The ability to more rapidly assess changes in clinical status will allow us to be more conservative in our approach to treatment in many patients, since failures of treatments can quickly be remedied with the addition of other agents or changes in the treatment altogether.— Tanya M. Spektor, PhD, and James R. Berenson, MD
The treatment of multiple myeloma is becoming increasingly complicated. This is not only because of the complexity of the disease, but also because of the increasing number of effective combination treatments and continuous development of new drugs. This has resulted in an ever-increasing number of therapies that have been used in patients with newly diagnosed and relapsed/refractory myeloma.
Role of Combination Therapy
Early historical data provided evidence that combination chemotherapy with cytotoxic agents did not accomplish greater efficacy and caused higher rates of toxicities than the standard of care.1 However, during the past 15 years, major advances in drug development have produced agents with different mechanisms of action and more favorable toxicity profiles, including proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors, and, more recently, monoclonal antibodies. These new classes of drugs have been shown to improve antimyeloma activity by overcoming resistance to other treatments and potentially improving the efficacy of combination therapy.
These developments revived the idea of combination-based therapy for myeloma patients. Specifically, combination therapy consisting of an immunomodulatory agent and a proteasome inhibitor demonstrated synergy, first in the laboratory,2 which provided the rationale for clinical trials evaluating this combination in multiple myeloma.
Interestingly, the immunomodulatory agent lenalidomide (Revlimid) and proteasome inhibitor bortezomib (Velcade) were found to act through a number of shared pathways including caspase-mediated apoptosis and inhibition of nuclear factor–κB signaling.3 This dual activation generated synergistic signals that also enhanced the antimyeloma clinical activity of dexamethasone.4
Early clinical trials appeared to support the clinical benefits of three-drug combinations for patients with myeloma compared to when they were used as doublets.5,6 In a phase III trial for relapsed myeloma, patients receiving the combination of bortezomib, the immunomodulatory agent thalidomide (Thalomid), and dexamethasone (VTD) were shown to achieve deeper responses and a longer time to disease progression than seen among patients receiving only thalidomide and dexamethasone (TD).6
Similar responses were observed among newly diagnosed myeloma patients, where 79% of patients receiving VTD achieved a very good partial response or better compared with only 58% of patients receiving TD.7 Although combination therapies containing thalidomide showed some clinical benefit, lenalidomide, a newer-generation immunomodulatory agent that is a derivative of thalidomide, was found to be more potent than thalidomide, also resulting in much less peripheral neuropathy than the older agent.8
As a result, a single-arm phase I/II clinical trial using the triplet bortezomib/lenalidomide/dexamethasone (VRd) was conducted for patients with previously untreated multiple myeloma. This regimen appeared to show greater efficacy than steroids with either the proteasome inhibitors or immunomodulatory agent alone.9
The phase I/II study became a platform for the first prospective randomized phase III trial (SWOG S0777) directly comparing the three-drug combination VRd to the two-drug combination of lenalidomide and dexamethasone (Rd) for previously untreated myeloma patients10 meeting CRAB criteria (calcium elevation, renal impairment, anemia, bone involvement).11 Results were recently reported by Durie et al in The Lancet10 and are reviewed in this issue of The ASCO Post.
Patients were randomly assigned to receive treatment with VRd or Rd; all patients continued lenalidomide at 25 mg daily for 21 days followed by 7 days off and dexamethasone, whereas those randomized to VRd also initially received eight 3-week cycles of bortezomib at the standard dose of 1.3 mg/m2 on days 1, 4, 8, and 11.
The primary study endpoint was progression-free survival from the time of randomization, and secondary endpoints included overall survival, overall response rate, and safety. The baseline characteristics of the 471 patients who received study treatment were mostly balanced between the two arms of the study, except more women and older patients were treated on the Rd arm.
After a median follow-up of 55 months, the median progression-free survival was 43 months in the VRd group vs 30 months in the Rd-treated patients (P = .0037). In addition, median overall survival was improved among patients receiving the triplet compared to those in the doublet arm (75 vs 64 months, P = .025).
To address the issue of differences in age between the arms, the authors performed an age-adjusted analysis of both progression-free and overall survival, which also showed significant differences favoring patients treated with the bortezomib-containing regimen. Interestingly, although the complete response rate was nearly double with the triplet (15.7% vs 8.4%), overall response rates were not different between the arms. Compared to single-agent bortezomib, the doublet of bortezomib and pegylated liposomal doxorubicin similarly showed an improvement in progression-free survival without a difference in overall response rate in the relapsed/refractory multiple myeloma setting.12
Analysis of adverse events as defined by Common Toxicity Criteria category as well as specific toxic effects was used to monitor safety, showing a fairly well-balanced distribution of common adverse events between the two groups, except that grade 3 or worse neurologic toxic effects were more frequently observed in the VRd group than in the Rd group (33% vs 11%, P < .0001). These neurologic toxicities were most likely attributable to bortezomib, which was administered intravenously at a higher dose and using a shorter 3-week cycle than in other clinical trials that have shown a lower incidence of peripheral neuropathy overall and especially grade ≥ 3 events.13
Somewhat less frequent occurrences of secondary primary cancers (commonly attributed to lenalidomide) were observed in this trial as compared to meta-analysis data14 for lenalidomide-containing treatments (4.8% vs 6.9% in the meta-analysis). This may reflect the lack of alkylator therapy in this trial, which appears to increase the risk of secondary cancers among patients receiving lenalidomide-based treatment.15
In summary, the SWOG S0777 trial has demonstrated compelling evidence that the triplet VRd regimen is more effective than Rd in the front-line setting for patients with multiple myeloma. Similar data now exist in the relapsed/refractory–myeloma setting using the newer proteasome inhibitors carfilzomib (Kyprolis) or oral ixazomib (Ninlaro) with Rd compared to Rd alone.16,17 In addition, triplet studies with either of the recently approved monoclonal antibodies, elotuzumab (Empliciti) or daratumumab (Darzalex), also show superior progression-free survival compared with Rd treatment in the relapsed/refractory–myeloma setting.18,19
Despite these encouraging results for triplet combination therapies to treat myeloma patients in the front-line and relapsed/refractory settings, several important issues need to be considered for the management of patients with multiple myeloma, especially in the front-line setting. As myeloma has evolved from an acute to a chronic disease, there has been a marked increase in the costs associated with the overall treatment of myeloma patients. These higher costs are due to the longer overall survival20 and ongoing supportive care of these patients as well as the use of increasingly expensive drugs, which now are being given continuously during periods of disease responsiveness as well as disease progression.
Also, as a heterogeneous disease with many genetically distinct populations of subclones associated with different modes of presentation (even within individual patients, let alone in different patients),15 optimal treatment to maximize the individual’s quality and length of life should be the goal. Although guidelines have been written to suggest risk-adapted therapies for different groups of myeloma patients based on a number of prognostic factors in the front-line setting,21 the demonstration that they have improved outcomes for patients overall or individually is lacking.
It is imperative that we begin to develop treatments that are individualized based on disease and patient characteristics. Although differences in both progression-free and overall survival favoring the VRd triplet combination were demonstrated in the SWOG S0777 trial, it is likely that many patients could have benefited equally from Rd without the unnecessary cost and toxicity, especially peripheral neuropathy from the addition of bortezomib. Moreover, it is likely that subgroups of patients may benefit from the addition of a fourth agent or other classes of drugs such as the monoclonal antibodies.
It is also important to determine who actually benefits from long-term maintenance treatment with drugs such as lenalidomide, which is both expensive and associated with side effects. Recently published data show that although patients with multiple myeloma receiving bortezomib-, lenalidomide-, or carfilzomib-based treatments show more benefits during their initial treatment, these drugs can continue to be quite effective when used in different combinations subsequently.22 Thus, the thinking that failure of a drug used once means it cannot continue to be effective in other regimens is not true for the treatment of myeloma patients.
The ability to more rapidly assess changes in clinical status—in days instead of months—will allow us to be more conservative in our approach to treatment in many patients, since failures of treatments can quickly be remedied with the addition of other agents or changes in the treatment altogether. The recent identification of newer biomarkers to do this, including serum B-cell maturation antigen,23 with its much shorter serum half-life than conventional immunoglobulin markers,24 may allow these types of clinical approaches. Early results suggest that serum B-cell maturation antigen changes much more rapidly and accurately than other conventional biomarkers used to follow myeloma patients undergoing new treatments.25
For the present, we are limited to the data clearly showing that, overall, the use of the VRd triplet is superior to doublet therapy for treating patients with newly diagnosed myeloma, but, ultimately, the “devil will be in the details”—ie, we will need to figure out who really needs the triplet in this setting as we consider both the costs to the health-care system and the negative impact on quality of life with the addition of more drugs. ■
Dr. Spektor is a medical writer at Oncotherapeutics, West Hollywood, California. Dr. Berenson is Chief Executive Officer, Oncotherapeutics; Medical and Scientific Director, Institute for Myeloma & Bone Cancer Research; and President and Chief Executive Officer, James R. Berenson, MD, Inc, West Hollywood, California.
Disclosure: Dr. Spektor reported no potential conflicts of interest. Dr. Berenson has received consulting fees, honoraria for speaking, and research support from Takeda Pharmaceuticals and Celgene.
1. Oken MM, Harrington DP, Abramson N, et al: Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: Results of Eastern Cooperative Oncology Group Study E2479. Cancer 79:1561-1567, 1997.
2. Mitsiades N, Mitsiades CS, Poulaki V, et al: Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: Therapeutic implications. Blood 99:4525-4530, 2002.
3. Verma R, Mai Z, Xu M, et al: Identification of cereblon-independent protein degradation pathway in residual myeloma cells treated with immunomodulatory drugs. 2015 ASH Annual Meeting. Abstract 913.
4. Hideshima T, Richardson P, Chauhan D, et al: The proteasome inhibitor PS-341 inhibits growth, induces apoptosis and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61:3071-3076, 2001.
6. Garderet L, Iacobelli S, Moreau P, et al: Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: The MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 30:2475-2482, 2012.
7. Cavo M, Tacchetti P, Patriarca F, et al: 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 randomised phase 3 study. Lancet 376:2075-2085, 2010.
10. Durie BG, Hoering A, Abidi MH, et al: 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, 2016.
12. Orlowski RZ, Nagler A, Sonneveld P, et al: Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: Combination therapy improves time to progression. J Clin Oncol 25:3892-3901, 2007.
13. Berenson JR, Yellin O, Chen CS, et al: A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone is effective and well tolerated for previously untreated multiple myeloma patients. Br J Haematol 155:580-587, 2011.
14. Palumbo A, Bringhen S, Lupparelli G, et al: Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: A meta-analysis of individual patient data. Lancet Oncol 15:333-342, 2014.
18. Richardson PG, Jagannath S, Moreau P, et al: Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: Final phase 2 results from the randomized, open-label, phase 1b-2 dose-escalation study. Lancet Haematol 2:e516-e527, 2015.
23. Ghermezi M, Li M, Vardanyan S, et al: Serum B-cell maturation antigen: A novel biomarker to predict outcomes for multiple myeloma patients. Haematologica. December 29, 2016 (early release online).
25. Udd K, Chen H, Li M, et al: Changes in serum B-cell maturation antigen levels are a rapid and reliable indicator of treatment efficacy for patients with multiple myeloma, accepted to International Myeloma Workshop, India, March 2017.