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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.

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.

Abstract Introduction: Multiple myeloma (MM) accounts for about 20% of deaths from hematological cancers and remains incurable despite conventional and high-dose chemotherapy. Two phase III trials in patients with relapsed or refractory MM (MM-009 and MM-010) showed that lenalidomide combined with dexamethasone resulted in significantly improved response rates and significantly prolonged median time to progression (TTP) and overall survival (OS) compared with dexamethasone alone. This current sub-analysis of lenalidomide plus dexamethasone therapy assessed whether there was a survival benefit in maintaining patients on therapy after achieving their best response and what the impact of early discontinuation on TTP and OS was. Methods: Of the 353 patients from MM-009 and MM-010 treated with lenalidomide plus dexamethasone, 32 did not respond. Of the remaining 321 responding patients, 214 had a partial response (PR) or better and 107 patients had stable disease (SD). In this post-hoc sub-analysis, we first assessed the outcome of continuing treatment for ≤10 months vs. >10 months in all 321 patients who achieved SD or better, after they achieved their best response. In this landmark analysis, OS was measured from the time of achieving best response to death from any cause or to last contact. In a second analysis, we assessed the impact of early discontinuation due to adverse events or withdrawn consent on OS and TTP in all patients who achieved SD or better. Therefore, we excluded patients who discontinued treatment due to disease progression, death, or lack of efficacy. Patients who achieved SD or better and who continued on therapy were compared with those who discontinued. OS and TTP were assessed from time of randomization. Results: In the landmark analysis, of the 321 responding patients (≥PR, n=214; SD, n=107), 223 patients received treatment for ≤10 months after achieving their best response and 98 patients for >10 months after achieving their best response. Patients who continued therapy for >10 months after achieving their first best response had significantly longer OS vs. those who received therapy for ≤10 months (not reached vs. 23.4 months; p<0.0001). At 24 months after achieving their best response, significantly more patients were alive if they continued therapy >10 months vs. ≤10 months (93.8% vs. 48.4%, p<0.0001). In the second analysis, in order to evaluate the impact of discontinuation in patients achieving SD or better, we excluded 134 patients due to disease progression, death, or lack of efficacy. Of the remaining 187 responding patients, 72 discontinued treatment for AE (n=42) or withdrew consent (n=30), while the remaining 115 patients continued treatment. Median OS and TTP were significantly longer for patients who continued vs. those who discontinued treatment (median OS: not reached vs. 29.5 months, p<0.0001; median TTP: not reached vs. 13.6 months, p<0.0001). Conclusions: In patients achieving SD or better, prolonged duration of treatment was associated with significantly longer OS and TTP. In contrast, early discontinuation of treatment led to reduced OS and TTP. Therefore, efforts should be made to manage adverse events while maintaining patients on therapy. Furthermore, maintaining treatment with lenalidomide and dexamethasone after achieving the optimal response ensures a significant improvement in OS for patients with relapsed or refractory MM.

Abstract Background: The use of low-dose dexamethasone (Dex) in combination with lenalidomide (Len), an immunomodulatory compound, improves overall survival (OS) compared with high-dose Dex plus Len in patients (pts) with newly diagnosed multiple myeloma (MM) (Rajkumar et al. 2007). Two phase III randomised trials of pts with relapsed/refractory MM showed that Len/Dex had significantly better overall response (OR), complete response (CR), OS and time to progression (TTP) than Dex alone. Dex dose reductions were permitted in relation to severity of adverse events (AEs). We investigated the effect of Dex dose reductions on efficacy and tolerability of Len/Dex in relapsed/refractory MM. Methods: Data were pooled from the MM-009/010 studies for pts treated in the Len/Dex group who had an unchanged Len dose (n=233). Pts were treated with Len (25mg/day on day 1–21 of each 28-day cycle) and Dex 40mg on day 1–4, 9–12, and 17–20 (for the first four cycles). After four cycles, Dex 40mg/day was administered only on day 1–4. Dex dose reductions were: 40mg day 1–4 every 2 weeks (level -1), 40mg day 1–4 every 4 weeks (level -2), and 20mg day 1–4 every 4 weeks (level -3). Response to therapy, TTP, OS, and progression-free survival (PFS), as well as AEs were assessed. Response rate and TTP were based on data obtained before unblinding (June/August 2005 [MM-009/010]. Results: Of 233 pts in this post-hoc analysis, 177 pts were treated with Dex 40 mg/day throughout the study and 46 received Dex dose reductions. Forty-one pts received a dose reduction due to AEs. Baseline characteristics were balanced between treatment groups. Pts who received Dex dose reductions had a significantly higher OR rate, including a higher CR, compared with those who received standard Dex dose (Table). Pts in the Dex reductions group had significantly longer median TTP, median OS, and median PFS, compared with those who received Dex at the assigned dose. At the end of the study, rates of serious AEs, grade 3–4 AEs, treatment-related AEs and withdrawals because of AEs were comparable between pts who received Dex dose reductions and those who received an unchanged Dex dose. Although most Dex dose reductions were made for an AE, by reducing the dose pts were able to maintain a similar safety profile to those who did not require dose reductions. Grade 3–4 haematological AEs in pts who received Dex dose reductions and those who did not were neutropenia (23.7% and 32.6%, respectively), thrombocytopenia (8.5% and 6.8%, respectively) and anaemia (6.8% and 6.2%, respectively). No febrile neutropenia was reported in these pts. Conclusion: Dex dose reductions improved the efficacy of Len/Dex without affecting tolerability in pts with relapsed/refractory MM. Len/Dex Dex unchanged (n=177) Dex reduced (n=46) P *Most conservative median estimate obtained assuming all censored patients die right right after the censor date Response, % OR 50.8 69.6 <0.05 CR 13.0 23.9 <0.01 nCR 19.8 37.0 <0.01 PR 18.1 8.7 <0.01 Median TTP, weeks* >24.1 >59.9 0.002 Median OS, weeks* >109.7 >121.9 0.19 Median PFS, weeks* >24.1 >59.9 0.001

Abstract Lenalidomide (Len), an analog of thalidomide (thal) is a novel, oral, immunomodulatory agent that is effective against multiple myeloma (MM). In 2 prospective, randomized, double-blind, placebo-controlled Phase III trials. Len with dexamethasone (Dex) induced a significantly higher overall response rate (OR) and complete remission rate (CR), as well as longer time-to-progression (TTP) in comparison with Dex alone. This prospective analysis assessed whether prior thalidomide exposure might induce subsequent resistance to Len/Dex. We evaluated 704 patients (pts) from both trials (MM009, MM010) who had relapsed or refractory multiple myeloma, had not been resistant to Dex and were randomized to receive either oral Len (25 mg daily for 3 weeks every 4 weeks) plus Dex (40 mg on days 1–4, 9–12, 17–20 every 4 weeks for 4 cycles) or placebo plus Dex. Two hundred seventy four pts (39%) received prior thal, while 430 (61%) had not. The prior thal exposed pts and thal-naive pts were similar in regard to age, Beta-2-microglobulin, hemoglobin, serum M protein, albumin and history of previous transplantation. The frequency of deep venous thrombosis and pulmonary embolism (DVT/PE) with prior thal exposure was higher at 14% with Len/Dex than 4% with Dex alone (p < 0.01). However, the frequency of DVT/PE with no prior thal exposure was similar at 8% with Len/Dex to 6% with Dex alone (p = 0.49). In the prior thal pts, severe neuropathy occurred in 4% with Len/Dex, not significantly different from the 1% with Dex alone (p=0.2). The pooled data from all 704 pts showed that pts treated with Len/Dex, compared with those treated with Dex alone, had superior median Time-To-Progression (TTP) (48 vs 20 weeks) and OR (60% vs 22%, p <0.001). Similarly, among the subgroups exposed or not exposed to thal, Len/Dex was superior to Dex alone in OR and TTP. For the 126 patients who received prior thal, the OR with Len/Dex was significantly less (43%) among 54 Pts resistant to thal than that observed for 72 Pts who had been sensitive to thal (63%, p < 0.05). Multivariate analysis using Cox proportion hazards model indicated that after controlling for treatment (Len/Dex vs Dex) and baseline disease characteristics, independent and significant predictors of shorter TTP included prior thal exposure, duration of myeloma and number of prior therapies. Len in combination with Dex was more effective than Dex in patients with relapsed or refractory multiple myeloma despite prior thal exposure. Results with Len/Dex were superior for those not exposed to thal, suggesting some, but not complete, cross resistance between Len and thal. Len/Dex vs Dex with or without Prior Thal Thal (N=274) No Thal (N=430) LD D p LD D p Intent-to-Treat (n) 126 148 227 203 TTP (med. weeks) 36.9 19.9 <.001 61.3 20.4 <.001 OR (%) 54.0 14.9 <.001 63.4 27.6 <.001 PR (%) 42.1 12.8 <.001 32.2 23.2 <.05 NCR (%) 4.0 0.7 <.001 13.2 2.0 <.001 CR (%) 7.9 1.4 <.01 18.1 2.5 <.001

Abstract Abstract 3723 Background: Waldenström macroglobulinemia (WM), a lymphoproliferative disorder with marrow infiltration by lymphoplasmacytic lymphoma cells and production of monoclonal IgM, is characterized clinically by good initial responses to standard therapeutic approaches. However, a minority of patients achieve a complete remission, and most inevitably relapse, indicating a need for validation of new, targeted therapies. Notably, B-cell receptor signaling has been linked to clonal evolution in WM, and Spleen tyrosine kinase (Syk) is over-expressed in primary patient cells. Also, a recent phase I/II study of the Syk inhibitor fostamatinib in patients with a variety of non-Hodgkin lymphomas showed evidence of activity in three patients with WM. These findings supported our central hypothesis, which proposed that Syk could be a rational new target for therapy of WM, which we pursued first with pre-clinical studies. Methods: Studies of fostamatinib were performed using the WM cell line MWCL-1, and the IgM-producing cell line BWCM.1, as well as in primary cells from patients with WM, and in a novel murine xenograft model utilizing MWCL-1 cells. Results: Fostamatinib induced a time- and dose-dependent reduction in viability of MWCL-1 and BWCM.1 cells, with median inhibitory concentrations (IC50) that were in the physiologically relevant range of approximately 0.25 and 1 μM, respectively, at 3 days. Cell cycle analysis showed a decrease in cells at S-phase and at G2/M, while an increase was seen in cells in G1, and in the sub-G1fraction, suggesting induction of apoptosis. Consistent with the possibility that there was activation of type I programmed cell death, increased staining was seen in fostamatinb-treated cells with an antibody to Annexin V. Interestingly, evidence was seen of the induction of type II programmed cell death, or autophagy, as measured by an increase in cells staining with the lysotropic dye acridine orange. At the molecular level, fostamatinib blocked signaling through p44/42 mitogen-activated protein kinase (MAPK), MAPK kinase (MEK), protein kinase B/Akt, and Zeta-chain-associated protein kinase (ZAP)-70/Syk, as judged by a reduction in the phosphorylated forms of these intermediates by Western blotting. Notably, the viability of primary cells isolated from patients with WM was also reduced in association with blockade of p44/42 MAPK. Finally, a novel murine xenograft model was generated by injection of MWCL-1 cells into immunodeficient mice, which developed measurable tumors. When these were treated with fostamatinib, a delay in tumor growth was demonstrable. Conclusions: Targeting Syk with fostamatinib is an attractive strategy against pre-clinical models of WM both in vitro and in vivo. These findings lend further support for translation of fostamatinib to the clinic for patients with relapsed, and possibly even newly diagnosed WM. Disclosures: No relevant conflicts of interest to declare.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, workup, treatment, follow-up, and supportive care for patients with monoclonal gammopathy of renal significance, solitary plasmacytoma, smoldering myeloma, and multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates and changes in the 1.2020 version of the NCCN Guidelines for Multiple Myeloma.

Abstract Purpose: Waldenström macroglobulinemia (WMG) is a lymphoproliferative disorder characterized by good initial responses to standard therapeutics, but only a minority of patients achieve complete remissions, and most inevitably relapse, indicating a need for novel agents. B-cell receptor signaling has been linked to clonal evolution in WMG, and Spleen tyrosine kinase (Syk) is overexpressed in primary cells, suggesting that it could be a novel and rational target. Experimental Design: We studied the impact of the Syk inhibitor fostamatinib on BCWM.1 and MWCL-1 WMG-derived cell lines both in vitro and in vivo, as well as on primary patient cells. Results: In WMG-derived cell lines, fostamatinib induced a time- and dose-dependent reduction in viability, associated with activation of apoptosis. At the molecular level, fostamatinib reduced activation of Syk and Bruton's tyrosine kinase, and also downstream signaling through MAPK kinase (MEK), p44/42 MAPK, and protein kinase B/Akt. As a single agent, fostamatinib induced tumor growth delay in an in vivo model of WMG, and reduced viability of primary WMG cells, along with inhibition of p44/42 MAPK signaling. Finally, fostamatinib in combination with other agents, including dexamethasone, bortezomib, and rituximab, showed enhanced activity. Conclusions: Taken together, these data support the translation of approaches targeting Syk with fostamatinib to the clinic for patients with relapsed and possibly even newly diagnosed WMG. Clin Cancer Res; 21(11); 2538–45. ©2015 AACR.

Abstract This analysis assessed the efficacy and safety of lenalidomide + dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. Of 704 patients, 39% were thalidomide exposed. Thalidomide-exposed patients had more prior lines of therapy and longer duration of myeloma than thalidomide-naive patients. Lenalidomide + dexamethasone led to higher overall response rate (ORR), longer time to progression (TTP), and progression-free survival (PFS) versus placebo + dexamethasone despite prior thalidomide exposure. Among lenalidomide + dexamethasone-treated patients, ORR was higher in thalidomide-naive versus thalidomide-exposed patients (P = .04), with longer median TTP (P = .04) and PFS (P = .02). Likewise for dexamethasone alone-treated patients (P = .03 for ORR, P = .03 for TTP, P = .06 for PFS). Prior thalidomide did not affect survival in lenalidomide + dexamethasone-treated patients (36.1 vs 33.3 months, P > .05). Thalidomide-naive and thalidomide-exposed patients had similar toxicities. Lenalidomide + dexamethasone resulted in higher rates of venous thromboembolism, myelosuppression, and infections versus placebo + dexamethasone, independent of prior thalidomide exposure. Lenalido-mide + dexamethasone was superior to placebo + dexamethasone, independent of prior thalidomide exposure. Although prior thalidomide may have contributed to inferior TTP and PFS compared with thalidomide-naive patients, these parameters remained superior compared with placebo + dexamethasone; similar benefits compared with placebo + dexamethasone were not evident for thalidomide-exposed patients in terms of overall survival. Studies were registered at http://www.clinicaltrials.gov under NCT00056160 and NCT00424047.