NCCN: Continuing Education
Target Audience: This activity is designed to meet the educational needs of physicians, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Medicine (ACCME): NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nursing (ANCC): NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacy (ACPE): NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-19-012-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/86150; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.
Release date: October 10, 2019; Expiration date: October 10, 2020
Learning Objectives:
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for Multiple Myeloma
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Multiple Myeloma
Disclosure of Relevant Financial Relationships
The NCCN staff listed below discloses no relevant financial relationships:
Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.
Individuals Who Provided Content Development and/or Authorship Assistance:
Shaji K. Kumar, MD, Panel Chair, has disclosed that he receives consulting fees/honoraria from Adaptive Technologies and Oncopeptides.
Natalie S. Callander, MD, Panel Vice Chair, has disclosed that she has no relevant financial relationships.
Jens Hillengass, MD, Panel Member, has disclosed that he receives consulting fees/honoraria from Amgen Inc, Janssen Pharmaceutica Products, LP, Adaptive Biotech, DRG LLC, Oncotracker, and Xian Janssen.
Michaela Liedtke, MD, Panel Member, has disclosed that she receives consulting fees/honoraria from Amgen, and serves as a scientific advisor for Celgene Corporation, Janssen Pharmaceutica Products, LP, and Jazz Pharmaceuticals Inc.
Alyse Johnson-Chilla, MS, Guidelines Coordinator, NCCN, has disclosed that she has no relevant financial relationships.
Jennifer Keller, MSS, Guidelines Layout Specialist, NCCN, has disclosed that she has no relevant financial relationships.
To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx.
This activity is supported by educational grants from AstraZeneca, Celgene Corporation, Clovis Oncology, Eisai, Genentech, Genomic Health, Inc., Novartis, Taiho Oncology, Inc., and TESARO. This activity is supported by an independent educational grant from AbbVie. This activity is supported by educational funding provided by Amgen. This activity is supported by an unrestricted educational grant from Gilead Sciences, Medical Affairs.
Overview
Multiple myeloma (MM) accounts approximately 1.8% of all cancers and slightly more than 17% of hematologic malignancies in the United States.1 Myeloma is most frequently diagnosed in people aged 65 to 74 years, with the median age being 69 years.2 The American Cancer Society has estimated 32,110 new myeloma cases will be diagnosed in the United States in 2019, with an estimated 12,960 deaths.3
The NCCN Multiple Myeloma Panel has developed guidelines for the management of patients with various plasma cell neoplasms, including solitary plasmacytoma, smoldering myeloma, multiple myeloma, systemic light chain amyloidosis, and Waldenström macroglobulinemia. These guidelines are updated annually, and sometimes more often if new high-quality clinical data become available.
Significant updates have been made to the 1.2020 version of the NCCN Guidelines for Multiple Myeloma. These NCCN Guidelines Insights focus only on the updates specific to imaging recommendations for MM; treatment options for newly diagnosed transplant-eligible and transplant-ineligible candidates, maintenance therapy, and previously treated MM; and management of renal disease in patients with MM. A complete list of updates to the 1.2020 version is available at NCCN.org.
Updates to Imaging Recommendations
Imaging for Initial Diagnostic Workup
A skeletal survey has been the standard for assessing bone disease in any individual with suspected myeloma for decades.4 However, this technique has significant limitations related to lower sensitivity compared with advanced imaging.
CT alone or in combination with FDG-PET has been shown to be significantly superior regarding the sensitivity to detect osteolytic lesions in patients with monoclonal plasma cell disorders. A multicenter analysis by the International Myeloma Working Group (IMWG) comparing conventional skeletal survey with whole-body CT scans from 212 patients with monoclonal plasma cell disorders found that whole-body CT was positive in 25.5% of patients with a negative skeletal survey. The sensitivity of skeletal survey and whole-body low-dose CT in the long bones is not significantly different; the difference is mainly in detection of abnormalities in spine and pelvis.5,6 In a study of 29 patients, CT showed osteolytic lesions in 5 patients (17%), whereas skeletal survey results were negative.7 Studies have shown that whole-body low-dose CT is superior to skeletal survey radiographs in areas that are difficult to visualize using skeletal surveys, such as the skull and ribs.8
FDG-PET/CT also has been shown to identify more lesions than plain radiographs and to detect lesions in patients with negative skeletal surveys.9–11 It is important to note that if PET/CT is selected instead of whole-body low-dose CT, the imaging quality of the CT part of the PET/CT should be equivalent to a whole-body low-dose CT. Usually the CT part is used only for attenuation correction, which is not sufficient to assess myeloma bone disease and stability of the spine.
MRI is useful for discerning smoldering myeloma from MM. Because the disease burden in patients with smoldering myeloma is lower than in those with MM, imaging techniques with high sensitivity must be used, and MRI is a sensitive technique for detecting marrow infiltration by myeloma.12,13
NCCN Recommendations
For initial diagnostic workup of patients with suspected MM, the NCCN panel recommends either whole-body low-dose CT or FDG-PET/CT (see MYEL-1, page opposite page). The panel also noted that skeletal survey is acceptable when advanced imaging is not available.
Imaging for Follow-up
Residual focal lesions detected by either FDG-PET/CT or MRI have been shown to be of adverse prognostic significance.14–17 Zamagni et al17 reported progression-free survival (PFS) of 44 months in patients with residual focal lesions on FDG-PET/CT versus 84 months for those with no residual focal lesions after systemic treatment (P=.0009). In the IMAJEM trial, both PFS (P=.011) and overall survival (OS; P=.033) were significantly better in patients with negative FDG-PET/CT results before initiation of maintenance therapy.15 An analysis by Walker et al16 showed that conventional MRI normalizes over a prolonged period of time, making FDG-PET/CT superior for follow-up. However, in small cohorts, functional imaging sequence for MRI called diffusion-weighted imaging was shown to have superior sensitivity to detect residual disease compared with FDG-PET/CT.18–20 Furthermore, unlike FDG-PET/CT, MRI does not expose patients to radiation.
NCCN Recommendations
For follow-up of patients with MM after primary treatment (see MYEL-5, page 1158), the NCCN panel recommends advanced imaging (ie, whole-body FDG-PET/CT, low-dose CT scan, whole-body MRI without contrast) as clinically indicated, and using the same imaging modality used during the initial workup for the follow-up assessments.
Updates to Treatment Options for Newly Diagnosed MM
The panel added new regimen options in the 1.2020 version for both transplant-eligible and transplant-ineligible patients with newly diagnosed MM.
Daratumumab/Lenalidomide/Dexamethasone
In transplant-ineligible patients with newly diagnosed MM, results of a recently reported phase III trial (MAIA) showed that daratumumab/lenalidomide/dexamethasone significantly reduced the risk of disease progression or death by 44% (hazard ratio [HR], 0.56; 95% CI, 0.43–0.73; P<.001).21 The addition of daratumumab to lenalidomide/dexamethasone resulted in deeper responses compared with lenalidomide/dexamethasone, including increased rates of complete response or better (48% vs 25%), very good partial response (VGPR) or better (79% vs 53%), and overall response (93% vs 81%).21 Rates of pneumonia, neutropenia, and leukopenia were higher in patients receiving daratumumab.21 Based on the results of this study, the FDA approved the use of daratumumab/lenalidomide/dexamethasone in this setting.
Carfilzomib/Cyclophosphamide/Dexamethasone
The efficacy seen with bortezomib in combination with cyclophosphamide and dexamethasone in patients with MM led to studies of other proteasome inhibitors in combination with cyclophosphamide and dexamethasone.
The carfilzomib/cyclophosphamide/dexamethasone regimen has been studied in phase I/II trials of transplant-ineligible patients with newly diagnosed MM. Trials have investigated both once-weekly and twice-weekly carfilzomib dosing combined with a fixed dose of cyclophosphamide and dexamethasone.22,23 A pooled analysis of 2 phase I and II studies comparing 2 alternative schedules of carfilzomib showed similar response rates in transplant-ineligible patients with newly diagnosed MM treated with once-weekly carfilzomib at 70 mg/m2 and those treated with twice-weekly carfilzomib at 36 mg/m2. The PFS and OS were also similar. Median PFS was 35.7 months in the once-weekly group and 35.5 months in the twice-weekly group (HR, 1.39; P=.26). The 3-year OS was 70% and 72%, respectively (HR, 1.27; P=.5).24
Consistent with these results, the more recent phase Ib CHAMPION-2 study evaluated the safety and tolerability of twice-weekly carfilzomib (3 different doses) in combination with cyclophosphamide and dexamethasone for the treatment of patients with newly diagnosed MM. This study found that that 56 mg/m2 of carfilzomib combined with weekly cyclophosphamide and dexamethasone was effective and had manageable toxicity.25
Ixazomib/Cyclophosphamide/Dexamethasone
In a phase I trial, ixazomib/cyclophosphamide/dexamethasone was shown to be a convenient, all-oral combination that is well tolerated and effective in patients with newly diagnosed MM.26 Subsequently, a multicenter phase II trial investigated the efficacy and toxicity of weekly oral ixazomib, cyclophosphamide, and low-dose dexamethasone as induction, followed by single-agent ixazomib maintenance, in elderly (median age, 73 years) transplant-ineligible patients with newly diagnosed MM.27 The overall response rate after initial therapy with ixazomib/cyclophosphamide/dexamethasone was 73%. After a median follow-up of 26.1 months, the PFS was 23.5 months.
NCCN Recommendations for Primary Myeloma Therapy
In the 1.2020 version of the NCCN Guidelines, the NCCN panel included carfilzomib/cyclophosphamide dexamethasone and ixazomib/cyclophosphamide/dexamethasone for both transplant and nontransplant settings as options useful in certain circumstances, such as in patients with renal insufficiency and/or peripheral neuropathy. The panel has also noted that carfilzomib can be given once or twice weekly at different doses (see MYEL-F, pages 1159–1161).
The NCCN panel also included daratumumab/lenalidomide/dexamethasone as a preferred category 1 option for patients with newly diagnosed MM who are transplant-ineligible (see MYEL-F, pages 1159–1161). Also, because regimens containing melphalan are rarely used in North America, daratumumab in combination with bortezomib/lenalidomide/dexamethasone has now been listed under “Other Recommended Regimens” in this setting.
The doublet regimens were removed from the page listing therapies for transplant candidates with the rationale that doublets would be recommended for patients who would not be considered for initial treatment with a 3-drug regimen, such as those not initially eligible for transplant. Therefore, for transplant-ineligible patients, the 2-drug regimens are still listed as options with a note stating that triplet regimens should be used as standard therapy for patients with MM, but that those who could not be considered for treatment initiation with a 3-drug regimen can be started with a 2-drug regimen, with a third drug added once performance status improves.
Updates to Maintenance Therapy Recommendations
In the 1.2020 version, the NCCN panel clarified the maintenance regimens appropriate for patients who received autologous hematopoietic cell transplant (AHCT) versus those who did not, and classified these regimens as either “Preferred,” “Other Recommended,” or “Useful in Certain Circumstances.”
Lenalidomide
Multiple randomized phase III trials have shown a PFS benefit of lenalidomide maintenance after AHCT28,29 and in transplant-ineligible patients after primary therapy.30–32 Furthermore, a meta-analyses showed improved OS benefit with lenalidomide maintenance after AHCT,33 with an OS at 7 years of 62% in the group receiving lenalidomide maintenance versus 50% in those receiving placebo.33
NCCN Recommendations for Lenalidomide Maintenance
Given the high-level data, the NCCN panel continues to list single-agent lenalidomide as a category 1 preferred maintenance regimen for both transplant-eligible and transplant-ineligible patients (see MYEL-F, pages 1159–1161).
Bortezomib
Maintenance with proteasome inhibitors has also been evaluated in randomized trials. The HOVON trial compared bortezomib versus thalidomide as maintenance therapy after AHCT for 2 years34,35 and showed that bortezomib maintenance prolonged PFS; however, in a subset analysis, the benefit of bortezomib maintenance was primarily seen in patients with high-risk myeloma (median OS not reached at 54 vs 24 months; HR, 0.36, 95% CI, 0.18–0.74).34
A multicenter phase III trial showed that consolidation with bortezomib after autologous stem cell transplant improved PFS only in patients not achieving at least VGPR.36 Results of the phase III UPFRONT study also showed that maintenance with single-agent bortezomib was well-tolerated when administered after treatment with bortezomib-based primary therapy.37
NCCN Recommendations for Bortezomib Maintenance
Because none of the clinical trials discussed previously were designed to assess the contribution of bortezomib as maintenance therapy (bortezomib was given during induction and continued as maintenance,34,36,37 or the control arm had a different induction therapy regimen plus maintenance therapy34), the panel included bortezomib as a category 2A “Other Recommended” maintenance option for both transplant-eligible and transplant-ineligible patients (see MYEL-F, pages 1159–1161). For high-risk patients, the panel considers bortezomib/lenalidomide an option for maintenance therapy, and therefore has included this combination as “Useful in Certain Circumstances.”38
Ixazomib
The phase III trial TOURMALINE-MM3, which studied 2 years of maintenance with ixazomib versus placebo in patients who had achieved at least a partial response following induction therapy and a single AHCT, showed that ixazomib improved PFS (median, 26.5 months [95% CI, 23.7–33.8] vs 21.3 months [95% CI, 18.0–24.7]; HR, 0.72; 95% CI, 0.58–0.89).39 The risk of developing secondary malignancies was similar in the control arm and in patients receiving maintenance ixazomib.
NCCN Recommendations for Ixazomib Maintenance
Based on the positive results of the TOURMALINE-MM3 trial, designed specifically to study the benefit of maintenance ixazomib, the NCCN panel included ixazomib as a category 1 “Other Recommended” maintenance option for transplant-eligible patients (see MYEL-F, pages 1159–1161).
Updates to Treatment Options for Previously Treated MM
A variety of therapies continue to be listed as options for previously treated MM. The choice of appropriate therapy for a patient would depend on the context of clinical relapse, such as prior treatment and duration of response. New regimens were included as options for the treatment of relapsed/refractory MM in the 1.2020 version of the NCCN Guidelines (see MYEL-F, pages 1159–1161).
Daratumumab/Carfilzomib/Dexamethasone
Combination daratumumab/carfilzomib/dexamethasone was studied in a phase Ib, open-label, nonrandomized, multicenter study in patients (n=82) with relapsed/refractory MM. At a median follow-up of 16 months, the overall response rate was 84%. In the overall treatment population, although the median PFS was not reached, the 12- and 18-month PFS rates were 74% and 66%, respectively.40 Based on these data, the NCCN panel included this regimen as an “Other Recommended” option for relapsed/refractory MM.
Ixazomib/Cyclophosphamide/Dexamethasone
Combination ixazomib/cyclophosphamide/dexamethasone has been shown to be tolerable and efficacious in patients with newly diagnosed MM.26,27 A phase II study evaluating this regimen in the relapsed/refractory setting in patients with a median age of 63.5 years also found it to be well tolerated. At a median follow-up of 15.2 months, the median PFS was 14.2 months, with a trend toward better PFS in patients aged ≥65 versus <65 years (median, 18.7 vs 12.0 months; HR, 0.62; P=.14).41 Therefore, the NCCN panel included this all-oral regimen as an “Other Recommended” option for relapsed/refractory MM.
Pomalidomide/Bortezomib/Dexamethasone
Results were recently published of the phase III, open-label, multicenter, randomized OPTIMISMM study that evaluated the safety and efficacy of pomalidomide/bortezomib/dexamethasone (n=281) versus bortezomib/dexamethasone (n=278) in patients with relapsed/refractory MM who previously received lenalidomide.42 After a median follow-up of 15.9 months, significantly improved PFS was seen in the pomalidomide arm (median, 11.20 vs 7.10 months; HR, 0.61; 95% CI, 0.49–0.77; P<.0001). The most commonly reported grade 3/4 treatment-related adverse events in the pomalidomide arm were neutropenia, infections, and thrombocytopenia.42
Based on these phase III trial results, the NCCN panel included pomalidomide/bortezomib/dexamethasone as a category 1 therapeutic option for patients who received at least 2 prior therapies, including an immunomodulatory agent (IMiD) and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy.
Carfilzomib/Cyclophosphamide/Thalidomide/Dexamethasone
Results of the phase I/II CYCLONE trial showed that the 4-drug carfilzomib/cyclophosphamide/thalidomide/dexamethasone regimen is efficacious, with an overall response rate of 91%, and 76% of patients with MM achieving a VGPR or greater after 4 cycles.43 This regimen has now been included under the list of regimens “Useful in Certain Circumstances” for relapsed/refractory MM.
Selinexor/Dexamethasone
Selinexor was recently approved for the treatment of myeloma. This agent induces apoptosis of MM cells by selectively inhibiting nuclear export compound that blocks exportin 1 (XPO1), forcing nuclear accumulation and activation of tumor suppressor proteins, and inhibiting nuclear factor κB and the translation of oncoprotein mRNAs, such as c-myc and cyclin-D. Selinexor in combination with dexamethasone was studied in the phase IIb STORM trial in patients with relapsed/refractory MM who had multiple prior therapies and were refractory to IMiDs (lenalidomide and pomalidomide), proteasome inhibitors (bortezomib and carfilzomib), and the CD38 antibody (daratumumab).44 A total of 122 patients were included in the intent-to-treat population. Partial response or better was observed in 26% of patients (95% CI, 19%–35%).
The most common adverse events reported during treatment were thrombocytopenia in 73% of patients, fatigue in 73%, nausea in 72%, and anemia in 67%.
Based on these results, the NCCN panel included selinexor/dexamethasone in the list of regimens “Useful in Certain Circumstances” as an option for patients with relapsed/refractory MM who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 IMiD agents, and an anti-CD38 monoclonal antibody.
Management of Renal Disease in Patients With MM
In patients with MM and monoclonal gammopathies, renal disease usually results from the production of monoclonal immunoglobulin or light/heavy chains by a clonal proliferation of plasma cells or B cells. Renal disease is seen in 20% to 50% of patients with myeloma and has been observed to negatively affect outcomes.45–47 In the 1.2020 version of the NCCN Guidelines, the panel added a new page outlining management of renal disease in MM (see MYEL-H, page 1162).
In patients with myeloma, renal insufficiency, defined as elevated serum creatinine level of >2 mg/dL or established glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2, is usually due to light chain cast nephropathy, but other causes must be considered, including hypercalcemia, volume depletion, and hyperuricemia as well as nephrotoxic medications or intravenous contrast. In addition, concomitant amyloidosis and monoclonal immunoglobulin deposition should be suspected when renal insufficiency or albuminuria is present without high levels of light chains.
Diagnostic Tests
According to the NCCN panel, diagnostic workup of patients with symptomatic myeloma should include serum creatinine measurement, electrolytes assessment, eGFR, electrophoresis of a sample from a 24-hour urine collection, serum electrophoresis, and serum free light chain measurement. If proteinuria predominantly consists of light chains with high serum levels of free light chain, and the cause of renal insufficiency can be attributed to myeloma, a renal biopsy may not be necessary. However, patients without a clear and complete explanation for their renal insufficiency should undergo renal biopsy to assess for other pathophysiology, such as monoclonal immunoglobulin deposition disease or membranoproliferative glomerulonephritis.
Treatment Options
Initial treatment of cast nephropathy includes administering appropriate myeloma therapy and providing adequate supportive care.
Myeloma Therapy
Myeloma therapy using bortezomib-containing regimens should be initiated as soon as possible to decrease the production of nephrotoxic clonal immunoglobulin.48 Bortezomib/dexamethasone containing regimens can be administered to patients with severe renal impairment and those on dialysis and do not require renal dose adjustment.46 If the 2-drug bortezomib/dexamethasone regimen is used as initial treatment, a third drug that does not require dose adjustment can be added, including cyclophosphamide, thalidomide, an anthracycline, or daratumumab. Other agents available for myeloma therapy should be used with caution and with dose adjustments based on the degree of renal function impairment, as recommended by the IMWG.49 A retrospective study evaluated lenalidomide and dexamethasone based on 2 phase III trials of lenalidomide/low-dose dexamethasone in patients with relapsed/refractory myeloma and a serum creatinine level of <2.5 mg/dL.50 Patients grouped by creatinine clearance >60 mL/min (n=243), 30 to 60 mL/min (n=82), and <30 mL/min (n=16) showed no difference in response rates to lenalidomide/low-dose dexamethasone. Those with renal insufficiency had higher rates of thrombocytopenia and lenalidomide discontinuation than those without renal insufficiency. The NCCN panel outlined recommendations for lenalidomide dosing based on degree of renal function in patients with MM and renal impairment. Although prospective data to define optimal dosing are often lacking, pomalidomide has been studied in patients with relapsed myeloma in 3 different categories of renal insufficiency (eGFR 30–40 mL/min/1.73 m2, eGFR <30 mL/min/1.73 m2, and those requiring dialysis), and full-dose pomalidomide of 4 mg/d was found to be safe in all 3 groups.51 High-dose chemotherapy and autologous stem cell transplantation can be safely performed in patients with renal insufficiency, including those on dialysis. Conditioning with reduced-dose melphalan has outcomes comparable to standard-dose melphalan and should be considered in those who are otherwise eligible for the procedure.52,53
Supportive Care
Intravenous fluids should be started promptly in patients with MM and renal disease to decrease the renal tubular light chain concentration, with a goal urine output of 100 to 150 mL/h. Careful assessment of fluid status is critical to avoid hypervolemia, especially in patients with oliguria renal failure.
In addition, nephrotoxic medications should be discontinued and other metabolic abnormalities corrected, such as hypercalcemia and hyperuricemia. Hydration, bisphosphonates, denosumab, and/or calcitonin are recommended to reduce calcium levels in the case of hypercalcemia. In patients with renal disease, pamidronate and zoledronic acid should be used with caution; the NCCN panel has provided recommended dosing of these agents (see MYEL-H, page 1162).
Dialysis may be required in selected patients, in addition to prompt institution of antimyeloma therapy. Mechanical removal of light chains may be considered on a case-by-case basis. Although the benefit of mechanical removal of free light chains has not been established, limited evidence supports the use of plasmapheresis or high-cutoff dialysis to reduce pathogenic light chains.
Conclusions
These NCCN Guidelines Insights highlight important updates and changes specific to treatment options for MM in the 1.2020 version of the NCCN Guidelines. The NCCN Guidelines are in continuous evolution; they are updated annually, and sometimes more often if new high-quality clinical data become available in the interim. Recommendations in the NCCN Guidelines, with few exceptions, are based on evidence from clinical trials. Expert medical clinical judgment is required when applying these guidelines in the context of individual clinical circumstances in order to provide optimal care. The physician and patient have the responsibility to jointly explore and select the most appropriate option from among the available alternatives. When possible, consistent with NCCN philosophy, the panel strongly encourages patient/physician participation in prospective clinical trials.
References
- 2.↑
National Cancer Institute. Cancer Stat Facts: Myeloma. Available at: http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed August 30, 2019.
- 4.↑
International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121:749–757.
- 5.↑
Hillengass J, Moulopoulos LA, Delorme S, et al.. Findings of whole body computed tomography compared with conventional skeletal survey in patients with monoclonal plasma cell disorders—a study of the International Myeloma Working Group. Blood 2016;128:4468–4468.
- 6.↑
Hinge M, Andersen KT, Lund T, et al.. Baseline bone involvement in multiple myeloma—a prospective comparison of conventional x-ray, low-dose computed tomography, and 18flourodeoxyglucose positron emission tomography in previously untreated patients. Haematologica 2016;101:e415–418.
- 7.↑
Kröpil P, Fenk R, Fritz LB, et al.. Comparison of whole-body 64-slice multidetector computed tomography and conventional radiography in staging of multiple myeloma. Eur Radiol 2008;18:51–58.
- 8.↑
Princewill K, Kyere S, Awan O, et al.. Multiple myeloma lesion detection with whole body CT versus radiographic skeletal survey. Cancer Invest 2013;31:206–211.
- 9.↑
Nanni C, Zamagni E, Farsad M, et al.. Role of 18F-FDG PET/CT in the assessment of bone involvement in newly diagnosed multiple myeloma: preliminary results. Eur J Nucl Med Mol Imaging 2006;33:525–531.
- 10.↑
Siontis G, Kumar S, Dispenzieri A, et al.. Positron emission tomography-computed tomography in the diagnostic evaluation of smoldering multiple myeloma: identification of patients needing therapy. Blood Cancer J 2015;5:e364.
- 11.↑
Zamagni E, Nanni C, Gay F, et al.. 18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease. Leukemia 2016;30:417–422.
- 12.↑
Hillengass J, Fechtner K, Weber MA, et al.. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 2010;28:1606–1610.
- 13.↑
Merz M, Hielscher T, Wagner B, et al.. Predictive value of longitudinal whole-body magnetic resonance imaging in patients with smoldering multiple myeloma. Leukemia 2014;28:1902–1908.
- 14.↑
Bartel TB, Haessler J, Brown TL, et al.. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood 2009;114:2068–2076.
- 15.↑
Moreau P, Attal M, Caillot D, et al.. Prospective evaluation of magnetic resonance imaging and [18F]fluorodeoxyglucose positron emission tomography-computed tomography at diagnosis and before maintenance therapy in symptomatic patients with multiple myeloma included in the IFM/DFCI 2009 trial: results of the IMAJEM study. J Clin Oncol 2017;35:2911–2918.
- 16.↑
Walker R, Barlogie B, Haessler J, et al.. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol 2007;25:1121–1128.
- 17.↑
Zamagni E, Nanni C, Mancuso K, et al.. PET/CT improves the definition of complete response and allows to detect otherwise unidentifiable skeletal progression in multiple myeloma. Clin Cancer Res 2015;21:4384–4390.
- 18.↑
Pawlyn C, Fowkes L, Otero S, et al.. Whole-body diffusion-weighted MRI: a new gold standard for assessing disease burden in patients with multiple myeloma? Leukemia 2016;30:1446–1448.
- 19.↑
Rasche L, Alapat D, Kumar M, et al.. Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma. Leukemia 2019;33:1713–1722.
- 20.↑
Rasche L, Angtuaco E, McDonald JE, et al.. Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma. Blood 2017;130:30–34.
- 21.↑
Facon T, Kumar S, Plesner T, et al.. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med 2019;380:2104–2115.
- 22.↑
Bringhen S, Petrucci MT, Larocca A, et al.. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood 2014;124:63–69.
- 23.↑
Bringhen S, D’Agostino M, De Paoli L, et al.. Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. Leukemia 2018;32:979–985.
- 24.↑
Bringhen S, Mina R, Petrucci MT, et al.. Once-weekly versus twice-weekly carfilzomib in patients with newly diagnosed multiple myeloma: a pooled analysis of two phase I/II studies. Haematologica 2019;104:1640–1647.
- 25.↑
Boccia RV, Bessudo A, Agajanian R, et al.. A multicenter, open-label, phase 1b study of carfilzomib, cyclophosphamide, and dexamethasone in newly diagnosed multiple myeloma patients (CHAMPION-2). Clin Lymphoma Myeloma Leuk 2017;17:433–437.
- 26.↑
Kumar SK, Buadi FK, LaPlant B, et al.. Phase 1/2 trial of ixazomib, cyclophosphamide and dexamethasone in patients with previously untreated symptomatic multiple myeloma. Blood Cancer J 2018;8:70.
- 27.↑
Dimopoulos MA, Grosicki S, Jędrzejczak WW, et al.. All-oral ixazomib, cyclophosphamide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma. Eur J Cancer 2019;106:89–98.
- 28.↑
Attal M, Lauwers-Cances V, Marit G, et al.. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1782–1791.
- 29.↑
McCarthy PL, Owzar K, Hofmeister CC, et al.. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1770–1781.
- 30.↑
Palumbo A, Hajek R, Delforge M, et al.. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 2012;366:1759–1769.
- 31.↑
Hulin C, Belch A, Shustik C, et al.. Updated outcomes and impact of age with lenalidomide and low-dose dexamethasone or melphalan, prednisone, and thalidomide in the randomized, phase III FIRST trial. J Clin Oncol 2016;34:3609–3617.
- 32.↑
Holstein SA, Jung SH, Richardson PG, et al.. Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial. Lancet Haematol 2017;4:e431–442.
- 33.↑
McCarthy PL, Holstein SA, Petrucci MT, et al.. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol 2017;35:3279–3289.
- 34.↑
Goldschmidt H, Lokhorst HM, Mai EK, et al.. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia 2018;32:383–390.
- 35.↑
Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al.. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol 2012;30:2946–2955.
- 36.↑
Mellqvist UH, Gimsing P, Hjertner O, et al.. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood 2013;121:4647–4654.
- 37.↑
Niesvizky R, Flinn IW, Rifkin RM, et al.. Phase 3b UPFRONT study: safety and efficacy of weekly bortezomib maintenance therapy after bortezomib-based induction regimens in elderly, newly diagnosed multiple myeloma patients [abstract]. Blood 2010;116:Abstract 619.
- 38.↑
Nooka AK, Kaufman JL, Muppidi S, et al.. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia 2014;28:690–693.
- 39.↑
Dimopoulos MA, Gay F, Schjesvold F, et al.. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet 2019;393:253–264.
- 40.↑
Chari A, Martinez-Lopez J, Mateos MV, et al.. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood 2019;134:421–431.
- 41.↑
Kumar SK, Grzasko N, Delimpasi S, et al.. Phase 2 study of all-oral ixazomib, cyclophosphamide and low-dose dexamethasone for relapsed/refractory multiple myeloma. Br J Haematol 2019;184:536–546.
- 42.↑
Richardson PG, Oriol A, Beksac M, et al.. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol 2019;20:781–794.
- 43.↑
Mikhael JR, Reeder CB, Libby EN, et al.. A phase I/II trial of cyclophosphamide, carfilzomib, thalidomide and dexamethasone (CYCLONE) in patients with newly diagnosed multiple myeloma: final results of MTD expansion cohort. Blood 2013;122:3179–3179.
- 44.↑
Chari A, Vogl DT, Gavriatopoulou M, et al.. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med 2019;381:727–738.
- 45.↑
Bladé J, Fernández-Llama P, Bosch F, et al.. Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med 1998;158:1889–1893.
- 46.↑
Knudsen LM, Hippe E, Hjorth M, et al.. Renal function in newly diagnosed multiple myeloma—a demographic study of 1353 patients. Eur J Haematol 1994;53:207–212.
- 47.↑
Knudsen LM, Hjorth M, Hippe E. Renal failure in multiple myeloma: reversibility and impact on the prognosis. Eur J Haematol 2000;65:175–181.
- 48.↑
Dimopoulos MA, Roussou M, Gavriatopoulou M, et al.. Bortezomib-based triplets are associated with a high probability of dialysis independence and rapid renal recovery in newly diagnosed myeloma patients with severe renal failure or those requiring dialysis. Am J Hematol 2016;91:499–502.
- 49.↑
Dimopoulos MA, Sonneveld P, Leung N, et al.. International Myeloma Working Group recommendations for the diagnosis and management of myeloma-related renal impairment. J Clin Oncol 2016;34:1544–1557.
- 50.↑
Dimopoulos MA, Christoulas D, Roussou M, et al.. Lenalidomide and dexamethasone for the treatment of refractory/relapsed multiple myeloma: dosing of lenalidomide according to renal function and effect on renal impairment. Eur J Haematol 2010;85:1–5.
- 51.↑
Dimopoulos M, Weisel K, van de Donk NW, et al.. Pomalidomide plus low-dose dexamethasone in patients with relapsed/refractory multiple myeloma and renal impairment: results from a phase II trial. J Clin Oncol 2018;36:2035–2043.
- 52.↑
Ballester OF, Tummala R, Janssen WE, et al.. High-dose chemotherapy and autologous peripheral blood stem cell transplantation in patients with multiple myeloma and renal insufficiency. Bone Marrow Transplant 1997;20:653–656.
- 53.↑
Mahindra A, Hari P, Fraser R, et al.. Autologous hematopoietic cell transplantation for multiple myeloma patients with renal insufficiency: a Center for International Blood and Marrow Transplant Research Analysis. Bone Marrow Transplant 2017;52:1616–1622.
NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel's discussion, including the literature reviewed.
The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.
The complete and most recent version of these guidelines is available free of charge at NCCN.org.
© National Comprehensive Cancer Network, Inc. 2019. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
