Multiple myeloma medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Treatment

Treatment for multiple myeloma is focused on disease containment and suppression. If the disease is completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow population but no end-organ damage), treatment may be deferred. Such patients need to be treated when they develop symptoms such as anemia, hypercalcemia, progressive lytic lesions, renal dysfunction, rise in serum M component or Bence jones proteins. Those with solitary bone plasmacytomas and extramedullary plasmacytomas can be treated with a local radiation therapy of about 40 Gy.[1]

Those patients who present with symptomatic or progressive disease need medical and supportive therapy. The medical therapy is to check the progression of disease itself, while supportive therapy helps to treat the complications of the disease as well as the medical therapy, and thus eventually reduce morbidity associated with the condition. The initial therapy is based on whether a patient is a candidate for transplantation or not. If a patient is considered a candidate for transplantation, alkylating agents are avoided so as to reduce the load of potential stem cells.[2]

Although allogeneic stem cell transplant might cure the cancer, it is considered investigational given the high treatment-related mortality of 5-10% associated with the procedure. In addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g. pamidronate or zoledronic acid) are routinely administered to prevent fractures and erythropoietin to treat anemia.

Initial therapy

Multiple therapeutic agents are available for induction therapy, either alone or in combinations.[3] These include the following:

  • Steroids (dexamethasone and prednisone)
  • Immunomodulatory drugs:
  • Thalidomide
  • Lenalidomide
  • Pomalidomide
  • Proteasome inhibitors:
  • Bortezomib
  • Carfilzomib

Alkylating agents (melphalan and cyclophosphamide) Other cytotoxic drugs (e.g., vincristine, doxorubicin, and liposomal doxorubicin)

Initial treatment is aimed at treating symptoms and reducing disease burden. Commonly used induction regimens include dexamethasone with lenalidomide and bortezomib for a period of 8 months based on the side effect profile and associated co-morbidities.[4] [5] Lenalidomide is orally administered and increases the risk for deep vein thrombosis, while bortezomib is given IV and preferred in patients with renal impairment. Patients with high risk disease are considered for additional management therapy. Dexamethasone is used alone at a dose of 40 mg for 4 days consecutively, and equals efficacy to that shown by a combination with VAD (vincristine, adriamycin, and dexamethasone). In a trial performed by Facon T etal, no higher efficacy was noticed with melphalan plus prednisone, as well as other dexamethasone combination regimens as compared with dexamethasone alone.[6] [7]

Thalidomide: A number of trials were conducted to assess the efficacy of thalidomide as an independent induction agent. All of them found improved response rates with thalidomide and no reduction in stem cell load.[8] [9] [10]

Conventional therpay: The VAD regimen (vincristine, adriamycin, and dexamethasone) has shown efficacy ranging from 60 to 80%, in previously treated and untreated patients. This regimen is beneficial in the manner that it avoids early exposure to alkylating agents thus reducing the risks of myelosuppression and further leukemia's, without compromising on efficacy.[11] [12] [13] Alkylating agents are equal in efficacy when combined with VAD regimens, two of the most common ones being melphalan and oral cyclophosphamide plus prednisolone.[14]

Combination Therapy

Based on years of clinical trials, following drug combinations are being used to treat multiple myeloma:

  1. Bortezomib + dexamethasone[15][16]
  2. Lenalidomide + dexamethasone[5][17]
  3. Bortezomib + lenalidomide + dexamethasone[15][16]
  4. Bortezomib + cyclophosphamide + dexamethasone[18]
  5. Bortezomib + lenalidomide + cyclophosphamide + dexamethasone[19]
  6. Lenalidomide + cyclophosphamide + dexamethasone[20]
  7. Bortezomib + melphalan + prednisone[21]
  8. Bortezomib + liposomal doxorubicin +/- dexamethasone
  9. Melphalan + prednisone + thalidomide
  10. Melphalan + prednisone

Low-dose therapy with melphalan combined with prednisone can be used to palliate symptoms in patients who cannot tolerate aggressive therapy.Plasmapheresis can be used to treat symptomatic protein proliferation (hyperviscosity syndrome).

In younger patients, therapy may include high-dose chemotherapy, melphalan, and autologous stem cell transplantation. This can be given in tandem fashion, i.e. an autologous transplant followed by a second transplant. Nonmyeloablative (or "mini") allogeneic stem cell transplantation is being investigated as an alternative to autologous stem cell transplant, or as part of a tandem transplant following an autologous transplant (also known as an "auto-mini" tandem transplant).

A 2007 trial indicated that the addition of thalidomide to reduced-intensity chemotherapy (melphalan and prednisone, MP) in patients between 65-75 led to a marked prolongation (median 51 versus 33 months) in survival. Reduced intensity melphalan followed by a stem cell transplant was inferior to the MP-thalidomide regimen (median survival 38 months).[22]

Consolidation Chemotherapy

Use of high doses of alkylating agents is associated with a 10 to 35% event free survival and about 20 to 50% reduction in optimal survival. However, it makes harvesting of hemopoietic stem cells virtually impossible, and hence is not considered the best therapy available.

Single autologous bone marrow or peripheral stem cell transplantation: Two meta-analyses of almost 3,000 patients showed no survival advantage.[23] [24] Since the advent of newer therapeutic agents, the focus seems to be shifting from stem cell transplantation.

Tandem autologous bone marrow or peripheral stem cell transplantation: Another approach to high-dose therapy has been the use of two sequential episodes of high-dose therapy with stem cell support, however no definite benefit has been shown by several multi center trials. High-dose chemotherapy: Allogeneic bone marrow or peripheral stem cell transplantation

Evidence (high-dose chemotherapy: allogeneic bone marrow or peripheral stem cell transplantation):

Maintenance Therapy

After a few months of induction therapy, the drop in M protein seems to plateau, and the advantages of continuing the same therapy seems to be limited. This phase is being followed up with maintenance therapy with one of the newer agents such as thalidomide, lenalidomide or bortezomib. However, further clinical trials are needed to establish the efficacy of each of these agents.

Use of bisphosphonates to manage lytic lesions and radiation therapy to manage lesion of spine are also being used.

References

  1. ↑ Suh, YG.; Suh, CO.; Kim, JS.; Kim, SJ.; Pyun, HO.; Cho, J. (2012). "Radiotherapy for solitary plasmacytoma of bone and soft tissue: outcomes and prognostic factors". Ann Hematol. 91 (11): 1785–93. doi:10.1007/s00277-012-1510-6. PMID 22752147. Unknown parameter |month= ignored (help)
  2. ↑ Goldschmidt, H.; Hegenbart, U.; Wallmeier, M.; Hohaus, S.; Haas, R. (1997). "Factors influencing collection of peripheral blood progenitor cells following high-dose cyclophosphamide and granulocyte colony-stimulating factor in patients with multiple myeloma". Br J Haematol. 98 (3): 736–44. PMID 9332333. Unknown parameter |month= ignored (help)
  3. ↑ Palumbo, A.; Rajkumar, SV. (2009). "Treatment of newly diagnosed myeloma". Leukemia. 23 (3): 449–56. doi:10.1038/leu.2008.325. PMID 19005483. Unknown parameter |month= ignored (help)
  4. ↑ Mateos, MV.; Richardson, PG.; Schlag, R.; Khuageva, NK.; Dimopoulos, MA.; Shpilberg, O.; Kropff, M.; Spicka, I.; Petrucci, MT. (2010). "Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial". J Clin Oncol. 28 (13): 2259–66. doi:10.1200/JCO.2009.26.0638. PMID 20368561. Unknown parameter |month= ignored (help)
  5. ↑ 5.0 5.1 Rajkumar, SV.; Jacobus, S.; Callander, NS.; Fonseca, R.; Vesole, DH.; Williams, ME.; Abonour, R.; Siegel, DS.; Katz, M. (2010). "Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial". Lancet Oncol. 11 (1): 29–37. doi:10.1016/S1470-2045(09)70284-0. PMID 19853510. Unknown parameter |month= ignored (help)
  6. ↑ Facon, T.; Mary, JY.; Pégourie, B.; Attal, M.; Renaud, M.; Sadoun, A.; Voillat, L.; Dorvaux, V.; Hulin, C. (2006). "Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy". Blood. 107 (4): 1292–8. doi:10.1182/blood-2005-04-1588. PMID 16174762. Unknown parameter |month= ignored (help)
  7. ↑ Shustik, C.; Belch, A.; Robinson, S.; Rubin, SH.; Dolan, SP.; Kovacs, MJ.; Grewal, KS.; Walde, D.; Barr, R. (2007). "A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7". Br J Haematol. 136 (2): 203–11. doi:10.1111/j.1365-2141.2006.06405.x. PMID 17233817. Unknown parameter |month= ignored (help)
  8. ↑ Rajkumar, SV.; Rosiñol, L.; Hussein, M.; Catalano, J.; Jedrzejczak, W.; Lucy, L.; Olesnyckyj, M.; Yu, Z.; Knight, R. (2008). "Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma". J Clin Oncol. 26 (13): 2171–7. doi:10.1200/JCO.2007.14.1853. PMID 18362366. Unknown parameter |month= ignored (help)
  9. ↑ Barlogie, B.; Tricot, G.; Anaissie, E.; Shaughnessy, J.; Rasmussen, E.; van Rhee, F.; Fassas, A.; Zangari, M.; Hollmig, K. (2006). "Thalidomide and hematopoietic-cell transplantation for multiple myeloma". N Engl J Med. 354 (10): 1021–30. doi:10.1056/NEJMoa053583. PMID 16525139. Unknown parameter |month= ignored (help)
  10. ↑ Palumbo, A.; Bringhen, S.; Liberati, AM.; Caravita, T.; Falcone, A.; Callea, V.; Montanaro, M.; Ria, R.; Capaldi, A. (2008). "Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial". Blood. 112 (8): 3107–14. doi:10.1182/blood-2008-04-149427. PMID 18505783. Unknown parameter |month= ignored (help)
  11. ↑ Alexanian, R.; Barlogie, B.; Tucker, S. (1990). "VAD-based regimens as primary treatment for multiple myeloma". Am J Hematol. 33 (2): 86–9. PMID 2301376. Unknown parameter |month= ignored (help)
  12. ↑ Segeren, CM.; Sonneveld, P.; van der Holt, B.; Baars, JW.; Biesma, DH.; Cornellissen, JJ.; Croockewit, AJ.; Dekker, AW.; Fibbe, WE. (1999). "Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma". Br J Haematol. 105 (1): 127–30. PMID 10233375. Unknown parameter |month= ignored (help)
  13. ↑ Anderson, H.; Scarffe, JH.; Ranson, M.; Young, R.; Wieringa, GS.; Morgenstern, GR.; Fitzsimmons, L.; Ryder, D. (1995). "VAD chemotherapy as remission induction for multiple myeloma". Br J Cancer. 71 (2): 326–30. PMID 7841049. Unknown parameter |month= ignored (help)
  14. ↑ "Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists' Collaborative Group". J Clin Oncol. 16 (12): 3832–42. 1998. PMID 9850028. Unknown parameter |month= ignored (help)
  15. ↑ 15.0 15.1 Fonseca, R.; Rajkumar, SV. (2008). "Consolidation therapy with bortezomib/lenalidomide/ dexamethasone versus bortezomib/dexamethasone after a dexamethasone-based induction regimen in patients with multiple myeloma: a randomized phase III trial". Clin Lymphoma Myeloma. 8 (5): 315–7. doi:10.3816/CLM.2008.n.046. PMID 18854289. Unknown parameter |month= ignored (help)
  16. ↑ 16.0 16.1 Richardson, PG.; Sonneveld, P.; Schuster, MW.; Irwin, D.; Stadtmauer, EA.; Facon, T.; Harousseau, JL.; Ben-Yehuda, D.; Lonial, S. (2005). "Bortezomib or high-dose dexamethasone for relapsed multiple myeloma". N Engl J Med. 352 (24): 2487–98. doi:10.1056/NEJMoa043445. PMID 15958804. Unknown parameter |month= ignored (help)
  17. ↑ Dimopoulos, M.; Spencer, A.; Attal, M.; Prince, HM.; Harousseau, JL.; Dmoszynska, A.; San Miguel, J.; Hellmann, A.; Facon, T. (2007). "Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma". N Engl J Med. 357 (21): 2123–32. doi:10.1056/NEJMoa070594. PMID 18032762. Unknown parameter |month= ignored (help)
  18. ↑ Reece, DE.; Rodriguez, GP.; Chen, C.; Trudel, S.; Kukreti, V.; Mikhael, J.; Pantoja, M.; Xu, W.; Stewart, AK. (2008). "Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma". J Clin Oncol. 26 (29): 4777–83. doi:10.1200/JCO.2007.14.2372. PMID 18645194. Unknown parameter |month= ignored (help)
  19. ↑ Khan, ML.; Reeder, CB.; Kumar, SK.; Lacy, MQ.; Reece, DE.; Dispenzieri, A.; Gertz, MA.; Greipp, P.; Hayman, S. (2012). "A comparison of lenalidomide/dexamethasone versus cyclophosphamide/lenalidomide/dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly diagnosed multiple myeloma". Br J Haematol. 156 (3): 326–33. doi:10.1111/j.1365-2141.2011.08949.x. PMID 22107129. Unknown parameter |month= ignored (help)
  20. ↑ Kumar, SK.; Lacy, MQ.; Hayman, SR.; Stewart, K.; Buadi, FK.; Allred, J.; Laumann, K.; Greipp, PR.; Lust, JA. (2011). "Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial". Am J Hematol. 86 (8): 640–5. doi:10.1002/ajh.22053. PMID 21630308. Unknown parameter |month= ignored (help)
  21. ↑ San Miguel, JF.; Schlag, R.; Khuageva, NK.; Dimopoulos, MA.; Shpilberg, O.; Kropff, M.; Spicka, I.; Petrucci, MT.; Palumbo, A. (2013). "Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma". J Clin Oncol. 31 (4): 448–55. doi:10.1200/JCO.2012.41.6180. PMID 23233713. Unknown parameter |month= ignored (help)
  22. ↑ Facon T, Mary JY, Hulin C; et al. (2007). "Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99–06): a randomised trial". Lancet. 370: 1209–1218. doi:10.1016/S0140-6736(07)61537-2.
  23. ↑ Koreth, J.; Cutler, CS.; Djulbegovic, B.; Behl, R.; Schlossman, RL.; Munshi, NC.; Richardson, PG.; Anderson, KC.; Soiffer, RJ. (2007). "High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: A systematic review and meta-analysis of randomized controlled trials". Biol Blood Marrow Transplant. 13 (2): 183–96. doi:10.1016/j.bbmt.2006.09.010. PMID 17241924. Unknown parameter |month= ignored (help)
  24. ↑ Lévy, V.; Katsahian, S.; Fermand, JP.; Mary, JY.; Chevret, S. (2005). "A meta-analysis on data from 575 patients with multiple myeloma randomly assigned to either high-dose therapy or conventional therapy". Medicine (Baltimore). 84 (4): 250–60. PMID 16010209. Unknown parameter |month= ignored (help)

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