Smoldering multiple myeloma

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Samuel M. Rubinstein, MD
Vanderbilt University
Nashville, TN

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Andrew J. Cowan, MD
University of Washington
Seattle, WA

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10 regimens on this page
10 variants on this page


All lines of therapy

Lenalidomide monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Lonial et al. 2019 (ECOG E3A06) Phase III (E) Observation Superior PFS

Chemotherapy

Supportive medications

28-day cycles

References

  1. ECOG E3A06: Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] link to original article contains verified protocol PubMed

MP

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MP: Melphalan & Prednisone

Note: This regimen is of historical significance

Variant #1, Six cycles of therapy

Study Evidence Comparator Comparative Efficacy
Riccardi et al. 2000 (MM87/MM90) Phase III (E) Observation Seems not superior

Note: Patients on the observation arm of this study received this regimen at progression to symptomatic MM

Chemotherapy

42-day cycle for six cycles

Variant #2, Indefinite therapy

Study Evidence Comparator Comparative Efficacy
Hjorth et al. 1993 Phase III (E) Observation Seems not superior

Chemotherapy

42-day cycles

References

  1. Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J; Myeloma Group of Western Sweden. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Eur J Haematol. 1993 Feb;50(2):95-102. link to original article contains protocol PubMed
  2. MM87/MM90: Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E; Cooperative Group of Study and Treatment of Multiple Myeloma. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Br J Cancer. 2000 Apr;82(7):1254-60. link to original article contains protocol PubMed

Observation

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Regimen

Study Evidence Comparator Comparative Efficacy
Hjorth et al. 1993 Phase III (C) MP Seems not superior
Riccardi et al. 2000 (MM87/MM90) Phase III (C) MP Seems not superior
Witzig et al 2012 (MC0289) Phase III (C) Thalidomide Seems to have inferior TTP
Mateos et al. 2013 (QUIREDEX) Phase III (C) Rd Seems to have inferior OS
Lonial et al. 2019 (ECOG E3A06) Phase III (C) Lenalidomide Inferior PFS

No treatment.

References

  1. Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J; Myeloma Group of Western Sweden. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Eur J Haematol. 1993 Feb;50(2):95-102. link to original article contains protocol PubMed
  2. MM87/MM90: Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E; Cooperative Group of Study and Treatment of Multiple Myeloma. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Br J Cancer. 2000 Apr;82(7):1254-60. link to original article contains protocol PubMed
  3. MC0289: Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 link to original article contains verified protocol PubMed
  4. QUIREDEX: Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. link to original article contains verified protocol PubMed
  5. ECOG E3A06: Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print]

Rd

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Regimen

Study Evidence Comparator Comparative Efficacy
Mateos et al. 2013 (QUIREDEX) Phase III (E) Observation Seems to have superior OS

Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.

Chemotherapy

Supportive medications

28-day cycle for 9 cycles

Subsequent treatment

References

  1. QUIREDEX: Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. link to original article contains verified protocol PubMed

Thalidomide monotherapy

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Variant #1, 200 mg/d, indefinite therapy

Study Evidence Comparator Comparative Efficacy
Barlogie et al. 2008 Phase II
Witzig et al. 2012 (MC0289) Phase III (E) Observation Seems to have superior TTP

Note: Zoledronic acid was received in both the control and experimental arms.

Chemotherapy

Supportive medications

Continued indefinitely

Variant #2, 200 -> 600 mg/d, indefinite therapy

Study Evidence
Weber et al. 2003 Phase II

Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day

Chemotherapy

  • Thalidomide (Thalomid) as follows:
    • Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29
    • Cycle 2 onwards: 600 mg PO once per day

Continued indefinitely

Variant #3, 200 -> 800 mg/d, indefinite therapy

Study Evidence
Rajkumar et al. 2001 Phase II

Chemotherapy

  • Thalidomide (Thalomid) as follows:
    • Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42
    • Cycle 2 onwards: 800 mg PO once per day

Continued indefinitely

References

  1. Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 link to original article contains protocol PubMed
  2. Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. link to original article contains protocol PubMed
  3. Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. link to original article contains protocol PubMed
  4. MC0289: Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 link to original article contains verified protocol PubMed