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Treatment Protocols

Treatment protocols for multiple myeloma are provided below. In addition to general treatment recommendations, treatment recommendations for the following are included:

Primary therapy (induction for stem cell transplantation)
Patients with relapse after transplant
Patients who are not transplant candidates

General treatment recommendations for multiple myeloma

The approval of new drugs continues to change the landscape of myeloma maintenance therapy. In general, the first decision made in the management of patients with myeloma who require systemic therapy is whether stem cell transplantation is part of the strategy. Considerations are as follows:

Minimal residual disease testing of the bone marrow is incorporated into the response evaluation to further determine disease burden in patients who achieve complete remission.
Alkylator and nitrosourea therapy is usually deferred or reduced in patients who may require autologous stem cell collection, to avoid injury to the stem cells.
All transplant-eligible multiple myeloma patients should receive a triplet induction therapy (immunomodulatory agents, proteasome inhibitor and dexamethasone). Bortezomib with lenalidomide and dexamethasone is the most commonly used regimen. ^[1]Although the combination of carfilzomib (second-generation proteasome inhibitor) with lenalidomide and dexamethasone showed higher efficacy in phase II trials, particularly in high-risk patients, interim analysis in an ongoing phase III clinical trial showed that progression-free survival (PFS) was not superior to that with bortezomib/lenalidomide/dexamethasone. Toxicity profiles did vary significantly, however, with higher rates of cardiopulmonary and renal toxicity with carfilzomib and higher rates of neuropathy with bortezomib. ^[2]
Monoclonal antibodies are a new drug class being integrated into the existing anti-myeloma regimens due to the deeper response rate and better PFS seen with the combinations.^{[3, 4, 5]}
High-dose melphalan followed by autologous stem cell transplant after induction has been associated with superior event-free survival compared with chemotherapy and is considered the preferred approach.^[6]
Post-transplantation maintenance therapy with low-dose lenalidomide yields improved PFS and overall survival (OS). Adverse effects include infection, thrombosis, and second primary malignancy.^[7] The oral proteasome inhibitor ixazomib showed improved PFS compared with placebo and may be an alternative choice for patients who do not tolerate lenalidomide.^[8]
Minimal residual disease testing of the bone marrow is incorporated into the response evaluation to further determine disease burden in patients who achieve complete remission. ^[9]
More sensitive skeletal imaging—including whole-body CT scan, MRI, or PET/CT—is incorporated in the diagnosis and response criteria. ^[10]
Frailty score predicts outcome in transplant-ineligible patients with newly diagnosed myeloma and is incorporated into the staging criteria. ^[11]
Continuous treatment with lenalidomide and dexamethasone ^[12] or bortezomib (Velcade), melphalan, and prednisone (VMP) ^[13] are the most active regimens for transplant-ineligible patients, although addition of the anti-CD38 monoclonal antibody daratumumab to these regimens to drive deeper response is likely to become the new standard of care. ^{[3, 4]}

Induction therapy for transplant-eligible patients

Patients who present with active (symptomatic) multiple myeloma are treated with induction therapy.^[14]Any one of the combination regimens below may be used for induction therapy.

Lenalidomide (Revlimid)/bortezomib/dexamethasone (VRd, RVd)^[6]:

Bortezomib 1.3 mg/m ² IV push (IVP)/ subcutaneous (SC) on days 1, 4, 8, and 11 plus lenalidomide 25 mg PO daily on days 1-14 plus dexamethasone 20 mg PO daily on days 1, 2, 4, 5, 8, 9, 11, and 12 or dexamethasone 40 mg PO daily on days 1, 8, and 15; 21-d cycle for three or four cycles

Daratumumab/bortezomib/thalidomide/dexamethasone (dara-VTD)^[5]:

Bortezomib 1.3 mg/m ²IVP/SC on days 1, 4, 8, and 11 plus thalidomide 100 mg PO daily plus oral or IV dexamethasone (40 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of cycles one and two; 40 mg on days 1 and 2 of cycles three and four; 20 mg on days 8, 9, 15, and 16 of cycles three and four plus daratumumab 16 mg/kg IV weekly in cycles one and two and once every 2 weeks during induction cycles three and four; 28-d cycle for four cycles

Bortezomib/cyclophosphamide/dexamethasone (CyBorD, VCD)

This combination is preferred for patients with acute kidney injury. It may be used in any of the following regimens^{[15, 16, 17]}:

Bortezomib 1.3 mg/m² IVP/SC on days 1, 4, 8, and 11 plus cyclophosphamide 300 mg/m²/day PO on days 1, 8, 15, and 22 plus dexamethasone 40 mg PO daily on days 1-4, 9-12, and 17-20; 28-d cycle for three or four cycles
Bortezomib 1.3 mg/m² IVP/SC on days 1, 4, 8, and 11 plus cyclophosphamide 500 mg/m²/day PO on days 1, 8, and 15 plus dexamethasone 40 mg PO daily on days 1, 8, and 15; 21-d cycle for three or four cycles
Bortezomib 1.3 mg/m² IVP/SC on days 1, 4, 8, and 11 plus cyclophosphamide 900 mg/m² IV over 1 h on day 1 plus dexamethasone 40 mg PO daily on days 1 2, 4, 5, 8, 9, 11, and 12; 21-d cycle for three or four cycles

Bortezomib/doxorubicin/dexamethasone

Either of the following two regimens may be used^{[18, 19]}:

Bortezomib 1.3 mg/m² IVP/SC on days 1, 4, 8, and 11 plus doxorubicin 9 mg/m² IV push on days 1-4 plus dexamethasone 40 mg PO daily on days 1-4, 8-11, and 15-18 (cycle 1), then days 1-4 (cycles two-four); 21-d cycle for three or four cycles
Bortezomib 1.3 mg/m² IVP/SC on days 1, 4, 8, and 11 plus doxorubicin 9 mg/m² continuous IV infusion over 24 h daily on days 1-4 plus dexamethasone 40 mg PO daily on days 1-4, 9-12, and 17-10; 28-d cycle for three or four cycles

Bortezomib/lenalidomide/dexamethasone

Bortezomib 1.3 mg/m²IVP/SC on days 1, 4, 8, and 11 plus lenalidomide 25 mg PO daily on days 1-14 plus dexamethasone 20 mg PO daily on days 1, 2, 4, 5, 8, 9, 11, and 12 or 40 mg PO daily on days 1, 8, and 15; 21d cycle for three or four cycles^{[20, 21]}

Bortezomib/thalidomide/dexamethasone

Bortezomib 1-1.3 mg/m² IVP/SC on days 1, 4, 8, and 11 plus thalidomide 50-200 mg (titrate to tolerance) PO daily at bedtime on days 1-21 plus dexamethasone 40 mg PO daily on days 1, 2, 4, 5, 8, 9, 11, and 12 or 40 mg on days 1-4 and 9-12 or 40 mg on days 1-4 and 8-11; 21d cycle for three or four cycles^{[22, 23]}

Lenalidomide/dexamethasone

Either of the following two regimens may be used^{[24, 25]}:

Lenalidomide 25 mg PO daily on days 1-21 plus dexamethasone 40 mg PO daily on days 1, 8, 15, and 22 or 40 mg PO daily on days 1-4, 9-12, and 17-20; 28-d cycle for three or four cycles
Lenalidomide 25 mg PO daily on days 1-28 plus dexamethasone 40 mg PO daily on days 1-4, 9-12, and 17-20; 28-d cycle for three or four cycles

Stem cell collection and autologous stem cell transplantation

Once a remission has been achieved, stem cells are harvested via apheresis. This is commonly carried out with the use of granulocyte colony-stimulating factor or high-dose cyclophosphamide with growth factors. Autologous stem cell transplantation utilizes high-dose melphalan 200 mg/m² or 140 mg/m², with total body irradiation as a conditioning regimen. Studies are under way to explore the incorporation of bortezomib in the conditioning regimen.^{[26, 27]}

Maintenance therapy after transplantation

Options include the following:

Lenalidomide 10 mg PO per day for the first 3 months, increased to 15 mg if tolerated ^{[28, 7]}
Ixazomib on days 1, 8, and 15 in 28-day cycles; 3 mg PO per day in cycles one through four, increased to 4 mg from cycle 5 if tolerated ^[8]
Bortezomib 1.3 mg/m ² IVP/SC on days 1, 4, 8 and 11 every 3 months ^[29]

Primary treatment (non-transplant candidates)

Therapy typically continues until disease progression. One of the following regimens may be used.

Lenalidomide/dexamethasone:

Lenalidomide 25 mg PO daily on days 1-21 plus dexamethasone 40 mg PO daily on days 1, 8, 15, and 22 (20 mg PO daily on days 1,8,15 and 22, for patients over 75 years of age)

Daratumumab, lenalidomide, dexamethasone (DRd):

Lenalidomide 25 mg PO daily on days 1-21 plus dexamethasone 40 mg PO daily on days 1, 8, 15, and 22 plus daratumumab 16 mg/kg IV weekly in cycles one and two and once every 2 weeks during induction cycles three and four, and every 4 weeks thereafter ^[3]

Daratumumab/bortezomib/melphalan/prednisone (dara-VMP):

Daratumumab 16 mg/kg IV (with dexamethasone 20 mg PO or IV to prevent infusion reactions) once weekly in cycle one, every 3 weeks in cycles two through nine, and every 4 weeks thereafter plus bortezomib 1.3 mg/m ²SC twice weekly on weeks 1, 2, 4, and 5 of cycle one and once weekly on weeks 1, 2, 4, and 5 of cycles 2 onward, plus melphalan 9 mg/m ²PO daily on days 1-4 plus prednisone 60 mg mg/m ² PO daily on days 2-4; 42-d cycle ^[4]

RVD lite:

Lenalidomide 15 mg PO on days 1–21 plus bortezomib 1.3 mg/m ² SC weekly on days 1, 8, 15, and 22 plus dexamethasone 20 mg PO on day of and after bortezomib; 35-day cycle for nine cycles, followed by six cycles of consolidation with lenalidomide and bortezomib ^[30]

Bortezomib/cyclophosphamide/dexamethasone (CyBorD, VCD); preferred regimen in patients with acute kidney injury)^{[15, 16, 17]}:

Bortezomib 1.3 mg/m ² IVP/SC on days 1, 4, 8, and 11 plus cyclophosphamide 300 mg/m ²/day PO on days 1, 8, 15, and 22 plus dexamethasone 40 mg PO daily on days 1-4, 9-12, and 17-20; 28-d cycle for three or four cycles or
Bortezomib 1.3 mg/m ² IVP/SC on days 1, 4, 8, and 11 plus cyclophosphamide 500 mg/m ²/day PO on days 1, 8, and 15 plus dexamethasone 40 mg PO daily on days 1, 8, and 15; 21-d cycle for three or four cycles or
Bortezomib 1.3 mg/m ² IVP/SC on days 1, 4, 8, and 11 plus cyclophosphamide 900 mg/m ² IV over 1 h on day 1 plus dexamethasone 40 mg PO daily on days 1 2, 4, 5, 8, 9, 11, and 12; 21-d cycle for three or four cycles

Bortezomib/dexamethasone (preferred regimen in patient with acute renal insufficiency, who may not tolerate triple regimen):

Bortezomib 1.3 mg/m ² IVP/SC on days 1, 4, 8, and 11 every 3 wk plus dexamethasone 20 mg on the day of and the day after bortezomib ^[31]

VMP:

Bortezomib 1-1.3 mg/m² IVP/SC on days 1, 4, 8, 11, 22, 25, 29, and 32, followed by a 10-d rest period plus melphalan 9 mg/m² PO plus prednisone 60 mg/m² PO, both on days 1-4; every 6 wk for four cycles then a maintenance phase consisting of bortezomib 1-1.3 mg/m² on days 1, 8, 22, and 29, followed by a 13-d rest period plus melphalan 9 mg/m² PO plus prednisone PO 60 mg/m²; every 5 wk^[32]

MPT:

Melphalan 0.25 mg/kg PO plus prednisone 2 mg/kg plus thalidomide 200 mg PO daily (escalating to 400 mg as tolerated) on days 1-4; every 6 wk^{[33, 34]}

MPR:

Lenalidomide 10 mg PO on days 1-21 plus melphalan 0.18 mg/kg PO on days 1-4 plus dexamethasone 40 mg PO weekly; every 28 d

Treatment recommendations for maintenance therapy

Meta-analysis suggests benefit in progression-free survival (PFS) and overall survival with lenalidomide maintenance therapy. The following regimens have been used successfully:

Lenalidomide 10 mg/day on days 1-21 every 28d ^[35] or
Lenalidomide 10 mg/day

PFS benefit was also observed in a phase III study of bortezomib and ixazomib compared with placebo. These agents can be alternatives to lenalidomide, particularly in patients with lenalidomide intolerance or kidney failure.^[8]Bortezomib-mediated neuropathy is common with long-term use, however, so patients require close monitoring and dose titration if side effects occur.

Treatment recommendations for relapsed disease

A second autologous stem cell transplant is an option for patients who relapse more than 12 mo after the first transplant (normally, enough cells are collected and cryopreserved for a tandem transplant). Patients who relapse within 12 mo of the initial transplant are best treated with agents they have not received before. Patients who relapse after the second autologous transplant may be candidates for allogeneic transplant or salvage chemotherapy.^[14]

Salvage therapy is used in the following^[14]:

Patients who have relapse following allogeneic or autologous stem cell transplant
Patients with primary progressive disease following initial autologous or allogeneic stem cell transplant
Patients who are ineligible for stem cell transplant with progressive or relapsing disease after initial induction therapy

Salvage therapy is used in the following^[14]:

Patients who have relapse following allogeneic or autologous stem cell transplant
Patients with primary progressive disease following initial autologous or allogeneic stem cell transplant
Patients who are ineligible for stem cell transplant with progressive or relapsing disease after initial induction therapy

Salvage therapy regimens

If a sustained remission was obtained with initial therapy, then consideration should be given to using it again. Salvage therapy also includes the regimens listed above that were not previously selected. Triplets yield higher response rate and progression free survival compared with doublets. Frailty and organ function at the time of relapse influence treatment choices. Other regimens are as follows:

Panobinostat 20 mg PO once every other day for three doses/week (on days 1, 3, 5, 8, 10, and 12) of weeks 1 and 2 of each 21-day cycle for eight cycles plus bortezomib and dexamethasone; consider continuing treatment for an additional eight cycles for patients with clinical benefit, unless they have unresolved severe or medically significant toxicity^[36]
Carfilzomib, a proteasome inhibitor, is indicated as monotherapy, in combination with dexamethasone, or in combination with lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma in patients who have received at least 1 prior line of therapy.^{[37, 38, 39]} (See below.)
Pomalidomide is a thalidomide analogue indicated for patients who have received at least two prior therapies (including lenalidomide and bortezomib) and have disease progression on or within 60 days of completion of the last therapy^[40]; pomalidomide dosage is 4 mg PO QD on days 1-21 of repeated 28-day cycles until disease progression; may be given in combination with dexamethasone
Daratumumab is indicated as monotherapy for patients who have received at least 3 prior treatments, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or whose disease is refractory to both a PI and an IMiD; dosage is 16 mg/kg IV infusion once weekly (weeks 1-8); reduce frequency to q2wk (weeks 9-24) and ultimately q4wk (week 25 and thereafter) until disease progression; dosing schedule is for combination therapy with lenalidomide or pomalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma and also for monotherapy^{[41, 42, 43, 44]}
Daratumumab is also indicated in combination with bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least 1 prior therapy; dosage is 16 mg/kg IV infusion once weekly (weeks 1-9); reduce frequency to q3wk (weeks 10-24) and ultimately q4wk (week 25 and thereafter) until disease progression^{[14, 45, 44]}
Ixazomib (Ninlaro) is a reversible proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for patients with multiple myeloma who have received at least 1 prior therapy; starting dose is 4 mg PO on days 1, 8, and 15 of a 28-day cycle until disease progression^[46] (See below.)
Elotuzumab (Empliciti) is a humanized IgG1 monoclonal antibody targeting SLAMF7 indicated in combination with lenalidomide and dexamethasone for multiple myeloma in patients who have received 1-3 prior therapies; the dose is 10 mg/kg IV weekly for the first two 28-day cycles, and then 10 mg/kg IV q2wk (on days 1 and 15)^[47]
Elotuzumab is also indicated in combination with pomalidomide and dexamethasone for multiple myeloma in patients who have received 2 or more prior therapies including lenalidomide and a proteasome inhibitor; the dose is 10 mg/kg IV weekly for the first two 28-day cycles, and then 20 mg/kg IV on Day 1 of each cycle starting with cycle 3^[48]
Isatuximab, an anti-CD38 monoclonal antibody, is indicated in combination with pomalidomide and dexamethasone in patients who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor; the isatuximab dose is 10 mg/kg actual body weight IV once weekly (cycle 1), and then every 2 weeks (cycles 2 and thereafter) plus pomalidomide 4 mg PO once daily on days 1-21 plus dexamethasone 40 mg PO/IV on days 1, 8, 15, and 22 of each 28-day cycle^[49]

Ixazomib/cyclophosphamide/dexamethasone (treatment option for patients with kidney failure and neuropathy) ^[50]:

Ixazomib 4 mg PO on days, 1, 8, and 15 plus cyclophosphamide 400 mg/m ² on days 1, 8, 15, and 22 plus dexamethasone 40 mg PO on days 1, 8, 15, and 22; 28-d cycle for four cycles

Carfilzomib/lenalidomide/dexamethasone (KRD, CRd, preferred in high-risk myeloma)^[38]:

Carfilzomib on days 1, 2, 8, 9, 15, and 16 during cycles one through 12 (starting dose, 20 mg/m ²10-minute IV infusion on days 1 and 2 of cycle one; target dose, 27 mg/m ²thereafter) and on days 1, 2, 15, and 16 during cycles 13 through 18, after which carfilzomib is discontinued plus lenalidomide 25 mg PO on days 1 through 21 plus dexamethasone 40 mg PO on days 1, 8, 15, and 22; 28-d cycle, repeat until disease progression or unacceptable toxicity
Carfilzomib on days 1, 2, 8, 9, 15, and 16 during cycles one through 12 (starting dose, 20 mg/m ²10-minute IV infusion on days 1 and 2 of cycle one; target dose, 36 mg/m ²thereafter) and on days 1, 2, 15, and 16 in cycles 13 through 18, after which carfilzomib is discontinued plus lenalidomide 25 mg PO on days 1 through 21 plus dexamethasone 20 mg PO on days 1, 2, 8, 9, 15, 16, 22, and 23; 28-d cycle, repeat until disease progression or unacceptable toxicity

Carfilzomib/cyclophosphamide/dexamethasone (treatment option for patients with kidney failure and neuropathy)

Carfilzomib 20 mg/m ² on days 1 and 2; if tolerated, escalate to 56 mg/m ² on days 8, 9, 15, and 16 plus cyclophosphamide 300 mg/m ²/day PO on days 1, 8, 15 plus dexamethasone 20 mg PO on days 1, 2, 8, 9, 15, 16, 22, and 23 in cycles one through eight; 28-d cycle, repeat until disease progression or unacceptable toxicity

Regimens for relapsed/refractory patients who received 4 or more prior therapies

Selinexor is indicated in combination with dexamethasone for adults with relapsed or refractory multiple myeloma who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody.^{[51, 52]}The regimen comprises selinexor 80 mg PO plus dexamethasone 20 mg PO on Days 1 and 3 of each week; continue until disease progression or unacceptable toxicity.

Belantamab mafodotin is indicated for relapsed or refractory multiple myeloma in patients who were previously treated with 4 or more prior therapies:

Belantamab mafodotin 2.5 mg/kg (actual body weight) IV q3wk; continue until disease progression or unacceptable toxicity. ^[53]

Teclistamab is indicated for relapsed or refractory multiple myeloma in adults who have received > 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.^[54]It is given on a step-up dosing schedule, as follows:

Administer pretreatment medications 1-3 hr before each step-up dose to reduce risk of cytokine release syndrome (CRS)
Day 1 (step-up dose 1): 0.06 mg/kg SC × 1 dose
Day 4 (step-up dose 2): 0.3 mg/kg SC ×1 dose; may give 2-4 days after step-up dose 1 or up to 7 days after step-up dose 1 to allow adverse reactions to resolv
Day 7 (first treatment dose): 1.5 mg/kg SC × 1 dose; may give 2-4 days after step-up dose 2 or up to 7 days after step-up dose 2 to allow adverse reactions to resolve

Subsequent treatment doses are as follows:

Pretreatment medications may be required prior to administration of subsequent doses for patients who repeated doses within the step-up schedule following a dose delay or who experienced CRS following prior dose
One week after first treatment dose and weekly thereafter: 1.5 mg/kg SC once weekly

Chimeric antigen receptor (CAR) T-cell therapy

Idecabtagene vicleucel is indicated for relapsed or refractory multiple myeloma after ≥4 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.^[55]Confirm availability of idecabtagene vicleucel before starting lymphodepleting chemotherapy. One treatment course consists of fludarabine- and cyclophosphamide-lymphodepleting chemotherapy followed by IV infusion of idecabtagene vicleucel. Lymphodepleting chemotherapy comprises the following:

Fludarabine 30 mg/m ² IV qDay for 3 days
Cyclophosphamide 300 mg/m ² IV qDay for 3 days starting with the first dose of fludarabine

Idecabtagene vicleucel IV infusion:

Administer 2 days after completing lymphodepleting chemotherapy
Premedicate with acetaminophen and diphenhydramine
Dose based on the number of CAR-positive viable T cells
Recommended dose range: 300-460 × 10 ⁶ CAR-positive viable T cells
Administer autologously prepared IV infusion for individual patient within 30 minutes by either gravity or peristaltic pump

Ciltacabtagene autoleucel (Carvykti) is indicated for relapsed or refractory multiple myeloma after ≥4 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.^[56]Confirm availability of ciltacabtagene autoleucel before starting lymphodepleting chemotherapy. One treatment course consists of fludarabine- and cyclophosphamide-lymphodepleting chemotherapy followed by IV infusion of ciltacabtagene autoleucel, as follows:

Administer 2-4 days after completing lymphodepleting chemotherapy
Premedicate with acetaminophen and diphenhydramine
Dose based on the number of CAR-positive viable T cells
Recommended dose range: 0.5-1 × 10 ⁶ CAR-positive viable T cells per kg of body weight

Adverse effects

Toxicity concerns in the treatment of patients with multiple myeloma include kidney impairment, thrombosis, infection, and skeletal events.

Kidney impairment:

The treatment of patients with kidney impairment from myeloma can be daunting due to concerns about clearance of drugs and further injury from treatment or diagnostic studies. Proteasome inhibitors are the preferred choice due to their safety profile in kidney failure.
A working group consensus statement has clarified that autologous transplantation is not absolutely contraindicated in patients with kidney impairment, but it should be reserved for younger patients with chemosensitive disease^[57]
Because kidney involvement is common in myeloma, the use of nephrotoxic agents—most notably, nonsteroidal anti-inflammatory drugs (NSAIDs) and IV contrast agents—should be minimized or avoided

Thrombosis

Anticoagulation is advised in patients receiving either thalidomide or lenalidomide regimens, due to the high incidence of venous thrombosis observed.^[58] A guideline from the American Society of Clinical Oncology recommends that patients who are receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone be offered prophylaxis with either aspirin or low molecular weight heparin (LMWH) if they are at lower risk, or with LMWH if they are at higher risk.^[59]

Infection

Measures to prevent infection include the following:

Pneumococcal infections are common in patients with multiple myeloma, especially during the first 3 mo of treatment, so vaccination should be completed at the time of diagnosis to minimize preventable illness.
Antiviral prophylaxis for herpes infections is recommended for patients receiving bortezomib; low-dose acyclovir appears to be sufficient.^[60]
Antiviral, antiparasitic (Pneumocystis jirovecii pneumonia [PCP]), and antifungal prophylaxis should be considered for patients receiving high-dose steroid regimens.

Skeletal events

Bisphosphonate treatment (eg, zoledronate) has been demonstrated in placebo-controlled studies to decrease the occurrence of skeletal-related events (defined as spinal cord compression, need for surgery, need for radiation, hypercalcemia, and pathologic fracture) in patients with myeloma bone disease. The exact duration of therapy and the role of these agents in patients without known bony disease remain ill defined.

Spinal cord compression is a common complication of multiple myeloma, occurring in as many as 20% of patients at some point during the course of their illness; a high index of suspicion is the key to diagnosis (although magnetic resonance imaging [MRI] is typically required to confirm). Physicians should be aware of the high frequency of multiple concurrent levels of compression and should screen accordingly.

Denosumab is approved by the US Food and Drug Administration for prevention of skeletal-related events (SREs) in patients with multiple myeloma. Denosumab is a human monoclonal antibody targeting and binding to RANKL; osteoclast-activating factors such as RANKL are implicated in an increased risk for SREs with multiple myeloma.

A phase III trial in 1718 patients with bone metastases found that denosumab was noninferior to zoledronic acid and showed an advantage in significantly reducing the risk for renal adverse events. A post hoc analysis at 15 months was also conducted, since many of the skeletal-related events (60%) occurred early, within 3 months, which led the authors to speculate that the data reflected events occurring before the treatment had enough time to take effect. Results did show superiority of denosumab (n = 450) over zoledronic acid (n = 459) in terms of time to the first SRE (hazard ratio [HR], 0.66; P = 0.039). Median PFS with denosumab versus zoledronic acid was 46.09 versus 35.38 months, respectively (HR, 0.82; P = 0.036). No difference in overall survival was noted between the treatment groups.^[61]

Questions & Answers

Overview

How does stem cell transplantation affect other treatment decisions in patients with multiple myeloma?

Which induction therapy regimens are used for primary therapy in patients with multiple myeloma who are transplant candidates?

What are the maintenance therapy regimens following stem cell transplant for multiple myeloma?

How is relapsed multiple myeloma treated in patients who have received a stem cell transplantation?

Which induction therapy regimens are used for primary therapy in patients with multiple myeloma who are not transplant candidates?

How are stem cells collected for transplantation in patients with multiple myeloma (MM)?

Which regimens are used for maintenance therapy in multiple myeloma?

Which salvage therapy regimens are used in the treatment of multiple myeloma?

How is multiple myeloma treated in patients with renal impairment?

What is the role of anticoagulation therapy in the treatment of multiple myeloma?

How are infections prevented in patients with multiple myeloma?

How are skeletal-related events (SREs) prevented in multiple myeloma?

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Author

Attaya Suvannasankha, MD Associate Professor of Clinical Medicine, Division of Hematology and Oncology, Indiana University School of Medicine; Staff Physician in Medicine Service/Hematology, Roudebush Veterans Administration Medical Center

Attaya Suvannasankha, MD is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, Central Society for Clinical and Translational Research

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Janssen Oncology, Karyopharm<br/>Received research grant from: Janssen Oncology, Celgene, Bristol Myer Squib, Glaxo Smith Klein.

Coauthor(s)

Sara J Grethlein, MD, MBA, FACP Executive Medical Director and Medical Oncologist, Swedish Cancer Institute

Sara J Grethlein, MD, MBA, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Women's Association, American Society of Clinical Oncology, American Society of Hematology, Gold Humanism Honor Society, Leukemia and Lymphoma Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Christopher D Braden, DO Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee

Christopher D Braden, DO is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.