NCCN Guidelines® Insights: Multiple Myeloma, Version 3.2022

Featured Updates to the NCCN Guidelines

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  • 1 University of Wisconsin Carbone Cancer Center;
  • | 2 Fred & Pamela Buffett Cancer Center;
  • | 3 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 4 UT Southwestern Simmons Comprehensive Cancer Center;
  • | 5 University of Michigan Rogel Cancer Center;
  • | 6 Dana-Farber/Brigham and Women’s Cancer Center | Massachusetts General Hospital Cancer Center;
  • | 7 UC San Diego Moores Cancer Center;
  • | 8 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • | 9 St. Jude Children's Research Hospital/The University of Tennessee Health Science Center;
  • | 10 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • | 11 Abramson Cancer Center at the University of Pennsylvania;
  • | 12 O'Neal Comprehensive Cancer Center at UAB;
  • | 13 Roswell Park Comprehensive Cancer Center;
  • | 14 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
  • | 15 City of Hope National Medical Center;
  • | 16 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 17 Memorial Sloan Kettering Cancer Center;
  • | 18 Duke Cancer Institute;
  • | 19 UCLA Jonsson Comprehensive Cancer Center;
  • | 20 Stanford Cancer Institute;
  • | 21 UCSF Helen Diller Family Comprehensive Cancer Center;
  • | 22 Patient advocate;
  • | 23 Huntsman Cancer Institute at the University of Utah;
  • | 24 Moffitt Cancer Center;
  • | 25 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;
  • | 26 The University of Texas MD Anderson Cancer Center;
  • | 27 National Comprehensive Cancer Network; and
  • | 28 Mayo Clinic Cancer Center.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with various plasma cell neoplasms, including multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates/changes specific to the treatment of patients with multiple myeloma in the 2022 version of the guidelines.

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of oncologists, 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.

Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-22-001-H01-P

Physician Assistants: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until January 10, 2023. PAs should only claim credit commensurate with the extent of their participation.

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/91062; 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: January 10, 2022; Expiration date: January 10, 2023

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

None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

Individuals Who Provided Content Development and/or Authorship Assistance:

Shaji K. Kumar, MD, Panel Chair, has the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed have been mitigated. Scientific advisor for and grant/research support from AbbVie, Inc., Amgen Inc., Bristol-Myers Squibb Company, GlaxoSmithKline, Janssen Pharmaceutica Products, LP, Karyopharm Therapeutics, Regeneron Pharmaceuticals, Inc., Roche Laboratories, Inc., Sanofi-aventis US, and Takeda Pharmaceuticals North America, Inc.; and has received honoraria from BeiGene.

Natalie S. Callander, MD, Panel Vice Chair, has as no relevant financial relationship(s) with ineligible companies to disclose.

Muhamed Baljevic, MD, Panel Member, has the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed have been mitigated. Scientific advisor for Karyopharm Therapeutics, Bristol-Myers Squibb/Celgene, Janssen Research & Development, LLC, Oncopeptides, and Sanofi-Genzyme; and honoraria from Karyopharm Therapeutics, Cardinal Health Specialty Solutions, and CurioScience.

Ryan A. Berardi, MSc, Guidelines Layout Specialist, NCCN, has no relevant financial relationship(s) with ineligible companies to disclose.

Rashmi Kumar, PhD, Director, Clinical Information Operations, NCCN, has no relevant financial relationship(s) with ineligible companies to disclose.

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; BeiGene; Exact Sciences; Gilead Sciences, Inc.; GlaxoSmithKline; Lantheus Medical Imaging Inc.; Novartis; Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC; and Taiho Oncology, Inc. This activity is supported by an independent educational grant from Astellas. This activity is supported by an education grant from Astellas and Seagen Inc. This activity is supported by a medical education grant from Karyopharm® Therapeutics. This activity is supported through an Independent Medical Education grant from Merck & Co., Inc.

Overview

Multiple myeloma (MM) is a malignant neoplasm of the plasma cells that accumulate in bone marrow, leading to renal failure, hypercalcemia, bone destruction, and anemia due to marrow failure. MM accounts for approximately 1.8% of all cancers and 18.7% of hematologic malignancies in the United States.1 MM is most frequently diagnosed among people aged 65 to 74 years, with the median age being 69 years.2 The American Cancer Society has estimated 34,920 new MM cases will be diagnosed in the United States in 2021, with an estimated 12,410 deaths.1

The NCCN MM Panel has developed guidelines for managing patients with various plasma cell neoplasms, including monoclonal gammopathy of renal and neurologic significance, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), solitary plasmacytoma with and without minimal marrow involvement, smoldering myeloma, MM, systemic light-chain amyloidosis, and Waldenström macroglobulinemia. These guidelines are updated annually, or more often if new high-quality clinical data become available.

Significant updates have been made to the 2022 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MM. These NCCN Guidelines Insights focus only on those updates specific to recommendations for newly diagnosed transplant-eligible and transplant-ineligible candidates, maintenance, and previously treated MM, and principles of management of venous thromboembolism (VTE). For a complete list of updates to the 3.2022 version, visit NCCN.org.

General Considerations for MM Therapy

The panel has included a new page on general considerations for MM therapy. The content on this page was previously included in footnotes on the pages that include a list of options for myeloma therapy. This page contains general principles for consideration, screening and prophylaxis recommendations, important dosing and administration considerations, and a few noteworthy side effects and laboratory testing considerations. This year, the panel has noted that for elderly patients with MM, an assessment of frailty or calculation of frailty score is recommended using the tool developed by the International Myeloma Working Group (http://www.myelomafrailtyscorecalculator.net/) to predict mortality and the risk of toxicity3 (see MYEL-F, page 10).

Updates to the Treatment Options for Newly Diagnosed MM

During the annual guidelines update this year, the panel reviewed the preference categories of all the regimens and reclassified a few based on updated data and/or panel consensus. The panel also added new regimens for both transplant-eligible as well as transplant-ineligible patients with newly diagnosed MM.

The bortezomib/cyclophosphamide/dexamethasone regimen was moved from the “preferred” category to “useful in certain circumstances” for transplant candidates. The rationale for this reclassification is that this regimen is used only in circumstances when patients do not have immediate access to bortezomib/lenalidomide/dexamethasone or if they have renal insufficiency. The regimen continues to be listed under “useful in certain circumstances” for nontransplant candidates (see MYEL-G 1 of 4, page 11).

The panel added the 4-drug regimen daratumumab/carfilzomib/lenalidomide/dexamethasone for transplant-eligible patients with newly diagnosed MM to the list of regimens in the “useful in certain circumstances” category (see MYEL-G 1 of 4, page 11). It was included as an option for nontransplant daratumumab/carfilzomib/lenalidomide/dexamethasone candidates in Version 1.2021.

The data for daratumumab/carfilzomib/lenalidomide/dexamethasone in the transplant setting come from 2 trials. In the first nonrandomized clinical trial in patients with newly diagnosed multiple myeloma (n=41),4 daratumumab/carfilzomib/lenalidomide/dexamethasone therapy was associated with high rates of minimal residual disease (MRD) negativity (29 of 41 evaluable patients were MRD-negative after 8 cycles of therapy).4 At 11 months of the median follow-up, the trial reported 1-year progression-free survival (PFS) and overall survival (OS) rates of 98% (95% CI, 93%–100%) and 100%, respectively.4

In the ongoing phase II MASTER trial, 123 patients received daratumumab/carfilzomib/lenalidomide/dexamethasone for 4 cycles as induction, followed by autologous stem cell transplant and then consolidation with the induction regimen according to MRD status. Patients who were MRD-positive at the end of consolidation received lenalidomide maintenance. Those were MRD-negative on 2 consecutive tests were moved to observation only. The percent of patients who were MRD-negative was 42% after induction, 73% after autologous hematopoietic cell transplant (HCT), and 82% during consolidation. MRD negativity rates were similar between the standard-risk and high-risk cytogenetic groups.5 Carfilzomib was given weekly in both trials to optimize tolerability.

This regimen is included under the category “useful in certain circumstances,” and the panel noted in a footnote that it is generally an option reserved for those with aggressive disease (see MYEL-G 1 of 4, page 11).

The panel also added the modified bortezomib/lenalidomide/dexamethasone (VRd-lite) for nontransplant patients. This is based on the following phase II study that evaluated modified dose and schedule of the triple combination of bortezomib/lenalidomide/dexamethasone (VRd-lite) in older transplant-ineligible patients with MM. The median age of patients in this trial was 73 years. VRd-lite administered in a 35-day cycle consisted of subcutaneous bortezomib at 1.3 mg/m2 on days 1, 8, 15, and 22; dexamethasone at 20 mg orally on the day of and the day after bortezomib administration for those aged ≤75 years, and at 20 mg orally on the same days as bortezomib only for those aged ≥75 years; and lenalidomide at 15 mg on days 1 through 21. In 48 evaluable patients at a median follow-up of 17.2 months, the 1-year PFS was 95% and the 2-year PFS was 68%.6 At a follow-up of 61 months, continued improvement in PFS was seen. The median PFS was 41.9 months and median OS was not reached. The 5-year OS was 61.3%7 (see MYEL-G 2 of 4, page 12).

Because VRd-lite is a well-tolerated regimen and provides an effective option of using a 3-drug regimen with modifications in dose and schedule without compromising efficacy in older, frail, transplant-ineligible patients, the panel has included this as an option for transplant-ineligible patients with MM.

Updates to Maintenance Therapy Recommendations

The TOURMALINE-MM3 trial studied 2 years of maintenance with ixazomib versus placebo in patients who had achieved at least a partial response after induction therapy and a single autologous HCT8 and the TOURMALINE-MM4 trial studied ixazomib maintenance in transplant-ineligible patients with newly diagnosed MM.9

Recently, the manufacturers of ixazomib released an information letter to healthcare providers stating that interim survival analyses of the TOURMALINE-MM3 and MM4 trials indicated slightly inferior 3- and 5-year OS in patients receiving ixazomib maintenance. These results are not published and the company has not released additional data. Considering this update, the panel changed the designation for ixazomib maintenance to a category 2B recommendation.

Extrapolating from the induction therapy, a single institution explored lenalidomide/bortezomib/dexamethasone as maintenance for up to 3 years followed by single-agent lenalidomide in patients with high-risk disease after autologous HCT (n=45). The results reported a median PFS of 32 months and a 3-year OS of 93% with the triple-drug regimen as maintenance/consolidation therapy.10

A retrospective study evaluated the efficacy of lenalidomide/bortezomib/dexamethasone in patients (n=1,000) with newly diagnosed MM with subsequent administration of maintenance therapy based on myeloma risk stratification. Maintenance therapy options included lenalidomide alone or lenalidomide/bortezomib. Overall, 753 patients in the trial received maintenance; 600 (60.7%) received lenalidomide alone as maintenance therapy based on standard-risk cytogenetics, and 107 (10.7%) received immunomodulatory drug (IMiD) and proteasome inhibitor (PI) maintenance therapy, predominantly with lenalidomide/bortezomib/dexamethasone. The median PFS of patients with high-risk disease who received maintenance with lenalidomide and bortezomib maintenance therapy was 40.3 months (95% CI, 33.5–47 months), with a median OS of 78.2 months. At a median follow-up of 74 months, the median OS for this group was 78.2 months (95% CI, 62.2–94.2 months).11

The NCCN MM Panel has now included lenalidomide/bortezomib with dexamethasone as a maintenance therapy option for transplant-eligible patients (see MYEL-G 1 of 4, page 11).

Updates to Treatment Options for Previously Treated MM

A variety of therapies are available for previously treated MM. The choice of appropriate therapy for a patient depends on the context of the clinical relapse, such as prior treatment, duration of response, the class of agents previously received, and residual or emerging side effects of previous treatment. Patient-specific factors also need to be considered, such as frailty, availability and accessibility to clinical trials, proximity to clinic, previous autologous stem cell collection, and patient preferences for specific treatment.

The panel received several requests to provide additional guidance in therapy selection for relapsed/refractory (R/R) MM. As a result, the panel segregated the therapies as used for early relapse (1–3 prior therapies) and late relapse (>3 therapies) in the 2022 version (see MYEL-G 3 of 4, page 13). The panel also clarified in a footnote that “regimens included under 1–3 prior therapies can also be used later in the disease course. An attempt should be made to use drugs/drug classes that patients have not been exposed to or exposed to >1 line prior.” An example of this strategy would be to select a regimen that does not contain lenalidomide in a patient experiencing progression on that agent.

For the 2022 update, isatuximab-irfc/carfilzomib/dexamethasone and daratumumab/pomalidomide/dexamethasone were moved from the other recommended regimens to preferred regimens for early relapses (1–3 prior therapies) based on new data.

The multicenter, phase III, open-label IKEMA trial studied patients (n=302) with relapsed MM who had received 1 to 3 prior lines of therapy randomly assigned to receive carfilzomib/dexamethasone ± isatuximab-irfc until disease progression or unacceptable toxicity.12 After a median follow-up of 21 months, the median PFS was not reached in the isatuximab-irfc group versus 19 months in the control group (hazard ratio [HR], 0.53; 95% CI, 0.32–0.89). Serious adverse reactions were seen in 59% versus 57% of patients in the isatuximab-irfc versus the control group, respectively. The most common adverse reactions with isatuximab-irfc were infusion-related reactions, fatigue, hypertension, diarrhea, upper respiratory tract infection, pneumonia, dyspnea, and bronchitis. Based on the results of the IKEMA trial, the panel included isatuximab-irfc/carfilzomib/dexamethasone as a category 1, preferred regimen option for patients with R/R MM. Previously, this regimen was included under “other recommended regimens” as a category 2A recommendation.

The phase II MM-014 study investigated pomalidomide-containing therapies sequenced after a lenalidomide-based regimen in patients with R/R MM. The trial had 3 cohorts, one of which (cohort B) assessed triplet therapy with daratumumab/pomalidomide/dexamethasone in patients who had received 1 to 2 prior treatments with a lenalidomide-containing regimen in the immediate prior line. In cohort B, all patients had prior lenalidomide (75% had lenalidomide-refractory disease) and 77.7% had prior bortezomib. Most patients received 1 versus 2 prior lines of therapy (62.5% vs 37.5%). At a median follow-up of 28.4 months, the overall response rate (ORR) in cohort B (n=112) was 77.7%, and 52.7% achieved a very good partial response or better; median PFS was 30.8 months.13 In an updated analysis of MM-014, the ORR in patients with lenalidomide-relapsed (disease relapse >60 days of receiving lenalidomide-containing regimen) and lenalidomide-refractory disease was 82.1% and 76.2%, respectively. The most frequently occurring hematologic grade 3 or 4 treatment-related adverse events in the daratumumab/pomalidomide/dexamethasone arm were neutropenia (64.3%), anemia (17.9%), and thrombocytopenia (14.3%).14

An open-label, multicenter phase III study (APOLLO) investigated daratumumab/pomalidomide/dexamethasone versus pomalidomide/dexamethasone in patients who received ≥1 prior line of therapy, including lenalidomide and a PI.15 At a median follow-up of 16.9 months, the addition of daratumumab to pomalidomide/dexamethasone demonstrated an ORR of 69% versus 46% and improved median PFS of 12.4 versus 6.9 months (HR, 0.63; 95% CI, 0.47–0.85). The most common grade 3 or 4 adverse events seen in the daratumumab group included neutropenia, anemia, and thrombocytopenia.15

Based on these data, the panel has included daratumumab/pomalidomide/dexamethasone as a category 1, preferred treatment option for patients with R/R MM who have received at least 2 prior therapies, including an IMiD and a PI.

Earlier this year, the FDA granted accelerated approval for melphalan flufenamide, a peptide-drug conjugate with a unique delivery mechanism for melphalan and desethyl-melflufen in combination with dexamethasone. This approval was based on the results of a multicenter, single-arm trial (HORIZON) of melphalan flufenamide/dexamethasone in patients (n=157) with R/R MM, the ORR was 29% and the estimated median PFS was 4.2 months.16

Based on these data, NCCN Guidelines included melphalan flufenamide/dexamethasone as a treatment option for patients with late relapses (≥4 prior therapies) and whose disease was refractory to at least one PI, one IMiD, and one CD38-directed monoclonal antibody. However, subsequently, concerns were raised about its efficacy and safety based on a preliminary analysis of a randomized trial (OCEAN) comparing melphalan flufenamide/dexamethasone with pomalidomide/dexamethasone that demonstrated a decrease in OS (data in abstract form only).17 Following the recent withdrawal of this drug from the market by the manufacturer,18 the panel voted unanimously to remove this regimen as an option for patients with late relapses (≥4 prior therapies).

The phase II KarMMa trial evaluated the efficacy and safety of idecabtagene vicleucel (ide-cel), an anti–B-cell maturation antigen (BCMA) CAR T-cell therapy, in patients with R/R MM who received 3 prior lines of therapy.19 After a follow up of 13.3 months, 94 of 128 patients experienced a response. The ORR was 73%, and the estimated median PFS was 8.8 months (95% CI, 5.6–11.6 months).19 Common adverse effects included anemia (70%) and thrombocytopenia (63%); cytokine release syndrome was seen in 84% (5% were grade ≥3) and neurotoxic effects were seen in 23% (3% were grade ≥3).19

Based on the results of the KarMMa trial and FDA approval of this agent, the panel included this therapy as a treatment option for patients with relapsed MM who received at least 4 previous therapies (including a PI, an IMiD, and an anti-CD38 monoclonal antibody).

Management of VTE in Patients With MM

In the updated version of the guidelines for MM, the panel has included recommendations specific to VTE risk assessment and VTE prophylaxis for patients with MM (see MYEL-I, pages 15–17).

VTE Risk Stratification

Patients with MM have a 9-fold increase in VTE risk compared with the general population.20 In MM, the use of IMiDs (thalidomide, lenalidomide, or pomalidomide) with steroids or multiagent chemotherapy creates a significant risk for VTE,21 which is mostly seen within 6 months of treatment initiation, irrespective of the treatment regimen.22,23

For patients with MM, risk scores may be obtained using 2 scoring systems. This risk score helps identify patients with high risk who would benefit from anticoagulation therapy versus those with low risk for whom treatment with anticoagulants may be avoided. Predictors of VTE, used to obtain the IMPEDE score,24 include risk scoring based on immunomodulatory agent; body mass index ≥25 kg/m2; pelvic, hip, or femur fracture; erythropoietin-stimulating agent; dexamethasone/doxorubicin; Asian ethnicity/race; VTE history; tunneled line/central venous catheter; and existing thromboprophylaxis. Predictors of VTE used to obtain the SAVED score25 include previous surgery, Asian race, VTE history, age ≥80 years, and dexamethasone dose. The details on how many score points are associated with each of the predictors of VTE risk are included on MYEL-I 1 of 3, page 15.

VTE Prophylaxis

Administration of VTE prophylaxis is based on risk as long as there are no contraindications to anticoagulation or antiplatelets agents. The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease (available at NCCN.org) outline the contraindications for anticoagulation prophylaxis. All anticoagulants carry an increased risk of bleeding. Therefore, careful consideration is needed regarding risks and benefits for each patient.

The optimal choice of VTE prophylaxis agent depends on several patient-related factors, such as risk of bleeding (eg, concurrent coagulopathy, disseminated intravascular coagulation, hyperviscosity), cytopenia (eg, platelet count ± hemoglobin), concurrent medications (eg, strong cytochrome P inducers/inhibitors, single/dual antiplatelets), renal function (eg, creatinine clearance), extremes of body weight, and history of heparin-induced thrombocytopenia. It is also dependent on the availability of reversal agents in case of emergency bleeding, type of myeloma therapy received (eg, with carfilzomib, IMiD, dexamethasone), patient choice (eg, preference for mode of administration, dietary restrictions), and insurance coverage/restrictions (including cost of therapy).

Use of prophylactic anticoagulation agents may be considered if the risk of VTE is deemed high, particularly with IMiD-based induction therapy.21,26,27 One phase III trial has evaluated VTE prophylaxis specifically in patients with newly diagnosed MM undergoing treatment with thalidomide-based regimens. In this study, low-dose low-molecular-weight heparin (LMWH) was compared with fixed-dose warfarin or aspirin. Of 659 analyzed patients, 43 had serious thromboembolic events (6.5%). No statistically significant differences were observed among the 3 arms.28

Direct oral anticoagulants (DOACs) are effective for the treatment of cancer-associated thrombosis and have the advantage of oral administration without requiring intense laboratory monitoring. The AVERT and CASSINI studies evaluated their benefit for primary VTE prophylaxis in intermediate-risk to high-risk ambulatory patients with cancer.29,30

Currently, apixaban and rivaroxaban are the only DOACs with evidence from randomized control trials for primary VTE prophylaxis in patients with cancer.2931 However, generalizing their use in patients with MM is a challenge. The AVERT trial with apixaban included only 2.6% of patients with myeloma,29 and patients with MM were excluded from the CASSINI trial with rivaroxaban altogether.30 Nevertheless, based on these studies showing the efficacy and safety of DOACs for VTE prophylaxis in patients with cancer, recent smaller trials have investigated prophylaxis with DOACs in patients with MM.3235 The results of these trials are encouraging, but they need to be confirmed by larger studies.

The decision for VTE prophylaxis should be made after considering the risk of both VTE and bleeding, as well as patients’ preference and values. Patients receiving VTE prophylaxis should be monitored for bleeding complications and any adverse effects impacting quality of life. A minority of patients may be deemed inappropriate for VTE prophylaxis, and such decisions should be reevaluated as the patients’ clinical situation evolves.

In summary, the VTE prophylaxis recommendation for patients with ≤3 points by IMPEDE score or <2 points by SAVED score is aspirin at 81 to 325 mg once daily.

For those with ≥4 points by IMPEDE score or ≥2 points by SAVED score, the recommendation is enoxaparin (40 mg/d subcutaneously), warfarin (target international normalized ratio, 2.0–3.0), fondaparinux (2.5 mg/d subcutaneously),36 or a DOAC, such as rivaroxaban at 10 mg/d orally or apixaban at 2.5 mg orally twice daily.37 A less common and less well-studied choice of LMWH includes dalteparin at 5,000 units daily subcutaneously (category 2B).

Duration of VTE prophylaxis

The duration of VTE prophylaxis is indefinite while on MM therapy, or 3 to 6 months followed by aspirin (longer periods of anticoagulation may be considered in the presence of additional patient-specific, treatment-specific, or transient VTE risk factors). For any patients who develop VTE on IMiD-based therapy, the panel recommends continuing the therapeutic dose of anticoagulation for as long as IMiD-based therapy is indicated.

Conclusions

These NCCN Guidelines Insights highlight the important updates/changes specific to the treatment options for MM in the 2022 version of the NCCN Guidelines for MM. 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. The 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 to provide optimal care. The physician and the 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.

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    Siegel DS, Schiller GJ, Samaras CJ, et al. Pomalidomide, dexamethasone, and daratumumab after lenalidomide treatment in relapsed refractory multiple myeloma: updated results from an open-label, multicenter, phase 2 trial [abstract]. Blood 2020;136(Suppl 1):1617.

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    • Search Google Scholar
    • Export Citation
  • 15.

    Dimopoulos MA, Terpos E, Boccadoro M, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol 2021;22:801812.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Richardson PG, Oriol A, Larocca A, et al. Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol 2021;39:757767.

  • 17.

    Schjesvold F, Robak P, Pour L, et al. OCEAN: a randomized phase III study of melflufen + dexamethasone to treat relapsed refractory multiple myeloma. Future Oncol 2020;16:631641.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Oncopeptides withdraws Pepaxto® in US, scale down organization and focus on R&D. Accessed November 24, 2021. Available at: https://www.oncopeptides.com/en/media/press-releases/oncopeptides-withdraws-pepaxto-in-us-scale-down-organization-and-focus-on-rd

    • Search Google Scholar
    • Export Citation
  • 19.

    Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 2021;384:705716.

  • 20.

    Kristinsson SY, Pfeiffer RM, Björkholm M, et al. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study. Blood 2010;115:49914998.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008;22:414423.

  • 22.

    Kristinsson SY. Thrombosis in multiple myeloma. Hematology (Am Soc Hematol Educ Program) 2010;2010:437444.

  • 23.

    Bradbury CA, Craig Z, Cook G, et al. Thrombosis in patients with myeloma treated in the Myeloma IX and Myeloma XI phase 3 randomized controlled trials. Blood 2020;136:10911104.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Sanfilippo KM, Luo S, Wang TF, et al. Predicting venous thromboembolism in multiple myeloma: development and validation of the IMPEDE VTE score. Am J Hematol 2019;94:11761184.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Li A, Wu Q, Luo S, et al. Derivation and validation of a risk assessment model for immunomodulatory drug-associated thrombosis among patients with multiple myeloma. J Natl Compr Canc Netw 2019;17:840847.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Ikhlaque N, Seshadri V, Kathula S, et al. Efficacy of prophylactic warfarin for prevention of thalidomide-related deep venous thrombosis. Am J Hematol 2006;81:420422.

  • 27.

    Baz R, Li L, Kottke-Marchant K, et al. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc 2005;80:15681574.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Palumbo A, Cavo M, Bringhen S, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol 2011;29:986993.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Carrier M, Abou-Nassar K, Mallick R, et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med 2019;380:711719.

  • 30.

    Khorana AA, Soff GA, Kakkar AK, et al. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med 2019;380:720728.

  • 31.

    Wang TF, Zwicker JI, Ay C, et al. The use of direct oral anticoagulants for primary thromboprophylaxis in ambulatory cancer patients: guidance from the SSC of the ISTH. J Thromb Haemost 2019;17:17721778.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Man L, Morris A, Brown J, et al. Use of direct oral anticoagulants in patients on immunomodulatory agents. J Thromb Thrombolysis 2017;44:298302.

  • 33.

    Storrar NPF, Mathur A, Johnson PRE, et al. Safety and efficacy of apixaban for routine thromboprophylaxis in myeloma patients treated with thalidomide- and lenalidomide-containing regimens. Br J Haematol 2019;185:142144.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Cornell RF, Goldhaber SZ, Engelhardt BG, et al. Apixaban for primary prevention of venous thromboembolism in patients with multiple myeloma receiving immunomodulatory therapy. Front Oncol 2019;9:45.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Pegourie B, Pernod G, Karlin L, et al. Evaluation of an oral direct anti-Xa anticoagulant, apixaban, for the prevention of venous thromboembolism in patients with myeloma treated with IMiD* compounds: a pilot study (MYELAXAT) [abstract]. J Clin Oncol 2017;35(Suppl):Abstract 8019.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    van Doormaal FF, Raskob GE, Davidson BL, et al. Treatment of venous thromboembolism in patients with cancer: subgroup analysis of the Matisse clinical trials. Thromb Haemost 2009;101:762769.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Piedra K, Peterson T, Tan C, et al. Comparison of venous thromboembolism incidence in newly diagnosed multiple myeloma patients receiving bortezomib, lenalidomide, dexamethasone (RVD) or carfilzomib, lenalidomide, dexamethasone (KRD) with aspirin or rivaroxaban thromboprophylaxis [published online August 15, 2021]. Br J Haematol, doi: 10.1111/bjh.17772

    • Search Google Scholar
    • Export Citation

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 NCCN Guidelines is available free of charge at NCCN.org.

© National Comprehensive Cancer Network, Inc. 2022.

All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

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    Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet 2021;397:23612371.

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    Siegel DS, Schiller GJ, Samaras C, et al. Pomalidomide, dexamethasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment. Leukemia 2020;34:32863297.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Siegel DS, Schiller GJ, Samaras CJ, et al. Pomalidomide, dexamethasone, and daratumumab after lenalidomide treatment in relapsed refractory multiple myeloma: updated results from an open-label, multicenter, phase 2 trial [abstract]. Blood 2020;136(Suppl 1):1617.

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    • Search Google Scholar
    • Export Citation
  • 15.

    Dimopoulos MA, Terpos E, Boccadoro M, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol 2021;22:801812.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Richardson PG, Oriol A, Larocca A, et al. Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol 2021;39:757767.

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    Schjesvold F, Robak P, Pour L, et al. OCEAN: a randomized phase III study of melflufen + dexamethasone to treat relapsed refractory multiple myeloma. Future Oncol 2020;16:631641.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Oncopeptides withdraws Pepaxto® in US, scale down organization and focus on R&D. Accessed November 24, 2021. Available at: https://www.oncopeptides.com/en/media/press-releases/oncopeptides-withdraws-pepaxto-in-us-scale-down-organization-and-focus-on-rd

    • Search Google Scholar
    • Export Citation
  • 19.

    Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 2021;384:705716.

  • 20.

    Kristinsson SY, Pfeiffer RM, Björkholm M, et al. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study. Blood 2010;115:49914998.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008;22:414423.

  • 22.

    Kristinsson SY. Thrombosis in multiple myeloma. Hematology (Am Soc Hematol Educ Program) 2010;2010:437444.

  • 23.

    Bradbury CA, Craig Z, Cook G, et al. Thrombosis in patients with myeloma treated in the Myeloma IX and Myeloma XI phase 3 randomized controlled trials. Blood 2020;136:10911104.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Sanfilippo KM, Luo S, Wang TF, et al. Predicting venous thromboembolism in multiple myeloma: development and validation of the IMPEDE VTE score. Am J Hematol 2019;94:11761184.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Li A, Wu Q, Luo S, et al. Derivation and validation of a risk assessment model for immunomodulatory drug-associated thrombosis among patients with multiple myeloma. J Natl Compr Canc Netw 2019;17:840847.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Ikhlaque N, Seshadri V, Kathula S, et al. Efficacy of prophylactic warfarin for prevention of thalidomide-related deep venous thrombosis. Am J Hematol 2006;81:420422.

  • 27.

    Baz R, Li L, Kottke-Marchant K, et al. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc 2005;80:15681574.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Palumbo A, Cavo M, Bringhen S, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol 2011;29:986993.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Carrier M, Abou-Nassar K, Mallick R, et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med 2019;380:711719.

  • 30.

    Khorana AA, Soff GA, Kakkar AK, et al. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med 2019;380:720728.

  • 31.

    Wang TF, Zwicker JI, Ay C, et al. The use of direct oral anticoagulants for primary thromboprophylaxis in ambulatory cancer patients: guidance from the SSC of the ISTH. J Thromb Haemost 2019;17:17721778.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Man L, Morris A, Brown J, et al. Use of direct oral anticoagulants in patients on immunomodulatory agents. J Thromb Thrombolysis 2017;44:298302.

  • 33.

    Storrar NPF, Mathur A, Johnson PRE, et al. Safety and efficacy of apixaban for routine thromboprophylaxis in myeloma patients treated with thalidomide- and lenalidomide-containing regimens. Br J Haematol 2019;185:142144.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Cornell RF, Goldhaber SZ, Engelhardt BG, et al. Apixaban for primary prevention of venous thromboembolism in patients with multiple myeloma receiving immunomodulatory therapy. Front Oncol 2019;9:45.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Pegourie B, Pernod G, Karlin L, et al. Evaluation of an oral direct anti-Xa anticoagulant, apixaban, for the prevention of venous thromboembolism in patients with myeloma treated with IMiD* compounds: a pilot study (MYELAXAT) [abstract]. J Clin Oncol 2017;35(Suppl):Abstract 8019.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    van Doormaal FF, Raskob GE, Davidson BL, et al. Treatment of venous thromboembolism in patients with cancer: subgroup analysis of the Matisse clinical trials. Thromb Haemost 2009;101:762769.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Piedra K, Peterson T, Tan C, et al. Comparison of venous thromboembolism incidence in newly diagnosed multiple myeloma patients receiving bortezomib, lenalidomide, dexamethasone (RVD) or carfilzomib, lenalidomide, dexamethasone (KRD) with aspirin or rivaroxaban thromboprophylaxis [published online August 15, 2021]. Br J Haematol, doi: 10.1111/bjh.17772

    • Search Google Scholar
    • Export Citation
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