Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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Advances in Clinical and Experimental Medicine

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doi: 10.17219/acem/168685

Publication type: review

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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Tyczyńska A, Zaucha J. At what point are we on the way to optimally treat multiple myeloma patients over 75 years of age in 2023? [published online as ahead of print on August 14, 2023]. Adv Clin Exp Med. 2024. doi:10.17219/acem/168685

At what point are we on the way to optimally treat multiple myeloma patients over 75 years of age in 2023?

Agata Tyczyńska1,A,B,C,D,E,F, Jan Zaucha1,A,C,D,E,F

1 Department of Hematology and Transplantology, University Clinical Center, Medical University of Gdańsk, Poland

Graphical abstract


Graphical abstracts

Abstract

Several novel drugs for multiple myeloma, including monoclonal and bispecific antibodies, immunomodulatory agents, and newer-generation proteasome inhibitors, have been introduced over the last decade. Based on the results of randomized clinical trials, the drugs have been incorporated into current treatment recommendations, with the most substantial changes observed in patients under the age of 75. However, new therapeutic options have been indirectly proposed for patients over 75, despite the lack of conclusive data from randomized prospective trials. This paper outlines the development of myeloma therapy and summarizes the current treatment recommendations for patients over 75 by systematically reviewing the most crucial studies involving this group of individuals, with a focus on evaluating treatment safety and efficacy. Melphalan–prednisone (MP), bortezomib plus MP (VMP), lenalidomide–dexamethasone (Rd), and bortezomib plus Rd (VRd) regimens have evolved over the past few years as therapies of choice for the first-line treatment of these patients. A breakthrough came with daratumumab, which increased response rates, extended median progression-free survival (PFS) and overall survival (OS) in the absence of significantly increased toxicity when added to the above regimens.

Key words: multiple myeloma, elderly, frailty, daratumumab, over 75 years of age

Background

Multiple myeloma patients over 75 years of age are an eminently heterogeneous group, ranging from very frail to relatively fit and independent. Tolerance of oncological treatments decreases with age and, as one ages, the presence of additional burdens, such as comorbidities, reduced compensatory capacity of internal organs, slower recovery, lower tolerance to adverse effects, simultaneous use of multiple drugs, psychomotor limitations, and less physical activity, develop. For these reasons, potential therapeutic options in this group of patients are limited. In addition, it is very difficult to predict individual tolerance to planned treatments. Myeloma-dedicated frailty status indices, such as the Myeloma Frailty Score, are helpful in treatment planning. Defining the intensity of treatment for an elderly myeloma patient should not only depend on the risk of the disease but also require an assessment of the mental, social and physical condition, an estimation of the life expectancy of the patient with and without myeloma, and predicting how the treatment and disease impact the patient’s quality of life. Therefore, the goal of therapy in this group of patients is not only to achieve a profound response and extend time free from disease progression but also to maintain intellectual and physical independence. The treatment of the elderly often requires a third person in terms of availability and organization of care.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11

Objectives

This literature review encompasses the available results of clinical trials published from 1960 to 2022 that involved patients over 75 years of age. An attempt was made to propose practical guidelines for clinicians on individualizing therapy in these patients in order to safely achieve the longest possible survival time with a preserved quality of life.

Epidemiology

Multiple myeloma accounts for approx. 13% of hematologic malignancies and 2% of all cancers in humans.2, 3, 4 Among the most common lymphoid tissue neoplasms, multiple myeloma is 2nd to chronic lymphocytic leukemia,1, 2, 3, 8, 9 and is one of the most common indications for hospitalization in hematology departments.2, 3

Multiple myeloma incidence increases with age, though its occurrence rates are influenced by increasing accessibility to a faster and earlier diagnosis.2, 3, 4, 5, 8 The highest incidence rates are observed in Australia and New Zealand (age-standardized incidence rates of 37.7/100,000 for males and 29.4/100,000 for females) and North America (16.4/100,000 for males and 11.7/100,000 for females), and the lowest in Asia (0.2/100,000 for both males and females in China), while in Europe the incidence rate is at 4.5–6/100,000. The incidence rate observed in Poland is similar to the European one: 4.36/100,000, including 4.84 for males and 3.89 for females.8, 9 The median age at diagnosis is 70 years,1, 2, 3, 4, 9 with more than 60% of patients over 65 and approx. 32–38% over 75 years of age.6, 7 The indications for treating multiple myeloma in elderly patients are the same as for younger patients. According to the International Myeloma Working Group (IMWG) guidelines, initiating treatment requires that symptomatic multiple myeloma is diagnosed along with Calcium Renal Anemia Bone (CRAB) symptoms with a score of 1–4 points, or one of the following changes are found in laboratory tests (so-called SLiM-Sixty, Light Chain, magnetic resonance imaging (MRI) criteria: points 5–7)1:

1. Hypercalcemia: serum calcium ≥1 mg/dL over the normal upper limit or >11 mg/dL (sign C);

2. Occurrence of renal failure associated with myeloma: creatinine >2 mg/dL or a glomerular filtration rate (GFR) <40 mL/min (sign R);

3. Anemia defined as a hemoglobin concentration of 2 g/dL below the normal lower limit or <10 g/dL (sign A);

4. Presence of bone disease in the course of myeloma (a minimum of 1 osteolytic focus detected by positron emission tomography (PET) or computed tomography (CT)) (sign B);

5. The percentage of clonal plasma cells in the bone marrow ≥60%;

6. A clonal to non-clonal light chain ratio >100, with a clonal light chain concentration of at least 100 mg/L;

7. Presence of at least 2 focal lesions on MRI of a minimum of 5 mm.

Treatment of elderly patients

The challenge in choosing the optimal treatment is to tailor it to the individual biology of the disease and the patient’s general condition. The first regimen used to treat multiple myeloma in elderly patients and those ineligible for an autotransplantation procedure was the melphalan–prednisone (MP) regimen, which has been in use since the 1960s.12 The addition of the first immunomodulatory drug, thalidomide, to the MP regimen (MPT) in 1999 increased progression-free survival (PFS) by approx. 6 months (from 18.5 to 24.1 months), and was based on a meta-analysis of 5 clinical trials (Table 1)13, 14, 15, 16, 17, 18, 19 that demonstrated overall survival (OS) to be prolonged by approx. 15 months.14 However, the improved treatment results were burdened by more than a 2.5-fold higher rate of grade 3 and 4 non-hematologic complications, mainly related to the use of thalidomide (the recommended dose at the time was as high as 200 mg/day), thromboembolic complications, peripheral polyneuropathies, lethargy, and skin lesions.13, 14, 19 The incidence of thromboembolic events was reduced in the GIMEMA and HOVON 49 trials by acetylsalicylic acid or low-molecular-weight heparin (2% to 3%) prophylaxis.13, 17 The IFM 01/01 study confirmed the safety and efficacy of the MPT regimen in patients older than 75, showing a prolonged median OS for MPT (44 months) compared to MP (29.1 months),14, 20 and it has been the recommended regimen in this age group since 2002.

In view of the relatively high toxicity of the 3-drug MPT regimen, an attempt was made to compare the 2-drug MP regimen to the thalidomide with dexamethasone (TD) regimen20, 21, 22, 23, 24 in elderly patients (trial No. NCT00205751). However, OS and PFS were shorter, despite achieving better responses in the experimental TD arm (19.8 months and 16.7 months compared to 41.3 months and 20.7 months for MP). In addition, the number of complications such as thromboembolic events, polyneuropathy, fatigue, infections, psychiatric disorders, and constipation was higher for the TD arm, mainly in patients over 75, which was probably related to the high doses of thalidomide and dexamethasone (the average dose administered was 200 mg/day of thalidomide and 40 mg of dexamethasone for the first 4 days of the cycle). The results indicated that the 3-drug regimen was more effective in older patients, but it was at the expense of greater toxicity, so the choice of the optimal treatment was still an open question.

New opportunities to determine optimal treatment in the elderly were created in 2005 with the registration of lenalidomide, a 2nd-generation immunomodulatory drug with less toxicity, especially in polyneuropathy and thrombotic events. The MM-015 trial, performed in patients over 65 and ineligible for transplantation, compared 3 regimens, namely MP, melphalan, prednisolone and lenalidomide (MPR) and MPR in the induction phase and maintenance treatment (MPR-R).22, 25, 26 The induction phase included 9 cycles of 28 days. The primary study endpoint was achieved, and there was a marked improvement in median PFS time with the MPR-R regimen (≥31 months) compared to MPR (14 months) and MP (13 months). The MPR regimen outperformed MP as an induction regimen in terms of response rate, quality of response and overall response rate. However, in patients older than 75, the median time of PFS for MPR-R was 19 months, for MPR – 12 months, and for MP – 15 months. The failure to demonstrate better efficacy using MPR in this age group may have been due to an increased incidence of adverse effects, particularly hematologic toxicity, which was associated with a more frequent need for dose modifications. The most important observation of this study was that maintenance treatment with lenalidomide (10 mg) alone, administered on days 1 to 21 over a 28-day cycle, was associated with improvements in PFS regardless of age (median PFS time of 31 months, and 19 months for patients >75 years old) and an acceptable rate of hematologic adverse events in the form of asymptomatic cytopenias.

Another attempt aimed at determining the optimal treatment in elderly patients was made during the EMN01 trial between 2009 and 2012, which randomized newly diagnosed myeloma patients aged over 65 to 3 treatment arms: lenalidomide–dexamethasone (Rd), MPR, and cyclophosphamide, lenalidomide and prednisone (CRP).25 The PFS time after a 31-month follow-up period was 23 months for Rd, 27 months for MRP and 23 months for CPR (Rd compared to MPR, p = 0.216; Rd compared to CPR, p = 0.872; MPR compared to CPR, p = 0.148), while the PFS time in the subgroup of patients older than 75 was 22 months for Rd, 18 months for MPR and 21 months for CPR (Rd compared to MPR, p = 0.572; Rd compared to CPR, p = 0.699; MPR compared to CPR, p = 0.914).26 Adding an alkylating drug (melphalan or cyclophosphamide) to the lenalidomide and steroid combination showed no benefit in terms of PFS time in all patients. In contrast, the MPR regimen was burdened with a more than 60% rate of hematologic complications.26, 27 The above study clearly indicated that the 3-drug treatment is recommended for younger patients and that the optimal treatment approach for patients aged >75 years is a 2-drug regimen, such as lenalidomide plus a steroid. However, the decision over which type of steroid to use (dexamethasone in lower doses (20 mg once a week) or appropriately dosed prednisone) remained an unresolved issue.26, 27, 28

The NCT00098475 study provided important guidance on the treatment of the elderly, and its main goal was to identify the optimal dose of dexamethasone combined with lenalidomide. Two 28-day, 2-drug regimens of lenalidomide with dexamethasone were compared, with 1 arm receiving high doses of dexamethasone (40 mg for 4 days with 4 days off) and the other receiving 40 mg every 7 days. The lenalidomide dosage was 25 mg in both arms. The study was terminated early due to the significant safety advantage of lower doses of dexamethasone. High doses of dexamethasone yielded higher response rates for complete remission and had a very good partial response; however, this did not result in an improved PFS time. Indeed, the median PFS time for the high dose was 19.1 months (15.7–26.3), while the low dose resulted in PFS time of 25.3 months (22.3 – not reached, p = 0.026),26 and there was no correlation between the depth of response and the length of response. However, the trial was stopped after 1 year due to the better OS achieved with low-dose dexamethasone compared to the high dose. Nonetheless, it should be remembered that in certain cases, such as acute renal failure due to myeloma nephropathy, myeloma cord compression or aggressive refractory disease, high-dose steroids still play an important role in therapy.

Based on the results of the study outlined above, the Frontline Investigation of Lenalidomide + Dexamethasone versus Standard Thalidomide Trial-MM-020/IFM 07 01 (FIRST) study was designed for patients over 65 years of age and compared MPT (12 cycles of 42 days), Rd (18 cycles, Rd18) and Rd continuous regimens until disease progression (Table 2). In the Rd arms, doses of lenalidomide (25 mg) and dexamethasone (40 mg) were administered on days 1, 8, 15, and 22. Approximately 1/3 of the study participants were older than 75 years.28, 29 After 3 years of follow-up, the median PFS was 26 months for the Rd continuous regimen, 21 months for Rd18, and 21.9 months for MPT. Meanwhile, the median OS time was 59.1 months for the Rd continuous arm, 62.3 months for Rd18, and 49.1 months for MPT. The highest rate of hematologic complications was observed with the MPT regimen (45%).30 The most important achievement of this study was that it demonstrated the highest efficacy in terms of the number of achieved responses (overall response rate (ORR) = 75.1%) and the duration of response in patients older than 75. As such, the Rd continuous regimen extended the time to 2nd progression or death to 35 months, prolonged PFS to 26 months, and significantly increased OS to 59 months. Since publishing the results of the FIRST study, the Rd continuous regimen has been the recommended treatment for patients ineligible for autologous transplantation and the elderly. A significant advantage of this treatment option is the oral route of drug administration.

Unfortunately, the Rd regimen is not sufficiently effective in all elderly patients. Therefore, attempts have been made to determine the role of proteasome inhibitors in treating this group. Bortezomib was the first effective proteasome inhibitor and is still recommended for the treatment of both younger and older patients.1 Its main advantage over lenalidomide is the lack of nephrotoxicity, though it induces polyneuropathy in some patients, which is not dose-dependent, as with thalidomide. The VISTA study compared bortezomib plus MP (VMP) and MP regimens, with 30% of patients being over 75 years of age.29, 30, 31 Median PFS was prolonged to approx. 22 months in the VMP arm compared to 16.6 months in the MP arm (Table 2).28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 However, better PFS outcomes were burdened by a higher number of non-hematologic adverse events, mainly peripheral polyneuropathy. Subsequent studies evaluating the safety and efficacy of multidrug regimens using bortezomib for transplant-ineligible patients (VMP and bortezomib, thalidomide dexamethasone (VTd)), namely the GIMEMA BIW, GIMEMA Q7 and GEM2005MAS655 trials (in all studies, patients over 75 years of age accounted for 30%, 26% and 32%, respectively), demonstrated the same efficacy. The VISTA (21.7 months), GIMEMA BIW (25.2 months), GIMEMA QW (22.2 months), and GEM2005MAS65 trials (38 months) reported an increased median PFS, which was associated with once-weekly bortezomib maintenance treatment for up to 3 years instead of twice-weekly administration.40 The peripheral neuropathy (grade 3 and 4) incidence in the VISTA study was 13%, 14% in the GIMEMA BIW trial, 7% in the GEM2005MAS65 trial, and 2% in the GIMEMA QW trial.41

The UPFRONT trial, dedicated to determining the role of bortezomib in the treatment of the elderly (half of the patients were >75 years old), randomized participants into bortezomib dexamethasone (Vd), VTd and VMP arms.31 The median PFS time was similar for each regimen, that being 14.7 months for Vd, 15.4 months for VTd, and 17.3 months for VMP, with no significant differences in the incidence in grade 3 and 4 peripheral polyneuropathies in the Vd (24%), VTd (29%) or VMP (21%) arms.31, 34 As such, the study indicated the possibility of using a 2-drug regimen (Vd) in elderly patients, as it provided the same benefit as 3-drug regimens. However, it should be noted that it was possible to reduce the incidence of neurological complications by using bortezomib once a week.29, 30, 31, 42, 43

The above studies, similar to those evaluating lenalidomide, demonstrated the advantages of 2-drug regimens in patients over 75 years of age. However, the partners for lenalidomide and bortezomib were alkylating drugs (melphalan or Endoxan) or the relatively toxic thalidomide (VTd). In this regard, a key study in the elderly, in which patients over 75 accounted for 25.5% of participants, was the US SWOG S0777 trial comparing the bortezomib plus Rd (VRd) regimen (bortezomib, lenalidomide and dexamethasone) to the Rd regimen (lenalidomide and dexamethasone).34 Median PFS for patients over 75 treated with VRd was 39 months, compared to 20 months for those treated with the Rd regimen (p = 0.0037), while the median OS time was 63 months (VRd) compared to 31 months (Rd, p = 0.0250) (Table 2).34 Grade 3 adverse events occurred in 82% of patients in the VRd arm and in 75% of patients in the Rd arm. The most common hematologic adverse events attributed to the treatments were ≥grade 3 cytopenias in all 4 cell lines, and the most common ≥grade 3 non-hematologic adverse events were muscle weakness, fatigue, cardiac disorders, hyperglycemia, thrombosis, embolism, and diarrhea. As expected, neurological events graded 3 or higher, mainly peripheral polyneuropathy, were more frequent in the VRd (33%) group than in the Rd group (11%, p < 0.0001), though there was a balance between the 2 groups for all other events.

The SWOG 0777 study unequivocally showed improved PFS, OS, depth of response, and response rates using the VRd regimen while maintaining a relatively comparable safety profile to the Rd regimen.34 In addition, lower toxicity and additional improvements in survival can be expected with weekly subcutaneous administration of bortezomib.43

The results of the presented studies indicate that it is possible to safely use a 3-drug regimen in patients over 75 years of age, as the treatment offers the greatest benefit, with long OS and relatively well-tolerated drug toxicity. The VRd appears to be the safest of the 3-drug regimens. On the other hand, the Rd regimen, in an indirect comparison with VTd and VMP, provides similar benefits with less toxicity and is a good alternative in the absence of a 3-drug regimen, mainly in the presence of contraindications to bortezomib. However, using the VRd regimen in the elderly, despite its advantages, is not appropriate for all patients, primarily due to the risk of developing polyneuropathy and causing a decline in quality of life.

An attractive proposal for improving the efficacy of the 2-drug Rd regimen was the addition of daratumumab, which has a completely different mechanism of action than the drugs used so far. Daratumumab (D) is a human monoclonal antibody of the immunoglobulin (Ig)G1 class and is effective against the cluster of differentiation (CD)38 antigen. After binding to CD38, it strongly inhibits cell growth and cell adhesion to the microenvironment and has a direct anti-tumor effect. In addition, it is highly immunologically active and uses complement-dependent cytotoxicity (CDC) to induce tumor cell lysis and tumor cell death through an effector function mediated, for example, by natural killer (NK) cells, which it activates by cross-binding with the Fc receptor (ADCC). Moreover, daratumumab induced antibody-dependent cellular phagocytosis (ADCP), in which macrophages play a major role. In addition, it exhibits immunomodulatory properties by increasing the levels of CD4+ and CD8+ T cells in the blood and bone marrow. The antibody also reduces the number of regulatory T cells (CD38+Tregs), B cells (CD38+Bregs) and myeloid-derived suppressor cells (CD38+MDSCs).

The comparison of the randomized MAIA Rd with the D-Rd trial, in which 43.2% of patients were over 75 years old, was crucial for results concerning older people. The median PFS time was not reached in the experimental arm after a 56-month follow-up, but it was reached in the control group after 34.4 months.36, 42, 44 Furthermore, the proportion of patients who had a complete response, or better, an almost doubled response, and negative or minimal residual disease was more than 3 times higher for the daratumumab group than the control group.36, 44, 45, 46, 47, 48, 49 However, reporting of grade 3 and 4 adverse events was more frequent in the daratumumab arm and included neutropenia (54% compared to 37%), pneumonia (19% compared to 11%) and lymphopenia (16% compared to 11%). Furthermore, treatment-related deaths were slightly higher in the daratumumab arm (4%) than in the control group (3%), and no new complications were observed.36, 45, 46, 47, 48, 49

An alternative partner to dexamethasone, instead of Rd, is the MPV regimen, which was used in the ALCYONE trial comparing daratumumab plus VMP (D-VMP) to VMP (29.9% were patients older than 75 years).37, 38, 46, 47, 48 As expected, PFS analyses showed consistent superiority of D-VMP over VMP across all subgroups, which included those over 75 years of age and prognostic factors (stage III ISS disease, renal failure or high-risk cytogenetic profile). Additionally, as in the MAIA trial, they did not reach the median PFS, but the PFS of 18.1 months was reported for the control group (values similar to the FIRST trial).27, 28, 36, 50 Grade 3 and 4 hematologic complications included neutropenia (39.9% of D-VMP patients compared to 38.7% of control patients), anemia (15.9% of D-VMP patients compared to 19.8% of control patients) and thrombocytopenia (34.4% of D-VMP patients compared to 37.6% of control patients). In addition, the percentage of grade 3 and 4 infections was higher in the D-VMP group (23.1%) than in the control group (14.7%). The most frequent grade 3 or 4 infection was pneumonia, which occurred more often in the D-VMP group (11.3%) than in the control group (4.0%), while peripheral polyneuropathy was more common in the control group (34.2% compared to 28.3%), with grade 3 and 4 infections occurring at 4% for the VMP and 1.4% for the D-VMP groups. Of course, it is important to keep in mind the adverse events associated with daratumumab administration, of which grades 1 and 2 affected 1 in 4 patients, and grades 3 and 4 occurred in 4.9% of patients. However, the number and quality of daratumumab-related events have been effectively minimized, with the introduction of a subcutaneous form. The efficacy and safety of a fixed dose (1800 mg) of subcutaneous daratumumab were demonstrated in the PLEIADES trial, in which all events associated with subcutaneous daratumumab administration accounted for 7.5% (15/199), with 1 case involving grade 3 and the rest grade 1 or 2.51 Furthermore, no drug-related events were reported with the 2nd administration, and only 3 grade 1 and 2 cases (1.5%; 3/199) were reported in subsequent administrations.

Overall toxicity did not increase when using daratumumab in combination with VMP. Except for respiratory tract infections (3 times more common in the daratumumab group), there was a balance between the daratumumab and control groups in terms of adverse events, although peripheral sensory neuropathy rates were lower in the daratumumab group. In addition, in the ALCYONE trial evaluating patients’ quality of life, both arms showed early and sustained improvements in health-related quality of life (HRQoL), function and reduced disease symptoms.37

Both D-Rd and D-VMP regimens can be used in patients over 75 years of age, but due to toxicity, the D-Rd regimen is the safer and more convenient form of treatment. A study comparing the D-Rd regimen with VRD lite is currently being planned, the results of which may change the sequence of recommended regimens (study No. NCT05561387).

Carfilzomib is a novel selective and irreversible proteasome inhibitor recommended for refractory multiple myeloma and/or relapse. A phase I/II trial for a first-line treatment of patients over 65 years of age, combining carfilzomib with melphalan and prednisone (KMP) reported a PFS of 21 months and a response rate of 90%. The study formed the basis for the Phase 3 CLARION trial, which directly compared VMP and KMP arms. The study included 31.3% of patients over 75 years of age and confirmed the safety of carfilzomib as first-line treatment, primarily in terms of polyneuropathy incidence (incidence of minimum grade 2 polyneuropathy was 2.5% in the KMP arm and 35.1% in the VMP arm), but showed no statistical differences in PFS time (22.3 months for KMP compared to 22.1 months for VMP).35 In contrast, the ENDURANCE trial compared VRd to carfizomib, lenalidomide and dexamethasone (KRd). The study included 32% of patients over 70 years of age and showed no increase in PFS time after carfilzomib treatment. The regimen was more toxic in this group of patients.52

Ixazomib is an oral proteasome inhibitor (like 2nd-generation carfilzomib) that was studied in the first-line treatment of transplant-ineligible patients (those over 75 years of age accounted for 43.5%). The TOURMALINE-MM2 study compared ixazomib in combination with Rd to Rd alone, and the results suggested a clinically significant PFS benefit for this group of patients, with a median PFS in the ixazomib arm of 27.9 months and 20.5 months for Rd, and a hazard ratio (HR) of 0.87, but this was not statistically significant.39 The PFS benefit of ixazomib-Rd was observed primarily in patients with renal failure, high-risk cytogenetics and grade 3 injury severity score (ISS). Furthermore, the toxicity profile was acceptable but markedly higher in the ixazomib group, though it did not reduce the patient’s quality of life, with rash and diarrhea grade 3 and above being more common in the investigational regimen group. The ixazomib regimen in combination with Rd may be considered in patients who can only take oral medications, are high-risk, or those with renal failure.

Studies evaluating the safety and efficacy of regimens combining lenalidomide and dexamethasone with ixazomib, elotuzumab, isatuximab, bispecific antibodies, or chimeric antigen receptor (CAR)-T therapy for first-line treatment are currently underway, and some studies may include patients aged over 75.

The results of the CAR-T therapies, namely idecabtagene vicleucel (ide-target) and ciltacabtagene autoleucel (cilta-cel), both targeting the myeloma B-cell maturation antigen (BCMA), are eagerly awaited. Both therapies are undergoing intensive first-line trials in transplant-ineligible patients, such as CARTITUDE 5. However, patients over 80 are not included in the study (NCT04923893). Bispecific antibodies, on the other hand, are most often administered subcutaneously cyclically (every 1–4 weeks) and do not require time-consuming production for each patient. For this antibody (bispecific antibodies), one target is CD3 on T cells, and the other is an antigen found on myeloma cells such as BCMA (teclistamab, elranatamab, linvoseltamab), GPRC5D (talquetamab) and FcRH5 (cevostamab). Importantly, the trials on teclistamab and elranatamab (EudraCT No. 2021-000803-20) for non-transplant patients as first-line treatment have recently been started, with no age limit.53 The most serious complications of both therapies are infectious complications accompanied by hypogammaglobulinemia, cytokine release syndrome (CRS) and neurological disorders (ICONS). From the data obtained so far, the percentage of grade 3 and 4 complications is acceptable.

Patients over 75 have the highest mortality rate, which did not significantly improved in the analysis up to 2012.54 Factors that increase the risk of death, along with early death (up to 12 months after the diagnosis of the disease), include limited function according to the Eastern Cooperative Oncology Group (ECOG) status,55, 56, 57 advanced disease (ISS 3), and comorbidities such as cardiovascular diseases, including hypertension and chronic kidney disease.58, 59, 60 In a retrospective meta-analysis of 4 randomized trials, it was shown that patients older than 75 have an increased risk of death (HR: 1.44, 95% confidence interval (95% CI): 1.20–1.72, p < 0.001).44 Additionally, the aggressiveness of the therapy contributes to this state of affairs. Indeed, there was a 3.02-fold increase in patients receiving VTd/bortezomib–melphalan–prednisone–thalidomide (VMPT), a 1.62-fold increase in patients receiving VMP, and a slight increase in those receiving MP/MPT.20, 21, 41, 50, 61

Conclusions

The treatment of multiple myeloma patients, including elderly patients over 75 years of age, has undergone significant changes over the past 20 years. The MPT regimen based on the FIRST trial, which was groundbreaking in the early 2000s, has been replaced by the Rd regimen. The VRd 3-drug regimen, its “light” version in particular, has been considered an equally interesting option. However, based on the ALCYONE and MAIA trials, the D-Rd regimen is the most effective and safest treatment option.

The Rd regimen with ixazomib did not show a significant benefit over Rd in patients over 75, although it is an attractive treatment option due to its complete ambulatory nature (all drugs are administered orally). In contrast, there are no data on the use of the Rd regimen with carfilzomib as a first-line therapy in patients over 75, as the ENDURANCE trial only included patients between the ages of 70 and 75. The only available treatment recommendations for patients over 75 are those by the National Comprehensive Cancer Network (NCCN). The NCCN panel does not recommend separate treatment for patients over 75 years of age; however, for frail patients, the VRD lite regimen is recommended.

Therapeutic decisions should be made after assessing the risk of the disease, the severity of CRAB symptoms, especially renal failure, and other comorbidities, as well as the patient’s situation (place of residence, commuting, availability of care by a third person, for example). The treatment of renal failure patients who do not yet need renal replacement therapy may be a challenge, though VTd can be considered for this group. The VTd regimen may also be appropriate for patients at high risk of thromboembolism. Switching from lenalidomide to melphalan can be considered (VMP regimen based on the UPFRONT and CLARION trials).

Regimens with bortezomib are recommended for patients with high cytogenetic or thromboembolic risks, those with renal failure, and those with a contraindication to anticoagulants. The neurotoxicity of bortezomib can be reduced without affecting OS if administered once a week.38, 50, 62 On the other hand, lenalidomide is indicated for patients with pre-existing polyneuropathy.

Undoubtedly, patients over 75 constitute a minority in clinical trials, and those over 80 are often ineligible for trials. Therefore, the access to clinical data collected by treatment centers is also important to build real treatment guidelines for this group of patients.

Given that age alone increases the risk of death in elderly patients, deciding on the type of therapy remains a challenge and requires further follow-up and prospective analyses.

Tables


Table 1. Characteristics of registration trials for the melphalan–prednisone–thalidomide and melphalan–prednisone regimens for people aged over 75 years

Characteristics

Study group

GIMEMA

HOVON

IFM-II

NMSG

TMSG

Name of the study, reference

GIMEMA18

HOVON 4915

IFM01/0117

NMSG1219

TMSG16

Country/region

Italy

The Netherlands, Belgium

France

Northern Europe

Turkey

Number of patients

331

333

229

357

114

Years of recruitment

2002–2005

2002–2007

2002–2006

2002–2007

2006–2009

Age [years]

>65

>65

>75

>65

>55

Patients ≥75 years of age, n (%)

110 (33%)

121 (36%)

227 (99%)

159 (45%)

36 (31%)

Advancement, according to Durie–Salmon staging

II, III

Ib, II, III

II, III, and I high-risk

I–III symptoms

I–III symptoms

WHO status (ECOG)

0–4

0–3

0–4

0–4

0–2

Placebo

no

no

yes

yes

no

Dose of melphalan

4 mg/m2

day 1–4

0.25 mg/kg

day 1–5

0.20 mg/kg

day 1–4

0.25 mg/kg

day 1–4

9 mg/m2

day 1–4

Dose of prednisone

40 mg/m2

day 1–7

1 mg/kg

day 1–5

2 mg/kg

day 1–4

100 mg

day 1–4

60 mg/m2

day 1–4

Number of cycles/cycle length [weeks]

6/4

8/4

12/6

up to the plateau period/6

8/6

Thalidomide [mg/day]

100

200

100

200–400

100

Duration of treatment

until progression

8 cycles

12 cycles

until progression

8 cycles

Shift to MPT from MP

no

no

no

no

18%

Median OS MP vs. MPT [months]

47.6 vs. 45

31 vs. 40

29.1 vs. 44

32 vs. 29

26 vs. 28

Median PFS MP vs. MPT [months]

14.5 vs. 21.8

11 vs. 15

24.1 vs. 29

14 vs. 15

N/A

ECOG – Eastern Cooperative Oncology Group; MP – melphalan–prednisone; MPT – melphalan–prednisone–thalidomide; OS – overall survival; WHO – World Health Organization; N/A – not applicable.
Table 2. Registration trials of currently used treatment regimens

Name of the study, year

Regimens used

Regimen details

Median progression-free survival (mPFS)

[months]

Median overall survival (mOS)

[months]

VISTA,
200829

VMP

9 cycles, 42 days

bortezomib: 1.3 mg/m2 IV; days 1, 4, 8, 11, 22, 25, 29, 32 (cycles 1–4); days 1, 8, 22, 29 (cycles 5–9)

24

56.4

MP

9 cycles, 42 days

melphalan: 9 mg/m2; days 1–4

prednisolone: 60 mg/m2; days 1–4; continuous

18

43

FIRST, 201427, 28, 30

Rd

continuous, 28 days

28-day regimen: lenalidomide: 25 mg; days 1–21

dexamethasone: 40 mg; days 1, 8, 15, 22

26

59.1

Rd

18 cycles, 28 days

lenalidomide: 25 mg; days 1–21

dexamethasone: 40 mg; days 1, 8, 15, 22

21

62.3

MPT

12 cycles, 42 days

melphalan: 0.25 mg/kg; days 1–4

prednisolone: 2 mg/kg; days 1–4

thalidomide: 200 mg daily

21.9

49.1

UPFRONT, 201531

VD

8 cycles, 21 days

bortezomib: 1.5 mg/m2 IV; days 1, 4, 8, 11

dexamethasone: 20 mg; days 1, 2, 4, 5, 8, 9, 11, 12 (cycles 1–4); days 1, 2, 4, 5 (cycles 5–8)

14.7

49.8

VTd

8 cycles, 21 days

bortezomib: 1.5 mg/m2 IV; days 1, 4, 8, 11

dexamethasone: 20 mg; days 1, 2, 4, 5, 8, 9, 11, 12 (cycles 1–4); days 1, 2, 4, 5 (cycles 5–8)

thalidomide: 100 mg; days 1–21

15.4

51.5

VMP

8 cycles, 21 days; maintenance with bortezomib IV 1.5 mg/m2, days 1, 8, 15, 22

bortezomib: 1.5 mg/m2 IV; days 1, 4, 8, 11

prednisolone: 60 mg/m2; days 1–4

melphalan: 9 mg/m2; days 1–4

17.3

53.1

SWOG SO7777, 201734

VRd

8 cycles, 21 days

bortezomib: 1.3 mg/m2 IV; days 1, 4, 8, 11

lenalidomide: 25 mg; days 1–14

dexamethasone: 20 mg; days 1, 2, 4, 5, 8, 9, 11, 12

43

75

Rd

6 cycles, 28 days

lenalidomide: 25 mg; days 1–21

dexamethasone: 40 mg; days 1, 8, 15, 22

30

64

CLARION, 201935

KMP

9 cycles, 42 days

carfilzomib: 20 mg/m2 IV on days 1 and 2 in cycle 1, 36 mg/m2 IV in others; days 1, 2, 8, 9, 22, 23, 29, 30

melphalan: 9 mg/m2; days 1–4

prednisolone: 60 mg/m2; days 1–4

22.3

no data

VMP

9 cycles, 42 days

bortezomib: 1.3 mg/m2 SC or IV on days 1, 4, 8, 11, 22, 25, 29, 32 (cycles 1–4); days 1, 8, 22, 29 (cycles 5–9)

melphalan: 9 mg/m2; days 1–4

prednisolone: 60 mg/m2; days 1–4

22.1

no data

ALCYONE, 201837, 38

DaraVMP

9 cycles, 42 days

daratumumab: 16 mg/kg IV/week in cycle 1; every 3 weeks until cycle 29, then every 4 weeks

bortezomib: 1.3 mg/m2 SC or IV on days 1, 4, 8, 11, 22, 25, 29, 32 (cycles 1–4); days 1, 8, 22, 29 (cycles 5–9)

melphalan: 9 mg/m2; days 1–4

prednisolone: 60 mg/m2; days 1–4

not reached

under evaluation

VMP

9 cycles, 42 days

bortezomib: 1.3 mg/m2 SC or IV on days 1, 4, 8, 11, 22, 25, 29, 32 (cycles 1–4); days 1, 8, 22, 29 (cycles 5–9)

melphalan: 9 mg/m2; days 1–4

prednisolone: 60 mg/m2; days 1–4

19.3

under evaluation

MAIA,
201936

Dara-Rd

28-day cycles

daratumumab: 16 mg/kg IV/week (cycles 1 and 2); every 2 weeks (cycles 3–6); then every 4 weeks

lenalidomide: 25 mg; days 1–21

dexamethasone: 40 mg weekly

not reached

under evaluation

Rd

continuous, 28-day cycles

lenalidomide: 25 mg; days 1–21

dexamethasone: 40 mg weekly

31.9

under evaluation

TOURMALINE-MM232, 39

IRd

9 cycles, 28 days

ixazomib: 4 mg; days 1, 8, 15

lenalidomide: 25 mg; days 1–21

dexamethasone: 40 mg; days 1, 8, 15, and 22 (20 mg for patients >75 years old)

35.3

no data

Rd

9 cycles, 28 days

lenalidomide: 25 mg; days 1–21

dexamethasone: 40 mg; days 1, 8, 15, and 22 (20 mg for patients >75 years old)

21.8

no data

VRd lite,
201433

VRd

35 days

bortezomib: 1.3 mg/m2 IV; days 1, 8, 15, 22

lenalidomide: 15 mg; days 1–21

dexamethasone: 20 mg; days 1, 2, 8, 9, 15, 16, 22, 23

35.1

not reached

MP – melphalan–prednisone; VMP – bortezomib plus MP; Rd – lenalidomide–dexamethasone; MPT – melphalan–prednisone–thalidomide; VTd – bortezomib–thalidomide–dexamethasone; VRd – bortezomib plus RD; KMP – carfilzomib–melphalan–prednisone; IV – intravenous; SC – subcutaneous; VD – bortezomib–dexamethasone; IRd – Ixazomib–lenalidomide–dexamethasone.

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