Multiple Myeloma Treatment Protocols 

Updated: Aug 19, 2020
Author: Attaya Suvannasankha, MD; Chief Editor: Emmanuel C Besa, MD 

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 to 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 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) 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
  • Subcutaneous administration of bortezomib can be considered when neuropathic adverse effects are a concern.

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

  • Bortezomib 1.3 mg/m 2 SC on days 1, 4, 8, and 11  plus  thalidomide 100 mg PO daily plus  oral or intravenous 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 renal insufficiency. It may be used in any of the following regimens[15, 16, 17] :

  • Bortezomib 1.3 mg/m2 IVP on days 1, 4, 8, and 11 pluscyclophosphamide 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 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 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 on days 1, 4, 8, and 11 plusdoxorubicin 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 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/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[20, 21]

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[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 IV 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 2 SC 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 2 PO 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 renal insufficiency)[15, 16, 17] :

  • Bortezomib 1.3 mg/m 2 IVP 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 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 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 IV 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 on days 1, 4, 8, 11, 22, 25, 29, and 32, followed by a 10-d rest period plus melphalan 9 mg/m2 PO plusprednisone 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 renal 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 therapyosage is 16 mg/kg IV infusion once weekly (weeks 19); 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 renal 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 10-minute IV infusion on days 1 and 2 of cycle  one; target dose, 27 mg/m thereafter) 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 10-minute IV infusion on days 1 and 2 of cycle one; target dose, 36 mg/m thereafter) 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 renal 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

Penta-refractory regimen

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]

Adverse effects

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

Renal impairment:

  • 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. Proteasome inhibitors are the preferred choice due to their safety profile in renal failure. 

  • 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[54]

  • 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.[55]  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.[56]

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.[57]

  • 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.

In January 2018, denosumab was approved by the US Food and Drug Administration for prevention of skeletal-related events (SREs) in patients with multiple myeloma. It was originally indicated for SREs in patients with solid tumors. 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.[58]

 

Questions & Answers