Multiple myeloma medical therapy: Difference between revisions

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==Overview==
==Overview==
Pharmacological regimens for patients with active (symptomatic) multiple myeloma include [[steroid therapy]], immune modulator therapy, and [[chemotherapy]].<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref> Patients with smoldering (asymptomatic) multiple myeloma are managed by observation and follow up tests every 3 to 6 months.<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref> The optimal therapy for active multiple myeloma depends on whether or not a patient is eligible for [[bone marrow transplantation]].<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref> Pharmacologic medical therapy for active multiple myeloma patients '''who are''' eligible for a bone marrow transplant includes either [[dexamethasone]], [[lenalidomide]], [[bortezomib]], [[thalidomide]], [[carfilzomib]], [[cyclophosphamide]], [[vincristine]], or [[doxorubicin]].<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref> In addition to the aforementioned agents, pharmacological regimens used for treatment of active multiple myeloma patients '''who are not''' eligible for a bone marrow transplant include either [[melphalan]] or [[prednisone]].<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
First-line therapies include [[bortezomib]], [[lenalidomide]], [[dexamethasone]], [[melphalan]], and [[cyclophosphamide]]. Second-line therapies (used for relapsed or refractory disease) include [[ixazomib]], [[carfilzomib]], [[daratumumab]], [[elotuzumab]], and [[pomalidomide]]. [[Stem cell transplant|Autologous stem cell transplant]] is done after remission is achieved with [[chemotherapy]]. The choice of the treatment regimen partly depends on [[Organ transplant|transplant]] eligibility. Supportive therapy is an important component of care while patients are receiving anti-cancer therapy.
[[Alkylating antineoplastic agents|Alkylating agents]] are not recommended among transplant eligible patients, as the toxicity of such agents makes the harvest process of bone marrow [[stem cell]] difficult later in the course of the disease.<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>


==Medical Therapy==
==Medical Therapy==


===Monoclonal gammopathy of undetermined significance (MGUS)===
===Monoclonal gammopathy of undetermined significance (MGUS)===
There is no specific therapy for monoclonal gammopathy of undetermined significance (MGUS).<ref name="pmid20473362">{{cite journal| author=Weiss BM, Kuehl WM| title=Advances in understanding monoclonal gammopathy of undetermined significance as a precursor of multiple myeloma. | journal=Expert Rev Hematol | year= 2010 | volume= 3 | issue= 2 | pages= 165-74 | pmid=20473362 | doi=10.1586/ehm.10.13 | pmc=2869099 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20473362  }} </ref> A typical management plan includes routine monitoring of various laboratory measures.<ref name="pmid20473362">{{cite journal| author=Weiss BM, Kuehl WM| title=Advances in understanding monoclonal gammopathy of undetermined significance as a precursor of multiple myeloma. | journal=Expert Rev Hematol | year= 2010 | volume= 3 | issue= 2 | pages= 165-74 | pmid=20473362 | doi=10.1586/ehm.10.13 | pmc=2869099 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20473362  }} </ref> The risk stratification can guide the frequency with which blood count monitoring should be done. Laboratory measures that should be monitored include:
There is no specific therapy for [[monoclonal gammopathy of undetermined significance]] (MGUS). A typical management plan includes routine monitoring of various laboratory measures. The risk stratification can guide the frequency with which blood count monitoring should be done. Laboratory measures that should be monitored include:<ref name="pmid20473362">{{cite journal| author=Weiss BM, Kuehl WM| title=Advances in understanding monoclonal gammopathy of undetermined significance as a precursor of multiple myeloma. | journal=Expert Rev Hematol | year= 2010 | volume= 3 | issue= 2 | pages= 165-74 | pmid=20473362 | doi=10.1586/ehm.10.13 | pmc=2869099 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20473362  }} </ref>
*[[Complete blood count]] (CBC)
*[[Complete blood count]] (CBC)
*[[Serum protein electrophoresis]] (SPEP)
*[[Serum protein electrophoresis]] (SPEP)
*[[Serum free light chains]] (SFLC)
*Serum free [[Light chain|light chains]] (SFLC)
*[[Urine protein electrophoresis]] (UPEP)
*Urine [[protein electrophoresis]] (UPEP)
*[[Urine free light chains]] (UFLC)
*Urine free [[Light chain|light chains]] (UFLC)
 


===Smoldering multiple myeloma===
=== Smoldering multiple myeloma ===
Patients with smoldering (asymptomatic) multiple myeloma have a bone marrow plasma cell burden greater than 10% or a serum monoclonal protein of greater than 3 g/dl but no end-organ damage. There are two broad options for management of patients with [[smoldering multiple myeloma]]: observation or chemotherapy.
Patients with smoldering (asymptomatic) multiple myeloma have a bone marrow plasma cell burden greater than 10% or a serum monoclonal protein of greater than 3 g/dl but no end-organ damage. There are two broad options for management of patients with [[smoldering multiple myeloma]]: observation or chemotherapy.
====Observation====
====Observation====
In the past, most patients with [[smoldering multiple myeloma]] were managed by observation and follow up tests every 3 to 6 months.<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref> The management for smoldering multiple myeloma was similar to that of MGUS. This observation (or watchful waiting) approach involves monitoring of laboratory measures including:
In the past, most patients with [[smoldering multiple myeloma]] were managed by observation and follow up tests every 3 to 6 months.<ref name="NCCN">Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2">Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref> The management for smoldering multiple myeloma was similar to that of MGUS. This observation (or watchful waiting) approach involves monitoring of laboratory measures including:
*[[Complete blood count]] (CBC)
*[[Complete blood count]] (CBC)
*[[Serum protein electrophoresis]] (SPEP)
*[[Serum protein electrophoresis]] (SPEP)
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*Free light chain ratio <0.125 or >8
*Free light chain ratio <0.125 or >8


The decision about whether to given chemotherapy for high-risk [[smoldering multiple myeloma]] must weigh the risks and benefits, including consideration of the underlying comorbidities of patients, the adverse effects of chemotherapy, and the likelihood of progression to active multiple myeloma. Ongoing clinical trials are evaluating various agents including celecoxib, lenalidomide, anti-killer immunoglobulin receptor (KIR) monoclonal antibody, elotuzumab (anti-SLAMF7 monoclonal antibody), and siltuximab (anti-IL-6 monoclonal antibody). These agents are currently not FDA=approved for the treatment of smoldering multiple myeloma but may soon become a standard of care.
The decision about whether to given chemotherapy for high-risk [[smoldering multiple myeloma]] must weigh the risks and benefits, including consideration of the underlying comorbidities of patients, the adverse effects of chemotherapy, and the likelihood of progression to active multiple myeloma. Ongoing clinical trials are evaluating various agents including celecoxib, lenalidomide, anti-killer immunoglobulin receptor (KIR) monoclonal antibody, elotuzumab (anti-SLAMF7 monoclonal antibody), and siltuximab (anti-IL-6 monoclonal antibody). These agents are currently not FDA-approved for the treatment of smoldering multiple myeloma but may soon become a standard of care.


===Active multiple myeloma===
===Active multiple myeloma===
*The optimal therapy for active multiple myeloma depends on whether or not a patient is eligible for bone marrow transplantation.<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
The optimal therapy for active multiple myeloma depends on whether or not a patient is eligible for bone marrow transplantation.<ref name="NCCN">Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2">Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref> The decision about whether a patient is a candidate for bone marrow transplantation depends on a number of risk factors that include:<ref name="NCCN">Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2">Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
*Deciding whether a patient is a candidate for bone marrow transplantation depends on a number of risk factors that include:<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
*Type of chromosomal aberrancies
**Type of chromosomal mutation
*Age
**Age
*Presence of current associated diseases
**Presence of current associated diseases
*[[Liver function]]
**Patient's [[liver function]]
*[[Kidney function]]
**Patient's [[kidney function]]


===='''Induction therapy'''====
===='''Induction therapy'''====
*The VAD regimen ([[vincristine]], [[doxorubicin|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 leukemias, without compromising on efficacy.<ref name="Alexanian-1990">{{Cite journal  | last1 = Alexanian | first1 = R. | last2 = Barlogie | first2 = B. | last3 = Tucker | first3 = S. | title = VAD-based regimens as primary treatment for multiple myeloma. | journal = Am J Hematol | volume = 33 | issue = 2 | pages = 86-9 | month = Feb | year = 1990 | doi =  | PMID = 2301376 }}</ref><ref name="Segeren-1999">{{Cite journal  | last1 = Segeren | first1 = CM. | last2 = Sonneveld | first2 = P. | last3 = van der Holt | first3 = B. | last4 = Baars | first4 = JW. | last5 = Biesma | first5 = DH. | last6 = Cornellissen | first6 = JJ. | last7 = Croockewit | first7 = AJ. | last8 = Dekker | first8 = AW. | last9 = Fibbe | first9 = WE. | title = Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. | journal = Br J Haematol | volume = 105 | issue = 1 | pages = 127-30 | month = Apr | year = 1999 | doi =  | PMID = 10233375 }}</ref><ref name="Anderson-1995">{{Cite journal  | last1 = Anderson | first1 = H. | last2 = Scarffe | first2 = JH. | last3 = Ranson | first3 = M. | last4 = Young | first4 = R. | last5 = Wieringa | first5 = GS. | last6 = Morgenstern | first6 = GR. | last7 = Fitzsimmons | first7 = L. | last8 = Ryder | first8 = D. | title = VAD chemotherapy as remission induction for multiple myeloma. | journal = Br J Cancer | volume = 71 | issue = 2 | pages = 326-30 | month = Feb | year = 1995 | doi =  | PMID = 7841049 }}</ref>
In the past, a commonly used regimen was VAD ([[vincristine]], [[doxorubicin|adriamycin]], and dexamethasone), which 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 leukemias, without compromising on efficacy.<ref name="Alexanian-1990">{{Cite journal  | last1 = Alexanian | first1 = R. | last2 = Barlogie | first2 = B. | last3 = Tucker | first3 = S. | title = VAD-based regimens as primary treatment for multiple myeloma. | journal = Am J Hematol | volume = 33 | issue = 2 | pages = 86-9 | month = Feb | year = 1990 | doi =  | PMID = 2301376 }}</ref><ref name="Segeren-1999">{{Cite journal  | last1 = Segeren | first1 = CM. | last2 = Sonneveld | first2 = P. | last3 = van der Holt | first3 = B. | last4 = Baars | first4 = JW. | last5 = Biesma | first5 = DH. | last6 = Cornellissen | first6 = JJ. | last7 = Croockewit | first7 = AJ. | last8 = Dekker | first8 = AW. | last9 = Fibbe | first9 = WE. | title = Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. | journal = Br J Haematol | volume = 105 | issue = 1 | pages = 127-30 | month = Apr | year = 1999 | doi =  | PMID = 10233375 }}</ref><ref name="Anderson-1995">{{Cite journal  | last1 = Anderson | first1 = H. | last2 = Scarffe | first2 = JH. | last3 = Ranson | first3 = M. | last4 = Young | first4 = R. | last5 = Wieringa | first5 = GS. | last6 = Morgenstern | first6 = GR. | last7 = Fitzsimmons | first7 = L. | last8 = Ryder | first8 = D. | title = VAD chemotherapy as remission induction for multiple myeloma. | journal = Br J Cancer | volume = 71 | issue = 2 | pages = 326-30 | month = Feb | year = 1995 | doi =  | PMID = 7841049 }}</ref> However, in the current era, [[proteosome inhibitors]] are included in the induction chemotherapy regimen. For patients who are candidates for autologous stem cell transplant, the optimal chemotherapy regimen includes the combination of bortezomib (proteasome inhibitor), lenalidomide, and dexamethasone. This regimen is typically given for 8 months and has an overall tolerable  adverse effect profile.<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 associated with peripheral neuropathy.<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>
*One of the 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 abnormal renal function tests.<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>
First line therapy options include:<ref name="pmid21447828">{{cite journal| author=Cavo M, Rajkumar SV, Palumbo A, Moreau P, Orlowski R, Bladé J et al.| title=International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. | journal=Blood | year= 2011 | volume= 117 | issue= 23 | pages= 6063-73 | pmid=21447828 | doi=10.1182/blood-2011-02-297325 | pmc=3293742 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21447828  }} </ref>
*[[Bortezomib]] is given IV and preferred in patients with abnormal renal function tests.<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>
{|
*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).<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>
| valign="top" |
*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>
|+
*Alkylating agents are equal in efficacy when combined with VAD regimens, two of the most common ones being melphalan and oral cyclophosphamide plus prednisolone.<ref name="-1998">{{Cite journal  | title = 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. | journal = J Clin Oncol | volume = 16 | issue = 12 | pages = 3832-42 | month = Dec | year = 1998 | doi =  | PMID = 9850028 }}</ref>
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Therapy}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Mechanism of Action}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Dosing}}
! style="background: #4479BA; width: 400px;" | {{fontcolor|#FFF|Adverse Effects}}
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
Bortezomib
| style="padding: 5px 5px; background: #F5F5F5;" |
*Reversibly inhibits the 26S proteasome, preventing recycling of proteins and inducing cell cycle arrest and apoptosis
| style="padding: 5px 5px; background: #F5F5F5;" |
*Cycles 1-4: 1.3mg/m2 IV/SC on days 1, 4, 8, 11, 22, 25, 29, 32
*Cycles 5-9: 1.3mg/m2 IV/SC on days 1, 8, 22, 29
| style="padding: 5px 5px; background: #F5F5F5;" |
Peripheral neuropathy, VZV reactivation, hepatic impairment, asthenia, diarrhea, nausea, constipation, arthralgia, edema, dizziness
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
Lenalidomide
| style="padding: 5px 5px; background: #F5F5F5;" |
*Thalidomide analog that inhibits angiogenesis
*Stimulates T cell proliferation
| style="padding: 5px 5px; background: #F5F5F5;" |
*25mg PO daily on days 1-21 of a 28-day cycle
| style="padding: 5px 5px; background: #F5F5F5;" |
Anemia, thrombocytopenia, thrombosis, rash, peripheral edema
|-
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold" |
Dexamethasone
| style="padding: 5px 5px; background: #F5F5F5;" |
*Suppresses polymorphonuclear leukocytes
*Inhibits prostaglandins and proinflammatory cytokines
*Suppresses lymphocyte proliferation
| style="padding: 5px 5px; background: #F5F5F5;" |
*40mg PO weekly
| style="padding: 5px 5px; background: #F5F5F5;" |
Infections, immunosuppression, bone loss, cataract formation, glaucoma, muscular atrophy
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
Melphalan
| style="padding: 5px 5px; background: #F5F5F5;" |
*Inhibits DNA and RNA synthesis
*Crosslinks DNA and causes DNA replication failure
| style="padding: 5px 5px; background: #F5F5F5;" |
*6mg PO daily for 2-3 weeks, OR
*10mg PO daily for 7-10 days, OR
*0.15mg/kg daily PO for 7 days, THEN
*1-3mg or 0.05mg/kg PO daily after counts recover
| style="padding: 5px 5px; background: #F5F5F5;" |
Myelosuppression, nausea, vomiting, pulmonary fibrosis, stomatitis
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
Cyclophosphamide
| style="padding: 5px 5px; background: #F5F5F5;" |
*Alkylating agent
*Crosslinks DNA and causes DNA replication failure
| style="padding: 5px 5px; background: #F5F5F5;" |
*40-50mg/kg weekly
| style="padding: 5px 5px; background: #F5F5F5;" |
Myelosuppression, nausea, vomiting, hemorrhagic cystitis, secondary malignancies
|-
|}


=====Preferred Regimens=====
=====Preferred Regimens=====
*'''Preferred pharmacological regimens in treatment of patients who are eligible for bone marrow transplant include:'''<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
*'''Preferred pharmacological regimens in treatment of patients who are eligible for bone marrow transplant include:'''<ref name="NCCN">Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2">Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
**[[Bortezomib]]/[[dexamethasone]]
**[[Bortezomib]]/[[dexamethasone]]
**Bortezomib {{and}} dexamethasone {{and}} [[lenalidomide]]
**Bortezomib {{and}} dexamethasone {{and}} [[lenalidomide]]
Line 69: Line 125:
**Melphalan AND prednisone AND thalidomide
**Melphalan AND prednisone AND thalidomide
**[[Melphalan]] AND [[prednisone]] AND bortezomib
**[[Melphalan]] AND [[prednisone]] AND bortezomib
**[[Daratumumab]] AND [[melphalan]] AND [[prednisone]] AND bortezomib


====Treatment of relapsed or refractory multiple myeloma====
====Treatment of relapsed or refractory multiple myeloma====
In the past five years, must agents have been FDA-approved for treatment of relapsed or refractory multiple myeloma.<ref name="pmid28291589">{{cite journal| author=Dingli D, Ailawadhi S, Bergsagel PL, Buadi FK, Dispenzieri A, Fonseca R et al.| title=Therapy for Relapsed Multiple Myeloma: Guidelines From the Mayo Stratification for Myeloma and Risk-Adapted Therapy. | journal=Mayo Clin Proc | year= 2017 | volume= 92 | issue= 4 | pages= 578-598 | pmid=28291589 | doi=10.1016/j.mayocp.2017.01.003 | pmc=5554888 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28291589  }} </ref>
In the past five years, many agents have been FDA-approved for treatment of relapsed or refractory multiple myeloma.<ref name="pmid28291589">{{cite journal| author=Dingli D, Ailawadhi S, Bergsagel PL, Buadi FK, Dispenzieri A, Fonseca R et al.| title=Therapy for Relapsed Multiple Myeloma: Guidelines From the Mayo Stratification for Myeloma and Risk-Adapted Therapy. | journal=Mayo Clin Proc | year= 2017 | volume= 92 | issue= 4 | pages= 578-598 | pmid=28291589 | doi=10.1016/j.mayocp.2017.01.003 | pmc=5554888 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28291589  }} </ref>


{| style="border: 0px; font-size: 90%; margin: 3px; width: 600px" align=center
{| valign="top" |
|valign=top|
|+
|+
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Therapy}}
! style="background: #4479BA; width: 200px;" | {{fontcolor|#FFF|Therapy}}
Line 98: Line 154:
*''Cycle 1'': 20mg/m2 on days 1-2, 8-9, 15-16
*''Cycle 1'': 20mg/m2 on days 1-2, 8-9, 15-16
*''Cycles 2-12'': 56mg/m2 on days 1-2, 8-9, 15-16
*''Cycles 2-12'': 56mg/m2 on days 1-2, 8-9, 15-16
*To be used with dexamethasone, or the combination of lenalidomide plus dexamethasone
*To be used with dexamethasone, or the combination of lenalidomide plus dexamethasone, in patients who have received 1-3 prior lines of therapy
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
Anemia, fatigue, thrombocytopenia, nausea, renal failure, congestive heart failure, thrombotic microangiopathy, pulmonary complications
Anemia, fatigue, thrombocytopenia, nausea, renal failure, congestive heart failure, thrombotic microangiopathy, pulmonary complications
Line 126: Line 182:
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
[[Smoldering multiple myeloma]]
Elotuzumab
| style="padding: 5px 5px; background: #F5F5F5;" |
*Anti-SLAMF7 (CD319) humanized IgG1 ''kappa'' monoclonal antibody
*Binds to SLAMF7 on myeloma cells
*Activates natural killer (NK) cells to kill myeloma cells
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*Presence of M-spike that quantitates > 3 g/dl on protein electrophoresis, ''or''
*10 mg/kg IV weekly during cycles 1-2
*Presence of bone marrow plasma cell burden of > 10% but < 60%
*10 mg/kg IV every 2 weeks after cycle 2
''plus''
*Absence of end-organ damage such as anemia, hypercalcemia, renal dysfunction, or osseous lesions
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*Monitoring of [[complete blood count]] at specified intervals, depending on risk stratification
Fatigue, fever, diarrhea, anemia
*Chemotherapy with lenalidomide and dexamethasone for high-risk patients
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
| style="padding: 5px 5px; background: #DCDCDC;font-weight: bold" |
[[Active multiple myeloma]]
Pomalidoamide
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*Presence of M-spike that quantitates > 3 g/dl on protein electrophoresis, ''or''
*Angiogenesis inhibitor
*Presence of bone marrow plasma cell burden of > 10% but < 60%
*Upregulates IL-2, IL-10, and IFN-''gamma''
''plus''
*Presence of at least one of the following: anemia, hypercalcemia, renal dysfunction, osseous lesions, bone marrow plasma cell burden > 60%, serum free light chain ratio (of involved to uninvolved light chain) > 100, MRI showing > 1 bony lesion of at least 5mm
| style="padding: 5px 5px; background: #F5F5F5;" |
| style="padding: 5px 5px; background: #F5F5F5;" |
*Induction chemotherapy with bortezomib, lenalidomide, and dexamethasone
*4 mg PO on days 1-21 of a 28-day cycle, in combination with dexamethasone
*High-dose therapy plus autologous stem cell transplantation
*To be used with lenalidomide plus bortezomib in patients who have received at least 2 prior lines of therapy
*Post-transplant lenalidomide maintenance
| style="padding: 5px 5px; background: #F5F5F5;" |
(''Please see Therapy section for details''
Fatigue, asthenia, diarrhea, thrombocytopenia, thromboembolism, second primary malignancy, teratogenicity
|-
|-
|}
|}


===='''Supportive therapy'''====
===='''Supportive therapy'''====
*Supportive therapy is recommended based on patient's symptoms and medication side effects.<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
*Supportive therapy is recommended based on patient's symptoms and medication side effects.<ref name="NCCN">Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2">Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
*Supportive therapy for active multiple myeloma includes:<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
*Supportive therapy for active multiple myeloma includes:<ref name="NCCN">Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2">Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
:*[[Bisphosphonates]] to prevent [[osteoporosis]]
:*[[Bisphosphonates]] to prevent [[osteoporosis]]
:*[[Erythropoietin]] to prevent anemia  
:*[[Erythropoietin]] to prevent anemia  
Line 161: Line 216:


===='''Maintenance therapy'''====
===='''Maintenance therapy'''====
*After a few months of induction therapy the advantages of continuing the same therapy seems to be limited.<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
*After a few months of induction therapy the advantages of continuing the same therapy seems to be limited.<ref name="NCCN">Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2">Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
*Therefore, this phase is being followed up with maintenance therapy with one of the newer agents such as thalidomide, lenalidomide or bortezomib.<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
*Therefore, this phase is being followed up with maintenance therapy with one of the newer agents such as thalidomide, lenalidomide or bortezomib.<ref name="NCCN">Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2">Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
*However, further clinical trials are needed to establish the efficacy of each of these agents.<ref name="NCCN"> Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2"> Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>
*However, further clinical trials are needed to establish the efficacy of each of these agents.<ref name="NCCN">Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref><ref name="NCCN2">Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015</ref>


==Stratification of Treatment Based on Transplant Eligibility==
==Stratification of Treatment Based on Transplant Eligibility==
Line 183: Line 238:
{{familytree | | D01 | | D02 | | D03 | | D04 | | D01=<div style="width: 9em; padding:1em;">[[Bortezomib]]-[[lenalidomide]]-[[dexamethasone]] for > 1 year</div>|D02=<div style="width: 9em; padding:1em;">[[Bortezomib]]-based therapy for > 1 year</div>|D03=<div style="width: 9em; padding:1em;">Consider [[lenalidomide]] maintenance</div>|D04=<div style="width: 18em; padding:1em;">Continue [[lenalidomide]]-[[dexamethasone]]</div>}}
{{familytree | | D01 | | D02 | | D03 | | D04 | | D01=<div style="width: 9em; padding:1em;">[[Bortezomib]]-[[lenalidomide]]-[[dexamethasone]] for > 1 year</div>|D02=<div style="width: 9em; padding:1em;">[[Bortezomib]]-based therapy for > 1 year</div>|D03=<div style="width: 9em; padding:1em;">Consider [[lenalidomide]] maintenance</div>|D04=<div style="width: 18em; padding:1em;">Continue [[lenalidomide]]-[[dexamethasone]]</div>}}
{{familytree/end}}
{{familytree/end}}
<br><br>


===Transplant-Ineligible Patients===
=== Transplant-Ineligible Patients ===
*According to the Myeloma Mayo Stratification of Myeloma and Risk-Adapted Therapy (Myeloma M-SMART), medical therapy for transplant-ineligible patients is also individualized based on the patient risk.<ref name="pmid23541011">{{cite journal| author=Mikhael JR, Dingli D, Roy V, Reeder CB, Buadi FK, Hayman SR et al.| title=Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. | journal=Mayo Clin Proc | year= 2013 | volume= 88 | issue= 4 | pages= 360-76 | pmid=23541011 | doi=10.1016/j.mayocp.2013.01.019 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23541011  }} </ref>
*According to the Myeloma Mayo Stratification of Myeloma and Risk-Adapted Therapy (Myeloma M-SMART), medical therapy for transplant-ineligible patients is also individualized based on the patient risk.<ref name="pmid23541011">{{cite journal| author=Mikhael JR, Dingli D, Roy V, Reeder CB, Buadi FK, Hayman SR et al.| title=Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. | journal=Mayo Clin Proc | year= 2013 | volume= 88 | issue= 4 | pages= 360-76 | pmid=23541011 | doi=10.1016/j.mayocp.2013.01.019 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23541011  }} </ref>
*The algorithm is shown below:
*The algorithm is shown below:
Line 198: Line 252:
{{familytree | | | | | | C02 | | C03 | | | | | | C02=<div style="width: 15em; padding:1em;">[[Bortezomib]] maintenance</div>|C03=<div style="width: 18em; padding:1em;">Observation</div>}}
{{familytree | | | | | | C02 | | C03 | | | | | | C02=<div style="width: 15em; padding:1em;">[[Bortezomib]] maintenance</div>|C03=<div style="width: 18em; padding:1em;">Observation</div>}}
{{familytree/end}}
{{familytree/end}}
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}


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Latest revision as of 22:47, 29 July 2020

Multiple myeloma Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2] Shyam Patel [3]

Overview

First-line therapies include bortezomib, lenalidomide, dexamethasone, melphalan, and cyclophosphamide. Second-line therapies (used for relapsed or refractory disease) include ixazomib, carfilzomib, daratumumab, elotuzumab, and pomalidomide. Autologous stem cell transplant is done after remission is achieved with chemotherapy. The choice of the treatment regimen partly depends on transplant eligibility. Supportive therapy is an important component of care while patients are receiving anti-cancer therapy.

Medical Therapy

Monoclonal gammopathy of undetermined significance (MGUS)

There is no specific therapy for monoclonal gammopathy of undetermined significance (MGUS). A typical management plan includes routine monitoring of various laboratory measures. The risk stratification can guide the frequency with which blood count monitoring should be done. Laboratory measures that should be monitored include:[1]

Smoldering multiple myeloma

Patients with smoldering (asymptomatic) multiple myeloma have a bone marrow plasma cell burden greater than 10% or a serum monoclonal protein of greater than 3 g/dl but no end-organ damage. There are two broad options for management of patients with smoldering multiple myeloma: observation or chemotherapy.

Observation

In the past, most patients with smoldering multiple myeloma were managed by observation and follow up tests every 3 to 6 months.[2][3] The management for smoldering multiple myeloma was similar to that of MGUS. This observation (or watchful waiting) approach involves monitoring of laboratory measures including:

Chemotherapy

It is now known that smoldering multiple myeloma carries an inevitable risk of progression to active multiple myeloma. Smoldering multiple myeloma carries a higher risk of progression to active multiple myeloma compared to that of MGUS. Most patients with smoldering multiple myeloma will have eventual progression of disease. Therefore, there is currently a trend towards the use of chemotherapy for patients with high-risk smoldering multiple myeloma. In a randomized clinical trial from 2013, it was shown that the combination of lenalidomide plus dexamethasone resulted in improved 2-year progression-free survival compared to observation alone (92% vs. 30%).[4] Therefore, patients with high-risk smoldering multiple myeloma should be strongly considered for chemotherapy with lenalidomide and dexamethasone. Other therapies that have been used in clinical trials for smoldering multiple myeloma include the combination fo melphalan and prednisone, bisphosphonates such as zoledronate or pamidronate, thalidomide, curcumin, and anakinra (IL-1 antagonist).[4] High-risk features that may warrant the use of chemotherapy in smoldering multiple myeloma include[4]:

  • Bone marrow plasma cell burden >10%
  • M-spike >3g/dl
  • Free light chain ratio <0.125 or >8

The decision about whether to given chemotherapy for high-risk smoldering multiple myeloma must weigh the risks and benefits, including consideration of the underlying comorbidities of patients, the adverse effects of chemotherapy, and the likelihood of progression to active multiple myeloma. Ongoing clinical trials are evaluating various agents including celecoxib, lenalidomide, anti-killer immunoglobulin receptor (KIR) monoclonal antibody, elotuzumab (anti-SLAMF7 monoclonal antibody), and siltuximab (anti-IL-6 monoclonal antibody). These agents are currently not FDA-approved for the treatment of smoldering multiple myeloma but may soon become a standard of care.

Active multiple myeloma

The optimal therapy for active multiple myeloma depends on whether or not a patient is eligible for bone marrow transplantation.[2][3] The decision about whether a patient is a candidate for bone marrow transplantation depends on a number of risk factors that include:[2][3]

Induction therapy

In the past, a commonly used regimen was VAD (vincristine, adriamycin, and dexamethasone), which 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 leukemias, without compromising on efficacy.[5][6][7] However, in the current era, proteosome inhibitors are included in the induction chemotherapy regimen. For patients who are candidates for autologous stem cell transplant, the optimal chemotherapy regimen includes the combination of bortezomib (proteasome inhibitor), lenalidomide, and dexamethasone. This regimen is typically given for 8 months and has an overall tolerable adverse effect profile.[8][9] Lenalidomide is orally administered and increases the risk for deep vein thrombosis, while bortezomib is associated with peripheral neuropathy.[10][11]

First line therapy options include:[12]

Therapy Mechanism of Action Dosing Adverse Effects

Bortezomib

  • Reversibly inhibits the 26S proteasome, preventing recycling of proteins and inducing cell cycle arrest and apoptosis
  • Cycles 1-4: 1.3mg/m2 IV/SC on days 1, 4, 8, 11, 22, 25, 29, 32
  • Cycles 5-9: 1.3mg/m2 IV/SC on days 1, 8, 22, 29

Peripheral neuropathy, VZV reactivation, hepatic impairment, asthenia, diarrhea, nausea, constipation, arthralgia, edema, dizziness

Lenalidomide

  • Thalidomide analog that inhibits angiogenesis
  • Stimulates T cell proliferation
  • 25mg PO daily on days 1-21 of a 28-day cycle

Anemia, thrombocytopenia, thrombosis, rash, peripheral edema

Dexamethasone

  • Suppresses polymorphonuclear leukocytes
  • Inhibits prostaglandins and proinflammatory cytokines
  • Suppresses lymphocyte proliferation
  • 40mg PO weekly

Infections, immunosuppression, bone loss, cataract formation, glaucoma, muscular atrophy

Melphalan

  • Inhibits DNA and RNA synthesis
  • Crosslinks DNA and causes DNA replication failure
  • 6mg PO daily for 2-3 weeks, OR
  • 10mg PO daily for 7-10 days, OR
  • 0.15mg/kg daily PO for 7 days, THEN
  • 1-3mg or 0.05mg/kg PO daily after counts recover

Myelosuppression, nausea, vomiting, pulmonary fibrosis, stomatitis

Cyclophosphamide

  • Alkylating agent
  • Crosslinks DNA and causes DNA replication failure
  • 40-50mg/kg weekly

Myelosuppression, nausea, vomiting, hemorrhagic cystitis, secondary malignancies

Preferred Regimens
  • Preferred pharmacological regimens in treatment of patients who are ineligible for bone marrow transplant include:[2][3]

Treatment of relapsed or refractory multiple myeloma

In the past five years, many agents have been FDA-approved for treatment of relapsed or refractory multiple myeloma.[13]

Therapy Mechanism of Action Dosing Adverse Effects

Ixazomib

Borinic acid derivative that inhibits the proteasome, preventing recycling of proteins

  • 4mg PO on days 1, 8, and 15 of a 28-day cycle (3 weeks on, 1 week off)
  • To be used with lenalidomide plus dexamethasone in patients who have received at least 1 prior line of therapy

Nausea, diarrhea, constipation, peripheral neuropathy, thrombocytopenia, rash

Carfilzomib

Epoxyketone tetrapeptide that irreversibly inhibits the proteasome, preventing recycling of proteins

  • Cycle 1: 20mg/m2 on days 1-2, 8-9, 15-16
  • Cycles 2-12: 56mg/m2 on days 1-2, 8-9, 15-16
  • To be used with dexamethasone, or the combination of lenalidomide plus dexamethasone, in patients who have received 1-3 prior lines of therapy

Anemia, fatigue, thrombocytopenia, nausea, renal failure, congestive heart failure, thrombotic microangiopathy, pulmonary complications

Panobinostat

Pan-histone deacetylase (HDAC) inhibitor; aggresome pathway inhibitor

  • 20mg PO every other day (3 doses weekly) on days 1, 3, 5, 8, 10, 12) on weeks 1 and 2 of a 21-day cycle for 8 cycles
  • To be used in combination with bortezomib plus dexamethasone for patients who have received at least 2 prior lines of therapy

Thrombocytopenia, lymphopenia, anemia, fatigue, diarrhe, nausea, hyperbilirubinemia

Daratumumab

  • Anti-CD38 IgG1 kappa monoclonal antibody
  • Exerts antibody-dependent cell-mediated cytotoxicity (ADCC)
  • Exerts complement-mediated cytotoxicity
  • 16 mg/kg IV infusion weekly during weeks 1-8
  • 16 mg/kg IV infusion every 2 weeks during weeks 9-24
  • 16 mg/kg IV infusion every 4 weeks starting week 25 and onwards

Infusion reaction, lymphopenia, neutropenia, fatigue, anemia, back pain, false positive indirect Coombs' test

Elotuzumab

  • Anti-SLAMF7 (CD319) humanized IgG1 kappa monoclonal antibody
  • Binds to SLAMF7 on myeloma cells
  • Activates natural killer (NK) cells to kill myeloma cells
  • 10 mg/kg IV weekly during cycles 1-2
  • 10 mg/kg IV every 2 weeks after cycle 2

Fatigue, fever, diarrhea, anemia

Pomalidoamide

  • Angiogenesis inhibitor
  • Upregulates IL-2, IL-10, and IFN-gamma
  • 4 mg PO on days 1-21 of a 28-day cycle, in combination with dexamethasone
  • To be used with lenalidomide plus bortezomib in patients who have received at least 2 prior lines of therapy

Fatigue, asthenia, diarrhea, thrombocytopenia, thromboembolism, second primary malignancy, teratogenicity

Supportive therapy

  • Supportive therapy is recommended based on patient's symptoms and medication side effects.[2][3]
  • Supportive therapy for active multiple myeloma includes:[2][3]

Maintenance therapy

  • After a few months of induction therapy the advantages of continuing the same therapy seems to be limited.[2][3]
  • Therefore, this phase is being followed up with maintenance therapy with one of the newer agents such as thalidomide, lenalidomide or bortezomib.[2][3]
  • However, further clinical trials are needed to establish the efficacy of each of these agents.[2][3]

Stratification of Treatment Based on Transplant Eligibility

Transplant-Eligible Patients

  • According to the Myeloma Mayo Stratification of Myeloma and Risk-Adapted Therapy (Myeloma M-SMART), medical therapy for transplant-eligible patients is individualized based on the patient risk.[14]
  • The algorithm is shown below:


 
 
 
 
 
Treatment for patients with multiple myeloma who are transplant-eligible
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
High risk
 
Intermediate risk
 
 
 
Standard risk
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Autologous stem cell transplant (especially if patient is not in complete remission)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bortezomib-based therapy for > 1 year
 
Consider lenalidomide maintenance
 
 

Transplant-Ineligible Patients

  • According to the Myeloma Mayo Stratification of Myeloma and Risk-Adapted Therapy (Myeloma M-SMART), medical therapy for transplant-ineligible patients is also individualized based on the patient risk.[14]
  • The algorithm is shown below:


 
 
 
 
 
Treatment for patients with multiple myeloma who are transplant-ineligible
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
High risk
 
Intermediate risk
 
Standard risk
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bortezomib maintenance
 
Observation
 
 
 
 
 

References

  1. ↑ Weiss BM, Kuehl WM (2010). "Advances in understanding monoclonal gammopathy of undetermined significance as a precursor of multiple myeloma". Expert Rev Hematol. 3 (2): 165–74. doi:10.1586/ehm.10.13. PMC 2869099. PMID 20473362.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 Treatment guide active multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 Treatment guide smoldering multiple myeloma. National comprehensive cancer network(2015) http://www.nccn.org/patients/guidelines/myeloma/#44/z Accessed on September, 20th 2015
  4. ↑ 4.0 4.1 4.2 Ghobrial IM, Landgren O (2014). "How I treat smoldering multiple myeloma". Blood. 124 (23): 3380–8. doi:10.1182/blood-2014-08-551549. PMC 4246036. PMID 25298034.
  5. ↑ 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)
  6. ↑ 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)
  7. ↑ 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)
  8. ↑ 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)
  9. ↑ 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)
  10. ↑ 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)
  11. ↑ 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)
  12. ↑ Cavo M, Rajkumar SV, Palumbo A, Moreau P, Orlowski R, Bladé J; et al. (2011). "International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation". Blood. 117 (23): 6063–73. doi:10.1182/blood-2011-02-297325. PMC 3293742. PMID 21447828.
  13. ↑ Dingli D, Ailawadhi S, Bergsagel PL, Buadi FK, Dispenzieri A, Fonseca R; et al. (2017). "Therapy for Relapsed Multiple Myeloma: Guidelines From the Mayo Stratification for Myeloma and Risk-Adapted Therapy". Mayo Clin Proc. 92 (4): 578–598. doi:10.1016/j.mayocp.2017.01.003. PMC 5554888. PMID 28291589.
  14. ↑ 14.0 14.1 Mikhael JR, Dingli D, Roy V, Reeder CB, Buadi FK, Hayman SR; et al. (2013). "Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013". Mayo Clin Proc. 88 (4): 360–76. doi:10.1016/j.mayocp.2013.01.019. PMID 23541011.
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