Multiple Myeloma Treatment Protocols 

Multiple Myeloma Treatment Protocols 

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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

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:

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

A single autologous stem cell transplant has been associated with superior event-free survival compared with chemotherapy and is considered the preferred approach [1]

As newer agents (bortezomib, thalidomide, and lenalidomide) are studied, the role of transplantation will continue to evolve

Induction chemotherapy followed by autologous stem cell support is widely used as treatment in patients with multiple myeloma; however, there is growing evidence that only the subset of patients who achieve complete remission (CR) actually benefit from this approach [2]

Complete remission is defined as negative serum and urine immunofixation, disappearance of soft-tissue plasmacytomas, and < 5% plasma cells in bone marrow [3]

Patients who present with active (symptomatic) multiple myeloma are treated with induction therapy. [3] Any one of the combination regimens below, most of them based on bortezomib, may be used for induction therapy.

Bortezomib/cyclophosphamide/dexamethasone

This combination may be used in any of the following regimens:

Bortezomib 1.3 mg/m2 IVP 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 [4, 5, 6]

Bortezomib 1.3 mg/m2 IVP 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 [4, 5, 6]

Bortezomib 1.3 mg/m2 IVP 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 [4, 5, 6] or

Bortezomib/dexamethasone

Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 plus  dexamethasone 40 mg PO on days 1-4 and days 9-12 (cycles 1 and 2), then 40 mg PO on days 1-4 (cycles 3 and 4); 21-d cycle for three or four cycles [7, 8]

Bortezomib/doxorubicin/dexamethasone

Either of the following two regimens may be used:

Bortezomib 1.3 mg/m2 IVP 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 [9, 10]

Bortezomib 1.3 mg/m2 IVP 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 [9, 10] or

Bortezomib/lenalidomide/dexamethasone

Bortezomib 1.3 mg/m2 IVP 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 [11, 12]

Bortezomib/thalidomide/dexamethasone

Bortezomib 1-1.3 mg/m2 IVP 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 [13, 14]

Lenalidomide/dexamethasone

Either of the following two regimens may be used:

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 [15, 16]

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 [15, 16]

Alternative regimens

Any of the following four regimens may be used:

Dexamethasone 40 mg/day for 4 d beginning on days 1, 9, and 17 for the first two cycles and 40 mg/day for 4 d beginning on day 1 for the next 10 cycles [17] ; every 6 wk for 12 cycles

Pegylated liposomal doxorubicin 40 mg/m2plus vincristine 1.4 mg/m2 (maximum, 2.0 mg) as an IV infusion on day 1 plus  reduced-dose dexamethasone 40 mg PO on days 1-4 [18]

Lenalidomide 25 mg PO on days 1-21 plus  dexamethasone 40 mg daily on days 1-4, 9-12, and 17-20; every 28 d [18]

Thalidomide 200 mg PO daily plus  dexamethasone 40 mg PO on days 1-4 and 15-18 on even cycles and on days 1-4 on odd cycles; every 28 d [19]

Once a remission has been achieved, stem cells are harvested via apheresis. This is commonly carried out with the use of high-dose cyclophosphamide with growth factors, although it can be done with stem cells alone. 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. [1, 20]

Recommendations are as follows:

A second (tandem) autologous stem cell transplant is recommended 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 [2, 21, 22]

One of the following six regimens may be used:

Bortezomib 1-1.3 mg/m2 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 for five cycles [23]

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 [24, 25]

Lenalidomide 25 mg PO on days 1-21 plus  dexamethasone 40 mg PO daily on days 1-4, 9-12, and 17-20; every 28 d [18]

Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 every 3 wk plus  dexamethasone 20 mg on the day of and the day after bortezomib [26]

Twelve 6-wk cycles of chemotherapy, including melphalan 0.25 mg/kg PO plus  prednisone 2 mg/kg PO for 4 d [27]

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

Alternative treatment recommendations

One of the following may be used:

Pegylated liposomal doxorubicin 40 mg/mplus  vincristine 1.4 mg/m2 (maximum, 2.0 mg) as an IV infusion on day 1 plus  reduced-dose dexamethasone 40 mg PO on days 1-4 [28]

Vincristine 0.4 mg/day plus  doxorubicin 9 mg/m2/day by continuous infusion on days 1-4 plus  dexamethasone 40 mg/day on days 1-4, 9-12, and 17-20 (odd cycles) and 40 mg/day for 4 d on even cycles; every month [29]

Thalidomide may be added to standard regimens in patients with myeloma who are not transplant candidates; a meta-analysis of trials demonstrated improved survival with this approach [30]

Once the best remission has been achieved, maintenance therapy with lenalidomide or thalidomide, with or without steroids, can prolong remission, although not survival. Newer studies are defining the role of bortezomib-based maintenance therapy. [31] The American Society of Hematology has published evidence-based guidelines addressing this question. [32] Regimens are as follows:

Lenalidomide 10 mg/day on days 1-21 every 28d [33] or

Thalidomide 50 mg/day to start, escalated to 200 mg/day, titrated to tolerance [34]

Salvage therapy is used in the following [3] :

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, as well as the following:

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 [35]

Lenalidomide 25 mg/day PO on days 1-21 plus dexamethasone 40 mg/day PO on days 1-4, 9-12, and 17-20 of each 28-d cycle for the first four cycles of therapy and then 40 mg/day PO on days 1-4 thereafter, every 28 d, has been approved for patients with multiple myeloma who have received at least one prior treatment

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 [36] ; 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

Carfilzomib (Kyprolis), 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, 47]

Lenalidomide or thalidomide can be used as single agents in salvage therapy

Daratumumab (Darzalex) is an anti-CD38 monoclonal antibody. It 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 to 8); reduce frequency to q2wk (weeks 9-24) and ultimately q4wk (week 25 and thereafter) until disease progression [39, 40]

Daratumumab is also indicated in combination with lenalidomide and dexamethasone, or 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 to 9); reduce frequency to q3wk (weeks 10-24) and ultimately q4wk (week 25 and thereafter) until disease progression [3, 48, 49]

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 [41]

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) [42]

Elotuzumab is also indicated in combination with pomalidomide and dexamethasone for MM 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 [52]

Concerns in the treatment of patients with multiple myeloma include renal impairment, thrombosis, infection, and skeletal events.

Renal impairment

Considerations are as follows:

The treatment of patients with renal impairment from myeloma can be daunting due to concerns about clearance of drugs and further injury from treatment or diagnostic studies

In patients with case nephropathy, the combination of bortezomib and high-dose dexamethasone is the preferred therapy

A working group consensus statement has clarified that autologous transplantation is not absolutely contraindicated in patients with renal impairment, but it should be reserved for younger patients with chemosensitive disease [43]

Because of the common occurrence of renal involvement 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. [44]

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; 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 [45]

Antiviral, antiparasitic (Pneumocystis jiroveci 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.

In January 2018, denosumab was approved by the FDA for prevention of skeletal-related events (SREs) in patients with multiple myeloma. It was originally indicated for SREs in patients with solid tumors. Denosumab, 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.

In a phase 3 trial of denosumab compared with zoledronic acid in patients (n=1718) with bone metastases, denosumab was noninferior 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 the endpoint of time to the first SRE (hazard ratio [HR], 0.66; P = 0.039). Median progression-free survival showed difference of more than 10 months was observed between the denosumab (46.09 months) and zoledronic acid (35.38 months) groups (HR, 0.82; P = 0.036). No difference in overall survival was noted between the treatment groups. [50]

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Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, et al. Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. N Engl J Med. 2018 Nov 8. 379 (19):1811-1822. [Medline].

Sara J Grethlein, MD Associate Dean for Undergraduate Medical Education, Indiana University School of Medicine

Sara J Grethlein, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Hematology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

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.

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.

Multiple Myeloma Treatment Protocols 

Research & References of Multiple Myeloma Treatment Protocols |A&C Accounting And Tax Services
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