Key Points
- In 2018, an estimated 30,770 new cases of multiple myeloma will be diagnosed in the United States, representing 1.8% of all new cancer cases.
- The estimated number of deaths from multiple myeloma in 2018 is 12,770, representing 2.1% of all cancer deaths.
- Despite significant advances and improvements in overall survival, multiple myeloma remains incurable and additional treatments are needed.
- The median survival is just over 5 years and most patients receive 4 or more different lines of therapy throughout their disease course.
Treatment
Transplant Eligible
- Patients should be referred to a transplant center to determine transplant eligibility. (Moderate Recommendation; EB-I-B)
- Chronologic age and renal function should not be the sole criteria used to determine eligibility for stem cell transplantation (SCT). (Moderate Recommendation; EB-I-B)
- The optimal regimen and number of cycles remain unproven. However, at least 3-4 cycles of induction therapy including an immunomodulatory drug, proteasome inhibitor and steroids is advised prior to stem cell collection. (Moderate Recommendation; EB-I-B)
- Upfront transplant should be offered to all transplant-eligible patients. Delayed initial SCT may be considered in select patients. (Strong Recommendation; EB-H-B)
- Agents associated with stem cell toxicity, such as melphalan and/or prolonged immunomodulatory drugs exposure (more than 4 cycles), should be avoided in patients who are potential candidates for SCT. (Moderate Recommendation; EB-I-B)
- Ample stem cell collection (sufficient for more than one SCT) should be considered upfront, due to concern for limited ability for future stem cell collection after prolonged treatment exposure. (Moderate Recommendation; EB-I-B)
- The level of minimal response required to proceed to SCT is not established for patients receiving induction therapy – patients should be referred for SCT independent of depth of response. (Moderate Recommendation; EB-I-B)
- High-dose melphalan is the recommended conditioning regimen for Auto SCT. (Strong Recommendation; EB-H-B)
- Tandem autologous SCT should not be routinely recommended. (Strong Recommendation; EB-I-B/H)
- Salvage or delayed SCT may be used as consolidation at first relapse for those not choosing to proceed to transplant initially. (Moderate Recommendation; EB-I-B)
- Allogeneic transplant for multiple myeloma is not routinely recommended but may be considered in select high risk patients or in the context of a clinical trial. (Strong Recommendation; EB-I-B)
- Consolidation therapy is not routinely recommended but may be considered in the context of a clinical trial. For patient’s ineligible or unwilling to consider maintenance therapy, consolidation therapy for at least 2 cycles may be considered. (Moderate Recommendation; EB-I-B)
- Lenalidomide maintenance therapy should be routinely offered to standard risk patients starting at approximately day 90-110 at 10-15 mg daily until progression. A minimum of 2 years of maintenance therapy is associated with improved survival, and efforts to maintain therapy for at least this duration are recommended. (Strong Recommendation; EB-H-B)
- For patients intolerant of or unable to receive lenalidomide, bortezomib maintenance every 2 weeks may be considered. (Moderate Recommendation; IC/EB-L/I-B)
- For high-risk patients, maintenance therapy with a proteasome inhibitor +/- lenalidomide may be considered. (Moderate Recommendation; IC/EB-L/I-B)
- There is insufficient evidence to make modifications to maintenance therapy based on depth of response, including minimal residual disease (MRD) status. (Moderate Recommendation; IC/EB-L/I-B)
- The quality and depth of response should be assessed by IMWG (International Myeloma Working Group) criteria. (Strong Recommendation; EB-H-B)
- The goal of initial therapy for transplant eligible patients should be achievement of the best depth of remission. MRD negative status has been associated with improved outcomes, but it should not be used to guide treatment goals outside the context of a clinical trial. (Moderate Recommendation; EB-H-B)
- It is recommended that depth of response be assessed with each cycle. Frequency of assessment once best response is attained or on maintenance therapy may be assessed less frequently but at minimum every 3 months. (Weak Recommendation; EB-L-B)
- Whole-body low dose CT scan has been shown to be superior to skeletal survey done with plain x-rays and is the preferred method for baseline and routine bone surveillance. FDG-PET/CT and/or MRI may be used as alternatives at baseline. They may also be used in select situations (e.g. risk stratifying smoldering myeloma, for monitoring response of non-secretory and oligosecretory myeloma and if CT or skeletal survey is inconclusive). (Moderate Recommendation; EB-H-B)
Transplant Ineligible
- Initial treatment recommendations for patients with multiple myeloma who are transplant ineligible should be individualized based on shared decision-making between physicians and patients. Multiple factors should be considered; disease-specific factors such as stage and cytogenetic abnormalities, patient-specific factors including age, comorbidities, functional status, frailty status and patient preferences should also be considered. (Strong Recommendation; EB-I-B)
- Initial treatment for patients with multiple myeloma who are transplant ineligible should include at minimum a novel agent (immunomodulatory drug or proteasome inhibitor) and a steroid if possible. (Strong Recommendation; EB-H-B)
- Triplet therapies for patients with multiple myeloma who are transplant ineligible, including bortezomib-lenalidomide-dexamethasone should be considered. Daratumumab + bortezomib + melphalan + prednisone may also be considered. (Strong Recommendation; EB-H-B)
- Physicians/patients should balance the potential improvement in response and disease control with a possible increase in toxicity. Initial dosing should be individualized based on patient age, renal function, comorbidities, functional status and frailty status. Subsequent dosing may be tailored based on initial response and tolerability. (Moderate Recommendation; EB-I-B)
- Continuous therapy should be offered over fixed duration therapy when initiating an immunomodulatory drug or proteasome inhibitor-based regimen. (Strong Recommendation; EB-H-B)
- The goal of initial therapy for transplant ineligible patients should be achievement of the best quality and depth of remission. (Moderate Recommendation; EB-I-B)
- Depth of response for all patients should be assessed by IMWG criteria (Table 5) regardless of transplant eligibility. (Moderate Recommendation; EB-H-B)
- There is insufficient evidence to support change in type and length of therapy based on depth of response as measured by conventional IMWG approaches or MRD. (Moderate Recommendation; IC-L-H)
- Upon initiation of therapy, one should define patient specific goals of therapy. Quality of life assessment (including symptom management and tolerability of treatment) should be assessed at each visit to determine if the goals of therapy are being maintained/met and this should influence the intensity and duration of treatment. Redefining the goals prospectively, based on response, symptoms and quality of life is recommended. (Moderate Recommendation; IC-L-B)
- It is recommended that patients be monitored closely with consideration of dose modifications based on levels of toxicity, neutropenia, fever/infection, tolerability of side effects, performance status, liver and kidney function and in keeping with the goals of treatment. (Moderate Recommendation; IC-L-B)
Relapsed Disease
- Treatment for biochemically relapsed myeloma should be individualized. Factors to consider include patient’s tolerance of prior treatment, rate of rise of myeloma markers, cytogenetic risk, presence of comorbidities (i.e. renal insufficiency), frailty, and patient preference. High-risk patients as defined by high-risk cytogenetics and early relapse post-transplant/initial therapy should be treated immediately. Close observation is appropriate for patients with slowly progressive and asymptomatic relapse. (Moderate Recommendation; IC/EB-I-B)
- All clinically relapsed patients with symptoms due to myeloma should be treated immediately. (Strong Recommendation; EB-H-B)
- Triplet therapy should be administered on first relapse, though the patient’s tolerance for increased toxicity should be considered. A triplet is defined as a regimen with two novel agents (proteasome inhibitors, immunomodulatory drugs or monoclonal antibodies). (Strong Recommendation; EB-H-B)
- Treatment of relapsed multiple myeloma may be continued until disease progression. There is not enough data to recommend risk based versus response-based duration of treatment (such as MRD). (Moderate Recommendation; EB-I-B)
- Prior therapies should be taken into consideration when selecting the treatment at first relapse. A monoclonal antibody-based regimen in combination with an immunomodulatory drugs and/or proteasome inhibitor should be considered. Triplet regimens are preferred based on tolerability and comorbidities. (Moderate Recommendation; EB-L-B)
- Autologous stem cell transplantation, if not received after primary induction therapy, should be offered to transplant eligible patients with relapsed multiple myeloma. Repeat stem cell transplant may be considered in relapsed multiple myeloma if PFS after first transplant is 18 months or greater. (Weak Recommendation; EB-L-B)
- The risk status of the patients should be assessed using the Revised ISS staging system for all patients at the time of diagnosis. (Strong Recommendation; EB-H-B)
- Repeat risk assessment at the time of relapse should be performed and should include bone marrow with FISH for myeloma abnormalities seen with progression including, 17p and 1q abnormalities. FISH for primary abnormalities (translocations and trisomies), if seen in the initial diagnostic marrow, does not need to be repeated. (Strong Recommendation; EB-H-B)
- Assessment of other risk factors such as renal insufficiency, age, presence of plasma cell leukemia, circulating plasma cells, extramedullary disease and frailty, should also be considered/performed. (Strong Recommendation; EB-H-B)
- In patients with genetic high-risk disease a triplet combination of proteasome inhibitor, immunomodulatory drug and a steroid should be the initial treatment, followed by one or two autologous SCT, followed by a proteasome inhibitor-based maintenance until progression. (Strong Recommendation; EB-H-B)
- In patients with renal insufficiency, drugs should be modified based on renal clearance. (Strong Recommendation; EB-H-B)
- In patients with plasma cell leukemia or extra medullary disease, cytotoxic chemotherapy may have a role. (Moderate Recommendation; EB-I-B)
- The IMWG revised response criteria should be used for response assessment. (Strong Recommendation; EB-H-B)
- All measurable parameters need to be followed including light and heavy chain analysis. (Strong Recommendation; EB-H-B)
- All responses excluding marrow and imaging should be confirmed as per IMWG criteria. (Strong Recommendation; EB-H-B)
- Response assessment should be performed after one cycle of therapy, and once a response trend is observed it may be done every other cycle and less frequently once patient is in a plateau. (Strong Recommendation; EB-H-B)
Figure 1. Algorithm On Management of Patients with Multiple Myeloma
1 Agents associated with stem cell toxicity, such as melphalan and/or prolonged immunomodulatory drugs exposure (more than 4 cycles), should be avoided in patients who are potential candidates for SCT.2Ample stem cell collection (sufficient for more than one SCT) should be considered upfront, due to concern for limited ability for future stem cell collection after prolonged treatment exposure.
3 The level of minimal response required to proceed to SCT is not established for patients receiving induction therapy — patients should be referred for SCT independent of depth of response.
4 Tandem autologous SCT should not be routinely recommended.
5 For patient’s ineligible or unwilling to consider maintenance therapy, consolidation therapy for at least 2 cycles may be considered.
6 For patients intolerant of or unable to receive lenalidomide, bortezomib maintenance every 2 weeks may be considered. For high-risk patients, maintenance therapy with a proteasome inhibitor +/- lenalidomide may be considered.
7 Initial dosing should be individualized based on patient age, renal function, comorbidities, functional status and frailty status. Subsequent dosing may be tailored based on initial response and tolerability.
8 Depth of response for all patients should be assessed by IMWG criteria.
9 Prior therapies should be taken into consideration when selecting the treatment at first relapse.
Table 1. Drugs Used in the Management of Patients With Multiple Myeloma
| Agent | Route | Dose | Schedule |
|---|---|---|---|
| Immunomodulatory drugs | |||
| Thalidomide | Oral | 50–200 mg | Daily |
| Lenalidomide | Oral | 5–25 mg | Daily for 21/28 days |
| Pomalidomide | Oral | 1–4 mg | Daily for 21/28 days |
| Proteasome Inhibitors | |||
| Bortezomib | Subcutaneous/ intravenous | 0.7–1.6 mg/m2 | 1–2x weekly |
| Carfilzomib | Intravenous | 20–70 mg/m2 | 1–2x weekly for 3–4 weeks |
| Ixazomib | Oral | 2.3–4 mg | Weekly for 3–4 weeks |
| Monoclonal antibodies | |||
| Daratumumab | Intravenous | 16 mg/kg | Weekly → every 2 weeks → monthly |
| Elotuzumab | Intravenous | 10 mg/kg | Weekly → every 2 weeks |
| Alkylators | |||
| Cyclophosphamide | Oral | 50 mg–500 mg/m2 | Daily Weekly |
| Melphalan | Oral | 9 mg/m2 | Daily × 4 days/cycle |
| Melphalan | Intravenous | 140–200 mg/m2 | Once for transplant |
| HDAC Inhibitors | |||
| Panobinostat | Oral | 10-20 mg | 3x weekly |
| Steroids | |||
| Dexamethasone | Oral | 20–40 mg | Weekly |
| Prednisone | Oral | 25–50 mg | Every other day |
| Anthracyclines | |||
| Doxorubicin HCl Liposomal | Intravenous | 30 mg/m2 | Every 3 weeks |
Table 2. Diagnostic Criteria for Active Multiple Myeloma
| 2014 IMWG Criteria |
|
| NEW Additional Criteria |
|
Table 3. Revised International Staging System (R-ISS)
|
Table 4. Comparison of Select Risk Prediction Models Relevant To Older Adults With Multiple Myeloma
| Factors associated with increased risk | International Myeloma Working Group | Revised-Myeloma Comorbidity Index | Geriatric Assessment in Hematology Scale | |||
|---|---|---|---|---|---|---|
| Parameter | pts | Parameter | pts | Parameter | pts | |
| Age | Age 76–80 | 1 | 60–69 | 1 | – | |
| Age >80 | 2 | ≥70 | 2 | – | ||
| Performance/ Functional status | Any ADL dependence | 1 | KPS 80–90 | 2 | Gait speed ≤0.8m/s | 1 |
| Any IADL dependence | 1 | KPS <70% | 3 | Any ADL dependence | 1 | |
| Comorbidities | Charlson Comorbidity Index ≥ 2 | 1 | Renal disease: eGFR<60 | 1 | Diabetes, BMI 25kg/m2 or Cancer, lung disease, heart failure or smokinga | 1 |
| Mod-severe pulmonary disease | 1 | |||||
| Medications/ polypharmacy | – | – | ≥5 medications | 1 | ||
| Nutrition | – | – | ≤8 on MNA-SF | 1 | ||
| Cognition | – | – | ≥3 error on SPMSQ | 1 | ||
| Psychosocial | – | – | Felt depressed 3–7 days of past week | 1 | ||
| Other | – | Moderate/severe frailty phenotype | 1 | Self-reported health fair or poor | 1 | |
| Cytogenetics | – | Unfavorable | 1 | – | ||
| Total score | Fit | 0 | Fit | 0–3 | Range | 0–8 |
| Intermediate fit | 1 | Intermediate | 4–6 | |||
| Frail | 2 | Frail | 7–9 | |||
Table 5. IMWG Response Criteria
| Response | IMWG criteria1 |
|---|---|
| sCR | CR as defined below plus normal free light chain (FLC) ratio and absence of clonal cells in bone marrow2 by immunohistochemistry or immunofluorescence3 |
| CR | Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow2 |
| VGPR | Serum and urine M-protein detectable by immunofixation but not on electrophoresis or >90% reduction in serum M-protein plus urine M-protein level <100 mg/24 h |
| PR | ≥50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by ≥90% or to <200 mg/24 h If the serum and urine M-protein are unmeasurable,4 a ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria If serum and urine M-protein are not measurable, and serum free light assay is also not measureable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30% In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is also required |
| MR | NA |
| No change/Stable disease | Not meeting criteria for CR, VGPR, PR, or progressive disease |
| Plateau | NA |
| Progressive disease4 | Increase of ≥25% from lowest response value in any one or more of the following:
|
| Relapse | Clinical relapse requires one or more of: Direct indicators of increasing disease and/or end organ dysfunction (CRAB features).5 It is not used in calculation of time to progression or progression-free survival but is listed here as something that can be reported optionally or for use in clinical practice
|
| Relapse from CR4 (To be used only if the end point studied is DFS)7 | Any one or more of the following:
|
1 A clarification to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is by serum FLC levels: CR in such patients is defined as a normal FLC ratio of 0.26/1.65 in addition to CR criteria listed above. VGPR in such patients is defined as a >90% decrease in the difference between involved and uninvolved free light chain (FLC) levels.
2 Confirmation with repeat bone marrow biopsy not needed.
3 Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is kappa/lambda of >4:1 or <1:2.
4 All relapse categories require two consecutive assessments made at anytime before classification as relapse or disease progression and/or the institution of any new therapy. In the IMWG criteria, CR patients must also meet the criteria for progressive disease shown here to be classified as progressive disease for the purposes of calculating time to progression and progression-free survival. The definitions of relapse, clinical relapse and relapse from CR are not to be used in calculation of time to progression or progression-free survival.
5 For progressive disease, serum M-component increases of ≥1 gm/dL are sufficient to define relapse if starting M-component is ≥5 g/dL.
6 Relapse from CR has the 5% cut-off versus 10% for other categories of relapse.
7 For purposes of calculating time to progression and progression-free survival, CR patients should also be evaluated using criteria listed above for progressive disease.
Table 6. Estimated Cost of Drugs for Multiple Myeloma
| Approximate Drug Cost per Year1 (in U.S. Dollars) | Comment | |
|---|---|---|
| Drugs | ||
| Thalidomide | 60,000 | |
| Lenalidomide | 168,000 | |
| Pomalidomide | 192,000 | |
| Bortezomib | 50,000 | |
| Ixazomib | 111,000 | |
| Carfilzomib | 130,000 | 260,000 (at 56 mg/m2) |
| Daratumumab | 120,000 | |
| Elotuzumab | 120,000 | |
| Panobinostat | 96,000 | |
| Cyclophosphamide | 5,800 | |
| Melphalan IV | 10,000 | Per transplant |
| Dexamethasone | 3,400 | |
| Regimens | ||
| VRd | 220,000 | |
| KRd | 300,000 | |
| VCd | 60,000 | |
| DRd | 290,000 | |
| D-VRd | 340,000 | |
| D-KRd | 590,000 | |
