Recovery of Renal Impairment by Bortezomib-Doxorubicin-Dexamethasone (BDD) in Multiple Myeloma (MM) Patients with Acute Renal Failure. Results from an Ongoing Phase II Study.

Acute renal failure (ARF) is a severe complication of MM often leading to permanent renal dysfunction and dependence on chronic hemodialysis. Reversal of kidney failure can only be achieved by fast and substantial suppression of pathogenic light-chains by effective anti-MM therapy. In a previous pilot study we were able to reverse renal impairment with bortezomib based therapy in 5 of 9 pts (Haematologica 2007). Here, we present preliminary data from an ongoing phase II study in pts with ARF using the BDD regimen. Up to now 37 pts with MM induced ARF (age: median 64 yrs, range 41–82 yrs, DS stage I: 13%, II: 10%, III: 77%; IgGλ: 18%, IgGκ: 23%; Light chainκ: 32%, Light chainλ: 27%) have been enrolled. Seventeen (46%) pts presented with de novo MM, and 20 with progressive disease. ARF was defined as reduction of GFR to <50ml/min due to MM nephropathy in newly diagnosed pts, and as reduction of GFR by >25% and to <60ml/min in pts with previously treated MM and GFR of >60ml/min within the last 4 weeks and with signs of tumor progression. Treatment regimen: Bortezomib 1.0mg/m², d1,4,8,11, doxorubicin 9mg/m², d1,4,8,11 until first safety analysis after enrollment of the first 5 pts and thereafter of 9mg², d1,4, and dexamethasone 40mg d1,4,8,11. Cycles were repeated every 21 days. 22 pts have completed at least 3 cycles and are evaluable for response as yet. Overall response rate was 73% including 8 pts achieving CR, 4 nCR, 4 PR; 3 pts achieved MR. Median GFR at baseline was 17ml/min (range: 4 – 45ml/min) and improved to 45,5 ml/min (range: 11 – 134ml/min). A significant increase in GFR (>75ml/min) was achieved in 9 of the 16 pts with CR-PR while in pts with MR or NC/PD no improvement in GFR was seen. Toxicity was assessed in 25 pts including 3 pts not evaluable for response. Grade 1–2 toxicities (>10% of pts): anemia 40%, neutropenia 23%, thrombopenia 27%, fatigue 50%, infections/fever 64%, neuropathy 36%, edema 32%; diarrhea 27%, nausea 27%, mucositis 23%; Grade 3–4 toxicities: anemia 9%, neutropenia 23%, thrombopenia 9%, infections 18%, neuropathy 1%. Three of the infectious complications were due to herpes virus infections/reactivations. Three pts died during the first treatment cycle; 2 pts from pneumonia (including 1 with sepsis) and 1 pt (age 81 yrs) from myocardial infarction. This led to an adaptation of the treatment regimen including a reduction in the frequency of doxorubicin administration to days 1 and 4 (instead of d1,4,8,11), abandonment of the planned dose increase of bortezomib (to 1.3mg/m²), and addition of mandatory antibacterial and antiviral prophylaxis. In conclusion, overall anti-myeloma response rate in the 22 evaluable pts was 73%, with 12 (54%) pts achieving CR/nCR; ARF could be reverted in 9 pts. (41% of total or 56% of pts. with CR-PR). After dose reduction of the initial regimen, treatment was well tolerated in this high-risk and often multimorbid patient population.