Multiple myeloma medical therapy

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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

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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

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### Monoclonal gammopathy of undetermined significance (MGUS)

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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]

* Complete blood count (CBC)
* Serum protein electrophoresis (SPEP)
* Serum free light chains (SFLC)
* Urine protein electrophoresis (UPEP)
* Urine free light chains (UFLC)

### Smoldering multiple myeloma

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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

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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:

* Complete blood count (CBC)
* Serum protein electrophoresis (SPEP)
* Serum free light chains (SFLC)
* Urine protein electrophoresis (UPEP)
* Urine free light chains (UFLC)
* Bone marrow biopsy if suspicion for active multiple myeloma is high

#### Chemotherapy

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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

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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]

* Type of chromosomal aberrancies
* Age
* Presence of current associated diseases
* Liver function
* Kidney function

#### Induction therapy

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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

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* Preferred pharmacological regimens in treatment of patients who are eligible for bone marrow transplant include:[2][3]
* Bortezomib/dexamethasone
* Bortezomib AND dexamethasone AND lenalidomide
* Dexamethasone AND lenalidomide
* Bortezomib AND dexamethasone AND doxorubicin
* Bortezomib AND dexamethasone AND thalidomide
* Bortezomib AND dexamethasone AND cyclophosphamide

* Preferred pharmacological regimens in treatment of patients who are ineligible for bone marrow transplant include:[2][3]
* Bortezomib AND dexamethasone
* Low dose dexamethasone AND lenalidomide
* Melphalan AND prednisone AND thalidomide
* Melphalan AND prednisone AND bortezomib
* Daratumumab AND melphalan AND prednisone AND bortezomib

#### Treatment of relapsed or refractory multiple myeloma

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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

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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

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

* Bisphosphonates to prevent osteoporosis
* Erythropoietin to prevent anemia
* Vaccines to prevent recurrent infections
* Blood thinners to prevent blood clots
* Plasmapheresis to prevent hyperviscosity and renal failure

#### Maintenance therapy

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* 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

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### Transplant-Eligible Patients

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* 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

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High risk

Intermediate risk

Standard risk

4 cycles of bortezomib-lenalidomide-dexamethasone

4 cycles of cyclophosphamide-bortezomib-dexamethasone

4 cycles of either bortezomib-lenalidomide-dexamethasone or cyclophosphamide-bortezomib-dexamethasone

Collect stem cells

Collect stem cells

Collect stem cells

Autologous stem cell transplant (especially if patient is not in complete remission)

Autologous stem cell transplant

Autologous stem cell transplant

Bortezomib-lenalidomide-dexamethasone for > 1 year

Bortezomib-based therapy for > 1 year

Consider lenalidomide maintenance

Continue lenalidomide-dexamethasone

### Transplant-Ineligible Patients

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* 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

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High risk

Intermediate risk

Standard risk

Bortezomib-lenalidomide-dexamethasone

Either melphalan-prednisone \+ weekly bortezomib or weekly cyclophosphamide-bortezomib-dexamethasone

Either lenalidomide-dexamethasone or melphalan-prednisone-thalidomide

Bortezomib maintenance

Observation

## References

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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. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 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. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)