Multiple myeloma medical therapy: Difference between revisions
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==Treatment== | ==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. | 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.<ref name="Suh-2012">{{Cite journal | last1 = Suh | first1 = YG. | last2 = Suh | first2 = CO. | last3 = Kim | first3 = JS. | last4 = Kim | first4 = SJ. | last5 = Pyun | first5 = HO. | last6 = Cho | first6 = J. | title = Radiotherapy for solitary plasmacytoma of bone and soft tissue: outcomes and prognostic factors. | journal = Ann Hematol | volume = 91 | issue = 11 | pages = 1785-93 | month = Nov | year = 2012 | doi = 10.1007/s00277-012-1510-6 | PMID = 22752147 }}</ref> | ||
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.<ref name="Goldschmidt-1997">{{Cite journal | last1 = Goldschmidt | first1 = H. | last2 = Hegenbart | first2 = U. | last3 = Wallmeier | first3 = M. | last4 = Hohaus | first4 = S. | last5 = Haas | first5 = R. | title = Factors influencing collection of peripheral blood progenitor cells following high-dose cyclophosphamide and granulocyte colony-stimulating factor in patients with multiple myeloma. | journal = Br J Haematol | volume = 98 | issue = 3 | pages = 736-44 | month = Sep | year = 1997 | doi = | PMID = 9332333 }}</ref> | |||
Although [[bone marrow transplant|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, [[bisphosphonate]]s (e.g. [[pamidronate]] or [[zoledronic acid]]) are routinely administered to prevent fractures and [[erythropoietin]] to treat anemia. | Although [[bone marrow transplant|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, [[bisphosphonate]]s (e.g. [[pamidronate]] or [[zoledronic acid]]) are routinely administered to prevent fractures and [[erythropoietin]] to treat anemia. | ||
===Initial therapy=== | ===Initial therapy=== | ||
Initial treatment is aimed at treating symptoms and reducing disease burden. Commonly used induction regimens include [[dexamethasone]] with | Multiple therapeutic agents are available for induction therapy, either alone or in combinations.<ref name="Palumbo-2009">{{Cite journal | last1 = Palumbo | first1 = A. | last2 = Rajkumar | first2 = SV. | title = Treatment of newly diagnosed myeloma. | journal = Leukemia | volume = 23 | issue = 3 | pages = 449-56 | month = Mar | year = 2009 | doi = 10.1038/leu.2008.325 | PMID = 19005483 }}</ref> 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.<ref name="Mateos-2010">{{Cite journal | last1 = Mateos | first1 = MV. | last2 = Richardson | first2 = PG. | last3 = Schlag | first3 = R. | last4 = Khuageva | first4 = NK. | last5 = Dimopoulos | first5 = MA. | last6 = Shpilberg | first6 = O. | last7 = Kropff | first7 = M. | last8 = Spicka | first8 = I. | last9 = Petrucci | first9 = MT. | title = 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. | journal = J Clin Oncol | volume = 28 | issue = 13 | pages = 2259-66 | month = May | year = 2010 | doi = 10.1200/JCO.2009.26.0638 | PMID = 20368561 }}</ref> | |||
<ref name="Rajkumar-2010">{{Cite journal | last1 = Rajkumar | first1 = SV. | last2 = Jacobus | first2 = S. | last3 = Callander | first3 = NS. | last4 = Fonseca | first4 = R. | last5 = Vesole | first5 = DH. | last6 = Williams | first6 = ME. | last7 = Abonour | first7 = R. | last8 = Siegel | first8 = DS. | last9 = Katz | first9 = M. | title = 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. | journal = Lancet Oncol | volume = 11 | issue = 1 | pages = 29-37 | month = Jan | year = 2010 | doi = 10.1016/S1470-2045(09)70284-0 | PMID = 19853510 }}</ref> 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]], [[doxorubicin|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.<ref name="Facon-2006">{{Cite journal | last1 = Facon | first1 = T. | last2 = Mary | first2 = JY. | last3 = Pégourie | first3 = B. | last4 = Attal | first4 = M. | last5 = Renaud | first5 = M. | last6 = Sadoun | first6 = A. | last7 = Voillat | first7 = L. | last8 = Dorvaux | first8 = V. | last9 = Hulin | first9 = C. | title = Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. | journal = Blood | volume = 107 | issue = 4 | pages = 1292-8 | month = Feb | year = 2006 | doi = 10.1182/blood-2005-04-1588 | PMID = 16174762 }}</ref> | |||
<ref name="Shustik-2007">{{Cite journal | last1 = Shustik | first1 = C. | last2 = Belch | first2 = A. | last3 = Robinson | first3 = S. | last4 = Rubin | first4 = SH. | last5 = Dolan | first5 = SP. | last6 = Kovacs | first6 = MJ. | last7 = Grewal | first7 = KS. | last8 = Walde | first8 = D. | last9 = Barr | first9 = R. | title = 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. | journal = Br J Haematol | volume = 136 | issue = 2 | pages = 203-11 | month = Jan | year = 2007 | doi = 10.1111/j.1365-2141.2006.06405.x | PMID = 17233817 }}</ref> | |||
'''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.<ref name="Rajkumar-2008">{{Cite journal | last1 = Rajkumar | first1 = SV. | last2 = Rosiñol | first2 = L. | last3 = Hussein | first3 = M. | last4 = Catalano | first4 = J. | last5 = Jedrzejczak | first5 = W. | last6 = Lucy | first6 = L. | last7 = Olesnyckyj | first7 = M. | last8 = Yu | first8 = Z. | last9 = Knight | first9 = R. | title = Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. | journal = J Clin Oncol | volume = 26 | issue = 13 | pages = 2171-7 | month = May | year = 2008 | doi = 10.1200/JCO.2007.14.1853 | PMID = 18362366 }}</ref> | |||
<ref name="Barlogie-2006">{{Cite journal | last1 = Barlogie | first1 = B. | last2 = Tricot | first2 = G. | last3 = Anaissie | first3 = E. | last4 = Shaughnessy | first4 = J. | last5 = Rasmussen | first5 = E. | last6 = van Rhee | first6 = F. | last7 = Fassas | first7 = A. | last8 = Zangari | first8 = M. | last9 = Hollmig | first9 = K. | title = Thalidomide and hematopoietic-cell transplantation for multiple myeloma. | journal = N Engl J Med | volume = 354 | issue = 10 | pages = 1021-30 | month = Mar | year = 2006 | doi = 10.1056/NEJMoa053583 | PMID = 16525139 }}</ref> | |||
<ref name="Palumbo-2008">{{Cite journal | last1 = Palumbo | first1 = A. | last2 = Bringhen | first2 = S. | last3 = Liberati | first3 = AM. | last4 = Caravita | first4 = T. | last5 = Falcone | first5 = A. | last6 = Callea | first6 = V. | last7 = Montanaro | first7 = M. | last8 = Ria | first8 = R. | last9 = Capaldi | first9 = A. | title = Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. | journal = Blood | volume = 112 | issue = 8 | pages = 3107-14 | month = Oct | year = 2008 | doi = 10.1182/blood-2008-04-149427 | PMID = 18505783 }}</ref> | |||
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 ''[[bone marrow transplant|autologous stem cell transplantation]]''. This can be given in ''tandem'' fashion, i.e. an autologous transplant followed by a second transplant. | In younger patients, therapy may include high-dose [[chemotherapy]], [[melphalan]], and ''[[bone marrow transplant|autologous stem cell transplantation]]''. This can be given in ''tandem'' fashion, i.e. an autologous transplant followed by a second transplant. | ||
Revision as of 00:32, 16 February 2014
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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]
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).[11]
Relapse
The natural history of myeloma is of relapse following treatment. Depending on the patient's condition, the prior treatment modalities used and the duration of remission, options for relapsed disease include re-treatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide or dexamethasone, alone or in combination), and a second autologous stem cell transplant.
Later in the course of the disease, "treatment resistance" occurs. This may be a reversible effect, and some new treatment modalities may re-sensitize the tumor to standard therapy. For patients with relapsed disease, bortezomib (or Velcade®) is a recent addition to the therapeutic arsenal, especially as second line therapy. Bortezomib is a proteasome inhibitor. Finally, lenalidomide (or Revlimid®), a less toxic thalidomide analog, is showing promise for treating myeloma.
Renal failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute renal failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic renal failure is dependent on the type of renal failure and may involve dialysis.
References
- ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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.