Guideline sources The following summarized guidelines for the evaluation and management of multiple myeloma (MM) are prepared by our editorial team based on guidelines from the Canadian Myeloma Research Group Consensus Guideline Consortium (CMRG-CGC 2023), the European Hematology Association (EHA/ESMO 2021), the United Kingdom Myeloma Society (UKMS/BSH 2021), the Cancer Care Ontario Foundation (CCO/ASCO 2019), and the American Society of Clinical Oncology (ASCO 2018). 1 2 3 4 5 Calculator Calculator Calculator Asymptomatic myeloma progno International Staging System for Revised in Guidelines https://web.pathway.md/diseases/recRbZoja8UfUac3a 1/10 6/30/23, 1:05 AM Multiple myeloma Pathway 1. Classification and risk stratification Risk assessment: As per BSH 2021 guidelines: Use the 2014 International Myeloma Working Group diagnostic criteria for staging MM. A Use the revised International Staging System in all patients with newly diagnosed MM. A As per ASCO 2019 guidelines, use the Revised International Staging System to assess the risk status in all patients at the time of diagnosis. A Frailty assessment: Consider obtaining a frailty assessment using a validated tool, such as the International Myeloma Working Group frailty index, C in all older adult patients before treatment decision- making. B Target any deficits identified for a frailty assessment for further intervention using a multidisciplinary approach. B Eligibility for HSCT: Refer patients to a transplant center to determine transplant eligibility. B Do not use chronologic age and renal function as the sole criteria to determine eligibility for stem cell transplantation. D 2. Diagnostic investigations Laboratory tests: Obtain the following laboratory tests in patients with suspected or confirmed MM: Situation Guidance CBC Screening tests Urea and creatinine Calcium, immunoglobulins and serum electrophoresis SFLC Immunofixation of serum Diagnostic tests -2 microglobulin Tests to estimate tumor burden and prognosis LDH Albumin. B Show 2 more Diagnostic imaging: obtain positron emission tomography-CT, whole-body MRI (diffusion- weighted preferably), or low-dose whole-body CT for the diagnosis of MM. B https://web.pathway.md/diseases/recRbZoja8UfUac3a 2/10 6/30/23, 1:05 AM Multiple myeloma Pathway Show 2 more 3. Diagnostic procedures Bone marrow examination: perform bone marrow aspirate and trephine biopsy with plasma cell phenotyping to establish the diagnosis of MM. B Show 3 more Renal biopsy: consider performing a renal biopsy if the level of sFLC is < 500 mg/L in patients with renal impairment with myeloma as the suspected cause. B 4. Medical management General principles: discuss all cases of newly diagnosed MM at a multidisciplinary meeting. B Show 2 more Watchful waiting: offer watchful waiting in patients with smoldering MM. Encourage high-risk patients to participate in randomized trials (phase III) powered for overall survival advantage of the experimental treatment modality. B Landmark trials: LenDex in High-Risk Smoldering Myeloma In patients with high-risk smoldering myeloma, early treatment was superior to observation with respect to survival at 5 years. Mateos MV et al. N Engl J Med. 2013 Aug 1. Induction therapy, transplant eligible: As per ESMO/EHA 2021 guidelines, offer induction therapy of 4-6 cycles followed by high-dose melphalan and ASCT in < 70 years old patients without comorbidities. A Show 2 more As per CCO/ASCO 2019 guidelines, consider offering at least 3-4 cycles of induction therapy, including an immunomodulatory drug, a proteasome inhibitor, and a corticosteroid, before stem cell collection. C Show 3 more Induction therapy, transplant ineligible: As per CMRG-CGC 2023 guidelines, offer daratumumab, lenalidomide, and dexamethasone as first-line therapy in transplant-ineligible fit patients with MM. Include an anti-CD38 antibody in first-line therapies. A Show 5 more As per ESMO/EHA 2021 guidelines, offer the four-drug combinations of daratumumab, lenalidomide, and dexamethasone or daratumumab, bortezomib, melphalan, and prednisone as https://web.pathway.md/diseases/recRbZoja8UfUac3a 3/10 6/30/23, 1:05 AM Multiple myeloma Pathway the standard of care in fit patients with MM. A Show 2 more As per CCO/ASCO 2019 guidelines, individualize initial treatment of transplant-ineligible patients based on shared decision-making between physicians and patients, taking into account disease-specific factors, such as stage and cytogenetic abnormalities, and patient-specific factors, including age, comorbidities, functional status, frailty status, and patient preferences. B Show 4 more Consolidation therapy: As per EHA 2021 guidelines, insufficient evidence to recommend consolidation therapy after ASCT as standard therapy. Consider offering 2 cycles of bortezomib, lenalidomide, and dexamethasone consolidation in patients received bortezomib, cyclophosphamide, and dexamethasone induction. I As per ASCO 2019 guidelines, do not offer consolidation therapy routinely in patients with MM except in the context of a clinical trial. Consider offering consolidation therapy for at least 2 cycles in patients ineligible or unwilling to receive maintenance therapy. D Maintenance therapy: As per EHA 2021 guidelines, consider offering maintenance with lenalidomide as the standard of care in all patients with MM after ASCT. B Consider offering bortezomib in patients with high- risk disease. C As per ASCO 2019 guidelines, offer lenalidomide maintenance (starting at approximately day 90-110 at 10-15 mg daily until progression) routinely in standard-risk patients. Attempt to maintain maintenance therapy for at least 2 years for improved survival. A Show 3 more Bone-modifying agents (initiation): do not use bisphosphonates in patients with solitary plasmacytoma or smoldering (asymptomatic) or indolent myeloma. D Show 7 more Bone-modifying agents (monitoring): monitor serum creatinine before each dose of pamidronate or zoledronic acid. Do not monitor renal function in patients receiving denosumab. E Show 6 more 5. Therapeutic procedures Stem cell transplantation, indications: As per ESMO/EHA 2021 guidelines: Offer tandem ASCT in patients with genetically defined high-risk disease as well as in all patients received bortezomib, cyclophosphamide, and dexamethasone induction. B Do not offer allo-SCT following ASCT, as it does not improve overall survival compared with tandem ASCT, even in high-risk disease. https://web.pathway.md/diseases/recRbZoja8UfUac3a 4/10 6/30/23, 1:05 AM Multiple myeloma Pathway As per CCO/ASCO 2019 guidelines, offer upfront transplantation in all transplant-eligible patients with MM. Consider offering delayed initial stem cell transplantation in selected patients. A Show 3 more Stem cell transplantation, conditioning: As per ESMO/EHA 2021 guidelines, administer high-dose melphalan (200 mg/m ) as the standard conditioning regimen before ASCT. A As per CCO/ASCO 2019 guidelines, administer high-dose melphalan as the conditioning regimen of choice for ASCT. A 6. Follow-up and surveillance Assessment of treatment response (transplant eligible): set the achievement of the best depth of remission as the goal of initial therapy in transplant-eligible patients. B Show 3 more Assessment of treatment response (transplant ineligible): set the achievement of the best quality and depth of remission as the goal of initial therapy in transplant-ineligible patients. B Show 4 more Management of relapsed/refractory disease (risk assessment): Repeat risk assessment using the Revised International Staging System at the time of relapse and include bone marrow with FISH for myeloma abnormalities seen with progression, including 17p and 1q abnormalities. Do not repeat FISH for primary abnormalities (translocations and trisomies) if seen in the initial diagnostic marrow. A Consider assessing other risk factors, such as renal insufficiency, age, presence of plasma cell leukemia/circulating plasma cells, extramedullary disease, and frailty. B Management of relapsed/refractory disease (general principles): individualize treatment of biochemically relapsed myeloma, taking into account patient's tolerance of prior treatment, rate of rise of myeloma markers, cytogenetic risk, presence of comorbidities (renal insufficiency), frailty, and patient's preference. B Show 3 more Management of relapsed/refractory disease, systemic therapy: As per ESMO/EHA 2021 guidelines, offer a lenalidomide and dexamethasone-based regimen (carfilzomib, lenalidomide, and dexamethasone; daratumumab, lenalidomide, and dexamethasone; ixazomib, lenalidomide, and dexamethasone; or elotuzumab, lenalidomide, and dexamethasone) in patients received bortezomib-based therapy upfront without lenalidomide or daratumumab. A Show 6 more Updated evidence: KarMMa-3 https://web.pathway.md/diseases/recRbZoja8UfUac3a 5/10 6/30/23, 1:05 AM Multiple myeloma Pathway In adults with triple-class-exposed relapsed and refractory multiple myeloma who had received 2-4 regimens previously, ide-cel was superior to standard regimen with respect to median progression-free survival. Paula Rodriguez-Otero et al. N Engl J Med. 2023 Mar 16. As per CCO/ASCO 2019 guidelines, take into account prior therapies when selecting treatment for the first relapse. Consider offering a monoclonal antibody-based regimen in combination with an immunomodulatory drug and/or proteasome inhibitor. Prefer triplet regimens based on tolerability and comorbidities. B Show 4 more Management of relapsed/refractory disease, stem cell transplantation: As per ESMO/EHA 2021 guidelines, consider offering second-line ASCT in patients received primary therapy with ASCT followed by lenalidomide maintenance and had an initial remission duration of 36 months. E As per CCO/ASCO 2019 guidelines: Consider offering salvage or delayed stem cell transplantation as consolidation at first relapse in patients not choosing to proceed to transplant initially. C Offer ASCT, if not received after primary induction therapy, in transplant-eligible patients with relapsed MM. Consider offering repeat stem cell transplantation in patients with relapsed MM if progression-free survival after the first transplant is 18 months. B Management of relapsed/refractory disease (assessment of response): obtain response assessment after one cycle of therapy and consider assessing it every other cycle once a response trend is observed and less frequently once the patient is in a plateau. A Show 3 more Management of treatment-related adverse events (neuropathy): Ensure early recognition of chemotherapy-induced peripheral neuropathy management, particularly bortezomib-induced peripheral neuropathy, and appropriate dose modification or discontinuation based on clinical severity. B Offer similar treatment for established bortezomib-induced peripheral neuropathy as in other chemotherapy-induced peripheral neuropathy, including modalities such as TCAs, selective SNRIs, gabapentin or pregabalin, opioids, antiepileptics and cannabinoids, topical therapies, and acupuncture. Management of treatment-related adverse events (infections): initiate prophylactic low-dose antivirals until at least one month after completing therapy in all patients receiving proteasome- inhibitor-based therapy or monoclonal antibodies. A Show 3 more Management of treatment-related adverse events (gastrointestinal dusturbances): Consider reducing the dose or discontinuing the offending agent in patients with clinically significant diarrhea. Focus on the management of diarrhea, if feasible, with interventions such https://web.pathway.md/diseases/recRbZoja8UfUac3a 6/10 6/30/23, 1:05 AM Multiple myeloma Pathway as dietary changes, loperamide, diphenoxylate plus atropine, and/or bile acid sequestrants to optimize treatment delivery. C Offer laxatives as required to maintain regular bowel movements, with dose titration or using > 1 one agent, in patients experiencing constipation. B Management of treatment-related adverse events (fatigue): Interrupt therapy in patients receiving lenalidomide and experiencing grade 3 treatment- related fatigue until resolution of fatigue and then reduce the dose to the next dose level. B Consider advising exercise as a low-risk intervention to improve symptoms of fatigue in patients with myeloma. C Management of treatment-related adverse events (cytopenias): Interrupt therapy in patients with grade 3-4 hematologic toxicity due to lenalidomide or bortezomib until resolution to grade 2 toxicity and then reinitiate therapy at a 25% dose reduction for bortezomib or at the next lowest dose level for lenalidomide, with the following exceptions: A consider administering transfusion support as needed to maintain an adequate platelet count due to the cyclical and noncumulative nature of thrombocytopenia secondary to bortezomib A consider administering G-CSF for neutropenia to avoid dose reduction of bortezomib and/or lenalidomide. B Consider administering EPO-stimulating agents to decrease transfusion dependence only when the risks clearly outweigh the benefits due to the increased risk of arterial and venous thrombosis with these agents. C Management of treatment-related adverse events (thrombosis): Administer primary prophylaxis with aspirin or LMWH according to the International Myeloma Working Group criteria in patients receiving immunomodulatory agent-based therapy. Consider administering direct OACs as an alternative. A Initiate direct OACs or LMWH (over fondaparinux or vitamin K antagonists) as initial therapy, followed indefinitely by direct OACs or LMWH indefinitely for the treatment of myeloma- associated VTE. B Clinical findings Patient demographics Symptoms Elderly Bone pain Diarrhea Past medical history Fatigue Headache AKI Malaise Al amyloidosis Seizure Bone fracture Shortness of breath CKD https://web.pathway.md/diseases/recRbZoja8UfUac3a 7/10 6/30/23, 1:05 AM Multiple myeloma Pathway Gastrointestinal bleeding Visual disturbances Gaucher disease Social history HF Monoclonal gammopathy of undetermined significance Long-term exposure to pesticides Nephrotic syndrome Ocular exam Recurrent infections Rheumatoid arthritis Retinal hemorrhage Smoldering myeloma Integument exam Neurological exam Acrocyanosis Cranial nerve palsy Petechiae Peripheral neuropathy Purpura Abdominal exam Hematological findings Hepatomegaly Anemia Splenomegaly Genetic testing Lab findings T(11;14)(q13;q32) translocation Abnormal SPEP Hyperviscosity Serum monoclonal protein Urine Bence-Jones protein Urine monoclonal protein serum calcium serum creatinine serum monoclonal light chains serum osmolal gap urine protein serum anion gap serum immunoglobulins Imaging findings Osteolytic lesions Histological findings bone marrow plasma cells Studies 2023 KarMMa-3 https://web.pathway.md/diseases/recRbZoja8UfUac3a 8/10 6/30/23, 1:05 AM Multiple myeloma Pathway In adults with triple-class-exposed relapsed and refractory multiple myeloma who had received 2-4 regimens previously, ide-cel was superior to standard regimen with respect to median progression- free survival. Paula Rodriguez-Otero et al. N Engl J Med. 2023 Mar 16. 2013 LenDex in High-Risk Smoldering Myeloma In patients with high-risk smoldering myeloma, early treatment was superior to observation with respect to survival at 5 years. Mateos MV et al. N Engl J Med. 2013 Aug 1. References 1. M A Dimopoulos, P Moreau, E Terpos et al. Multiple myeloma: EHA ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021 Mar;32 3 309 322. Open 2. Jonathan Sive, Kirsty Cuthill, Hannah Hunter et al. Guidelines on the diagnosis, investigation and initial treatment of myeloma: a British Society for Haematology/UK Myeloma Forum Guideline. Br J Haematol. 2021 Apr;193 2 245 268. Open 3. Kenneth Anderson, Nofisat Ismaila, Patrick J Flynn et al. Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2018 Mar 10;36 8 812 818. Open 4. Julie C t , Rami Kotb, Debra J Bergstrom et al. 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