Patient Newly Diagnosed With MM and Ineligible for SCT With Relapse on Anti-CD38 and Lenalidomide-Based Therapy

A 78-year-old non-Latinx white male presented to his local emergency room with severe hip pain and limited range of motion of the bilateral lower extremities that had worsened over the past week. He noted that this pain had first begun roughly 1 year prior, which he attributed to arthritis, but now had become more bothersome, causing difficulty with ambulation. Upon physical examination, he reported tenderness over the right pelvic/hip region and discomfort with passive movement of his lower extremities.  

Past Medical History 

The patient’s past medical history was significant for type 2 diabetes mellitus, hyperlipidemia, and hypertension. 

Review of Systems 

A review of the patient’s systems was positive for bilateral lower extremity neuropathy (grade 1), bilateral hip pain, and limited range of motion of bilateral lower extremities. 

Radiology Data 

A PET/CT scan confirmed an FDG-avid lytic lesion in the anterolateral right iliac wing measuring 5.5 cm with associated cortical breakthrough and extension into the adjacent soft tissues. There were also severe degenerative changes at both sacroiliac joints.  

Laboratory Data  

A serum protein electrophoresis test confirmed an IgG lambda monoclonal band with a serum M-spike of 3.19 g/dL. UPEP was negative for a monoclonal gammopathy.  

Pathology Data 

A bone marrow biopsy confirmed 70% involvement of an IgG kappa multiple myeloma (MM) in a hypercellular marrow. Aspirate showed 25% atypical plasma cells. FISH studies were positive for hyperdiploidy and monosomy 13. 

Impression 

Upon review of all available data, the patient was diagnosed with R-ISS stage II multiple myeloma.  

Treatment Plan  

Treatment options were discussed with the patient and his family members. He began therapy with a combination of daratumumab, lenalidomide, and dexamethasone (DRd). Supportive medications included zoledronic acid monthly, which was switched to every 3 months after 1 year of therapy to prevent further skeletal-related events; acyclovir for antiviral prophylaxis; and aspirin 81 mg for venous thromboembolism (VTE) prophylaxis.  

The patient was assessed by the surgical oncology team to evaluate whether he was at risk for a pathologic fracture due to his disease burden. The team concluded that no surgical intervention was warranted. He was also followed closely by the pain service.  

The patient’s dexamethasone was discontinued after he had achieved a very good partial response due to chronic issues with hyperglycemia related to steroid usage and underlying diabetes mellitus. After 24 months of therapy with DRd, his serum M-spike began to rise, confirming progression of disease. At that point, he was switched to carfilzomib, pomalidomide, and dexamethasone (KPd), achieving a partial response that continues to this day. Given the increased risk of VTE events with carfilzomib-based therapy, he was switched from aspirin to a low dose of rivaroxaban for VTE prophylaxis. 

Discussion 

Considering his age and preference, the patient was deemed ineligible for an autologous stem cell transplant for consolidation therapy post induction. DRd has been known to significantly reduce the risk of disease progression or death in a population of newly diagnosed MM patients who are transplant ineligible based on the MAIA trial.¹ An updated analysis on this phase III randomized control trial demonstrated that at a median follow-up of 64.5 months, progression-free survival (PFS) was improved with DRd vs lenalidomide and dexamethasone (median 61.9 vs 34.4 months; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.45-0.67; p < .0001), as well as a statistically significant reduction in risk of death, higher overall response rates, higher minimal residual disease negativity rates, and higher overall survival (OS) rates.²

Bone disease, which is found in the majority of patients with MM at the time of diagnosis, can be painful and reduce quality of life. The interaction between malignant plasma cells and the bone microenvironment leads to osteoclastic bone destruction, reduced osteoblast function, and blocking of bone repair. In a population-based retrospective study, patients with MM were found to have a nine-fold increase in the risk of fractures after an MM diagnosis, as compared to expected fracture rates in the population.³ Usage of bone-modifying agents in multiple myeloma, such as zoledronic acid, can decrease bone pain and risk of pathologic fracture.⁴

When patients with MM relapse or demonstrate refractory disease, switching to a next-generation agent or switching the class of medications provides the highest likelihood of improved outcomes. The combination of carfilzomib, pomalidomide, and dexamethasone was chosen based on concern for worsening neuropathy with a bortezomib-based combination as well as the results of the EMN011/HOVON114 trial, which demonstrated that KPd is an effective and safe triple-drug regimen in the second line for patients who are refractory to lenalidomide.⁵ At a follow-up of 40 months, median PFS was 17 months for patients on KPd (HR 0.61, 95% CI, 0.37–1.00, p = .051) and median OS was 67 months. Prophylaxis with aspirin 81 mg with carfilzomib-based therapy can lead to a higher incidence of VTE. Prophylaxis with low-dose rivaroxaban thromboprophylaxis can mitigate this risk without an observable increase in bleeding rates.⁶

References 

1. Facon T, Kumar S, Plesner T, et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019 May 30;380(22):2104-2115. doi: 10.1056/NEJMoa1817249 

2. Weisel K, Kumar S, Moreau P, et al. Daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): updated analysis of the phase 3 MAIA STUDY. Hemasphere. 2023 May 9;7(suppl ):14-15. doi: 10.1097/01.HS9.0000936164.84357.ed 

3. Thorsteinsdottir S, Gislason G, Aspelund T, et al. Fractures and survival in multiple myeloma: results from a population-based study. Haematologica. 2020 Apr;105(4):1067-1073. doi: 10.3324/haematol.2019.230011. Epub 2019 Dec 2 

4. Hussain M, Khan F, Al Hadidi S. The use of bone-modifying agents in multiple myeloma. Blood Rev. 2023 Jan;57:100999. doi: 10.1016/j.blre.2022.100999. Epub 2022 Aug 13 

5. Sonneveld P, Zweegman S, Cavo M, et al. Carfilzomib, pomalidomide and dexamethasone (KPd) in patients with first progression of multiple myeloma refractory to bortezomib and lenalidomide. Final report of the EMN011/HOVON114 Trial. Blood 2021; 138 (suppl 1):1664. doi: https://doi.org/10.1182/blood-2021-149423 

6. 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. Br J Haematol. 2022 Jan;196(1):105-109. doi: 10.1111/bjh.17772. Epub 2021 Aug 15