Muhamed Baljevic, MD

Sarah A. Holstein, MD, PhD

Over the past 15 years, multiple myeloma has garnered among the highest number of regulatory approvals by the U.S. Food and Drug Administration (FDA) for the management of all phases of the disease. This fast-expanding repertoire of treatment options has pushed the median survival of multiple myeloma patients from a few years to 10 years and longer in the current era¹ and has cultivated an increasing belief that in most patients—with notable exceptions—the disease can be managed as a long-term, chronic condition. 

Such a prospect, as well as the expectation that treatment failures can quickly be compensated for by the addition of other agents, may imply a decreasing sense of urgency to adopt the most optimal therapy upfront. Nevertheless, the collective body of evidence suggests that 

placing the strongest treatment foot forward with an immunomodulatory drug– and proteasome inhibitor–based triplet may be the most optimal choice for all fit patients with newly diagnosed multiple myeloma, irrespective of their candidacy for autologous stem cell transplantation (ASCT). 

Early Immunomodulatory Drug/Proteasome Inhibitor Triplet Experience

With compelling preclinical evidence of immunomodulatory drug/proteasome inhibitor synergy in multiple myeloma,² the myeloma community has embraced the use of the bortezomib (Velcade)/lenalidomide (Revlimid)/dexamethasone (VRd) triplet combination since 2008, under the umbrella of major national guidelines,³ even before the first early-phase assessments were reported.^4-7 Nearly a decade later, the first prospective phase III trial comparing the VRd triplet to lenalidomide plus dexamethasone (Rd) demonstrated improvements in both progression-free and overall survival (43 vs 30 months, stratified hazard ratio [HR] = 0.712, one-sided P = .0018; and 75 vs 64 months, HR = 0.709, two-sided P = .025, respectively).⁸ 

This study also showed that although the overall response rates of the two regimens were similar, the rate of achieving at least a very good partial response was higher for the VRd arm (complete response rate = 15.7% vs 8.4%), and these deeper responses led to the longer progression-free and overall survivals. Toxicity and tolerability in both arms were comparable, aside from the grade ≥ 3 neurologic toxicities in the triplet arm, which were likely driven by the intravenous use of bortezomib. This route of administration has since largely been replaced by the subcutaneous use of bortezomib, given its relatively lesser association with peripheral neuropathy.⁹ 

Thalidomide does not abrogate the effect of high-risk cytogenetics, whereas both bortezomib and lenalidomide partially do so on an individual basis, and with an even greater potency when used in combination.

— Muhamed Baljevic, MD and Sarah A. Holstein, MD, PhD

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The superiority of an immunomodulatory drug/proteasome inhibitor triplet over doublet therapy in newly diagnosed multiple myeloma was demonstrated even earlier in a study comparing the bortezomib/thalidomide (Thalomid)/dexamethasone (VTD) triplet to the thalidomide and dexamethasone (Td) doublet.¹⁰ The same VTD triplet proved superior in achieving at least a very good partial response and preparing newly diagnosed multiple myeloma patients for ASCT when compared with the bortezomib/cyclophosphamide/dexamethasone (VCD) triplet.¹¹ 

These studies clearly demonstrated the importance of combining these classes of antimyeloma drugs in upfront treatment. With regard to the VTD combination, however, it is important to note that thalidomide does not abrogate the effect of high-risk cytogenetics, whereas both bortezomib and lenalidomide partially do so on an individual basis,¹² and with an even greater potency when used in combination. 

A recent meta-analysis of five trials (three of which employed an immunomodulatory drug/proteasome inhibitor–based triplet) evaluating triplet vs doublet therapies in the relapsed/refractory multiple myeloma setting also strongly demonstrated that triplet regimens yield improved progression-free survival, overall survival, overall response rates, very good partial response rates, and complete response rates when compared with doublets, though at an expense of higher grade 3 adverse events, including thrombocytopenia.¹³

Newer Immunomodulatory Drug/Proteasome Inhibitor Triplet Insights

The recent development and FDA approval of the first orally bioavailable proteasome inhibitor, ixazomib (Ninlaro), have led to the development of “all-oral” combination studies in both relapsed/refractory and newly diagnosed multiple myeloma. A phase I study of ixazomib/lenalidomide/dexamethasone (IRd) in newly diagnosed myeloma demonstrated good tolerability and activity,¹⁴ and a subsequent phase III study of IRd vs Rd in the relapsed/refractory myeloma setting showed a progression-free survival benefit for the triplet in all patient subgroups, including those with high-risk cytogenetic abnormalities, with an acceptable side-effect profile.¹⁵ 

Most recently, in patients with newly diagnosed myeloma, weekly IRd, followed by single-agent ixazomib maintenance after 12 cycles, was highly active, resulting in deep (overall response rate = 80%; very good partial response rate = 31%; complete response rate = 32%) and durable responses (median progression-free survival = 25.3 months, with a 3-year overall survival estimate of 87%).¹⁶ Impressively, deepening responses were seen on further exposure to therapy during the maintenance period (overall response rate = 100%, very good partial response rate = 32%, and complete response rate = 44%). 

The body of evidence suggests that the rate of MRD negativity should become the next logical step in assessing treatment responses and predicting long-term outcomes of myeloma patients.

— Muhamed Baljevic, MD and Sarah A. Holstein, MD, PhD

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Twice-weekly IRd tested in newly diagnosed multiple myeloma resulted in exceptional response rates among patients who did not proceed to ASCT but did receive maintenance therapy (overall response rate = 94%, very good partial response rate = 45%, and complete response rate = 44%).¹⁷ In this trial, most adverse events occurred during induction therapy. 

The use of carfilzomib (Kyprolis)/lenalidomide/dexamethasone (KRd) in both relapsed/refractory and newly diagnosed multiple myeloma has yielded truly impressive responses. In the relapsed/ refractory myeloma setting, the phase III study of KRd vs Rd demonstrated a 7.9-month median overall survival benefit for KRd (48.3 vs 40.4 months, HR = 0.79), becoming the first triplet vs doublet regimen to show an overall survival benefit in patients with relapsed/refractory multiple myeloma.¹⁸ 

In both studies of KRd in newly diagnosed myeloma, this triplet led to unprecedented deep responses (62% near-complete responses) with no increased peripheral neuropathy, and the benefit was independent of cytogenetic risk status.^19,20 The second of these studies also showed that minimal residual disease (MRD) negativity among patients achieving at least a near-complete response was 100% at 10^–5 multicolor flow cytometry sensitivity, translating to a progression-free survival hazard ratio of 0.10.²⁰ 

In a European dose-escalation phase II study in transplant-eligible newly diagnosed myeloma patients, a triplet consisting of carfilzomib, thalidomide, and dexamethasone (KTd) was also well tolerated. The regimen produced rates of at least a very good partial response after induction and consolidation of 68% and 89%, respectively, and a 60% complete response rate across different prognostic subgroups.²¹

A rationale underlining the need for using combination therapies in newly diagnosed multiple myeloma—particularly the immunomodulatory drug/proteasome inhibitor triplets over doublets—relates to the avoidance of drug resistance and prevention of clonal evolution in myeloma.^22,23 Several genetically distinct myeloma subclones usually present at the onset of disease tend to evolve, influenced by the milieu of microenvironmental factors as well as selective treatment effects, which may ultimately lead to treatment resistance and subsequent disease progression.^24-28 Hence, in addition to suppressing drug resistance, combination regimens that rely on different mechanisms of action and molecular pathways also work to more effectively address the intraclonal heterogeneity in myeloma, leading to stronger responses. 

With further incorporation of the recently developed and highly efficacious anti-CD38 therapies (eg, daratumumab [Darzalex]) into novel quadruplet regimens, we may very well see further proof of the importance of these concepts when it comes to the most optimal management of newly diagnosed multiple myeloma. Preliminary reports already suggest that very deep and durable responses can be achieved without the additional toxicity of further agents, as has been historically observed with more-than-triplet therapies in newly diagnosed myeloma.^29,30 

New Paradigms: Concluding Remarks

The evolving and continued success of newer treatments in multiple myeloma has brought on a new set of challenges to the field for consideration. The effectiveness of novel combinations is actively redefining what we consider timely and effective surrogate endpoints from the regulatory standpoint. Nevertheless, the myeloma community has had the foresight to embrace immunomodulatory drug/proteasome inhibitor triplet therapy in the management of newly diagnosed disease long before the evidence of an overall survival benefit from a prospective phase III study was available to settle the argument. 

The latest studies may propel the KRd regimen to the forefront of suggested triplets, not just for high-risk disease,³¹ but as is already the case in some centers, for all newly diagnosed myeloma patients.³ Ongoing prospective phase III studies are evaluating the efficacy of KRd vs VRd in newly diagnosed multiple myeloma. 

For fit newly diagnosed myeloma patients, regardless of age or ASCT candidacy, the use of immunomodulatory drug/proteasome inhibitor triplet therapy is based on a solid foundation of safety and efficacy.

— Muhamed Baljevic, MD and Sarah A. Holstein, MD, PhD

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The increasing prognostic importance of MRD-negative status and the ability of immunomodulatory drug/proteasome inhibitor triplets (as opposed to doublets) in achieving it^32-35 have resulted in the FDA’s supportive stance toward MRD-negative status becoming a valid regulatory endpoint for newly diagnosed myeloma in years to come.³⁶ The body of evidence suggests that the rate of MRD negativity should become the next logical step in assessing treatment responses and predicting long-term outcomes of myeloma patients³⁷ and argues against the notion that many patients achieve equivalent benefit from doublet therapy as compared with triplet therapy. 

The current version of the National Comprehensive Cancer Network Guidelines^® lists two preferred regimens (both triplets) for induction therapy in newly diagnosed transplant-eligible myeloma patients, one of which is VRd, and the other (bortezomib/doxorubicin/dexamethasone, and bortezomib/cyclophosphamide/dexamethasone) perhaps is more suitable in patients with acute renal failure on presentation.³⁸ Five out of six front-line treatment options for newly diagnosed myeloma recommended by the European Society for Medical Oncology are triplets, and two of them are immunomodulatory drug/proteasome inhibitor–based, with the observation that VRd is likely to become a more widely used regimen after regulatory approval by the European Medicines Agency.³⁹ And it is worth noting that the safety and tolerability signal of KRd vs Rd in relapsed/refractory myeloma is associated with an improved global health status/quality of life without negatively affecting patient-reported symptoms, likely encouraging an increasing use of this triplet.⁴⁰

Finally, it must be noted that roughly one-third of patients with newly diagnosed multiple myeloma are over age 75 years—some with significant frailty and/or coexisting comorbidities—and that the overwhelming majority of study patients over the years have had preserved cardiac and renal function.^41,42 It will be essential to obtain further data on the toxicity, tolerability, and safety of triplets vs doublets in this population, particularly examining dose reductions of the triplet combinations, rather than de-escalations to doublet therapies. 

Meanwhile, the approach to determining the optimal induction choice in this older population should be guided by prudent clinical decision-making. For the remainder of fit newly diagnosed myeloma patients, regardless of age or ASCT candidacy, the use of immunomodulatory drug/proteasome inhibitor triplet therapy is based on a solid foundation of safety and efficacy. ■

Dr. Baljevic is Assistant Professor, and Dr. Holstein is Associate Professor, Division of Hematology-Oncology, Department of Internal Medicine, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha. 

DISCLOSURE: Dr. Baljevic is an advisory board member for Takeda and Amgen, and Dr. Holstein is a consultant and advisory board member for Celgene and an advisory board member for Takeda. 

REFERENCES

1. Kristinsson SY, Anderson WF, Landgren O: Improved long-term survival in multiple myeloma up to the age of 80 years. Leukemia 28:1346-1348, 2014.

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, 2009.

3. Landgren O: Combination therapy for fit (younger and older) newly diagnosed multiple myeloma patients: Data support carfilzomib, lenalidomide, and dexamethasone independent of cytogenetic risk status. Semin Oncol 43:703-706, 2016.

4. Richardson PG, Weller E, Jagannath S, et al: Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol 27:5713-5719, 2009.

5. Richardson PG, Weller E, Lonial S, et al: Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116:679-686, 2010.

6. Kumar S, Flinn I, Richardson PG, et al: Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 119:4375-4382, 2012.

7. Roussel M, Lauwers-Cances V, Robillard N, et al: Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: A phase II study by the Intergroupe Francophone du Myelome. J Clin Oncol 32:2712-2717, 2014.

8. 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, 2017.

9. Moreau P, Pylypenko H, Grosicki S, et al: Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: A randomised, phase 3, non-inferiority study. Lancet Oncol 12:431-440, 2011.

10. 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.

11. Moreau P, Hulin C, Macro M, et al: VTD is superior to VCD prior to intensive therapy in multiple myeloma: Results of the prospective IFM2013-04 trial. Blood 127:2569-2574, 2016.

12. Sonneveld P, Avet-Loiseau H, Lonial S, et al: Treatment of multiple myeloma with high-risk cytogenetics: A consensus of the International Myeloma Working Group. Blood 127:2955-2962, 2016.

13. Sun Z, Zheng F, Wu S, et al: Triplet versus doublet combination regimens for the treatment of relapsed or refractory multiple myeloma: A meta-analysis of phase III randomized controlled trials. Crit Rev Oncol Hematol 113:249-255, 2017.

14. Kumar SK, Berdeja JG, Niesvizky R, et al: Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: An open-label phase 1/2 study. Lancet Oncol 15:1503-1512, 2014.

15. Moreau P, Masszi T, Grzasko N, et al: Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 374:1621-1634, 2016.

16. Kumar SK, Berdeja J, Niesvizky R, et al: Deep and durable responses with weekly ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: Long-term follow-up of patients who did not undergo SCT. 2017 European Hematology Association Congress. Abstract S408. Presented June 24, 2017.

17. Richardson P, Hofmeister C, Rosenbaum C, et al: Twice-weekly ixazomib plus lenalidomide-dexamethasone in patients with newly diagnosed multiple myeloma: Long-term follow-up data for patients who did not undergo stem cell transplantation. 2017 European Hematology Association Congress. Abstract S780. Presented June 25, 2017.

18. Second phase 3 study shows Kyprolis (carfilzomib) regimen significantly improves overall survival in patients with relapsed multiple myeloma. Amgen press release, July 12, 2017. Available at www.amgen.com. Accessed August 22, 2017.

19. Jakubowiak AJ, Dytfeld D, Griffith KA, et al: A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 120:1801-1809, 2012.

20. Korde N, Roschewski M, Zingone A, et al: Treatment with carfilzomib-
lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol 1:746-754, 2015.

21. Sonneveld P, Asselbergs E, Zweegman S, et al: Phase 2 study of carfilzomib, thalidomide, and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood 125:449-456, 2015.

22. Yang WC, Lin SF: Mechanisms of drug resistance in relapse and refractory multiple myeloma. Biomed Res Int 2015:341430, 2015.

23. Richardson P, Hájek R, Palumbo A, et al: Navigating the changing multiple myeloma treatment landscape. EMJ Hematol 4:55-65, 2016.

24. Bahlis NJ: Darwinian evolution and tiding clones in multiple myeloma. Blood 120:927-928, 2012.

25. Keats JJ, Chesi M, Egan JB, et al: Clonal competition with alternating dominance in multiple myeloma. Blood 120:1067-1076, 2012.

26. Bianchi G, Ghobrial IM: Biological and clinical implications of clonal heterogeneity and clonal evolution in multiple myeloma. Curr Cancer Ther Rev 10:70-79, 2014.

27. Bolli N, Avet-Loiseau H, Wedge DC, et al: Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun 5:2997, 2014.

28. Brioli A, Melchor L, Cavo M, et al: The impact of intra-clonal heterogeneity on the treatment of multiple myeloma. Br J Haematol 165:441-454,2014.

29. Jakubowiak AJ, Chari A, Lonial S, et al: Daratumumab in combination with carfilzomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma (MMY1001): An open-label, phase 1b study. 2017 ASCO Annual Meeting. Abstract 8000. Presented June 4, 2017.

30. 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.

31. Mayo Clinic: mSMART: Mayo stratification for myeloma and risk-adapted therapy: Newly diagnosed myeloma. Available at nebula.wsimg.com/e1520dd2009dae7c8ea5ca513775b8fa?AccessKeyId=A0994494BBBCBE4A0363&disposition=0&alloworigin=1. Accessed August 22, 2017.

32. Attal M, Lauwers-Cances V, Hulin C, et al: Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med 376:1311-1320, 2017.

33. Lahuerta JJ, Paiva B, Vidriales MB, et al: Depth of response in multiple myeloma: A pooled analysis of three PETHEMA/GEM clinical trials. J Clin Oncol 35:2900-2910, 2017.

34. Landgren O, Devlin S, Boulad M, et al: Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: A meta-analysis. Bone Marrow Transplant 51:1565-1568, 2016.

35. Paiva B, Vidriales MB, Cervero J, et al: Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood 112:4017-4023, 2008.

36. Gormley NJ, Turley DM, Dickey JS, et al: Regulatory perspective on minimal residual disease flow cytometry testing in multiple myeloma. Cytometry B Clin Cytom 90:73-80, 2016.

37. Landgren O, Giralt S: MRD-driven treatment paradigm for newly diagnosed transplant eligible multiple myeloma patients. Bone Marrow Transplant 51:913-914, 2016.

38. Kumar SK, Callander NS, Alsina M, et al: Multiple myeloma, version 3.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 15:230-269, 2017.

39. Moreau P, San Miguel J, Sonneveld P, et al: Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 28(suppl 4):iv52-iv61, 2017.

40. Stewart AK, Dimopoulos MA, Masszi T, et al: Health-related quality of life results from the open-label, randomized, phase III ASPIRE trial evaluating carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma. J Clin Oncol 32:3921-3920, 2017.

41. Zweegman S, Engelhardt M, Larocca A; EHA SWG on ‘Aging and Hematology’: Elderly patients with multiple myeloma: Towards a frailty approach? Curr Opin Oncol 29:315-321, 2017.

42. Wildes TM: Emerging therapies for multiple myeloma: Application in older adults. J Geriatr Oncol 8:413-416, 2017.