EHA 2016: Consolidation and maintenance therapy for multiple myeloma: is it the new standard? Professor Paul Richardson (Harvard Medical School, Boston, USA) and Professor Maria-Victoria Mateos (Salamanca, Spain) discuss the meta-analysis of OS in myeloma with maintenance therapy presented at ASCO and EHA this year, along with strategies for continuous therapies

Consolidation and maintenance therapy for multiple myeloma: is it the new standard?  

Professor Antonio Palumbo (University of Turin, Italy) and Professor Paul Richardson (Harvard Medical School, Boston, USA)

Consolidation and maintenance therapy using novel agent-containing regimens improves the depth of response and prolongs progression-free survival in MM and is part of the current MM treatment paradigm. Now a meta-analysis, presented at EHA 2016 by Professor Antonio Palumbo from Turin, clearly demonstrates a benefit in overall survival (OS) with lenalidomide maintenance following autologous stem cell transplant.¹

 

The treatment goals following induction therapy in stem cell transplantation (SCT)-eligible MM patients are to improve PFS and OS, paying attention the timing, duration, intensity and toxicity of the continued therapy to avoid treatment fatigue and ensure the therapy is easy to deliver and convenient for the patient.^2,3 The treatment decision should take into account risk factors such as age, co-morbidities, International Staging System (ISS) score, cytogenetic profile and features such as extramedullary disease,^4,5 said Professor Paul Richardson from the Dana-Farber Cancer Institute in Boston as he reviewed the key evidence. In the consolidation setting bortezomib has been shown to be effective for improving response rates and PFS post-SCT as monotherapy⁶ and added to thalidomide and dexamethasone (VTd).⁷ A recently published study reported a PFS of 33.6 months in patients receiving bortezomib consolidation therapy post-SCT compared with 27.8 months in the observation-only arm.⁸ Adding bortezomib to lenalidomide and dexamethasone (RVd) as consolidation therapy was associated with improved PFS and response rates, importantly not only with respect to patients achieving a very good partial response (VGPR) or complete response (CR) but also in terms of minimal residual disease: the proportion of patients achieving MRD negativity on flow cytometry rose from 16% at the end of induction to 58% at the end of the consolidation phase.⁹ Similar improvements in response rates were reported recently in a phase 3 study documenting RVd as consolidation therapy following SCT.¹⁰

 

Proteasome inhibitors have also demonstrated significant clinical benefits in the maintenance therapy setting post-SCT. The HOVON 65 MM/GMMG-HD4 study found that patients randomised to induction and maintenance therapy with bortezomib post-SCT had significantly higher PFS and response rates than patients receiving thalidomide maintenance therapy.¹¹ The clinical benefit of bortezomib was evident also in patients with increased serum creatinine at baseline¹²  and in patients with del(17p) cytogenetics. ¹¹

 

Lenalidomide currently constitutes the backbone in post-SCT maintenance therapy. In the CALGB 100104 study patients were randomised to post-SCT maintenance therapy with either lenalidomide or placebo; the results showed a significant improvement in time to progression (TTP; 53 versus 26 months; hazard ratio 0.54; p<0.001) and OS (not reached versus 76 months; HR 0.60; p=0.001) which was evident across all sub-groups.^13,14 The updated analysis of this study showed a small increase in the risk of developing a secondary primary malignancy (SPM) in the lenalidomide arm.¹⁴ In the IFM 2005-02 study PFS improved by 18 months in patients receiving lenalidomide maintenance therapy for 2 years post-SCT compared with placebo (42 versus 24 months).^15,16 Prolonged PFS with lenalidomide maintenance therapy compared with placebo was also demonstrated in an Italian phase 3 study; in this study, lenalidomide maintenance therapy reduced the risk of progression by 48% (p<0.0001) and the risk of death within 5 years by 38% (p=0.02). ¹⁷

 

None of the randomised controlled studies of lenalidomide maintenance therapy were powered for OS. However, a prospectively planned meta-analysis of the study results, reported in an oral presentation at EHA 2016 by Professor Palumbo, showed significantly higher OS at 5, 6 and 7 years compared with placebo (71% vs 66%, 65% vs 58%, and 62% vs 50%, respectively; p=0.001)¹. Median OS in the lenalidomide arm has not been reached, compared with 86 months in the placebo arm. The survival benefit with lenalidomide maintenance therapy was evident in all response categories. This large meta-analysis demonstrates that lenalidomide maintenance significantly prolonged OS vs control (placebo/no maintenance) post ASCT, including in patients who achieved CR, demonstrating benefit in patients in all response categories. Professor Palumbo said that lenalidomide maintenance following autologous stem cell transplant can now be considered a standard of care for people with multiple myeloma.

 

References

1. McCarthy PL, Palumbo A et al. A meta-analysis of overall survival in patients with multiple myeloma treated with lenalidomide maintenance after high-dose melphalan and autologous stem cell transplant. EHA 21 2016 presentation.
2. Mihelic R, Kaufman JL, Lonial S. Maintenance therapy in multiple myeloma. Leukemia 2007;21:1150-7.
3. Richardson PG, Laubach J, Mitsiades CS, et al. Managing multiple myeloma: the emerging role of novel therapies and adapting combination treatment for higher risk settings. Br J Haematol 2011;154:755-62.
4. McCarthy PL, Hahn T. Strategies for induction, autologous hematopoietic stem cell transplantation, consolidation, and maintenance for transplantation-eligible multiple myeloma patients. Hematology Am Soc Hematol Educ Program 2013;2013:496-503.
5. Ludwig H, Avet-Loiseau H, Blade J, et al. European perspective on multiple myeloma treatment strategies: update following recent congresses. Oncologist 2012;17:592-606.
6. Mellqvist UH, Gimsing P, Hjertner O, et al. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood 2013;121:4647-54.
7. Cavo M, Pantani L, Petrucci MT, et al. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood 2012;120:9-19.
8. Straka C, Vogel M, Muller J, et al. Results from two phase III studies of bortezomib (BTZ) consolidation vs observation (OBS) post-transplant in patients (pts) with newly diagnosed multiple myeloma (NDMM). ASCO Meeting Abstracts 2015;33:8511.
9. 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 Myélome. Journal of Clinical Oncology 2014;32:2712-2717.
10. Attal M, Lauwers-Cances V, Hulin C, et al. Autologous Transplantation for Multiple Myeloma in the Era of New Drugs: A Phase III Study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial) American Society of Hematology. Orlando, FL, 2015.
11. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol 2012;30:2946-55.
12. Scheid C, Sonneveld P, Schmidt-Wolf IG, et al. Bortezomib before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in newly diagnosed multiple myeloma: a subgroup analysis from the HOVON-65/GMMG-HD4 trial. Haematologica 2014;99:148-54.
13. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1770-81.
14. Holstein SA, Owzar K, Richardson PG, et al. Updated analysis of CALGB/ECOG/BMT CTN 100104: Lenalidomide (Len) vs. placebo (PBO) maintenance therapy after single autologous stem cell transplant (ASCT) for multiple myeloma (MM). ASCO Meeting Abstracts 2015;33:8523.
15. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1782-91.
16. Attal M, Lauwers-Cances Vr, Marit Gr, et al. Lenalidomide Maintenance After Stem-Cell Transplantation For Multiple Myeloma: Follow-Up Analysis Of The IFM 2005-02 Trial. Blood 2015;122:406.
17. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 2014;371:895-905.