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20-03-2018 | Multiple myeloma | Article

Patient-reported outcomes in relapsed/refractory multiple myeloma: a systematic review

Journal: Supportive Care in Cancer

Authors: Francesco Sparano, Michele Cavo, Pasquale Niscola, Tommaso Caravita, Fabio Efficace

Publisher: Springer Berlin Heidelberg

Abstract

Purpose

We performed a systematic review to quantify the amount of evidence-based data available on patient-reported outcomes (PRO) in Relapsed/Refractory Multiple Myeloma (RRMM) patients and to examine the added value of such studies in supporting clinical decision-making.

Methods

We conducted a search in PubMed/Medline and the Cochrane Library to identify studies published between January 1990 and May 2017. All studies, regardless of the design, including patients with RRMM and also evaluating PRO were considered. For each study, we collected both PRO and traditional clinical outcomes, such as survival and toxicity information, based on a predefined data extraction form.

Results

After having screened 1680 records, 11 studies were identified and these included six randomized controlled trials (RCT). Overall, there were five studies focusing on proteasome inhibitors (PIs), four on immunomodulatory drugs (IMiDs), one on both PIs and IMiDs, and one on monoclonal antibodies. Considering only RCTs, it was found that primary clinical efficacy endpoints frequently favored experimental arms, while (physician-reported) toxicity data did not. However, inspection of PRO data revealed novel information that often contrasted with standard toxicity, for example, by not indicating worse quality of life outcomes or symptom severity for patients enrolled in the experimental arms.

Conclusions

There is paucity of evidence-based data regarding the impact of therapies on quality of life and symptom burden of patients with RRMM. Inclusion of PRO in future studies of patients with RRMM is needed to better inform clinical decision-making.
Literature
1.
Mols F, Oerlemans S, Vos AH, Koster A, Verelst S, Sonneveld P, van de Poll-Franse LV (2012) Health-related quality of life and disease-specific complaints among multiple myeloma patients up to 10 yr after diagnosis: results from a population-based study using the PROFILES registry. Eur J Haematol 89 (4):311–319. doi:https://​doi.​org/​10.​1111/​j.​1600-0609.​2012.​01831.​x
2.
Schumacher M, Olschewski M, Schulgen G (1991) Assessment of quality of life in clinical trials. Stat Med 10(12):1915–1930CrossRefPubMed
3.
US Food and Drug Administration: Guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims. US Department of Health and Human Services Food and Drug Administration.December 2009. http://​www.​fda.​gov/​downloads/​Drugs/​GuidanceComplian​ceRegulatoryInfo​rmation/​Guidances/​UCM193282.​pdf. Accessed April 29, 2016
4.
Kurtin S (2013) Relapsed or relapsed/refractory multiple myeloma. Journal of the Advanced Practitioner in Oncology 4(Suppl. 1):5–14
5.
Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, Dingli D, Russell SJ, Lust JA, Greipp PR, Kyle RA, Gertz MA (2008) Improved survival in multiple myeloma and the impact of novel therapies. Blood 111(5):2516–2520. https://​doi.​org/​10.​1182/​blood-2007-10-116129 CrossRefPubMedPubMedCentral
6.
Wildes TM, Rosko A, Tuchman SA (2014) Multiple myeloma in the older adult: better prospects, more challenges. J Clin Oncol 32(24):2531–2540CrossRefPubMedPubMedCentral
7.
Brenner H, Gondos A, Pulte D (2008) Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 111(5):2521–2526. https://​doi.​org/​10.​1182/​blood-2007-08-104984 CrossRefPubMed
8.
Schaapveld M, Visser O, Siesling S, Schaar CG, Zweegman S, Vellenga E (2010) Improved survival among younger but not among older patients with multiple myeloma in the Netherlands, a population-based study since 1989. Eur J Cancer 46(1):160–169. https://​doi.​org/​10.​1016/​j.​ejca.​2009.​07.​006 CrossRefPubMed
9.
San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359(9):906–917. https://​doi.​org/​10.​1056/​NEJMoa0801479 CrossRefPubMed
10.
Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Blade J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA (2012) Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 366(19):1759–1769. https://​doi.​org/​10.​1056/​NEJMoa1112704 CrossRefPubMed
11.
Fayers PM, Palumbo A, Hulin C, Waage A, Wijermans P, Beksac M, Bringhen S, Mary JY, Gimsing P, Termorshuizen F, Haznedar R, Caravita T, Moreau P, Turesson I, Musto P, Benboubker L, Schaafsma M, Sonneveld P, Facon T (2011) Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood 118(5):1239–1247. https://​doi.​org/​10.​1182/​blood-2011-03-341669 CrossRefPubMed
12.
Laubach J, Garderet L, Mahindra A, Gahrton G, Caers J, Sezer O, Voorhees P, Leleu X, Johnsen HE, Streetly M, Jurczyszyn A, Ludwig H, Mellqvist UH, Chng WJ, Pilarski L, Einsele H, Hou J, Turesson I, Zamagni E, Chim CS, Mazumder A, Westin J, Lu J, Reiman T, Kristinsson S, Joshua D, Roussel M, O'Gorman P, Terpos E, McCarthy P, Dimopoulos M, Moreau P, Orlowski RZ, Miguel JS, Anderson KC, Palumbo A, Kumar S, Rajkumar V, Durie B, Richardson PG (2016) Management of relapsed multiple myeloma: recommendations of the international myeloma working group. Leukemia 30(5):1005–1017. https://​doi.​org/​10.​1038/​leu.​2015.​356 CrossRefPubMed
13.
Sonneveld P, Broijl A (2016) Treatment of relapsed and refractory multiple myeloma. Haematologica 101(4):396–406. https://​doi.​org/​10.​3324/​haematol.​2015.​129189 CrossRefPubMedPubMedCentral
14.
Anderson KC, Kyle RA, Rajkumar SV, Stewart AK, Weber D, Richardson P (2008) Clinically relevant end points and new drug approvals for myeloma. Leukemia 22(2):231–239. https://​doi.​org/​10.​1038/​sj.​leu.​2405016 CrossRefPubMed
15.
Larocca A, Palumbo A (2015) How I treat fragile myeloma patients. Blood 126(19):2179–2185. https://​doi.​org/​10.​1182/​blood-2015-05-612960 CrossRefPubMed
16.
Bringhen S, Mateos MV, Zweegman S, Larocca A, Falcone AP, Oriol A, Rossi D, Cavalli M, Wijermans P, Ria R, Offidani M, Lahuerta JJ, Liberati AM, Mina R, Callea V, Schaafsma M, Cerrato C, Marasca R, Franceschini L, Evangelista A, Teruel AI, van der Holt B, Montefusco V, Ciccone G, Boccadoro M, San Miguel J, Sonneveld P, Palumbo A (2013) Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials. Haematologica 98(6):980–987. https://​doi.​org/​10.​3324/​haematol.​2012.​075051 CrossRefPubMedPubMedCentral
17.
Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, Haessler J, Feather J, Hoering A, Moreau P, LeLeu X, Hulin C, Klein SK, Sonneveld P, Siegel D, Blade J, Goldschmidt H, Jagannath S, Miguel JS, Orlowski R, Palumbo A, Sezer O, Rajkumar SV, Durie BG (2012) Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia 26(1):149–157CrossRefPubMed
18.
Murray SA, Kendall M, Mitchell G, Moine S, Amblas-Novellas J, Boyd K (2017) Palliative care from diagnosis to death. BMJ 356:j878CrossRefPubMed
19.
Sonneveld P, Verelst SG, Lewis P, Gray-Schopfer V, Hutchings A, Nixon A, Petrucci MT (2013) Review of health-related quality of life data in multiple myeloma patients treated with novel agents. Leukemia 27(10):1959–1969. https://​doi.​org/​10.​1038/​leu.​2013.​185 CrossRefPubMedPubMedCentral
20.
Kvam AK, Fayers P, Hjermstad M, Gulbrandsen N, Wisloff F (2009) Health-related quality of life assessment in randomised controlled trials in multiple myeloma: a critical review of methodology and impact on treatment recommendations. Eur J Haematol 83(4):279–289CrossRefPubMed
21.
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC et al (1993) The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85(5):365–376CrossRefPubMed
22.
Nielsen LK, Jarden M, Andersen CL, Frederiksen H, Abildgaard N (2017) A systematic review of health-related quality of life in longitudinal studies of myeloma patients. Eur J Haematol 99:3–17. https://​doi.​org/​10.​1111/​ejh.​12882 CrossRefPubMed
23.
Palumbo A, Petrucci MT, Lauta VM, Musto P, Caravita T, Barbui AM, Nunzi M, Boccadoro M (2005) Correlation between fatigue and hemoglobin level in multiple myeloma patients: results of a cross-sectional study. Haematologica 90(6):858–860PubMed
24.
Kvam AK, Fayers P, Wisloff F (2010) What changes in health-related quality of life matter to multiple myeloma patients? A prospective study. Eur J Haematol 84(4):345–353. https://​doi.​org/​10.​1111/​j.​1600-0609.​2009.​01404.​x CrossRefPubMed
25.
Boland E, Eiser C, Ezaydi Y, Greenfield DM, Ahmedzai SH, Snowden JA (2013) Living with advanced but stable multiple myeloma: a study of the symptom burden and cumulative effects of disease and intensive (hematopoietic stem cell transplant-based) treatment on health-related quality of life. J Pain Symptom Manag 46(5):671–680. https://​doi.​org/​10.​1016/​j.​jpainsymman.​2012.​11.​003 CrossRef
26.
Jordan K, Proskorovsky I, Lewis P, Ishak J, Payne K, Lordan N, Kyriakou C, Williams CD, Peters S, Davies FE (2014) Effect of general symptom level, specific adverse events, treatment patterns, and patient characteristics on health-related quality of life in patients with multiple myeloma: results of a European, multicenter cohort study. Support Care Cancer 22(2):417–426. https://​doi.​org/​10.​1007/​s00520-013-1991-4 CrossRefPubMed
27.
Moher D, Liberati A, Tetzlaff J, Altman DG, The PG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6 (7):e1000097. doi:https://​doi.​org/​10.​1371/​journal.​pmed.​1000097
28.
Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hajek R, Rosinol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A (2015) Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 372(2):142–152. https://​doi.​org/​10.​1056/​NEJMoa1411321 CrossRefPubMed
29.
Stewart AK, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hajek R, Rosinol L, Siegel DS, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Buchanan J, Cocks K, Yang X, Xing B, Zojwalla N, Tonda M, Moreau P, Palumbo A (2016) 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 34:3921–3930. https://​doi.​org/​10.​1200/​jco.​2016.​66.​9648 CrossRefPubMedPubMedCentral
30.
Weisel K, Dimopoulos M, Song KW, Moreau P, Palumbo A, Belch A, Schey S, Sonneveld P, Sternas L, Yu X, Amatya R, Gibson CJ, Zaki M, Jacques C, San Miguel J (2015) Pomalidomide and low-dose dexamethasone improves health-related quality of life and prolongs time to worsening in relapsed/refractory patients with multiple myeloma enrolled in the MM-003 randomized phase III trial. Clin Lymphoma Myeloma Leuk 15(9):519–530. https://​doi.​org/​10.​1016/​j.​clml.​2015.​05.​007 CrossRefPubMed
31.
Song KW, Dimopoulos MA, Weisel KC, Moreau P, Palumbo A, Belch A, Schey S, Sonneveld P, Sternas L, Yu X, Amatya R, Monzini MS, Zaki M, Jacques C, Miguel JS (2015) Health-related quality of life from the MM-003 trial of pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed and/or refractory multiple myeloma. Haematologica 2:63–67. https://​doi.​org/​10.​3324/​haematol.​2014.​112557 CrossRef
32.
San Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M (2013) Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. The Lancet Oncology 14(11):1055–1066. https://​doi.​org/​10.​1016/​S1470-2045(13)70380-2 CrossRef
33.
Nooka AK, Kastritis E, Dimopoulos MA, Lonial S (2015) Treatment options for relapsed and refractory multiple myeloma. Blood 125(20):3085–3099 doi:blood-2014-11-568923 [pii]CrossRefPubMed
34.
Lee SJ, Richardson PG, Sonneveld P, Schuster MW, Irwin D, San Miguel JF, Crawford B, Massaro J, Dhawan R, Gupta S, Anderson KC (2008) Bortezomib is associated with better health-related quality of life than high-dose dexamethasone in patients with relapsed multiple myeloma: results from the APEX study. Br J Haematol 4:511–519. https://​doi.​org/​10.​1111/​j.​1365-2141.​2008.​07378.​x CrossRef
35.
Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Blade J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352(24):2487–2498. https://​doi.​org/​10.​1056/​NEJMoa043445 CrossRefPubMed
36.
Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, San Miguel JF, Cavenagh JD, Anderson KC (2007) Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myeloma. Br J Haematol 137(5):429–435. https://​doi.​org/​10.​1111/​j.​1365-2141.​2007.​06585.​x CrossRefPubMed
37.
Dubois D, Dhawan R, van de Velde H, Esseltine D, Gupta S, Viala M, de la Loge C (2006) Descriptive and prognostic value of patient-reported outcomes: the bortezomib experience in relapsed and refractory multiple myeloma. J Clin Oncol 24(6):976–982. https://​doi.​org/​10.​1200/​jco.​2005.​04.​0824 CrossRefPubMed
38.
Viala M, Bhakar AL, de la Loge C, van de Velde H, Esseltine D, Chang M, Dhawan R, Dubois D (2007) Patient-reported outcomes helped predict survival in multiple myeloma using partial least squares analysis. J Clin Epidemiol 60(7):670–679. https://​doi.​org/​10.​1016/​j.​jclinepi.​2006.​10.​006 CrossRefPubMed
39.
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348(26):2609–2617. https://​doi.​org/​10.​1056/​NEJMoa030288 CrossRefPubMed
40.
Hjorth M, Hjertner Ø, Knudsen LM, Gulbrandsen N, Holmberg E, Pedersen PT, Andersen NF, Andréasson B, Billström R, Carlson K, Carlsson MS, Flogegård M, Forsberg K, Gimsing P, Karlsson T, Linder O, Nahi H, Othzén A, Swedin A (2012) Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study. Eur J Haematol 88(6):485–496. https://​doi.​org/​10.​1111/​j.​1600-0609.​2012.​01775.​x CrossRefPubMedPubMedCentral
41.
Waage A, Gimsing P, Juliusson G, Turesson I, Gulbrandsen N, Eriksson T, Hjorth M, Nielsen JL, Lenhoff S, Westin J, Wisloff F (2004) Early response predicts thalidomide efficiency in patients with advanced multiple myeloma. Br J Haematol 125(2):149–155. https://​doi.​org/​10.​1111/​j.​1365-2141.​2004.​04879.​x [doi]
42.
Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG (2016) Oral Ixazomib, Lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 374(17):1621–1634. https://​doi.​org/​10.​1056/​NEJMoa1516282 CrossRefPubMed
43.
Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Rollig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P (2015) Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 373(7):621–631. https://​doi.​org/​10.​1056/​NEJMoa1505654 CrossRefPubMed
44.
Alegre A, Oriol-Rocafiguera A, Garcia-Larana J, Mateos MV, Sureda A, Martinez-Chamorro C, Cibeira MT, Aguado B, Knight R, Rosettani B (2012) Efficacy, safety and quality-of-life associated with lenalidomide plus dexamethasone for the treatment of relapsed or refractory multiple myeloma: the Spanish experience. Leuk Lymphoma 53(9):1714–1721. https://​doi.​org/​10.​3109/​10428194.​2012.​662643 [doi]
45.
Leleu X, Kyriakou C, Vande Broek I, Murphy P, Bacon P, Lewis P, Gilet H, Arnould B, Petrucci MT (2017) Prospective longitudinal study on quality of life in relapsed/refractory multiple myeloma patients receiving second- or third-line lenalidomide or bortezomib treatment. Blood Cancer J 7(3):e543. https://​doi.​org/​10.​1038/​bcj.​2017.​20 CrossRefPubMedPubMedCentral
46.
Callander N, Markovina S, Eickhoff J, Hutson P, Campbell T, Hematti P, Go R, Hegeman R, Longo W, Williams E, Asimakopoulos F, Miyamoto S (2014) Acetyl-L-carnitine (ALCAR) for the prevention of chemotherapy-induced peripheral neuropathy in patients with relapsed or refractory multiple myeloma treated with bortezomib, doxorubicin and low-dose dexamethasone: a study from the Wisconsin Oncology Network. Cancer Chemother Pharmacol 74(4):875–882. https://​doi.​org/​10.​1007/​s00280-014-2550-5 [doi]
47.
Cocks K, Cohen D, Wisloff F, Sezer O, Lee S, Hippe E, Gimsing P, Turesson I, Hajek R, Smith A, Graham L, Phillips A, Stead M, Velikova G, Brown J (2007) An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma. Eur J Cancer 43(11):1670–1678CrossRefPubMed
48.
Calhoun EA, Welshman EE, Chang CH, Lurain JR, Fishman DA, Hunt TL, Cella D (2003) Psychometric evaluation of the functional assessment of cancer therapy/gynecologic oncology group-neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer 13(6):741–748CrossRefPubMed
49.
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E (1997) Measuring fatigue and other anemia-related symptoms with the functional assessment of cancer therapy (FACT) measurement system. J Pain Symptom Manag 13(2):63–74CrossRef
50.
Morrison A, Polisena J, Husereau D, Moulton K, Clark M, Fiander M, Mierzwinski-Urban M, Clifford T, Hutton B, Rabb D (2012) The effect of English-language restriction on systematic review-based meta-analyses: a systematic review of empirical studies. Int J Technol Assess Health Care 28(2):138–144. https://​doi.​org/​10.​1017/​s026646231200008​6 CrossRefPubMed