Smoldering multiple myeloma

Page editor		Section editor
	Samuel M. Rubinstein, MD University of North Carolina Chapel Hill, NC		Andrew J. Cowan, MD University of Washington Seattle, WA LinkedIn

Note: due to its size/complexity, multiple myeloma has been split into sub-pages:

• Induction (transplant eligible and ineligible)
• First-line consolidation and maintenance
• Relapsed/refractory, including subsequent consolidation and maintenance
• Smoldering multiple myeloma [this page]

4 regimens on this page 7 variants on this page

Guidelines

"How I Treat"

• 2022: Vaxman & Gertz How I approach smoldering multiple myeloma

All lines of therapy

Lenalidomide monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lonial et al. 2019 (ECOG E3A06)	2011-2013	Phase 3 (E-esc)	Observation	Superior PFS PFS36: 91% vs 66% (HR 0.28, 95% CI 0.12-0.62)

Targeted therapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

Supportive therapy

• Aspirin 325 mg PO once per day

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. 2020 Apr 10;38(11):1126-1137. Epub 2019 Oct 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01169337

Lenalidomide & Dexamethasone (Rd)

Rd: Revlimid (Lenalidomide) & low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Mateos et al. 2013 (QUIREDEX)	2007-2010	Phase 3 (E-esc)	Observation	Superior OS OS36: 94% vs 80% (HR 0.31, 95% CI 0.10-0.91)

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.

Targeted therapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 12 to 15

Supportive therapy

• Aspirin 100 mg PO once per day

28-day cycle for 9 cycles

Subsequent treatment

• Lenalidomide maintenance

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 dosing details in manuscript PubMed NCT00480363
2. DETER-SMM: NCT03937635
3. EFC15992: NCT03941860
4. ITHACA: NCT04270409

Melphalan & Prednisone (MP)

MP: Melphalan & Prednisone Note: This regimen is of historical significance

Regimen variant #1, Six cycles of therapy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Riccardi et al. 2000 (MM87/MM90)	1987-1993	Phase 3 (E-esc)	Observation	Did not meet endpoint of OS

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

Chemotherapy

• Melphalan (Alkeran) 0.21 mg/kg PO once per day on days 1 to 4

Glucocorticoid therapy

• Prednisone (Sterapred) 0.5 mg/kg PO once per day on days 1 to 10

42-day cycle for six cycles

Regimen variant #2, Indefinite therapy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hjorth et al. 1993	1983-1988	Phase 3 (E-esc)	Observation	Did not meet endpoint of OS

Chemotherapy

• Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 4

Glucocorticoid therapy

• Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4

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 dosing details in abstract 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 dosing details in abstract link to PMC article PubMed

Observation

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hjorth et al. 1993	1983-1988	Phase 3 (C)	MP	Did not meet endpoint of OS
Riccardi et al. 2000 (MM87/MM90)	1987-1993	Phase 3 (C)	MP	Did not meet endpoint of OS
Witzig et al 2012 (MC0289)	2003-2008	Phase 3 (C)	Thalidomide	Seems to have inferior TTP
Mateos et al. 2013 (QUIREDEX)	2007-2010	Phase 3 (C)	Rd	Inferior OS
Lonial et al. 2019 (ECOG E3A06)	2011-2013	Phase 3 (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 dosing details in abstract 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 dosing details in abstract link to PMC article 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 dosing details in manuscript link to PMC article PubMed NCT00432458
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 dosing details in manuscript PubMed NCT00480363
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. 2020 Apr 10;38(11):1126-1137. Epub 2019 Oct 25. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01169337
6. AQUILA: NCT03301220

Thalidomide monotherapy

Regimen variant #1, 200 mg/d, indefinite therapy

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Barlogie et al. 2008 (UARK 98-036)	1998-NR	Phase 2
Witzig et al. 2012 (MC0289)	2003-2008	Phase 3 (E-esc)	Observation	Seems to have superior TTP

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

Targeted therapy

• Thalidomide (Thalomid) 200 mg PO once per day

Supportive therapy

• Zoledronic acid (Zometa) 4 mg IV once every three months

Continued indefinitely

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

Study	Dates of enrollment	Evidence
Weber et al. 2003	1999-2001	Phase 1/2

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

Targeted therapy

• Thalidomide (Thalomid) as follows:
  • 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 28
  • Cycle 2 onwards: 600 mg PO once per day

28-day cycles

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

Study	Dates of enrollment	Evidence
Rajkumar et al. 2001	NR	Phase 2

Targeted therapy

• Thalidomide (Thalomid) as follows:
  • 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
  • Cycle 2: 600 mg PO once per day on days 1 to 14, then 800 mg PO once per day on days 15 to 28
  • Cycle 3 onwards: 800 mg PO once per day

28-day cycles

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 dosing details in abstract 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 dosing details in abstract PubMed
3. UARK 98-036: 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. Epub 2008 Jul 31. link to original article contains dosing details in abstract link to PMC article PubMed NCT00083382
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 dosing details in manuscript link to PMC article PubMed NCT00432458