# Radiation Oncology/Multiple myeloma

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## Epidemiology

* Incidence comparable to Hodgkin's disease or CLL (2-3 per 100,000)
* In 2003: 16,000 new cases and 11,000 deaths
* Peak incidence 50-60s; male:female 1:1

## History

* First published case: (clinical case and postmortem)
** 1848 No PMID PDF Full text PDF (reprinted) -- "On a new substance occurring in the urine of a patient with mollities ossium." (Bence Jones H, Phil. Trans. R. Soc. Lond. January 1, 1848 138:55-62.)
*** Bence Jones protein
** 1850 PMID 20895930 -- "Case of Mollities and Fragilitas Ossium, accompanied with urine strongly charged with animal matter." (Macintyre W, Med Chir Trans. 1850;33:211-32.)

## Natural History

* Proliferation and accumulation of immunoglobulin-secreting cells derived from B-cell lymphocytes
* Believed to be monoclonal tumor cells from a single transformed cell
* Low growth-fraction tumor; subclinical phase 1-3 years
* MM is currently incurable: median survival 3 years
POEMS syndrome:
* polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes
* May be associated with plasma cell disorders

## Diagnosis

Guidelines:
Multiple Myeloma + General:
* 2003: International Myeloma Working Group PMID 12780789 — "Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group." (International Myeloma Working Group [no authors listed], Br J Haematol. 2003 Jun;121(5):749-57.)
** see also: 2003: International Myeloma Foundation Consensus - PMID 14671610 — "Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation." (Durie BG, Hematol J. 2003;4(6):379-98.)
* 2006: UK Myeloma Forum PMID 16412016 Full text -- "Guidelines on the diagnosis and management of multiple myeloma 2005." (Smith A, Br J Haematol. 2006 Feb;132(4):410-51.)
* 2009: PMID 18971951 -- "Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma." (Kyle RA, Leukemia. 2009 Jan;23(1):3-9.)
** See also chart in PMID 21181954 PDF
* 2010: Smoldering multiple myeloma (Review) PMID 20026810 -- "Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations." (Blade J, J Clin Oncol. 2010 Feb 1;28(4):690-7.)
* 2011: Workup (International Myeloma Workshop Consensus Panel) PMID 21292778 Full text -- "Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3." (Dimopoulos M, Blood. 2011 May 5;117(18):4701-5.)
* 2014: International Myeloma Working Group PMID 25439696 -- "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma." (Rajkumar SV, Lancet Oncol. 2014 Nov;15(12):e538-48.)
** Added biomarkers to MM definition.
** See also: IMWG criteria for the diagnosis of multiple myeloma
MGUS:
* 2010: MGUS, Consensus Statement PMID 20507313 -- "Monoclonal gammopathy of undetermined significance: a consensus statement." (Berenson JR, Br J Haematol. 2010 Jul;150(1):28-38.)
Smoldering (Asymptomatic) Multiple Myeloma:
* 2010: Smoldering MM, Review PMID 20026810 -- "Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations." (Bladé J, J Clin Oncol. 2010 Feb 1;28(4):690-7.)
Screening Tests:
* 2009: Mayo -- PMID 19520758 -- "Screening panels for detection of monoclonal gammopathies." (Katzmann JA, Clin Chem. 2009 Aug;55(8):1517-22.)
** Conclusion: "Serum IFE, PEL, and FLC combined with urine IFE and PEL is the most comprehensive and inclusive panel to screen for monoclonal gammopathies. However, because of the small incremental sensitivity provided by urine studies and serum IFE, the use of serum PEL plus FLC provides a simple and efficient initial diagnostic screen for the high-tumor-burden monoclonal gammopathies such as MM, WM, and SMM. Urine studies and serum IFE can be ordered more selectively."

### Definitions

Multiple myeloma:
* Clonal bone marrow plasma cells ≥10% or biopsy-proved bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events:
* Myeloma defining events:
* Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: (CRAB: hypercalcemia, renal failure, anemia, lytic lesions of bone)
** Hypercalcemia: calcium > 1 mg/dL higher than the upper limit of normal or > 11 mg/dL
** Renal insufficiency: creatinine clearance < 40 mL/min or serum creatinine > 2 mg/dL
** Anemia: Hgb of > 2 g/dL below the lower limit or normal or a value < 10 g/dL
** Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET/CT. * (If bone marrow has less than 10% clonal cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement.)
* Any 1 or more of the following biomarkers of malignancy:
** Clonal bone marrow plasma cell percentage ≥ 60%
** Involved:uninvolved serum free light chain ratio ≥ 100 * (The involved FLC must be ≥ 100 mg/L)
** More than 1 focal lesions on MRI studies * (Each lesion must be 5 mm or more in size)
Monoclonal gammopathy of undetermined significance (MGUS):
* Absence of symptoms
* M-protein < 3 g/dL
* < 10% plasma cells in bone marrow
* No CRAB clinical features
Light-chain MGUS:
* Abnormal FLC ratio (<0.26 or >1.65)
* Increased level of the involved light chain
* No Ig heavy chain expression on immunofixation
* Absence of CRAB clinical features or amyloidosis that can be attributed to the plasma cell proliferative disorder
* Clonal bone marrow plasma cells <10%
* Urinary monoclonal protein <500 mg/24 h
Smoldering multiple myeloma (SMM):
* Both criteria must be met:
** Serum monoclonal protein (IgG or IgA) ≥ 3.0 g/dL or urinary monoclonal protein ≥ 500 mg per 24 h and/or clonal bone marrow plasma cells 10-60%
** Absence of myeloma defining events or amyloidosis
Solitary Plasmacytoma
* Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
* Normal bone marrow
* Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
* Absence of CRAB clinical features
Solitary Plasmacytoma with minimal marrow involvement
* Clonal bone marrow plasma cells <10%
* Other features from solitary plasmacytoma definition (other than normal bone marrow)
Plasma cell labeling index (PCLI) can differentiate MGUS and SMM from MM:
* Elevated PCLI is indicative of MM
* 40% of pts with MM have a normal PCLI
Circulating plasma cells are rare in MGUS and SMM.

## Prognostic factors

* Plasma cell labeling index (PCLI)
    Uses monoclonal antibody BU-1 that reacts with 5-bromo-2-deoxyuridine
    High PCLI (>1%) predicts poor overall survival
* Beta-2 microglobulin
    Correlates with myeloma tumor burden. High value predicts poor survival.

## Staging

Durie-Salmon staging (1975):
Durie-Salmon staging :
| | Stage I | Stage II | Stage III |
| | All of the below: | Not Stage I or III | Any of the below: |
| Hemoglobin | > 10 g/dL | | <8.5 g/dL |
| Calcium | <= 12 g/dL | | >12 g/dL |
| Radiology | Normal bone X-rays or solitary bone lesion | | advanced lytic bone lesions ("extensive skeletal destruction and major fractures") |
| IgG | <5 g/dL | | >7 g/dL |
| IgA | <3 g/dL | | >5 g/dL |
| Urine M-protein | <4 g/24 hr | | >12 g/24 hr |
| Substage (for each stage) | A - creatinine < 2 mg/dL | B - creatinine >= 2 mg/dL |
| Median survival | 5 yrs | | 15 mo |
    Reference: PMID 1182674 — "A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival." Durie BG and Salmon SE. Cancer. 1975 Sep;36(3):842-54.
International Staging System (2005):
ISS Staging :
| | Stage I | Stage II | Stage III |
| B2-microglobulin | <3.5 mg/L | Not stage I or III | >=5.5 mg/L |
| Albumin | >=3.5 g/dL | | Any |
| Median survival | 62 mo | 44 mo | 29 mo |
    Reference: PMID 15809451 — "International staging system for multiple myeloma." Greipp PR et al. J Clin Oncol. 2005 May 20;23(15):3412-20.

## Treatment
### Treatment Overview

* Solitary plasmacytoma
** 45-50 Gy to involved bone
** Surgery reserved for neurologic emergencies (spinal cord compression, some spine instability)
** Chemotherapy reserved for those who progress to multiple myeloma
** >90% local control
** 50-60% progress to multiple myeloma
* Extramedullary plasmacytoma
** 45-50 Gy to affected area and LNs
** Surgery + RT better outcomes than either modality in upper aerodigestive tract (UAD), no benefit to surgery elsewhere
** No benefit demonstrated for chemotherapy
** 80% local control
** 15% progress to multiple myeloma
* Multiple myeloma
** Chemotherapy and/or BMT primary treatment
** Bisphosphonates IV
** RT palliative intent; 15-20 Gy considered sufficient
** Hemibody RT (7.5 Gy / 8.5 Gy) for refractory cases

### Radiotherapy

* Solitary plasmacytoma
** Dose >45 Gy in 2 Gy/fx
** 2-3 cm margin; in spine generally treat 1 above and 1 below
** No LN irradiation
* Extramedullary plasmacytoma
** Dose >45 Gy in 2 Gy/fx
** Elective LN irradiation recommended
* Multiple myeloma
** In MM intent is palliative.
** Disseminated MM of bone is considered radiosensitive, and doses 15-20 Gy are considered sufficient for pain control. However, for long-term functional outcomes in spinal cord compression, consider 30/10
** Hemibody irradiation (6 weeks after chemo) with 7.5 Gy single fx to upper body and 8.5 Gy single fx to lower body
Solitary Plasmacytoma
* Mayo, 1989 PMID 2912957 -- "Solitary plasmacytoma of bone: Mayo Clinic experience." (Frassica DA, Int J Radiat Oncol Biol Phys. 1989 Jan;16(1):43-8.)
** Retrospective. 46 patients with solitary plasmacytoma. 54% vertebral column. RT median 40 Gy (20-70 Gy). Median F/U 7.5 years
** Outcome: 54% developed multiple myeloma, 11% local recurrences
** Recurrence: median time-to-failure 18 months, but 23% >5 years. No local failure if RT >45 Gy
** OS: 5-year 74%, 10-year 45%.
Multiple myeloma
    For spinal cord compression in multiple myeloma, see also Radiation_Oncology/Palliation/Spinal_Cord_Compression
* MD Anderson, 2006 (1993-2005) PMID 16925080 -- "Multiple myeloma of the cervical spine: treatment strategies for pain and spinal instability." (Rao G, J Neurosurg Spine. 2006 Aug;5(2):140-5.)
** Retrospective. 35 patients with MM mets in cervical spine, treated with RT and/or surgery
** RT only (dose not reported): 19/20 experienced pain resolution.
** Spinal instability: 23/35 instability on x-ray, 15/23 treated with RT alone. No clinical progress of instability after RT
* Hamburg, 2006 (1994-2004) (Germany) PMID 16413695 -- "Short-course radiotherapy is not optimal for spinal cord compression due to myeloma." (Rades D, Int J Radiat Oncol Biol Phys. 2006 Apr 1;64(5):1452-7.)
** Retrospective. 172 patients irradiated for spinal cord compression. RT short (8/1 or 20/5) or long (30/10, 37.5/15, 40/20).
** Outcome: 52% functional improvement; 47% of nonambulatory patients gained ability to walk
** Motor function improvement: long RT 59% vs. short RT 39% at 1 month (NS), 67% vs. 43% at 6 months (SS), 76% vs. 40% at 1 year (SS) and 83% vs. 54% at 2 years (NS). No difference among long-term fractionation schemes. Local recurrence in 11% (short RT) vs 5%.
** Conclusion: 30/10 appropriate for long-term functional outcome
* U.Arizona, 1993 (1975-90) PMID 7683017 -- "Radiation therapy for the palliation of multiple myeloma." (Leigh BR, Int J Radiat Oncol Biol Phys. 1993 Apr 2;25(5):801-4.)
** Retrospective. 101 pts with MM treated with 316 courses.
** dose range: 3-60 Gy (mean 25 Gy; most common 25-30 Gy). Fraction size mean: 3.1 Gy.
** Pain relief: 26% complete, 71% partial, 3% none. Only 6% required retreatment (at a median time of 16 months). No relationship between pain relief rate or retreatment rate with dose. Good pain responses seen with doses > 10 Gy.
* Wash U, 1980 (1961-75) PMID 6153562 Full text -- "The role of radiation therapy in the management of plasma cell tumors." (Mill WB, Cancer. 1980 Feb 15;45(4):647-52.)
** Retrospective. 128 patients with MM and 16 patients with SPC
** MM: dose range up to 44 Gy. Most common 15-20 Gy. Only 6% fields needed re-treatment at later date. Palliation from pain: 21% complete, 70% partial, 9% none. Pain relief first noted after a median dose of 10-15 Gy.
** SPC: Recommend doses >50 Gy for improved local control

### Chemotherapy

* Adriamycin / pegylated doxorubicin
* Vincristine
* Bortezomib (Velcade) - inhibits proteasome / ubiquitin pathway. Inhibits NFKB (nuclear factor κ-B), several cytokines, VEGF, fibroblast growth factor
* Thalidomide - immunomodulator
* Lenalidomide (Revlimid) - analog of thalidomide. fewer side effects
* Dexamethasone - high dose [40mg per day X 4days on , 4 days off, repeated whole month] or low dose [40mg per day X4 days on 24 days off} every 28 days is used in combinations with the above therapies.
* Melphalan/Prednisone
* High dose Cyclophosphamide

#### Trials

* Italy, 2007 PMID 17360989 -- "A comparison of allografting with autografting for newly diagnosed myeloma." (Bruno B, N Engl J Med. 2007 Mar 15;356(11):1110-20.)
** Prospective. 162 patients with one sibling. Treated with VAD, followed by melphalan + autologous stem cell transplant. If HLA-identical sibling, followed by non-myeloablative TBI (2 Gy on day 0) and stem cell allograft. If no HLA-identical sibling, followed by myeloablative melphalan + second autologous stem cell transplant. Median F/U 3.7 years
** Median OS: allograft 6.7 years vs. autograft 4.5 years (SS). EFS 3 years vs. 2.4 years (SS)
** Conclusion: autograft+allograft from sibling better than tandem autograft
* IFM 99-06 (French) (2000-?)
** 447 pts randomized to three arms: 1) standard MP (melphalan-prednisone), 2) MP + thalidomide, 3) MP followed by autologous stem cell transplantation.
** ASCO 2006 Abstract — "Superiority of melphalan-prednisone (MP) + thalidomide over MP and autologous stem cel transplantation in the treatment of newly diagnosed elderly patients with multiple myeloma." Facon T et al.
*** Median f/u 37 months. Improved PFS for MP+Thalidomide (27.6 months) vs 17.1 (MP) vs 19.4 (xplant), SS for MP+T, NS for MP vs xplant. MS 53.6 vs 32.2 vs 38.6 mo.

### Evaluation of response

* International uniform response criteria:
** PMID 16855634 (2006) — "International uniform response criteria for multiple myeloma." Durie BG et al. Leukemia. 2006 Sep;20(9):1467-73.

## Solitary Plasmacytoma

* Mayo; 2006 (1960-95) PMID 16741249 -- "Immunoglobulin free light chains and solitary plasmacytoma of bone." (Dingli D, Blood. 2006 Sep 15;108(6):1979-83.)
** Retrospective. Included 116 pts with SBP for whom FLC assays were available prior to treatment. Excluded pts with M protein > 3 g/dL.
** 64% had a detectable serum M protein; was > 0.3 g/dL in 63 pts; in 11 detectable only by IFE. Median size of M protein was 0.5 g/dL. Abnormal FLC ratio in 47% at diagnosis.
** 43 pts progressed to MM at a median TTP of 1.8 yrs. Pts with abnormal FLC ratio at diagnosis had a higher chance of progression. Pts with persistent M protein (0.5 g/dL or higher) at 1-2 yrs from diagnosis also had a higher chance of progression. 5-yr probability of progression: 13% (normal FLC, normal M protein at 1-2 yrs), 26% (either risk factor abnormal), 62% (both risk factors abnormal)
** Conclusion: an abnormal FLC ratio can predict progression to myeloma

## Bisphosphonates

* ASCO 2007 Guideline PMID 17515569 -- "American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma." (Kyle RA, J Clin Oncol. 2007 Jun 10;25(17):2464-72.)
** If lytic destruction or spine compression fractures, recommend IV pamidronate 90mg over 2 hours or zoledronic acid 4 mg over 15 minutes q 3-4 weeks for 2 years. Outside of USA, also can use clodronate PO or IV

## Reviews

* MGUS: (2006) PMID 17192542 — "Monoclonal Gammopathy of Undetermined Significance." Blade J et al. New Engl J Med. 2006 Dec 28;355(26):2765-2770.
* 2005 PMID 16212152 -- "Multiple myeloma: diagnosis and treatment." (Rajkumar SV, Mayo Clin Proc. 2005 Oct;80(10):1371-82.)
* 2011 PMID 21181954 (free full text) -- "Multiple myeloma: 2011 update on diagnosis, risk-stratification, and management." (Rajkumar SV, Am J Hematol. 2011 Jan;86(1):57-65.)

## Official Guidelines

See Official Guidelines

## References

* Staging: 2005 - PMID 15809451 — "International staging system for multiple myeloma."Greipp PR et al. J Clin Oncol. 2005 May 20;23(15):3412-20.
* ↑ PMID 12456500 (Free full text) - "POEMS syndrome: definitions and long-term outcome." Dispenzieri A et al. Blood. 2003 Apr 1;101(7):2496-506.