Take home messages Incorporation of novel agents into the treatment paradigms for fit patients with newly diagnosed multiple myeloma has led to a remarkable increase in the rates of complete response and minimal residual disease negative status, ultimately translating into near tripling of median overall survival of this disease. In frail individuals who cannot tolerate multi-drug combinations treatment goals include improvement in the quality of life and avoidance of early treatment discontinuation due to drug toxicities.
Introduction
In a patient with newly diagnosed (ND) multiple myeloma (MM), start of therapy is immediately required if any one or more of myeloma defining events are detected. 1 The subsequent step in the selection of the most appropriate treatment strategy is to define if the patient is able, or not, to tolerate high-dose therapy (HDT) with autologous stem-cell transplantation (ASCT). Eligibility for ASCT is usually based on chronological age, performance status and comorbidities. In ASCT-ineligible patients, unfitness and frailty must be adequately assessed before making treatment decision. Geriatric assessment metrics, although underemployed in routine care, are a valuable tool to identify frailty and vulnerability. 2 In fit patients who can tolerate novel agent-based therapies at full doses, followed or not by ASCT, key treatment end points are to achieve undetectable minimal residual disease (MRD) and to sustain MRD negative status, as a way to significantly enhance progression-free survival (PFS) and overall survival (OS). 3
Current state of the art: ASCT candidates
Induction therapy in preparation for ASCT should include the first-in-class proteasome inhibitor (PI) bortezomib combined with dexamethasone (VD) and a third drug. 4 This latter should be preferably an immunomodulatory agent (IMiD), like thalidomide (VTD) or lenalidomide (VRD), but cyclophosphamide (VCD) or doxorubicin (PAD) might be alternative options 5▪ , 6 (Table 1 ). Several studies are currently investigating the efficacy and toxicity of 3 or 4 drug regimens incorporating a second generation PI like carfilzomib plus an IMiD and dexamethasone, or the first-in-class anti-CD38 monoclonal antibody (mAb) daratumumab combined with VTD or VRD. The number of preplanned cycles to be given before peripheral blood SC harvest is usually four. However, an increase up to 6 cycles may be considered, provided that there is no signal of emerging treatment-related peripheral neuropathy and response continues to deepen. Although the role of upfront ASCT has been debated in the current era, 7 it still remains the standard of care for eligible patients in European countries, based on the results from several prospective studies showing a significantly longer PFS with HDT in comparison with standard-dose therapies incorporating bortezomib. 8▪ , 9 The lack of OS benefit with upfront ASCT in studies not yet mature for OS analysis at the time of their initial publication does not justify the choice to delay ASCT at the time of relapse, since a possible divergence between survival curves might emerge with longer follow up. The role of double, or tandem, ASCT remains controversial, as confirmed by opposite results from 2 randomized studies recently conducted in Europe and the United States (US), partly related to major differences in their design. 10 , 11 A preplanned interim analysis of the European Myeloma Network (EMN) 02 study, showed that double ASCT following short-term bortezomib-based induction therapy (a design closely reflecting the current practice in most European centers) prolonged PFS and OS in comparison with a single ASCT. 9 Differences in outcomes between the 2 treatment arms were particularly remarkable in patients at high-risk according to adverse cytogenetics or advanced International Staging System (ISS) disease stage. Short-term consolidation therapy after ASCT more frequently comprises the same drug or multi-agent combination previously administered as induction before HDT and is aimed at further enhancing the rate and depth of response, as well as the length of PFS. Improved clinical outcomes reported with consolidation vs no consolidation therapy in the EMN02 study are currently reflected in the clinical practice across several European groups. 12 Whether prolonged induction therapy may abrogate the potential benefits seen with post-ASCT consolidation treatment following a limited number of induction cycles, as typically planned in European countries, remains an area of debate. 7 Maintenance therapy after ASCT is usually given until progression or for up to 2 to 3 years, in order to sustain the duration of response or MRD negative status and to prolong OS, while keeping toxicity minimal. Lenalidomide is actually the only novel agent approved by the European Medicines Agency (EMA) as maintenance therapy following ASCT, on the basis of the results of a meta-analysis of 3 randomized clinical trials designed to compare lenalidomide (R) vs placebo or observation. 13▪ PFS and OS benefits seen with R maintenance in the intention-to-treat population were retained across different subgroups of patients, although those with ISS stage 3 and a high-risk cytogenetic profile were likely to fail a significant improvement in OS. By the opposite, in several studies maintenance with bortezomib alone for up to 2 years following a VD-based induction therapy or with bortezomib and R improved or overcame the poor prognosis imparted by del(17p) or t(4;14), suggesting that exposure to PI after ASCT might be of benefit in patients carrying high-risk cytogenetics. 14 , 15 Unfortunately, the lack of phase III studies designed to prospectively address this issue or, more generally, to compare bortezomib maintenance vs placebo or observation in NDMM patients who have undergo ASCT prevents any formal recommendation about V use in this setting. More recently, the second generation oral PI ixazomib has been reported to prolong PFS in comparison with placebo following ASCT. These data taken in aggregate confirm the role of upfront ASCT in NDMM patients and provide evidence supporting the remarkable advances seen with incorporation of novel agents into HDT, ultimately leading to OS estimates at 10 years in the 60% range (Table 1 ).
Table 1
Design of clinical trials and reported outcomes for patients with newly diagnosed multiple myeloma who are eligible or not eligible for autologous stem-cell transplantation.
Current state of the art: non-ASCT candidates
Basically, treatment options for ASCT-ineligible patients can either include or exclude alkylators. Treatment approaches can also differ in terms of exposure duration to therapeutic agents, which can be either fixed or continuous until progression or toxicity. Over the past years, melphalan-prednisone (MP) was combined with thalidomide (MPT) or bortezomib (VMP) or R (MPR) in several phase III studies 16▪ , 17 18 19 (Table 1 ). All these triplets showed superior efficacy in comparison with MP and were approved by EMA for the treatment of patients who are not candidates for ASCT. Due to the high rate of severe neutropenia observed during induction therapy with MPR and the lack of benefit with this regimen in patients older than 75 years of age, its routine use has been limited. R-dexamethasone (Rd) until progression (Rd continuous) is another recent EMA-approved therapeutic option in the non-ASCT setting 20▪ (Table 1 ). VMP and Rd represent at this time the most popular gold standard therapies offered to ASCT-ineligible NDMM patients in European countries. The choice of one regimen vs another is based on various factors related to the disease itself (for example, renal failure and adverse cytogenetics which favor VMP) or to the host, including patient's fitness or frailty, as well as preference of the single individual. According to the latest guidelines provided by the European Society for Medical Oncology, alternative treatment options in the non-ASCT setting include VCD, cyclophosphamide-thalidomide-dexamethasone (CTD) and bendamustine-prednisone (BP). 6 Notably, not all these treatments have been backed by phase III studies and are EMA-approved, while some of them have got approval in particular clinical conditions (for example, BP in patients with peripheral neuropathy precluding their exposure to thalidomide or bortezomib). More recently, addition of bortezomib to Rd induction followed by Rd continuous (VRd) significantly improved outcomes in comparison with Rd continuous, and is likely to become a new standard of care, once approved in Europe 21 (Table 1 ). By the opposite, alternative treatment approaches including the sequential or alternating administration of both VMP and Rd for a fixed number of cycles, as well as continuous exposure to V-prednisone or V-thalidomide following induction therapy with either VMP or VMP plus thalidomide did not got approval by EMA and, although of clinical benefit, are not commonly used in European centers 17 (Table 1 ). Nevertheless, a paradigm shift toward the use of continuous therapies in the next few years can be predicted, in light of recent phase III studies that have established new gold standard treatments. In two of these studies, addition of daratumumab either to VMP induction followed by daratumumab until progression or to Rd continuous significantly improved clinical outcomes in comparison with VMP and Rd, respectively 18 (Table 1 ). In addition, both Rd and VRd have represented the backbone of other alkylator-free triplets or quadruplets which have been, or are currently being, explored in combination with ixazomib or daratumumab or the monoclonal antibodies elotuzumab and isatuximab targeting SLAMF7 and CD38 antigens, respectively. In summary, incorporation of novel agents at full doses into the treatment paradigms for fit ASCT-ineligible patients with NDMM has led to unprecedented rates of complete response and MRD negativity, ultimately translating into extended PFS and OS. Treatment goals for frail individuals who cannot tolerate multi-drug combinations at full doses are shifted towards patient-centered outcomes, and include improvement in the quality of life and avoidance of early treatment discontinuation due to drug toxicities.
Future perspectives
The treatment landscape for NDMM has been transformed with the introduction of PIs, IMiDs and mAbs, and still continues to evolve. Novel agents combined with each other and/or with standard of care regimens are already in the clinic for both ASCT-eligible and -ineligible patients. In the meantime, other newer therapies are under active evaluation. Treatments incorporating novel drugs with different, and often complementary, mechanisms of action bring an increased anti-MM activity with lower off target toxicity, and hold promise to further enhance the probability and depth of response. Achievement of MRD negativity rates, actually in the 30% to 60% range in ASCT-ineligible and -eligible patients, respectively, will hopefully translate in the coming years into furtherly extended PFS and OS, and are likely to offer a chance of cure to a fraction of NDMM patients at standard risk.
Citation: Cavo M, Tacchetti P, Zamagni E. Front-line Treatment of Multiple Myeloma. HemaSphere , 2019;00:00. http://dx.doi.org/10.1097/HS9.0000000000000242 .
Funding/support: None.
Disclosure: The authors have indicated they have no potential conflicts of interest to disclose.
References
1. Rajkumar SV Dimopoulos MA Palumbo A . International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma . Lancet Oncol 2014 ; 15 : e538 – e548 . 25439696 10.1016/S1470-2045(14)70442-5
2. Zweegman S Engelhardt M Larocca A . Elderly patients with multiple myeloma: towards a frailty approach? Curr Opinion Oncol 2017 ; 29 : 315 – 321 . 10.1097/CCO.0000000000000395 28763310
3. Munshi NC Avet-Loiseau H Rawstron AC . Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis . JAMA Oncol 2017 ; 3 : 28 – 35 . 27632282 10.1001/jamaoncol.2016.3160 PMC5943640
4. Sonneveld P Goldschmidt H Rosinol L . Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials . J Clin Oncol 2013 ; 31 : 3279 – 3287 . 23897961 10.1200/JCO.2012.48.4626
Cavo M Tacchetti P Patriarca F . Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before and consolidation therapy after double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomized phase 3 study . Lancet 2010 ; 376 : 2075 – 2085 . Phase 3, randomized, study establishing that a triplet bortezomib-IMiD-based induction therapy is a standard-of-care in NDMM patients who are candidates for ASCT. 21146205 10.1016/S0140-6736(10)61424-9
6. Moreau P San Miguel J Sonneveld P . Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up . Ann Oncol 2017 ; 28 (suppl_4) : 1 – 11 . 10.1093/annonc/mdx096 28453614
7. Kumar SK Buadi FK Rajkumar SV . Pros and cons of frontline autologous transplant in multiple myeloma: the debate over timing . Blood 2019 ; 633 : 652 – 659 . 10.1182/blood-2018-08-825349 30587528
Attal M Lauwers-Cances V Hulin C . Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma . N Engl J Med 2017 ; 376 : 1311 – 1320 . Phase 3, randomized, study showing superior clinical outcomes with incorporation of bortezomib and an IMiD into upfront ASCT in comparison with standard-dose bortezomib-IMiD-based intensification therapy in NDMM patients who are candidates for HDT. 28379796 10.1056/NEJMoa1611750 PMC6201242
9. Cavo M Hajek R Pantani L . Autologous stem cell transplantation versus bortezomib-melphalan-prednisone for newly diagnosed multiple myeloma: second interim analysis of the phase 3 EMN02/HO95 study . Blood 2017 ; 130 (Suppl 1) : 397 .28576879
10. Cavo M Gay F Patriarca F . Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of phase 3 EMN/HO95 study . Blood 2017 ; 130 (Suppl 1) : 401 .
11. Stadtmauer EA Pasquini MC Blackwell B . Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma . J Clin Oncol 2019 ; JCO1800685 [Epub ahead of print] . 10.1200/JCO.18.00685 PMC6553842 30653422
12. Sonneveld P Beksac M van der Holt B . Consolidation followed by maintenance therapy versus maintenance alone in newly diagnosed, transplant eligible patients with multiple myeloma (MM): a randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial) . Blood 2016 ; 128 : 242 .
McCarthy PL Holstein SA Petrucci MT . Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis . J Clin Oncol 2017 ; 35 : 3279 – 3289 . Meta-analysis demonstrating the significant improvement in OS and PFS with post-ASCT lenalidomide maintenance versus placebo in patients with NDMM. 28742454 10.1200/JCO.2017.72.6679 PMC5652871
14. Usmani SZ Seifter E . Treatment approach for young, fit, newly diagnosed multiple myeloma patients . Hematology Am Soc Hematol Educ Program 2018 ; 97 – 102 . 30504297 10.1182/asheducation-2018.1.97 PMC6246032
15. Giralt S Seifter E . Case-based roundtable on treatment approach for young, fit, newly diagnosed multiple myeloma patients . Hematology Am Soc Hematol Educ Program 2018 ; 103 – 109 . 30504298 10.1182/asheducation-2018.1.103 PMC6245961
Mateos MV Richardson PG Schlag R . Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial . J Clin Oncol 2010 ; 28 : 2259 – 2266 . Phase 3, randomized, study establishing that a fixed-duration, triplet bortezomib-melphalan-based regimen is a gold standard treatment for ASCT-ineligible patients with NDMM. 20368561 10.1200/JCO.2009.26.0638
17. Mateos MV Ocio EM Paiva B . Treatment for patients with newly diagnosed multiple myeloma in 2015 . Blood Rev 2015 ; 29 : 387 – 403 . 26094881 10.1016/j.blre.2015.06.001
18. Facon T Anderson K . Treatment approach for the older, unfit patient with myeloma from diagnosis to relapse: perspectives of a European hematologist . Hematology Am Soc Hematol Educ Program 2018 ; 83 – 87 . 30504295 10.1182/asheducation-2018.1.83 PMC6245965
19. Wildes TM Anderson KC . Approach to the treatment of the older, unfit patient with myeloma from diagnosis to relapse: perspectives of a US hematologist and a geriatric hematologist . Hematology Am Soc Hematol Educ Program 2018 ; 88 – 96 . 30504296 10.1182/asheducation-2018.1.88 PMC6245982
Facon T Dimopoulos MA Dispenzieri A . Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma . Blood 2018 ; 131 : 301 – 310 . Phase 3, randomized, study establishing that a continuous, alkylator-free, upfront therapy including an IMiD plus dexamethasone is a standard-of-care in the setting of NDMM not eligible for ASCT. 29150421 10.1182/blood-2017-07-795047 PMC5774211
21. Durie BGM Hoering A Abidi MH . 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 randomized, open-label, phase 3 trial . Lancet 2017 ; 389 : 519 – 527 . 28017406 10.1016/S0140-6736(16)31594-X PMC5546834