SUPPORTIVE THERAPY

 

Supportive care is as important as the anti-myeloma therapy. It includes:

 - Treatment/prevention of anemia: transfusions, erythropoietin
 - Treatment/prevention of renal insufficiency: hydration, plasma exchange
 - Prevention of thromboembolism: aspirin, low molecular weight heparin
 - Prevention of infections: antibiotics, IVIG, vaccinations
 - Prevention of bone fractures: bisphosphonates
 - Pain control: opioid medications, verteroplasty/kyphoplasty, radiation therapy
 - Treatment of neuropathy: e.g., gabapentin, amitriptyline

 

 


TREATMENT OF ANEMIA

 

BLOOD TRANSFUSIONS

Blood transfusions are often indicated if the hemoglobin decreases to <8 g/dL.

 

ERYTHROPOIETIN

For chemotherapy-related anemia,  subcutaneous injections of erythropoietin are given until the hemoglobin increases to 12 g/dL.

Several studies have suggested that EPO can have a direct antitumor effect in addition to its RBC-stimulating activity. EPO receptors are present on MM cells.

Erythropoietin induces tumor regression and antitumor immune responses in murine myeloma models.
Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5181-6.
Mittelman M, Neumann D, Peled A, Kanter P, Haran-Ghera N.

Erythropoietin has an anti-myeloma effect - a hypothesis based on a clinical observation supported by animal studies.
Eur J Haematol. 2004 Mar;72(3):155-65.
Mittelman M, Zeidman A, Kanter P, Katz O, Oster H, Rund D, Neumann D.

IgA multiple myeloma responding to erythropoietin monotherapy.
Am J Hematol. 2005 Oct;80(2):165-6.
Barrios M, Alliot C.

Data about EPO and survival in MM are controversial.

Recombinant human erythropoietin is associated with increased overall survival in patients with multiple myeloma.
Acta Haematol. 2007 Mar;117(3):162-7.
Baz R, Walker E, Choueiri TK, Abou Jawde R, Brand C, McGowan B, Yiannaki E, Andresen S, Hussein MA.
This study reviews outcomes of 257 patients with multiple myeloma. 127 of them received EPO for at least 1 month, and 130 did not. After adjusting for several variables, the use of EPO was found to be associated with improved overall survival (hazard ratio = 0.6) in patients with SWOG stages II, III and IV.

Erythropoiesis-stimulating agents are associated with reduced survival in patients with multiple myeloma.
Am J Hematol. 2008 Sep;83(9):697-701.
Katodritou E, Verrou E, Hadjiaggelidou C, Gastari V, Laschos K, Kontovinis L, Kapetanos D, Constantinou N, Terpos E, Zervas K.
In this study, 323 patients with MM found reduced overall survival and progression-free survival in patients treated with EPO. After a median follow-up of 31 months (range: 1-238):
  - Median survival: 31 months in patients treated with EPO, and 67 months in patients not treated with EPO (p < 0.001)
  - Median PFS: 14 months in patients treated with EPO, and 30 months in patients not treated with EPO (p < 0.001)

 

 


RENAL INSUFFICIENCY

 

For patients who present with renal failure, the most important goal for the recovery of renal function is a fast and deep response to chemotherapy.

 

HYDRATION

When the disease is active, patients should drink 2-3 L of fluids daily, in order to increase the urinary excretion of light chains, calcium, and uric acid.

 

PLASMA EXCHANGE

The use of plasma exchange in the treatment of MM remains controversial. The light chain response to plasma exchange is only transient, and anti-myeloma therapy should be instituted as soon as possible, to reduce the production of free light chains.

Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.
Kidney Int. 2008 Jun;73(11):1282-8.
Leung N, Gertz MA, Zeldenrust SR, Rajkumar SV, Dispenzieri A, Fervenza FC, Kumar S, Lacy MQ, Lust JA, Greipp PR, Witzig TE, Hayman SR, Russell SJ, Kyle RA, Winters JL.
This is a study of 40 patients with MM and renal failure who underwent plasma exchange. In most patients, renal insufficiency resolved when the serum free light chains decreased by at least 50%. The median time to response was about 2 months.

 

Three randomized controlled studies have assessed the role of plasma exchange in MM.

Controlled plasma exchange trial in acute renal failure due to multiple myeloma.
Kidney Int. 1988 Jun;33(6):1175-80.
Zucchelli P, Pasquali S, Cagnoli L, Ferrari G.
29 patients with MM and acute renal failure (24 patients required hemodialysis) were randomized to two groups, one treated with antimyeloma therapy (14 patients), and the other one with anti-myeloma therapy + plasma exchange (15 patients). Recovery of renal function was observed in 2 of 14 (14%) patients treated without plasma exchange, and 13 of 15 (87%) patients treated with plasma exchange. The one-year survival significantly higher in patients treated with plasma exchange (66% vs 28%, p <0.01).

Treatment of renal failure associated with multiple myeloma. Plasmapheresis, hemodialysis, and chemotherapy.
Arch Intern Med. 1990 Apr;150(4):863-9.
Johnson WJ, Kyle RA, Pineda AA, O'Brien PC, Holley KE.
This is a prospective, randomized trial of plasmapheresis in 21 MM patients, with the goal of preventing irreversible renal failure. 10 patients were randomized to chemotherapy, and 11 patients were randomized to chemotherapy + plasmapheresis. Plasmapheresis and chemotherapy lowered the serum myeloma protein value much more rapidly than chemotherapy alone. Improvement of renal function was observed in 5 of 10 (50%) patients treated with chemotherapy, and 7 of 11 (64%) patients treated with chemotherapy + plasmapheresis. Of 5 patients who were receiving hemodialysis, only 3 treated by plasmapheresis recovered.

Plasma exchange when myeloma presents as acute renal failure: a randomized, controlled trial.
Ann Intern Med. 2005 Dec 6;143(11):777-84.
Clark WF, Stewart AK, Rock GA, Sternbach M, Sutton DM, Barrett BJ, Heidenheim AP, Garg AX, Churchill DN; Canadian Apheresis Group.
This is a randomized trial conducted from 1998 to 2004 in 14 Canadian medical centers. 104 patients with acute renal failure at the onset of myeloma were randomly assigned to conventional therapy + 5-7 plasma exchanges for 10 days or conventional therapy alone. The primary outcome was a composite measure of death, dialysis dependence, or glomerular filtration rate <30 mL/min/1.73 m2. This end point occurred in 33 of 57 (57.9%) patients in the plasma exchange group and in 27 of 39 (69.2%) patients in the control group (P = 0.36). Therefore, there was no conclusive evidence that 5-7 plasma exchanges improve clinical results at 6 months in patients with acute renal failure at the onset of multiple myeloma. This study failed to demonstrate a benefit of the addition of plasma exchange therapy.

In conclusion: 2 of the 3 studies showed no survival benefit. Two of 3 studies showed a higher rate of discontinuation of dialysis with plasmapheresis, but the largest study failed to confirm this benefit. It seems that plasmapheresis does not produce a clinical benefit independent of chemotherapy.

 

High-cut off hemodialysis with specially designed dialyzers can reduce serum free light chains levels within a few hours, and it is potentially better than plasma exchange.

 

 


PROPHYLAXIS OF THROMBOEMBOLISM

Anticoagulation is important in patients taking thalidomide or lenalidomide, to prevent deep venous thrombosis and pulmonary embolism.

 

Thrombosis in multiple myeloma.
Expert Rev Anticancer Ther. 2007 Mar;7(3):307-15.
Zangari M, Elice F, Fink L, Tricot G.
[Review]

Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival.
Clin Lymphoma. 2003 Jun;4(1):32-5.
Zangari M, Barlogie B, Thertulien R, Jacobson J, Eddleman P, Fink L, Fassas A, Van Rhee F, Talamo G, Lee CK, Tricot G.
Evaluation of 535 patients treated with thalidomide and corticosteroids or several types or chemotherapy found a total of 82 patients who developed DVT. The frequency of DVT was affected by several factors, including newly diagnosed disease and concomitant therapy with doxorubicin. The development of DVT did not adversely influence survival.

Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation.
Br J Haematol. 2004 Sep;126(5):715-21.
Zangari M, Barlogie B, Anaissie E, Saghafifar F, Eddlemon P, Jacobson J, Lee CK, Thertulien R, Talamo G, Thomas T, Van Rhee F, Fassas A, Fink L, Tricot G.

Among 256 newly diagnosed myeloma patients randomized to thalidomide vs no thalidomide, DVT was observed more frequently in the thalidomide group (hazard ratio: 4.5). Low dose coumadin (1 mg/day) did not prevent venous thromboembolism, whereas LMWH (enoxaparin 40 mg SC qd) effectively prevented it.

Arterial thrombosis in four patients treated with thalidomide.
Leuk Lymphoma. 2005 Feb;46(2):239-42.
Scarpace SL, Hahn T, Roy H, Brown K, Paplham P, Chanan-Khan A, van Besien K, McCarthy PL Jr.
This is a report of 7 cases of arterial thrombotic events during therapy with thalidomide. 3 cases occurred in patients with other risk factors.

Hypercoagulable states in patients with multiple myeloma can affect the thalidomide-associated venous thromboembolism.
Blood Coagul Fibrinolysis. 2009 Jul;20(5):337-9.
Talamo G, Ibrahim S, Claxton D, Tricot GJ, Fink LM, Zangari M.

 

WARFARIN

Prospective evaluation of low-dose warfarin for prevention of thalidomide associated venous thromboembolism.
Leuk Lymphoma. 2006 Nov;47(11):2339-43.
Miller KC, Padmanabhan S, Dimicelli L, Depaolo D, Landrigan B, Yu J, Doran V, Marshal P, Chanan-Khan A.
This is a prospectively study of low-dose warfarin (1 or 2 mg) for the prevention of thalidomide-associated venous thromboembolism (VTE). The incidence of VTE was 6% (4 of 68 patients).

ASPIRIN

Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma.
Leuk Lymphoma. 2007 Dec;48(12):2330-7.
Niesvizky R, Martínez-Baños D, Jalbrzikowski J, Christos P, Furst J, De Sancho M, Mark T, Pearse R, Mazumdar M, Zafar F, Pekle K, Leonard J, Jayabalan D, Coleman M.
In this study, the prophylactic use of low-dose aspirin (81 mg) was effective in preventing an increased incidence of venous thromboembolism in patients with multiple myeloma treated with thalidomide or lenalidomide.

LMWH

Clinical outcomes of venous thromboembolism with dalteparin therapy in multiple myeloma patients.
Thromb Res. 2015 Nov;136(5):974-9.
Lee SE, Jeon YW, Yoon JH, Cho BS, Eom KS, Kim YJ, Kim HJ, Lee S, Cho SG, Kim DW, Lee JW, Min WS, Kim M, Min CK.
In this study, 44 patients with multiple myeloma who developed venous thromboembolism were treated with dalteparin. Median duration of therapy was 4.2 months. Median follow-up was 9 months. The treatment seemed to be efficacious, because only 5 patients (11%) developed recurrent venous thromboembolism. Major bleeding was observed in 3 patients.

ASPIRIN VS LMWH

Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide.
Blood. 2012 Jan 26;119(4):933-9.
Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A.
342 patients with newly diagnosed multiple myeloma were treated with lenalidomide and randomized to either aspirin 100 mg PO daily or enoxaparin 100 mg SC daily. Results:
  - Venous thromboembolism developed in 2.3% of patients in the aspirin group, and 1.2% in the enoxaparin group
  - Pulmonary embolism developed in 1.7% of patients in the aspirin group, and 0% in the enoxaparin group
  - No cases of arterial embolism were observed
The authors concluded that aspirin is sufficient in the prophylaxis of venous thromboembolism for patients receiving lenalidomide.

 

 


PROPHYLAXIS OF INFECTIONS

 

Infections in patients with multiple myeloma.
Semin Hematol. 2009 Jul;46(3):277-88.
Nucci M, Anaissie E.
[Review]

 

ANTIMICROBIALS

For preventing infections: prophylactic use of antibacterial and antiviral drugs, especially in patients receiving pulse dexamethasone, chemotherapy, or stem cell transplant.

The use of acyclovir or similar antiviral drugs is usually effective in the prevention of herpes zoster infections ("shingles").

Prophylactic antibiotics for the prevention of early infection in multiple myeloma.
Am J Med. 1996 Jun;100(6):624-8.
Oken MM, Pomeroy C, Weisdorf D, Bennett JM.
In this small randomized study, the prophylactic use of trimethoprim-sulphamethoxazole signifficantly decreased the risk of infection during the first 2 months of induction therapy with alkylating agent chemotherapy.

Acyclovir to prevent reactivation of varicella zoster virus (herpes zoster) in multiple myeloma patients receiving bortezomib therapy.
Cancer. 2009 Jan 1;115(1):229-32.
Vickrey E, Allen S, Mehta J, Singhal S.
In this retrospective study, 125 myeloma patients treated with bortezomib received routine acyclovir prophylaxis at the dose of 400 mg daily (alternatives, used in <20% of patients, were acyclovir 200 mg, valacyclovir 250 or 500 mg, and famciclovir 500 mg). After a median duration of bortezomib therapy of 16 weeks (range, 1-164 weeks), no episodes of herpes zoster were observed.

Varicella-zoster virus prophylaxis with low-dose acyclovir in patients with multiple myeloma treated with bortezomib.
Clin Lymphoma Myeloma. 2009 Apr;9(2):151-3.
Pour L, Adam Z, Buresova L, Krejci M, Krivanova A, Sandecka V, Zahradova L, Buchler T, Vorlicek J, Hajek R.
This study analyzed the effect of acyclovir prophylaxis in 98 consecutive patients with relapsed MM treated with bortezomib. Herpes zoster was seen in:
 - 4 of 11 (36%) patients without VZV prophylaxis
 - 0 of 32 patients who received acyclovir 400 mg 3 times daily
 - 0 of 55 patients who received acyclovir 400 mg once daily
Therefore, acyclovir 400 mg once daily is sufficient to protect from VZV reactivation in patients with MM treated with bortezomib.

Low-dose acyclovir prophylaxis for bortezomib-induced herpes zoster in multiple myeloma patients.
Br J Haematol. 2012 Oct;159(1):111-3.
Minarik J, Pika T, Bacovsky J, Langova K, Scudla V.
This is a retropsective analysis of 169 patients with myeloma treated with bortezomib. The development of herpes zoster was observed in:
  - 21 cases (27%) among 78 patients who did not receive acyclovir prophylaxis
  - 0% among 92 patients who received 200 mg daily (there was 1 case, but that patient was noncompliant with the medication)

 

IVIG

Indicated for recurrent, life-threatening infections.

Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple myeloma. The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma.
Lancet. 1994 Apr 30;343(8905):1059-63.
Chapel HM, Lee M, Hargreaves R, Pamphilon DH, Prentice AG.
This is a randomised, double-blind study of IVIG vs placebo in 82 patients with multiple myeloma. Patient received IVIG 400 mg/Kg or placebo monthly for 12 months. Patient did not receive prophylactic antibiotics. Results:
  - Number of episodes of sepsis or pneumonia was 10 with placebo, and 0 with IVIG (p= 0.002)
  - Number of serious infections was 38 with placebo, and 19 with IVIG (p= 0.02)

Incidence of infection according to intravenous immunoglobulin use in autologous hematopoietic stem cell transplant recipients with multiple myeloma.
Transpl Infect Dis. 2015 Oct;17(5):679-87.
Park S, Jung CW, Jang JH, Kim SJ, Kim WS, Kim K.
This is a retrospective study of 162 patients with myeloma who underwent an autologous stem cell transplant. The prophylactic use of IVIG did not seem to reduce the incidence of infections (35% without IVIG, and 31% with IVIG, p=0.63), and the incidence of infections requiring hospitalization.

 

VACCINATIONS

Vaccinations against pneumococcus and influenza are recommended. Consider vaccination against Haemophilus influenzae B.

 

 


BONE DISEASE

See specific section.

 


PAIN CONTROL

Options include:

  - Opioid medications
  - Vertebroplasty/kyphoplasty
  - Radiation therapy
 

Treatment of painful peripheral neuropathy or post-herpetic neuralgia:
  - Topical treatment: patches with 5% lidocaine, capsaicin 0.075% cream x 4/day
  - Tricyclic antidepressants
  - Gabapentin
  - Pregabalin
  - Opioid medications

 

Acupuncture combined with methylcobalamin for the treatment of chemotherapy-induced peripheral neuropathy in patients with multiple myeloma.
BMC Cancer. 2017 Jan 9;17(1):40.
Han X, Wang L, Shi H, Zheng G, He J, Wu W, Shi J, Wei G, Zheng W, Sun J, Huang H, Cai Z.
This is a clinical trial of 104 myeloma patients with a common problem, peripheral neuropathy, randomized into a group who received methylcobalamin (a form of vitamin B12) and another group who received methylcobalamin + three cycles of acupuncture. The group receiving acupuncture had a statistically significant improvement of the painful neuropathy.


 


Giampaolo Talamo, M.D.