Pinto A Weisel K Ludwig H Bahlis NJ Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma Blood 131 301 310 2018 10.1182/blood-2017-07-795047 29150421 PMC5774211
83 Benboubker L Dimopoulos MA Dispenzieri A Catalano J Belch AR Cavo M Pinto A Weisel K Ludwig H Bahlis N Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma N Engl J Med 371 906 917 2014 10.1056/NEJMoa1402551 25184863
84 Richardson PG Jacobus SJ Weller EA Hassoun H Lonial S Raje NS Medvedova E McCarthy PL Libby EN Voorhees PM Triplet Therapy, transplantation, and maintenance until progression in myeloma N Engl J Med 387 132 147 2022 10.1056/NEJMoa2204925 35660812 PMC10040899
85 Nucci M Anaissie E Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents Clin Infect Dis 49 1211 1225 2009 10.1086/605664 19769539
86 Kikuchi T Kusumoto S Tanaka Y Oshima Y Fujinami H Suzuki T Totani H Kinoshita S Asao Y Narita T Hepatitis B virus reactivation in a myeloma patient with resolved infection who received daratumumab-containing salvage chemotherapy J Clin Exp Hematop 60 51 54 2020 10.3960/jslrt.19034 32404569 PMC7337267
87 Kekre N Connors JM Venous thromboembolism incidence in hematologic malignancies Blood Rev 33 24 32 2019 10.1016/j.blre.2018.06.002 30262170
88 Piedra K Peterson T Tan C Orozco J Hultcrantz M Hassoun H Mailankody S Lesokhin A Shah U Lu S Comparison of venous thromboembolism incidence in newly diagnosed multiple myeloma patients receiving bortezomib, lenalidomide, dexamethasone (RVD) or carfilzomib, lenalidomide, dexamethasone (KRD) with aspirin or rivaroxaban thromboprophylaxis Br J Haematol 196 105 109 2022 10.1111/bjh.17772 34396516 PMC9527668
89 Bradbury CA Craig Z Cook G Pawlyn C Cairns DA Hockaday A Paterson A Jenner MW Jones JR Drayson MT Thrombosis in patients with myeloma treated in the Myeloma IX and Myeloma XI phase 3 randomized controlled trials Blood 136 1091 1104 2020 10.1182/blood.2020005125 32438407 PMC7453153
90 Bwire R Freeman J Houn F Managing the teratogenic risk of thalidomide and lenalidomide: An industry perspective Expert Opin Drug Saf 10 3 8 2011 10.1517/14740338.2011.527331 21121869
91 Somers GS Thalidomide and congenital abnormalities Lancet 1 912 913 1962 10.1016/s0140-6736(62)91943-8 13915092
92 Mueller M Lewis DJ Implementation of a pregnancy prevention programme (PPP) with a controlled distribution system (CDS) for the generic teratogenic phthalimides thalidomide, lenalidomide and pomalidomide Ther Innov Regul Sci 55 1155 1164 2021 10.1007/s43441-021-00327-3 34331266
93 Hui JY Fuchs A Kumar G Embryo-fetal exposure and developmental outcome of lenalidomide following oral administration to pregnant cynomolgus monkeys Reprod Toxicol 114 57 65 2022 10.1016/j.reprotox.2022.10.005 36309155
94 Zhu YX Shi CX Bruins LA Wang X Riggs DL Porter B Ahmann JM de Campos CB Braggio E Bergsagel PL Stewart AK Identification of lenalidomide resistance pathways in myeloma and targeted resensitization using cereblon replacement, inhibition of STAT3 or targeting of IRF4 Blood Cancer J 9 19 2019 10.1038/s41408-019-0173-0 30741931 PMC6370766
95 Cohen YC Zada M Wang SY Bornstein C David E Moshe A Li B Shlomi-Loubaton S Gatt ME Gur C Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing Nat Med 27 491 503 2021 10.1038/s41591-021-01232-w 33619369 PMC7612793
96 Bukowski K Kciuk M Kontek R Mechanisms of multidrug resistance in cancer chemotherapy Int J Mol Sci 21 3233 2020 10.3390/ijms21093233 32370233 PMC7247559
97 Mikhael J Manola J Dueck AC Hayman S Oettel K Kanate AS Lonial S Rajkumar SV Lenalidomide and dexamethasone in patients with relapsed multiple myeloma and impaired renal function: PrE1003, a PrECOG study Blood Cancer J 8 86 2018 10.1038/s41408-018-0110-7 30190454 PMC6127323
98 Chen N Zhou S Palmisano M Clinical pharmacokinetics and pharmacodynamics of lenalidomide Clin Pharmacokinet 56 139 152 2017 10.1007/s40262-016-0432-1 27351179 PMC5247551